Longevity Wiki - User contributions [en-GB]

Calcium channel blockers (CCBs)

2024-09-21T12:36:44Z

Dmitry Dzhagarov: /* Cinnarizine */

'''Calcium channel blockers (CCBs)''' use was associated with a 70% lower risk for frailty (95%CI = 0.09 to 0.77).<ref>Chuang, S. Y., Pan, W. H., Chang, H. Y., Wu, C. I., Chen, C. Y., & Hsu, C. C. (2016). Protective effect of calcium channel blockers against frailty in older adults with hypertension. Journal of the American Geriatrics Society, 64(6), 1356-1358.</ref> The use of CCBs in 75+ y.o. patients with renovascular disease. was associated with a significant reduction in overall mortality and cardiovascular death.<ref>Deshmukh, H., Barker, E., Anbarasan, T., Levin, D., Bell, S., Witham, M. D., & George, J. (2018). Calcium channel blockers are associated with improved survival and lower cardiovascular mortality in patients with renovascular disease. Cardiovascular Therapeutics, 36(6), e12474. PMID: 30372589 DOI: 10.1111/1755-5922.12474</ref>

The point estimates for calcium channel blockers (CCBs) indicated a decrease in seven [[Epigenetic clock|DNAmAges]] (a decrease of 0.57 to 1.74 years in five PCDNAmAges, a 0.03-year decrease of aging rate in DunedinPACE, and an elongation of 0.01 in PCDNAmTL), among which the estimates for PCHorvathAge (beta = − 1.28, 95%CI = − 2.34 to − 0.21), PCSkin&bloodAge (beta = − 1.34, 95%CI = − 2.61 to − 0.07), PCPhenoAge (beta = − 1.74, 95%CI = − 2.58 to − 0.89), and PCGrimAge (beta = − 0.57, 95%CI = − 0.96 to − 0.17) excluded the null. In addition to DNAmAges, CCBs was also associated with decreased functional biological ages, shown in FAI (beta = − 2.18, 95%CI = − 3.65 to − 0.71) and FI (beta = − 1.31, 95%CI = − 2.43 to − 0.18).<ref>Tang, B., Li, X., Wang, Y., Sjölander, A., Johnell, K., Thambisetty, M., ... & Hägg, S. (2023). Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging. GeroScience, 45(3), 2065-2078. PMID: 37032369 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400489/ PMC10400489] DOI: 10.1007/s11357-023-00784-8</ref>

Patients with hypertension who were treated with calcium channel blocker (CCB), but not in diuretics demonstrated an association between telomere attrition rate and the differences in antihypertensive treatment response - their analyzes showed that the increase of leukocyte telomere length is associated with the decrease of systolic blood pressure and pulse pressure.<ref>Zhang, S. Y., Li, R. X., Yang, Y. Y., Chen, Y., Yang, S. J., Li, J., ... & Zhang, W. L. (2019). P1693 The longitudinal associations between telomere attrition and the effects of blood pressure lowering and antihypertensive treatment. European Heart Journal, 40(Supplement_1), ehz748-0448. https://doi.org/10.1093/eurheartj/ehz748.0448</ref>

CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients.

== Classes ==

=== Dihydropyridine calcium channel blockers (dipines) ===
Dihydropyridine (DHP) calcium channel blockers are derived from the molecule dihydropyridine and often used to reduce systemic vascular resistance and arterial pressure.

* Amlodipine (Norvasc)
* Aranidipine (Sapresta)
* Azelnidipine (Calblock)
* Barnidipine (HypoCa)
* Benidipine (Coniel)
* Cilnidipine (Atelec, Cinalong, Siscard) Not available in US
* Clevidipine (Cleviprex)
* Efonidipine (Landel)
* Felodipine (Plendil)
* Isradipine (DynaCirc, Prescal)
* Lacidipine (Motens, Lacipil)
* Lercanidipine (Zanidip)
* Manidipine (Calslot, Madipine)
* Nicardipine (Cardene, Carden SR)
* Nifedipine (Procardia, Adalat)
* Nilvadipine (Nivadil)
* Nimodipine (Nimotop) This substance can pass the blood-brain barrier and is used to prevent cerebral vasospasm.
* Nisoldipine (Baymycard, Sular, Syscor)
* Nitrendipine (Cardif, Nitrepin, Baylotensin)
* Pranidipine (Acalas)

=== Non-dihydropyridine ===
Fendiline
Gallopamil
Verapamil (Calan, Isoptin)
Diltiazem (Cardizem)
Gabapentin
Pregabalin
Ziconotide

'''Magnesium''' have also been shown to act as calcium channel blocker when administered orally.

'''Ethanol''' also inhibits L-type calcium channel.<ref>Uhrig, S., Vandael, D., Marcantoni, A., Dedic, N., Bilbao, A., Vogt, M. A., ... & Hansson, A. C. (2017). Differential roles for L-type calcium channel subtypes in alcohol dependence. Neuropsychopharmacology, 42(5), 1058-1069. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506795/ PMC5506795] DOI: 10.1038/npp.2016.266
</ref>

== Verapamil ==
(also: nifedipine, amlodipine, lacidipine, nicardipine)
Verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity.<ref>Liu, W., Lin, H., Mao, Z., Zhang, L., Bao, K., Jiang, B., ... & Li, J. (2020). Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy. Aging (Albany NY), 12(6), 5300. PMID: 32208362 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138547 PMC7138547] DOI: 10.18632/aging.102951</ref>

== Cinnarizine ==
Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome, also as a nootropic drug (memory and cognitive function enhancer) and as adjunct therapy for peripheral arterial disease.<ref>Kirtane, M. V., Bhandari, A., Narang, P., & Santani, R. (2019). Cinnarizine: a contemporary review. Indian Journal of Otolaryngology and Head & Neck Surgery, 71, 1060-1068. PMID: 31750127 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841794/ PMC6841794] DOI: 10.1007/s12070-017-1120-7</ref> As a selective calcium channel blocker (SCCB), it reduces the entry of Ca2+ ions into cells and decreases their concentration in the plasma membrane depot, reduces the tone of the smooth muscles of arterioles, and enhances the vasodilating effect of carbon dioxide.
Сinnarizine dose-dependently inhibits the mammalian target of rapamycin (mTOR), and selectively mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2), which allows cinnarizine to be classified as an mTOR inhibitor (rapalog) that is a geroprotector.<ref>Allen, S. A., Tomilov, A., & Cortopassi, G. A. (2018). Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochemical pharmacology, 155, 298-304. PMID 30028993 doi:10.1016/j.bcp.2018.07.013</ref>

Chronic administration of the calcium channel blocker cinnarizine to senescent animals with significant aging-induced decreased density of dopamine D2 and especially D1 receptors, regain these pathological disorders.<ref>Camps, M., Ambrosio, S., Reiriz, J., Ballarin, M., Cutillas, B., & Mahy, N. (1993). Effect of age and cinnarizine treatment on brain dopamine receptors. Pharmacology, 46(1), 9-12. PMID: 8434032 DOI: 10.1159/000139023</ref>

== Fasudil ==
The small molecule fasudil, formerly known as HA1077 or AT‐877, is the ROCK inhibitor that has been used in Japan and China since 1995 for the treatment of vasospasms following subarachnoid haemorrhage, as well as to prevent the loss of intelligence and memory observed in stroke patients and the elderly.<ref>Suzuki, Y., Shibuya, M., Satoh, S. I., Sugimoto, Y., & Takakura, K. (2007). A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surgical neurology, 68(2), 126-131. PMID: 17586012 DOI: 10.1016/j.surneu.2006.10.037</ref> Fasudil also could ameliorate impairments in skeletal muscle blood flow observed in older adults<ref>Darvish, S., Coppock, M. E., & Murray, K. O. (2022). Age-related impairments in ATP release by red blood cells as an important contributor to declines in skeletal muscle blood flow in older adults. The Journal of physiology, 600(16), 3643. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378623/ PMC9378623]</ref> It is marketed under the name ERIL®. It was initially characterized as a calcium antagonist, different from previously known calcium channel blockers such as verapamil, diltiazem and nicardipine in that it could prevent arterial contraction in conditions where other calcium channel blockers had failed.<ref>Asano, T. O., Ikegaki, I. C., Satoh, S.,et al., & Hidaka, H. (1987). Mechanism of action of a novel antivasospasm drug, HA1077. Journal of Pharmacology and Experimental Therapeutics, 241(3), 1033-1040. PMID 3598899</ref>

Despite its successful introduction into clinical practice in Japan and China for almost 30 years, the use of fasudil in other countries faces certain limitations. Although fasudil inhibits both ROCK isoforms (ROCK1 and ROCK2) more potently than other kinases, some of its side effects, including hypotension, skin reactions and reversible renal dysfunction, are major barriers to its widespread use.<ref>Wolff, A. W., Peine, J., Höfler, J., Zurek, G., Hemker, C., & Lingor, P. (2024). SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants. CNS drugs, 38(4), 291-302. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980656/ PMC10980656]</ref>

== References ==
<references />

[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Main list]]

SLIT2

2024-09-21T10:45:07Z

Dmitry Dzhagarov:

'''SLIT2''' (Slit Guidance Ligand 2) is a protein coding gene that encode large secreted protein functioning as ligand for '''Roundabout (Robo)''' receptors.<ref>Blockus, H., & Chédotal, A. (2016). Slit-robo signaling. Development, 143(17), 3037-3044. PMID: 27578174 DOI: 10.1242/dev.132829</ref><ref>Wu, M. F., Liao, C. Y., Wang, L. Y., & Chang, J. T. (2017). The role of Slit-Robo signaling in the regulation of tissue barriers. Tissue Barriers, 5(2), e1331155. PMID: 28598714 PMCID: PMC5501134 DOI: 10.1080/21688370.2017.1331155</ref> The cleaved N-terminal fragment of SLIT2, N-SLIT2, acts via its receptor, Roundabout guidance receptor 1 (ROBO1), to attenuate inflammasome activation in macrophages by inhibiting macropinocytosis.<ref>Bhosle, V. K., Mukherjee, T., Huang, Y. W., Patel, S., Pang, B. W., Liu, G. Y., ... & Robinson, L. A. (2020). SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling. Nature communications, 11(1), 4112. PMID: 32807784 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431850/ PMC7431850] DOI: 10.1038/s41467-020-17651-1</ref> The SLIT family of genes consists of large extracellular matrix-secreted and membrane-associated glycoproteins.<ref>Little, M., Rumballe, B., Georgas, K., Yamada, T., & Teasdale, R. D. (2004). Conserved modularity and potential for alternate splicing in mouse and human Slit genes. International Journal of Developmental Biology, 46(4), 385-391.</ref><ref>Piper, M., & Little, M. (2003). Movement through Slits: cellular migration via the Slit family. Bioessays, 25(1), 32-38. PMID: 12508280 DOI: 10.1002/bies.10199</ref><ref>Wong, K., Park, H. T., Wu, J. Y., & Rao, Y. (2002). Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Current opinion in genetics & development, 12(5), 583-591. PMID: 12200164 DOI: 10.1016/s0959-437x(02)00343-x</ref> SLIT2 is located in chromosome 4p15.2 and encodes the human orthologue of the Drosophila Slit-2 protein.<ref>Georgas, K., Burridge, L., Smith, K., & Holmes, G. P. (1999). Assignment of the human slit homologue SLIT2 to human chromosome band 4p15. 2. Cytogenetic and Genome Research, 86(3/4), 246. PMID: 10575218 [https://doi.org/10.1159/000015351 DOI: 10.1159/000015351]</ref>
Slit was identified in ''Drosophila'' embryo as a gene involved in the patterning of larval cuticle. It was later shown that Slit is synthesized in the fly central nervous system by midline glia cells. Slit homologues have since been found in many vertebrate species, from amphibians, fishes, birds to mammals. There are three slit genes (slit1-slit3) in mammals, that have around 60% homology. All encodes large Extracellular matrix glycoproteins of about 200 kDa, comprising, from their N terminus to their C terminus, a long stretch of four leucine rich repeats (LRR) connected by disulphide bonds, seven to nine EGF (epidermal growth factor-like domain) repeats, laminin G-like module - a domain, named ALPS (Agrin, Perlecan, Laminin, Slit), and a cystein knot.<ref>Morlot, C., Thielens, N. M., Ravelli, R. B., Hemrika, W., Romijn, R. A., Gros, P., ... & McCarthy, A. A. (2007). Structural insights into the Slit-Robo complex. Proceedings of the National Academy of Sciences, 104(38), 14923-14928. PMID: 17848514 PMCID: PMC1975871 DOI: 10.1073/pnas.0705310104</ref> In vivo, Slit2 is cleaved into 140 kDa N-terminal (Slit2-N) and 55–60 kDa C-terminal (Slit2-C) fragments. Among them only recombinant Slit2-N showed a similar activity in stimulating branching and extension of dorsal root ganglia axons as reported for native Slit2-N purified from cells expressing wild-type full-length Slit2.<ref>Ba-Charvet, K. T. N., Brose, K., Ma, L., Wang, K. H., Marillat, V., Sotelo, C., ... & Chédotal, A. (2001). Diversity and specificity of actions of Slit2 proteolytic fragments in axon guidance. Journal of Neuroscience, 21(12), 4281-4289. PMID: 11404413 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762758/ PMC6762758] DOI: 10.1523/JNEUROSCI.21-12-04281.2001</ref>

SLIT family is involved in the epithelial-mesenchymal transition process that permits cancer cells to acquire migratory, invasive, and stem-like properties.<ref>Basha, S., Jin-Smith, B., Sun, C., & Pi, L. (2023). The SLIT/ROBO Pathway in Liver Fibrosis and Cancer. Biomolecules, 13(5), 785. PMID: 37238655 PMCID: PMC10216401 DOI: 10.3390/biom13050785</ref>
SLIT2 appears to function as a tumor suppressor gene. In addition, hypermethylation of its promoter region has been detected in various cancers, including breast and lung cancer, colorectal carcinoma, and gliomas.<ref>Jin, J., You, H., Yu, B., Deng, Y., Tang, N., Yao, G., ... & Qin, W. (2009). Epigenetic inactivation of SLIT2 in human hepatocellular carcinomas. Biochemical and Biophysical Research Communications, 379(1), 86-91. PMID: 19100240 DOI: 10.1016/j.bbrc.2008.12.022</ref>

<ref>Dallol, A., Da Silva, N. F., Viacava, P., Minna, J. D., Bieche, I., Maher, E. R., & Latif, F. (2002). SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer research, 62(20), 5874-5880. PMID: 12384551</ref>
<ref>Liu, J. W., Liu, H. T., & Chen, L. (2021). The therapeutic role of Slit2 in anti-fibrosis, anti-inflammation and anti-oxidative stress in rats with coronary heart disease. Cardiovascular Toxicology, 21(12), 973-983. PMID: 34410632 DOI: 10.1007/s12012-021-09688-5</ref>
<ref>Li, Q., Huang, L., Ding, Y., Sherchan, P., Peng, W., & Zhang, J. H. (2023). Recombinant Slit2 suppresses neuroinflammation and Cdc42-mediated brain infiltration of peripheral immune cells via Robo1–srGAP1 pathway in a rat model of germinal matrix hemorrhage. Journal of Neuroinflammation, 20(1), 249. PMID: 37899442 PMCID: PMC10613398 DOI: 10.1186/s12974-023-02935-2</ref>
<ref>Li, X., Zheng, S., Tan, W., Chen, H., Li, X., Wu, J., ... & Yang, F. H. (2020). Slit2 protects hearts against ischemia-reperfusion injury by inhibiting inflammatory responses and maintaining myofilament contractile properties. Frontiers in physiology, 11, 228. PMID: 32292352 PMCID: PMC7135862 DOI: 10.3389/fphys.2020.00228</ref>

SLIT2 progressively decreases as cells become senescent.<ref name="Mid-old" >Kim, Y. H., Lee, Y. K., Park, S. S., Park, S. H., Eom, S. Y., Lee, Y. S., ... & Park, T. J. (2023). Mid-old cells are a potential target for anti-aging interventions in the elderly. Nature Communications, 14(1), 7619. [https://doi.org/10.1038/s41467-023-43491-w DOI: 10.1038/s41467-023-43491-w]</ref> Treatment with '''recombinant human SLIT2 protein (rhSLIT2)''' resulted in decreased expression of inflammatory genes and proteins. In particular long-term treatment with rhSLIT2 protein resulted in upregulated expression of SOX2 and OCT4 and restored the morphology of mid-old (but not in old) fibroblasts, causing them to revert to a small and spindle-shaped morphology reminiscent of young cells. The proliferative capacity of such mid-old fibroblasts was recovered, accompanied by decreased levels of p21Waf1 mRNA and protein in a [[P53 protein involvement in Longevity|p53]]-independent manner.<ref name="Mid-old" />

In the animal experiments with 23-month-old male mice treated by rmSLIT2 10 times over a duration of several weeks, mouse aging-related characteristics significantly improved. Specifically, activity in the cage and hanging ability increased. However, blood analysis showed no significant difference between the control and rmSLIT2-treated groups.<ref name="Mid-old" />
Surprisingly, SLIT2 decreased inflammatory response and improved proliferative capacity only in mid-old, but not in old fibroblasts.<ref name="Mid-old" />

<ref>Zhao, H., Anand, A. R., & Ganju, R. K. (2014). Slit2–Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. The Journal of Immunology, 192(1), 385-393. PMID: 24272999 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908786/ PMC3908786] DOI: 10.4049/jimmunol.1302021</ref>
<ref>Jones, C. A., Nishiya, N., London, N. R., Zhu, W., Sorensen, L. K., Chan, A. C., ... & Li, D. Y. (2009). Slit2–Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nature cell biology, 11(11), 1325-1331. PMID: 19855388 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854659/ PMC2854659] DOI: 10.1038/ncb1976</ref>

During infection, Mycobacterium tuberculosis (Mtb) rewires distinct host signaling pathways that results in pathogen-favorable outcomes. In particular induced expression of the neuronal ligand SLIT2 which was due to the Mtb-mediated phosphorylation of the P38/[[Role of JNK in aging|JNK]] pathways. Activation of these kinases resulted in the loss of the repressive H3K27me3 signature on the Slit2 promoter.<ref>Borbora, S. M., Satish, B. A., Sundar, S., Bhatt, S., & Balaji, K. N. (2023). Mycobacterium tuberculosis elevates SLIT2 expression within the host and contributes to oxidative stress responses during infection. The Journal of Infectious Diseases, jiad126. PMID: 37158474 [https://doi.org/10.1093/infdis/jiad126 DOI: 10.1093/infdis/jiad126</ref> I noticed that many centenarians came from families where the incidence of tuberculosis was high (for example Jeanne Calment). This allows me to assume as a working hypothesis that perhaps activation of the Slit2 gene by Mtb is involved in their longevity.

== References ==
<references />
[[Category:Longevity genes]]
[[Category:Lifespan interventions]]
[[Category:Main list]]
[[Category:Drafts]]

Menin

2024-09-21T10:41:46Z

Dmitry Dzhagarov:

{| class="wikitable"
|+ List of PDB id codes
[https://www.rcsb.org/structure/3U84 3U84], [https://www.rcsb.org/structure/3U85 3U85], [https://www.rcsb.org/structure/3U86 3U86], [https://www.rcsb.org/structure/3U88 3U88], [https://www.rcsb.org/structure/4GPQ 4GPQ], [https://www.rcsb.org/structure/4GQ3 4GQ3], [https://www.rcsb.org/structure/4GQ4 4GQ4], [https://www.rcsb.org/structure/4I80 4I80], [https://www.rcsb.org/structure/4OG3 4OG3], [https://www.rcsb.org/structure/4OG4 4OG4], [https://www.rcsb.org/structure/4OG5 4OG5], [https://www.rcsb.org/structure/4OG6 4OG6], [https://www.rcsb.org/structure/4OG7 4OG7], [https://www.rcsb.org/structure/4OG8 4OG8], [https://www.rcsb.org/structure/4X5Y 4X5Y], [https://www.rcsb.org/structure/4X5Z 4X5Z], [https://www.rcsb.org/structure/5DDF 5DDF], [https://www.rcsb.org/structure/5DD9 5DD9], [https://www.rcsb.org/structure/5DDA 5DDA], [https://www.rcsb.org/structure/5DDE 5DDE], [https://www.rcsb.org/structure/5DDB 5DDB], [https://www.rcsb.org/structure/5DDD 5DDD], [https://www.rcsb.org/structure/5DDC 5DDC], [https://www.rcsb.org/structure/5DB0 5DB0], [https://www.rcsb.org/structure/5DB3 5DB3], [https://www.rcsb.org/structure/5DB1 5DB1], [https://www.rcsb.org/structure/5DB2 5DB2]
|-
! MEN1
|-
| [https://www.ncbi.nlm.nih.gov/gene MEN1 menin 1. Homo sapiens (human) Gene ID: 4221]
|-
| [https://www.ncbi.nlm.nih.gov/nuccore/U93236.1 Human menin (MEN1) mRNA], complete cds GenBank: U93236.1
|-
| Crystal Structure of Human Menin. [https://www.rcsb.org/structure/3U84 3U84]
|}
'''Menin''' is a 610-amino acid nuclear protein that in humans is encoded by the '''MEN1 (multiple endocrine neoplasia type 1) gene''', located on long arm of chromosome 11 (11q13).<ref>Guru, S. C., Goldsmith, P. K., Burns, A. L., Marx, S. J., Spiegel, A. M., Collins, F. S., & Chandrasekharappa, S. C. (1998). Menin, the product of the MEN1 gene, is a nuclear protein. Proceedings of the National Academy of Sciences, 95(4), 1630-1634. PMID: 9465067 PMCID: PMC19125 DOI: 10.1073/pnas.95.4.1630</ref><ref>Larsson, C., Skogseid, B., Öberg, K., Nakamura, Y., & Nordenskjöld, M. (1988). Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature, 332(6159), 85-87. PMID: 2894610 DOI: 10.1038/332085a0</ref> Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited endocrine disease (famous as Wermer disease) in which more than one endocrine gland develops tumors or grows excessively without forming tumors as a consequence of the MEN1 gene mutation.<ref>Bale, A. E., Norton, J. A., Wong, E. L., Fryburg, J. S., Maton, P. N., Oldfield, E. H., ... & Marx, S. J. (1991). Allelic Loss on Chromosome 11 in Hereditary and Sporadic Tumors Related to Familial Multiple Endocrine Neoplasia Type. Cancer research, 51(4), 1154-1157. PMID: 1671755</ref>
Menin represses MEN1 through inhibiting cell proliferation through multiple mechanisms.<ref>Wu, T., & Hua, X. (2011). Menin represses tumorigenesis via repressing cell proliferation. American journal of cancer research, 1(6), 726. PMID: 22016823 PMCID: PMC3195934</ref>
1) Menin interacts with various histonemodifying enzymes, such as MLL, EZH2 and HDACs, to affect gene transcription, leading to repression of cell proliferation. 2) Menin also interacts with various transcription factors, such as JunD, NF-κB, PPARγ and VDR, to induce or suppress gene transcription. As these various transcription factors are known to regulate cell proliferation, their interaction with menin may be relevant to menin's role in inhibiting cell proliferation. 3) Menin inhibits cell proliferation via TGF-β signaling and Wnt/β-catenin signaling pathways. 4) Menin represses certain pro-proliferative factors involved in endocrine tumors such as IGFBP-2, IGF2 and PTHrP to repress cell proliferation. 5) Menin affects cell cycle progression to inhibit cell proliferation.

<ref>Ren, F., Guo, Q., & Zhou, H. (2023). Menin represses the proliferation of gastric cancer cells by interacting with IQGAP1. Biomedical Reports, 18(4), 1-7. </ref>

MEN1 is an essential antifibrotic factor in renal fibrogenesis and could be a potential target for antifibrotic therapy. Since knockout of MEN1 resulted in chronic renal fibrosis and unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis (TIF), which is associated with an increased induction of epithelial-to-mesenchymal transition (EMT), G2/M arrest and [[Role of JNK in aging|JNK]] signaling. Mechanistically, menin recruits and increases H3K4me3 at the promoter regions of hepatocyte growth factor (HGF) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts5) genes and enhances their transcriptional activation.<ref>Jin, B., Zhu, J., Zhou, Y., Liang, L., Yang, Y., Xu, L., ... & Li, H. (2022). Loss of MEN1 leads to renal fibrosis and decreases HGF‐Adamts5 pathway activity via an epigenetic mechanism. Clinical and Translational Medicine, 12(8), e982. PMID: 35968938 PMCID: PMC9377152 DOI: 10.1002/ctm2.982</ref>
The levels of menin by degrees diminish with the progression of fibrosis in a mouse model of radiation‐induced pulmonary fibrosis. MEN1 plays a key role in the formation of pulmonary fibrosis by regulating the secretion of TGF-β and the activation of TGF-β/Smads signaling pathway.<ref>Wei, W., Zhang, H. Y., Gong, X. K., Dong, Z., Chen, Z. Y., Wang, R., ... & Jin, S. Z. (2018). Mechanism of MEN1 gene in radiation-induced pulmonary fibrosis in mice. Gene, 678, 252-260. PMID: 30099020 DOI: 10.1016/j.gene.2018.08.039</ref>

The expression of menin is reduced in the liver of aging mice. Hepatocyte-specific deletion of Men1 induces liver steatosis in aging mice. Menin deficiency promotes high-fat diet-induced liver steatosis in mice. Menin recruits SIRT1 to control hepatic CD36 expression and triglyceride accumulation through histone.<ref>Cao, Y., Xue, Y., Xue, L., Jiang, X., Wang, X., Zhang, Z., ... & Ning, G. (2013). Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation. Journal of Hepatology, 59(6), 1299-1306. PMID: 23867312 DOI: 10.1016/j.jhep.2013.07.011</ref>

Menin plays important roles in neuroinflammation and brain development.

<ref>Matkar, S., Thiel, A., & Hua, X. (2013). Menin: a scaffold protein that controls gene expression and cell signaling. Trends in biochemical sciences, 38(8), 394-402. PMID: 23850066 PMCID: PMC3741089 DOI: 10.1016/j.tibs.2013.05.005</ref>
<ref>Feng, Z., Ma, J., & Hua, X. (2017). Epigenetic regulation by the menin pathway. Endocrine-related cancer, 24(10), T147. PMID: 28811300 PMCID: PMC5612327 DOI: 10.1530/ERC-17-0298</ref>

'''The hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging''' and cognitive deficits.<ref name="Hypothal">Leng, L., Yuan, Z., Su, X., Chen, Z., Yang, S., Chen, M., ... & Zhang, J. (2023). Hypothalamic Menin regulates systemic aging and cognitive decline. Plos Biology, 21(3), e3002033. PMID: 36928253 PMCID: PMC10019680 DOI: 10.1371/journal.pbio.3002033</ref> '''Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers''', while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism.<ref name="Hypothal" /> Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.<ref name="Hypothal" />

Methylation of histone H3 lysine-79 (H3K79) plays key roles in gene regulation. The protein menin was identified as a reader of H3K79me2.<ref>Yang, Y. J., Song, T. Y., Park, J., Lee, J., Lim, J., Jang, H., ... & Cho, E. J. (2013). Menin mediates epigenetic regulation via histone H3 lysine 9 methylation. Cell death & disease, 4(4), e583-e583. PMID: 23579270 PMCID: PMC3668625 DOI: 10.1038/cddis.2013.98</ref><ref>Lin, J., Wu, Y., Tian, G., Yu, D., Yang, E., Lam, W. H., ... & Li, X. D. (2023). Menin “reads” H3K79me2 mark in a nucleosomal context. Science, 379(6633), 717-723. PMID: 36795828 DOI: 10.1126/science.adc9318</ref>

<ref>Agarwal, S. K. (2017). The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocrine-related cancer, 24(10), T119. PMID: 28899949 PMCID: PMC5679100 DOI: 10.1530/ERC-17-0199</ref>

== References ==
<references />
{{Draft-article}}

[[Category:Drafts]]
[[Category:Longevity genes]]
[[Category:Main list]]

ATF4 (activating transcription factor 4)

2024-09-21T10:36:24Z

Dmitry Dzhagarov:

'''Activating transcription factor 4 (ATF-4 or ATF4)'''; also known as '''GCN4''', is a multifunctional transcription regulatory protein which, according to a number of studies, regulates longevity through cooperation with certain longevity factors to enhance the activity of multiple mechanisms that protect cellular functions, thereby driving lifespan extension.<ref>Li, W., & Miller, R. A. (2015). Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 70(3), 263-272. PMID: 24691093 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351389 4351389] DOI: 10.1093/gerona/glu040</ref><ref>Li, W., Li, X., & Miller, R. A. (2014). ATF 4 activity: a common feature shared by many kinds of slow‐aging mice. Aging cell, 13(6), 1012-1018. PMID: 25156122 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326926 4326926] DOI: 10.1111/acel.12264</ref><ref>Statzer, C., Meng, J., Venz, R., Bland, M., Robida-Stubbs, S., Patel, K., ... & Ewald, C. Y. (2022). ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1. Nature communications, 13(1), 1-15. PMID: 35181679 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857226 8857226] DOI: 10.1038/s41467-022-28599-9</ref><ref>McIntyre, R. L., Molenaars, M., Schomakers, B. V., Gao, A. W., Kamble, R., Jongejan, A., ... & Janssens, G. E. (2023). Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4. Cell Reports, 42(1), 111928. PMID: 36640360 DOI: [https://doi.org/10.1016/j.celrep.2022.111928 10.1016/j.celrep.2022.111928]</ref><ref>Robbins, C. E., Patel, B., Sawyer, D. L., Wilkinson, B., Kennedy, B. K., & McCormick, M. A. (2022). Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/atf-4-dependent manner. Iscience, 25(11), 105410. PMID: 36388960 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647507 9647507] DOI: 10.1016/j.isci.2022.105410</ref><ref>Mittal, N., Guimaraes, J. C., Gross, T., Schmidt, A., Vina-Vilaseca, A., Nedialkova, D. D., ... & Zavolan, M. (2017). The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan. Nature communications, 8(1), 1-12. PMID: 28878244 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587724 5587724] DOI: 10.1038/s41467-017-00539-y</ref>

ATF4- is expressed in most mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, and growth factors. The context-dependent role of this transcriptional master-regulator varies across a spectrum of growth and starvation programs.<ref>Srinivasan, R., Walvekar, A. S., Rashida, Z., Seshasayee, A., & Laxman, S. (2020). Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program. PLoS Genetics, 16(12), e1009252. PMID: 33378328 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773203 7773203] DOI: 10.1371/journal.pgen.1009252</ref> Regardless of context, ATF-4/Gcn4 is required for amino acid biosynthesis (particularly lysine and arginine biosynthesis), and for repression of ribosomal genes. Through ATF4 networks, cells can couple translation with metabolism, and manage resource allocations to sustain anabolism.<ref>Wortel, I. M., van der Meer, L. T., Kilberg, M. S., & van Leeuwen, F. N. (2017). Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends in Endocrinology & Metabolism, 28(11), 794-806.PMID: 28797581 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951684 5951684] DOI: 10.1016/j.tem.2017.07.003</ref>

ATF-4 is hypothesized to mediate the lifespan extension effects of mTORC1 inhibition (target of [[rapamycin]]) and of translation inhibition.<ref>Statzer, C., Meng, J., Venz, R. ''et al.'' ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1. ''Nat Commun'' 13, 967 (2022). <nowiki>https://doi.org/10.1038/s41467-022-28599-9</nowiki></ref> In fact, mTORC1 inhibition requires ATF-4 activation, which promotes hydrogen sulphide production and cooperates with lifespan regulators [[FOXO longevity genes|FOXO]], [[Heat-shock response|Heat-Shock]] Factor 1 (HSF-1) and Nuclear Receptor Factor 1 (NRF-1).<ref>Statzer, C., Meng, J., Venz, R. ''et al.'' ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1. ''Nat Commun'' 13, 967 (2022). <nowiki>https://doi.org/10.1038/s41467-022-28599-9</nowiki></ref> ATF-4 additionally regulates stress responses in [[mitochondria]], up-regulating cytoprotective genes.<ref>Quirós, P. M., Prado, M. A., Zamboni, N., D’Amico, D., Williams, R. W., Finley, D., ... & Auwerx, J. (2017). Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. ''Journal of Cell Biology'', ''216''(7), 2027-2045.</ref>

== Identification of ATF4 ==
ATF4 was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1.<ref>Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21. PMID: 17466566 DOI: [https://doi.org/10.1016/j.biocel.2007.01.020 10.1016/j.biocel.2007.01.020]</ref><ref>Hai, T., & Curran, T. (1991). Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proceedings of the national academy of sciences, 88(9), [tel:3720-3724 3720-3724]. PMID: 1827203 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC51524 51524] DOI: 10.1073/pnas.88.9.3720</ref> The encoded protein was isolated and characterized as the cAMP-response element binding protein 2 (CREB-2).<ref>Karpinski, B. A., Morle, G. D., Huggenvik, J., Uhler, M. D., & Leiden, J. M. (1992). Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proceedings of the National Academy of Sciences, 89(11), [tel:4820-4824 4820-4824]. PMID: 1534408 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC49179 49179] DOI: 10.1073/pnas.89.11.4820</ref> It should be noted that ATF4 is not a functional transcription factor by itself, but one-half of many possible heterodimeric transcription factors. Because ATF4 can simultaneously participate in multiple distinct heterodimers, the overall set of genes that require ATF4 for maximal expression in a specific context (ATF4-dependent genes) can be a mixture of genes that are regulated by different ATF4 heterodimers, with some ATF4-dependent genes activated by one ATF4 heterodimer and other ATF4-dependent genes activated by other ATF4 heterodimers.<ref name="atrophy">Ebert, S. M., Rasmussen, B. B., Judge, A. R., Judge, S. M., Larsson, L., Wek, R. C., ... & Adams, C. M. (2022). Biology of activating transcription factor 4 (ATF4) and its role in skeletal muscle atrophy. The Journal of Nutrition, 152(4), 926-938. PMID:34958390 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970988 8970988] DOI:10.1093/jn/nxab440</ref>
== ATF4 as the effector of the ISR ==
ATF4 is a basic leucine zipper (bZIP) transcription factor that is selectively translated in response to specific forms of cellular stress to induce the expression of genes involved in program of adaptation to stress, known as the '''integrated stress response (ISR)'''.<ref>Costa-Mattioli, M., & Walter, P. (2020). The integrated stress response: From mechanism to disease. Science, 368(6489), eaat5314. PMID: 32327570 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997189 8997189] DOI: 10.1126/science.aat5314</ref><ref>Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., & Ron, D. (2000). Regulated translation initiation controls stress-induced gene expression in mammalian cells. Molecular cell, 6(5), 1099-1108. PMID: 11106749 DOI: [https://doi.org/10.1016/s1097-2765(00)00108-8 10.1016/s1097-2765(00)00108-8]</ref><ref>Kalinin, A., Zubkova, E., & Menshikov, M. (2023). Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence. International Journal of Molecular Sciences, 24(24), 17423. PMID: 38139251 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10743681/ PMC10743681] DOI: 10.3390/ijms242417423</ref> In particular, treatment with ISRIB, an ISR inhibitor, reduced the induction of ATF4 and several of its target genes.<ref>Quirós, P. M., Prado, M. A., Zamboni, N., D’Amico, D., Williams, R. W., Finley, D., ... & Auwerx, J. (2017). Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. Journal of Cell Biology, 216(7), 2027-2045. PMID: 28566324 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496626 5496626] DOI: 10.1083/jcb.201702058</ref><ref>Sasaki, K., Uchiumi, T., Toshima, T., Yagi, M., Do, Y., Hirai, H., ... & Kang, D. (2020). Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondrial unfolded protein response. Bioscience reports, 40(11). PMID: 33165592 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685009 7685009] DOI: 10.1042/BSR20201289</ref>

Prolonged or intense stimulation of the ISR can result in ATF4-driven expression of pro-apoptotic effectors to induce cell death.<ref>Nwosu, G. O., Powell, J. A., & Pitson, S. M. (2022). Targeting the integrated stress response in hematologic malignancies. Experimental Hematology & Oncology, 11(1), 1-15. PMID: 36348393 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9644628 9644628] DOI: 10.1186/s40164-022-00348-0</ref>

== Role of ATF4 in the response to hypoxic stress ==
Hypoxia is a stress condition in which oxygen levels are insufficient for typical cellular functions, such as protein translation and folding. It has been shown that at upon hypoxic exposure, ATF4 expression significantly increases. For example, in acute hypoxia, the cultured cells exhibited a 2.3-fold increase in ATF4 protein expression, while in chronic hypoxia, ATF4 levels increased by 5.7-fold compared with normoxia. <ref name="chronic" >Chee, N. T., Carriere, C. H., Miller, Z., Welford, S., & Brothers, S. P. (2023). Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells. Oncology Reports, 49(1), 1-14. PMID: 36416348 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9713860 9713860] DOI: 10.3892/or.2022.8451</ref>

== Role of ATF4 in cancer cells ==
ATF4 is frequently upregulated in cancer cells. As the tumor increases in size, cells in the tumor core are challenged by limited levels of oxygen, glucose, and amino acids, each of which triggers metabolic changes that tune anabolic and catabolic pathways towards the accumulation of biomass.<ref name="chronic"/> ATF4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells.<ref>Chee, N. T., Carriere, C. H., Miller, Z., Welford, S., & Brothers, S. P. (2023). Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells. ''Oncology Reports'', ''49''(1), 1-14.</ref> Additionally, inhibition of ATF4 expression reduces cell migration, invasion, and proliferation in breast cancer.<ref>González-González, A., Muñoz-Muela, E., Marchal, J. A., Cara, F. E., Molina, M. P., Cruz-Lozano, M., ... & Granados-Principal, S. (2018). Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 SignalingATF4, Biomarker, and Target in Triple-Negative Breast Cancer. Clinical Cancer Research, 24(22), [tel:5697-5709 5697-5709]. PMID: 30012564 DOI: [https://doi.org/10.1158/1078-0432.CCR-17-3125 10.1158/1078-0432.CCR-17-3125]</ref>

ATF4 target genes have been found to be critical for cell growth and cancer progression. Their activation depends on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) at Ser51. The eIF2α-ATF4 axis plays a critical role in amino acid metabolic reprogramming of cancer cells, especially when cells are in a stressful nutrient-scarce microenvironment. eIF2α‍-ATF4 maintains intracellular amino acid levels via multiple mechanisms.

== Role of ATF4 in anoikis resistance ==
Anoikis is a specialized form of cell death (apoptosis) caused by loss of contact with the extracellular matrix (ECM) or inappropriate cell adhesion.<ref name="metastasis">Simpson, C. D., Anyiwe, K., & Schimmer, A. D. (2008). Anoikis resistance and tumor metastasis. Cancer letters, 272(2), 177-185. </ref> Metastatic cancer cells have been shown to develop resistance to anoikis by activating several signaling pathways that impinge on extrinsic and mitochondria-mediated apoptosis. ATF4 plays a central role in mediating an antioxidant and proautophagic ISR that enables cancer cells to survive and migrate to secondary sites during tumor metastasis.<ref>Mo, H., Guan, J., Mo, L., He, J., Wu, Z., Lin, X., ... & Yuan, Z. (2018). ATF4 regulated by MYC has an important function in anoikis resistance in human osteosarcoma cells. Molecular Medicine Reports, 17(3), [tel:3658-3666 3658-3666]. PMID: 29257326 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802171 5802171] DOI: 10.3892/mmr.2017.8296</ref><ref>Dey, S., Sayers, C. M., Verginadis, I. I., Lehman, S. L., Cheng, Y., Cerniglia, G. J., ... & Koumenis, C. (2015). ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. The Journal of clinical investigation, 125(7), [tel:2592-2608 2592-2608]. PMID: 26011642 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563676 4563676] DOI: 10.1172/JCI78031</ref><ref>Yu, Y., Liu, B., Li, X., Lu, D., Yang, L., Chen, L., ... & Xing, Y. (2022). ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells. Cell death & disease, 13(1), 1-13. PMID: 35013120 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748688 8748688] DOI: 10.1038/s41419-021-04494-x</ref>

ATF4 also plays a critical role in the maintenance of survival and anti-tumor activities of CD8+ T cells,<ref>Lu, Z., Bae, E. A., Verginadis, I. I., Zhang, H., Cho, C., McBrearty, N., ... & Fuchs, S. Y. (2022). Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities. Cancer Immunology, Immunotherapy, 1-12. PMID: 36063172 DOI: [https://doi.org/10.1007/s00262-022-03286-2 10.1007/s00262-022-03286-2]</ref> and is required for the IFN-γ production by Th1 cells, particularly when T cells are in the higher oxidizing environment.<ref>Yang, X., Xia, R., Yue, C., Zhai, W., Du, W., Yang, Q., ... & Lu, B. (2018). ATF4 regulates CD4+ T cell immune responses through metabolic reprogramming. Cell reports, 23(6), 1754-1766. PMID: 29742431 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051420 6051420] DOI: 10.1016/j.celrep.2018.04.032</ref> Therefore, care must be taken when using agents that can undermine these ATF4 functions for anticancer therapy.

The most widely expressed type of a cell-surface chondroitin sulfate/heparan sulfate proteoglycan is the '''Transforming Growth Factor Beta Receptor III (TGFBR3)''' which acts as an anoikis mediator through the inhibition of ATF4. Inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling.<ref>Hsu, Y. J., Yin, Y. J., Tsai, K. F., Jian, C. C., Liang, Z. W., Hsu, C. Y., & Wang, C. C. (2022). TGFBR3 supports anoikis through suppressing ATF4 signaling. Journal of Cell Science, 135(17), jcs258396. PMID: 35912788 DOI: [https://doi.org/10.1242/jcs.258396 10.1242/jcs.258396]</ref>

== ATF4 in vascular injury ==
It has been shown that ATF4 up-regulation can induce vascular smooth muscle cells (VSMCs) to proliferate and ATF4 knockdown blocks injury-inducible intimal proliferation.<ref>Malabanan, K. P., & Khachigian, L. M. (2010). Activation transcription factor-4 and the acute vascular response to injury. Journal of molecular medicine, 88(6), 545-552. PMID: 20306012 DOI: [https://doi.org/10.1007/s00109-010-0615-4 10.1007/s00109-010-0615-4]</ref> ATF4 is involved in vascular injury through the activation of a signaling pathway involving PERK, eIF2α and CHOP, key molecules in endoplasmic reticulum stress.<ref name="Masuda">Masuda, M., Miyazaki‐Anzai, S., Levi, M., Ting, T. C., & Miyazaki, M. (2013). PERK‐eIF2α‐ATF4‐CHOP signaling Contributes to TNF α‐Induced vascular Calcification. Journal of the American Heart Association, 2(5), e000238. PMID: 24008080 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835225 3835225] DOI: 10.1161/JAHA.113.000238</ref><ref>Chin, M. T. (2008). ATF-4 and vascular injury: integration of growth factor signaling and the cellular stress response. Circulation research, 103(4), 331-333. PMID: 18703783 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747631 2747631] DOI: 10.1161/CIRCRESAHA.108.182246</ref>

Vascular calcification is essential risk factor for cardiovascular events. ATF4 was involved at least in part in the process of endoplasmic reticulum stress (ERS)-mediated apoptosis contributing to vascular calcification (VC) and ATF4 knockdown attenuated ERS-induced apoptosis in calcified vascular smooth muscle cells (VSMC)s.<ref>Duan, X. H., Chang, J. R., Zhang, J., Zhang, B. H., Li, Y. L., Teng, X., ... & Qi, Y. F. (2013). Activating transcription factor 4 is involved in endoplasmic reticulum stress-mediated apoptosis contributing to vascular calcification. Apoptosis, 18(9), 1132-1144. PMID: 23686245 DOI: [https://doi.org/10.1007/s10495-013-0861-3 10.1007/s10495-013-0861-3]</ref><ref name="Masuda"/> ISRIB treatment could ameliorate VC pathogenesis via blocking the elevation of ATF4 phosphorylation in the calcified aorta.<ref>Dong, J., Jin, S., Guo, J., Yang, R., Tian, D., Xue, H., ... & Wu, Y. (2022). Pharmacological Inhibition of eIF2α Phosphorylation by Integrated Stress Response Inhibitor (ISRIB) Ameliorates Vascular Calcification in Rats. Physiological Research, 71(3), 379-388. PMID: 35616039 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470096 9470096] DOI: 10.33549/physiolres.934797</ref>

Treatment with '''epigallocatechin-3-gallate (EGCG)''', the most bioactive and abundant polyphenolic compound in green tea, can initiate proapoptotic signaling pathways via targeting endoplasmic reticulum (ER) stress, but later, due to subsequent ATF4 activation, it helps the remaining cells to survive.<ref>Md Nesran, Z. N., Shafie, N. H., Ishak, A. H., Mohd Esa, N., Ismail, A., & Md Tohid, S. F. (2019). Induction of endoplasmic reticulum stress pathway by green tea epigallocatechin-3-gallate (EGCG) in colorectal cancer cells: activation of PERK/p-eIF2α/ATF4 and IRE1α. BioMed research international, 2019. PMID: 31930117 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942794 6942794] DOI: 10.1155/2019/3480569</ref><ref>Zhou, L., He, J. N., Du, L., Ho, B. M., Ng, D. S. C., Chan, P. P., ... & Chu, W. K. (2022). Epigallocatechin-3-Gallate Protects Trabecular Meshwork Cells from Endoplasmic Reticulum Stress. Oxidative Medicine and Cellular Longevity, 2022. PMID: 36406768 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671731 9671731] DOI: 10.1155/2022/7435754</ref>

== Role of ATF4 in skeletal muscle weakness and atrophy ==
ATF4 induction by skeletal muscle stresses such as fasting, muscle immobilization, and muscle denervation, results in muscle wasting.<ref name="atrophy"/>
ATF4 is an essential mediator of skeletal muscle aging. During skeletal muscle aging, ATF4 promotes induction of transcripts involved in inflammation, cellular senescence, and Rho GTPase signaling. During skeletal muscle aging, ATF4 promotes repression of transcripts involved in mitochondrial function, protein synthesis, and metabolism of amino acids, polyamines, glutathione, and nicotinamide.<ref>Miller, M. J., Marcotte, G. R., Basisty, N., Wehrfritz, C., Ryan, Z. C., Strub, M. D., ... & Adams, C. M. (2023). The transcription regulator ATF4 is a mediator of skeletal muscle aging. GeroScience, 1-19. PMID: 37014538 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071239 10071239] DOI: 10.1007/s11357-023-00772-y</ref> '''ATF4 promotes muscle atrophy by increasing the levels of specific mRNAs in skeletal muscle fibers, most notably ''Gadd45a'' (growth arrest and DNA damage-inducible 45 α).'''<ref>Ebert, S. M., Dyle, M. C., Kunkel, S. D., Bullard, S. A., Bongers, K. S., Fox, D. K., ... & Adams, C. M. (2012). Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. Journal of Biological Chemistry, 287(33), [tel:27290-27301 27290-27301]. PMID: 22692209 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431665 3431665] DOI: 10.1074/jbc.M112.374777</ref><ref>Adams, C. M., Ebert, S. M., & Dyle, M. C. (2017). Role of ATF4 in skeletal muscle atrophy. Current Opinion in Clinical Nutrition & Metabolic Care, 20(3), 164-168. PMID: 28376050 DOI: [https://doi.org/10.1097/MCO.0000000000000362 10.1097/MCO.0000000000000362]</ref> The Gadd45 gene encodes a ubiquitously expressed evolutionary conserved small, highly acidic proteins which do not have any known enzymatic activity, but nevertheless fulfill a plethora of different functions in the cell, mostly mediated via protein-protein interactions.<ref>Ebert, S. M., Bullard, S. A., Basisty, N., Marcotte, G. R., Skopec, Z. P., Dierdorff, J. M., ... & Adams, C. M. (2020). Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ. Journal of Biological Chemistry, 295(9), [tel:2787-2803 2787-2803]. PMID: 31953319 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">Ebert, S. M., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., Murry, D. J., Fox, D. K., ... & Adams, C. M. (2015). Identification and small molecule inhibition of an activating transcription factor 4 (ATF4)-dependent pathway to age-related skeletal muscle weakness and atrophy. Journal of Biological Chemistry, 290(42), [tel:25497-25511 25497-25511]. PMID: 26338703 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>

'''The induction of the ATF4 pathway can be dissociated from muscle atrophy'''. For example, hibernating bears (Ursidae family) are naturally resistant to muscle atrophy when facing two major atrophic inducers: prolonged fasting and physical inactivity. Fasting and physical inactivity in hibernating bears can last up to 5–7 months, however during this time Atf4 and ATF4-regulated Gadd45a are upregulated in skeletal muscle, compared to non-hibernating bears.<ref name="Halofuginone">Cussonneau, L., Coudy-Gandilhon, C., Deval, C., Chaouki, G., Djelloul-Mazouz, M., Delorme, Y., ... & Combaret, L. (2023). Induction of ATF4-Regulated Atrogenes Is Uncoupled from Muscle Atrophy during Disuse in Halofuginone-Treated Mice and in Hibernating Brown Bears. Int. J. Mol. Sci. 24(1), 621; PMID: 36614063 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>

==== Halofuginone improves muscle functions during physical inactivity ====
Halofuginone, a racemic halogenated derivative of plant alkaloid febrifugine, is capable of reducing fibrosis and inflammation and improve muscle functions in muscular dystrophies.<ref>Bodanovsky, A., Guttman, N., Barzilai-Tutsch, H., Genin, O., Levy, O., Pines, M., & Halevy, O. (2014). Halofuginone improves muscle-cell survival in muscular dystrophies. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1843(7), 1339-1347. PMID: 24703880 DOI: [https://doi.org/10.1016/j.bbamcr.2014.03.025 10.1016/j.bbamcr.2014.03.025]</ref> '''Halofuginone treatment has been shown to reproduced the muscle features of hibernating bears''' in gastrocnemius mice muscles with (I) the activation of ATF4-regulated atrogenes and (II) the concurrent inhibition of TGF-β signalling and promotion of BMP signalling, without resulting in muscle atrophy. These characteristics were associated with mitigated muscle atrophy during physical inactivity.<ref name="Halofuginone"/>

=== Gadd45a role in longevity ===
Gadd45a plays a pivotal role as a '''cellular stress sensor''', by interacting with and modulating the function of proteins regulating cell cycle control,<ref name="Sensor">Humayun, A., & Fornace Jr, A. J. (2022). GADD45 in stress signaling, cell cycle control, and apoptosis. In Gadd45 Stress Sensor Genes (pp. 1-22). Cham: Springer International Publishing. PMID: 35505159 DOI: [https://doi.org/10.1007/978-3-030-94804-7_1 10.1007/978-3-030-94804-7_1]</ref> DNA repair,<ref name="Demethylation">Chandramouly, G. (2022). Gadd45 in DNA Demethylation and DNA Repair. In Gadd45 Stress Sensor Genes (pp. 55-67). Springer, Cham. PMID: 35505162 DOI: [https://doi.org/10.1007/978-3-030-94804-7_4 10.1007/978-3-030-94804-7_4]</ref> and cell survival.<ref>Wang, Y., Gao, H., Cao, X., Li, Z., Kuang, Y., Ji, Y., & Li, Y. (2022). Role of GADD45A in myocardial ischemia/reperfusion through mediation of the [[Role of JNK in aging|JNK]]/p38 MAPK and STAT3/VEGF pathways. International Journal of Molecular Medicine, 50(6), 1-11. PMID: 36331027 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662138 9662138] DOI: 10.3892/ijmm.2022.5200</ref> In particular, in the absence of Gadd45α, the amount of DNA breaks accumulates due to the reduced efficiency of repair, while Histone Deacetylase Inhibitors (HDIs) dependent induction of Gadd45α promotes DNA repair.<ref name="Demethylation"/> It has been proposed that GADD45A mediates passive DNA demethylation via interaction with the catalytic domain of DNA (cytosine-5)-methyltransferase 1 (DNMT1).<ref>Lee, B., Morano, A., Porcellini, A., & Muller, M. T. (2012). GADD45α inhibition of DNMT1 dependent DNA methylation during homology directed DNA repair. Nucleic acids research, 40(6), [tel:2481-2493 2481-2493]. PMID: 22135303 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315326 3315326] DOI: 10.1093/nar/gkr1115</ref>

'''Gadd45a might promote epigenetic gene activation by repair-mediated DNA demethylation'''.<ref>Barreto, G., Schäfer, A., Marhold, J., Stach, D., Swaminathan, S. K., Handa, V., ... & Niehrs, C. (2007). Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. nature, 445(7128), 671-675. PMID: 17268471 DOI: [https://doi.org/10.1038/nature05515 10.1038/nature05515]</ref> There is also evidence that GADD45a induces the demethylation of CpG islands that are dependent on base excision repair to produce a permissible chromatin state for DNA damage response (DDR), especially in the short telomere/subtelomere regions. Depletion of GADD45a promotes chromatin condensation in the subtelomere regions.

'''GADD45a knockout can improve the function of intestinal stem cells and extend the lifespan of telomerase-deficient mice (G3Terc−/−)'''.<ref>Diao, D., Wang, H., Li, T., Shi, Z., Jin, X., Sperka, T., ... & Ju, Z. (2018). Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan. EMBO reports, 19(10), e45494. PMID: 30126922 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172461 6172461] DOI: 10.15252/embr.201745494</ref> Additionally, Gadd45a has been identified to be a RNA binding protein that can be recruited by an R-loop (RNA-DNA hybrid) formed on a CG-rich promoter region, which then guides the Tet enzyme for local DNA demethylation.<ref>Arab, K., Karaulanov, E., Musheev, M., Trnka, P., Schäfer, A., Grummt, I., & Niehrs, C. (2019). GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nature genetics, 51(2), 217-223. PMID: 30617255 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420098 6420098] DOI: 10.1038/s41588-018-0306-6</ref> Normally, CpG-rich regions have a relatively lower methylation rate, which correlates with gene activation, while gene-specific methylation on CpG normally induces gene silencing. This makes it possible to estimate age and the presence of age-related diseases, using a statistical method called the '''[[epigenetic clock]]''', which is based on the strongly correlated with age specific set of methylated loci.<ref>Higham, J., Kerr, L., Zhang, Q., Walker, R. M., Harris, S. E., Howard, D. M., ... & Sproul, D. (2022). Local CpG density affects the trajectory and variance of age-associated DNA methylation changes. Genome Biology, 23(1), 1-28. PMID: 36253871 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9575273 9575273] DOI: 10.1186/s13059-022-02787-8</ref>

Gadd45a can interact with key '''cell regulators''' such as p21,<ref>Kearsey, J. M., Coates, P. J., Prescott, A. R., Warbrick, E., & Hall, P. A. (1995). Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene, 11(9), 1675-1683. PMID: 7478594</ref> cdc2/cyclinB1, proliferating cell nuclear antigen, p38, and MAP kinase kinase kinase (MEKK4). Primary mouse embryo fibroblasts (MEFs) are cells with limited lifespan, which undergo [[Cellular senescence|senescence]] ''in vitro'' due to stress and hyperoxic conditions which result in accumulation of DNA damage. However, loss of Gadd45a in MEFs results in escape from senescence ''in vitro'' in response to Ras-driven tumorigenesis.<ref>Bulavin, D. V., Kovalsky, O., Hollander, M. C., & Fornace Jr, A. J. (2003). Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Molecular and cellular biology, 23(11), [tel:3859-3871 3859-3871]. PMID: 12748288 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC155214 155214] DOI: 10.1128/MCB.23.11.3859-3871.2003</ref><ref>Tront, J. S., Huang, Y., Fornace, A. A., Hoffman, B., & Liebermann, D. A. (2010). Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic StressGadd45a in Breast Tumorigenesis. Cancer research, 70(23), [tel:9671-9681 9671-9681]. PMID: 21098706 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199142 3199142] DOI: 10.1158/0008-5472.CAN-10-2177</ref>

Disruption of Gadd45a (Growth arrest and DNA-damage-inducible protein 45 alpha), a p53- and BRCA1-regulated stress-inducible gene, in mice results in genomic instability and increased carcinogenesis.<ref>Magimaidas, A., Madireddi, P., Maifrede, S., Mukherjee, K., Hoffman, B., & Liebermann, D. A. (2016). Gadd45b deficiency promotes premature senescence and skin aging. Oncotarget, 7(19), 26935. PMID: 27105496 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053623 5053623] DOI: 10.18632/oncotarget.8854</ref><ref>Zaidi, M. R., & Liebermann, D. A. (2022). Gadd45 in Senescence. In Gadd45 Stress Sensor Genes (pp. 109-116). Springer, Cham. PMID: 35505166 DOI: [https://doi.org/10.1007/978-3-030-94804-7_8 10.1007/978-3-030-94804-7_8]</ref> Therefore, Gadd45a appears to be an important component in the cellular defense network that is required for maintenance of genomic stability. The Gadd45a gene also plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis.<ref name="Sensor" /><ref>Zhan, Q. (2005). Gadd45a, a p53-and BRCA1-regulated stress protein, in cellular response to DNA damage. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 569(1-2), 133-143. PMID: 15603758 DOI: [https://doi.org/10.1016/j.mrfmmm.2004.06.055 10.1016/j.mrfmmm.2004.06.055]</ref> [[FOXO longevity genes|FOXO]] proteins (such as FOXO1), enhance the promoter activity of target genes in cooperation with C/EBPδ and ATF4,<ref>Oyabu, M., Takigawa, K., Mizutani, S., Hatazawa, Y., Fujita, M., Ohira, Y., ... & Kamei, Y. (2022). FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting. The FASEB Journal, 36(2), e22152. PMID: 35061305 DOI: [https://doi.org/10.1096/fj.202101385RR 10.1096/fj.202101385RR]</ref> and regulate longevity regulation pathways via promoting the expression of Gadd45a, Sod2, and Cat.<ref>Wu, Y., Wang, J., Zhao, T., Wei, Y., Han, L., Shen, L., ... & Wei, G. (2021). LncRNAs activate longevity regulation pathway due to aging of Leydig cells caused by DEHP exposure: A transcriptome-based study. Ecotoxicology and Environmental Safety, 209, 111798. PMID: 33360214 DOI: [https://doi.org/10.1016/j.ecoenv.2020.111798 10.1016/j.ecoenv.2020.111798]</ref>

Additionally, Gadd45a regulates beta-catenin distribution and maintains cell-cell adhesion/contact. Gadd45a is involved in the control of cell contact inhibition and cell-cell adhesion. Gadd45a can serve as an adapter to enhance the interaction between beta-catenin and Caveolin-1, and in turn induces beta-catenin translocation to cell membrane for maintaining cell-cell adhesion/contact inhibition.<ref>Ji, J., Liu, R., Tong, T., Song, Y., Jin, S., Wu, M., & Zhan, Q. (2007). Gadd45a regulates β-catenin distribution and maintains cell–cell adhesion/contact. Oncogene, 26(44), [tel:6396-6405 6396-6405]. PMID: 17452974 DOI: [https://doi.org/10.1038/sj.onc.1210469 10.1038/sj.onc.1210469]</ref>

=== Medications that could be used to preserve muscle mass during catabolic situations ===
==== Tomatidine ====
Tomatidine has been identified as a natural compound that inhibits skeletal muscle atrophy in mice via a system-based discovery strategy.<ref>Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., ... & Adams, C. M. (2014). Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. Journal of Biological Chemistry, 289(21), [tel:14913-14924 14913-14924]. PMID: 24719321 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031541 4031541] DOI: 10.1074/jbc.M114.556241</ref> It has been found that by inhibiting ATF4 tomatidine can reduce age-related skeletal muscle weakness and atrophy.<ref name="small"/> In ''C. elegans,'' tomatidine protects muscle function from age-related deterioration by activating the Nrf2/SKN-1-DCT-1 pathway and by up-regulating mitophagy and antioxidant cellular defences.<ref name="elegans">Fang, E. F., Waltz, T. B., Kassahun, H., Lu, Q., Kerr, J. S., Morevati, M., ... & Becker, K. G. (2017). Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Scientific reports, 7(1), 1-13. PMID: 28397803 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387417 5387417] DOI: 10.1038/srep46208</ref> The beneficial effects of tomatidine in counteracting age-related deterioration of muscle function in ''C. elegans'' are not the result of effects on muscle stem cells or immune cells, but instead, via the influence of either the muscle cells themselves, or the nervous system associated with muscle function, and therefore may be particularly relevant to processes occurring within skeletal muscle fibre cells in sarcopenia.<ref name="elegans"/>

==== Ursolic acid ====
Ursolic acid is a natural pentacyclic triterpenoid carboxylic acid found in apples (a major compound of apple wax) and other fruits; it is known to improve skeletal muscle function and reduce the aging related muscular atrophy pathways possibly by the suppression of p53/ATF4/p21 signaling.<ref>Zolfaghari, M., Faramarzi, M., Hedayati, M., & Ghaffari, M. (2022). The effect of resistance and endurance training with ursolic acid on atrophy‐related biomarkers in muscle tissue of diabetic male rats induced by streptozotocin and a high‐fat diet. Journal of Food Biochemistry, 46(8), e14202. PMID: 35593021 DOI: [https://doi.org/10.1111/jfbc.14202 10.1111/jfbc.14202]</ref><ref name="small"/>

== References ==
<references />
[[Category:Main list]]
[[Category:Longevity genes]]

Role of JNK in aging

2024-09-21T10:34:56Z

Dmitry Dzhagarov: Created page with "'''JNK (c-Jun N-terminal kinase)''' is a crucial signaling pathway that plays a significant role in normal physiological processes. The JNK signaling pathway exhibits a dual nature during the aging process. For instance, when JNK is activated in the brain, it leads to a prolonged lifespan, whereas moderate activation of JNK in midgut intestinal stem cells (ISCs) and enteroblasts significantly shortens lifespan.<ref>Gan, T., Fan, L., Zhao, L., Misra, M., Liu, M., Zhang, M..."

'''JNK (c-Jun N-terminal kinase)''' is a crucial signaling pathway that plays a significant role in normal physiological processes. The JNK signaling pathway exhibits a dual nature during the aging process. For instance, when JNK is activated in the brain, it leads to a prolonged lifespan, whereas moderate activation of JNK in midgut intestinal stem cells (ISCs) and enteroblasts significantly shortens lifespan.<ref>Gan, T., Fan, L., Zhao, L., Misra, M., Liu, M., Zhang, M., & Su, Y. (2021). JNK signaling in Drosophila aging and longevity. International Journal of Molecular Sciences, 22(17), 9649. PMID: 34502551 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431792 PMC8431792] DOI: 10.3390/ijms22179649</ref>
JNK demonstrates the ability to diminish telomerase reverse transcriptase activity, elevate β-galactosidase activity, and induce telomere shortening, thereby contributing to immune system aging. <ref name="JNK" >Li, Y., You, L., Nepovimova, E., Adam, V., Heger, Z., Jomova, K., ... & Kuca, K. (2024). c-Jun N-terminal kinase signaling in aging. Frontiers in Aging Neuroscience, 16, 1453710. PMID: 39267721 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390425/ PMC11390425] [https://doi.org/10.3389/fnagi.2024.1453710 DOI: 10.3389/fnagi.2024.1453710]</ref>

Studies in mice suggest that mammalian JNK exerts widespread and context-dependent effects in models of aging and diseases.<ref name="JNK" />

== JNK inhibitors ==
JNK inhibitors hold the potential to delay aging and treat age-associated conditions. Notable examples of JNK inhibitors include '''SP600125, CC-930, CC-401, CC-90001, and CEP-1347'''.<ref name="JNK" />

== References ==
<references />

[[Category:Longevity genes]]
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Drafts]]
[[Category:Stub]]

Mediterranean diet

2024-09-19T17:30:04Z

Dmitry Dzhagarov:

The '''Mediterranean diet''' (sometimes referred to as MedDiet) is a '''diet rich in seafood (fish), beans, fruits, vegetables, whole grains, nuts, cheese and healthy fats, such as olive oil'''.<ref name="Definition">Davis, C., Bryan, J., Hodgson, J., & Murphy, K. (2015). Definition of the Mediterranean diet: a literature review. Nutrients, 7(11), 9139-9153. PMID: 26556369 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663587 reference] DOI: 10.3390/nu7115459</ref> Occasionally also '''a moderate amount of red wine.'''<ref>Willett, W. C., Sacks, F., Trichopoulou, A., Drescher, G., Ferro-Luzzi, A., Helsing, E., & Trichopoulos, D. (1995). Mediterranean diet pyramid: a cultural model for healthy eating. The American journal of clinical nutrition, 61(6), 1402S-1406S.</ref><ref>Sofi, F., Abbate, R., Gensini, G. F., & Casini, A. (2010). Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. The American journal of clinical nutrition, 92(5), 1189-1196.</ref> On average, the MedDiet contains three to nine serves of vegetables, half to two serves of fruit, one to 13 serves of cereals and up to eight serves of olive oil daily. It contains approximately 9300 kJ: 37% as total fat, 18% as monounsaturated and 9% as saturated, and 33g of fibre per day.<ref name="Definition" />

The majority of studies emphasize the same key dietary components and principles for the benefits associated to the MedDiet: an increased intake of vegetables, wholegrains, and the preferential consumption of white meat as a substitute of red and processed meat, as well as abundant use of olive oil. However, the reporting of specific dietary recommendations for fruit, legumes, nuts, bread, red wine, and fermentable dairy products are generally less consistent or not reported.<ref name="Influence" /><ref>McClure, R., & Villani, A. (2019). Greater adherence to a Mediterranean Diet is associated with better gait speed in older adults with type 2 diabetes mellitus. Clinical nutrition ESPEN, 32, 33-39. PMID: 31221287 DOI:[https://doi.org/10.1016/j.clnesp.2019.05.009 reference]</ref>

== Heath benefits of the Mediterranean Diet ==
[[File:MedDiet.jpg|thumb|Mechanisms of Interplay between Mediterranean Diet and Aging (according to article.<ref name="Influence">Andreo-López, M. C., Contreras-Bolívar, V., Muñoz-Torres, M., García-Fontana, B., & García-Fontana, C. (2023). Influence of the Mediterranean Diet on Healthy Aging. International Journal of Molecular Sciences, 24(5), 4491. https://doi.org/10.3390/ijms24054491</ref> Molecules that promote aging are shown in yellow, while molecules with anti-aging properties are shown in light green. Red lines indicate inhibited or slowed pathways and blue lines indicate activated pathways that together promote healthy aging. GH (growth hormone); IGF-1 (insulin-like growth factor-1); mTOR (protein mammalian target of rapamycin); AMPK (adenosine monophosphate-activated protein kinase); FOXO (Forkhead Box); PGC-1α (peroxisome proliferator-activated receptor gamma 1-alpha); SIRT-1 (sirtuine-1).]]
Irrespective of the discordance in the interpretation of a MedDiet, a number of studies have reported '''health benefits''' such as improved glycaemic control and favorable cardiovascular outcomes with adherence to a Mediterranean-style diet.<ref>Villani, A., Sultana, J., Doecke, J., & Mantzioris, E. (2019). Differences in the interpretation of a modernized Mediterranean diet prescribed in intervention studies for the management of type 2 diabetes: how closely does this align with a traditional Mediterranean diet?. European journal of nutrition, 58, 1369-1380. PMID: 29943276 DOI:[https://doi.org/10.1007/s00394-018-1757-3 reference]</ref><ref>Allcock, L., Mantzioris, E., & Villani, A. (2022). Adherence to a Mediterranean Diet is associated with physical and cognitive health: A cross-sectional analysis of community-dwelling older Australians. Frontiers in Public Health, 10, 4360. PMID: 36466491 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709195 reference] DOI: 10.3389/fpubh.2022.1017078</ref><ref>Devranis, P., Vassilopoulou, Ε., Tsironis, V., Sotiriadis, P. M., Chourdakis, M., Aivaliotis, M., & Tsolaki, M. (2023). Mediterranean Diet, Ketogenic Diet or MIND Diet for Aging Populations with Cognitive Decline: A Systematic Review. Life, 13(1), 173. https://doi.org/10.3390/life13010173</ref> The Mediterranean diet (MedDiet) is recognised to reduce risk of coronary heart disease (CHD), in part, via its anti-inflammatory and antioxidant properties, which may be mediated via effects on body fat distribution.<ref>Bayerle, P., Beyer, S., Tegtbur, U., Kück, M., Adel, J., Kwast, S., ... & Busse, M. (2023). Exercise Capacity, Iron Status, Body Composition, and Mediterranean Diet in Patients with Chronic Heart Failure. Nutrients, 15(1), 36. PMID: 36615693 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9824214 reference] DOI: 10.3390/nu15010036</ref>

Several randomized controlled trials have showed the positive effects of the MedDiet style on several cardiovascular risk factors, such as body mass index, waist circumference, blood lipids, blood pressure, inflammatory markers and adhesion molecules, and diabetes and how these advantages of the MeDi are maintained in comparison of a low-fat diet. Some studies reported a positive effect of adherence to a Mediterranean Diet and heart failure incidence, whereas some studies showed that the incidence of major cardiovascular events was lower among those assigned to MedDiet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet.<ref>Tuttolomondo, A., Simonetta, I., Daidone, M., Mogavero, A., Ortello, A., & Pinto, A. (2019). Metabolic and vascular effect of the Mediterranean diet. International journal of molecular sciences, 20(19), 4716. PMID: 31547615 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801699 reference] DOI: 10.3390/ijms20194716</ref>

Mediterranean diet adherence had, in general, a positive role in muscle mass and muscle function with a lower risk of sarcopenia.<ref>Papadopoulou, S. K., Detopoulou, P., Voulgaridou, G., Tsoumana, D., Spanoudaki, M., Sadikou, F., ... & Nikolaidis, P. (2023). Mediterranean Diet and Sarcopenia Features in Apparently Healthy Adults over 65 Years: A Systematic Review. Nutrients, 15(5), 1104. PMID: 36904104 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005300 reference] DOI: 10.3390/nu15051104</ref><ref>Cacciatore, S., Calvani, R., Marzetti, E., Picca, A., Coelho-Júnior, H. J., Martone, A. M., ... & Landi, F. (2023). Low Adherence to Mediterranean Diet Is Associated with Probable Sarcopenia in Community-Dwelling Older Adults: Results from the Longevity Check-Up (Lookup) 7+ Project. Nutrients, 15(4), 1026. PMID: 36839385 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959184 reference] DOI: 10.3390/nu15041026</ref>

Cardiovascular events and cardiovascular mortality are significantly reduced when associated with the Mediterranean Diet.<ref>Sebastian, S. A., Padda, I., & Johal, G. (2024). Long-Term Impact of Mediterranean Diet on Cardiovascular Disease Prevention: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Current Problems in Cardiology, 102509. PMID: 38431146 DOI: 10.1016/j.cpcardiol.2024.102509</ref><ref>Barbosa, A. R., Pais, S., Marreiros, A., & Correia, M. (2024). Impact of a Mediterranean-Inspired Diet on Cardiovascular Disease Risk Factors: A Randomized Clinical Trial. Nutrients, 16(15), 2443. PMID: 39125324 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11314620/ PMC11314620] DOI: 10.3390/nu16152443</ref>

Adherence to the MedDiet was inversely related to type 2 diabetes risk in a dose-response manner.<ref>Zeraattalab-Motlagh, S., Jayedi, A., & Shab-Bidar, S. (2022). Mediterranean dietary pattern and the risk of type 2 diabetes: a systematic review and dose–response meta-analysis of prospective cohort studies. European journal of nutrition, 1-14. PMID: 35001218 DOI: 10.1007/s00394-021-02761-3</ref><ref>Sarsangi, P., Salehi-Abargouei, A., Ebrahimpour-Koujan, S., & Esmaillzadeh, A. (2022). Association between Adherence to the Mediterranean Diet and Risk of Type 2 Diabetes: An Updated Systematic Review and Dose–Response Meta-Analysis of Prospective Cohort Studies. Advances in Nutrition, 13(5), 1787-1798. PMID: 35472102 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9526848 reference] DOI: 10.1093/advances/nmac046</ref>
Higher adherence to a MedDiet was also associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.<ref>Shannon, O. M., Ranson, J. M., Gregory, S., Macpherson, H., Milte, C., Lentjes, M., ... & Stevenson, E. (2023). Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study. BMC medicine, 21(1), 1-13. PMID: 36915130 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10012551/ 10012551] DOI: 10.1186/s12916-023-02772-3</ref>
Adherence to Mediterranean diet is inversely associated with risk of [[frailty]] and pre-frailty in older adults and especially elders above 65 years old.<ref>Poursalehi, D., Lotfi, K., & Saneei, P. (2023). Adherence to the Mediterranean diet and risk of frailty and pre-frailty in elderly adults: A systematic review and dose-response meta-analysis with GRADE assessment. Ageing Research Reviews, 87, 101903. PMID: 36871780 DOI:[https://doi.org/10.1016/j.arr.2023.101903 10.1016/j.arr.2023.101903] </ref>

== Olive Oil in the Mediterranean Diet ==
One of the most examined oils for its health properties is olive oil, especially extra virgin olive oil (EVOO).<ref>Riolo, R., De Rosa, R., Simonetta, I., & Tuttolomondo, A. (2022). Olive Oil in the Mediterranean Diet and Its Biochemical and Molecular Effects on Cardiovascular Health through an Analysis of Genetics and Epigenetics. International Journal of Molecular Sciences, 23(24), 16002. PMID: 36555645 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782563 reference] DOI: 10.3390/ijms232416002</ref><ref>Fernández del Río, L., Gutiérrez-Casado, E., Varela-López, A., & Villalba, J. M. (2016). Olive oil and the hallmarks of aging. Molecules, 21(2), 163. PMID: 26840281 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273542 reference] DOI: 10.3390/molecules21020163</ref> Olive oil is rich in monounsaturated oleic acid and phenolic compounds, as well as squalene. The capacity of olive oil to stop or slow down the inflammatory processes linked to chronic degenerative disorders also supports its role as an anti-atherosclerotic, therefore improving the lipid profile. The phenolic components of olive oil, such as luteolin, apigenin, ferulic, coumaric acid, or caffeic acid, have antibacterial effects and promote the regeneration of fibroblasts.<ref>Melguizo-Rodríguez, L., Illescas-Montes, R., Costela-Ruiz, V. J., Ramos-Torrecillas, J., de Luna-Bertos, E., García-Martínez, O., & Ruiz, C. (2021). Antimicrobial properties of olive oil phenolic compounds and their regenerative capacity towards fibroblast cells. Journal of Tissue Viability, 30(3), 372-378. PMID: 33810929 DOI:[https://doi.org/10.1016/j.jtv.2021.03.003 reference]</ref>
The lipid fraction constituting about 98% of the olive oil composition and comprised of fatty acids (mainly in the form of triglycerides) such as oleic acid (monounsaturated omega-9 fatty acid accounting for about 55% and up to 83% of the total fatty acid content of the olive oil, depending on the reference cultivar and on the extraction techniques), linoleic acid (omega-6 polyunsaturated fatty acid accounting for 3–21% of the total fatty acid content of the olive oil), α-linolenic acid (omega-3 polyunsaturated fatty acid accounting for less than 1% of the total fatty acid content of the olive oil), and palmitic acid (long-chain saturated fatty acid accounting for 10–23% of the total fatty acid content of the olive oil). <ref name="EVOO" >Infante, R., Infante, M., Pastore, D., Pacifici, F., Chiereghin, F., Malatesta, G., ... & Della-Morte, D. (2023). An Appraisal of the Oleocanthal-Rich Extra Virgin Olive Oil (EVOO) and Its Potential Anticancer and Neuroprotective Properties. International Journal of Molecular Sciences, 24(24), 17323. PMID: 38139152 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10744258/ PMC10744258] DOI: 10.3390/ijms242417323</ref> The set of secondary metabolites (constituting about 1–2% of the Extra Virgin Olive Oil (EVOO) composition) is generally defined as that of the “minor compounds,” such as phenolic compounds and lipophilic compounds (like α-tocopherol or vitamin E). Hydrophilic phenolic compounds present in EVOO belong to different classes: secoiridoids, phenolic acids, phenolic alcohols, lignans and flavonoids.<ref name="EVOO" /> For the extra virgin olive oil quality index the most relevant approach is to select the concentrations of seven selected phenols, namely: gallic acid, β-tocopherol, oleuropein aglycone, ligstroside aglycone, oleacein, hydroxytyrosol and apigenin.<ref>Różańska, A., Russo, M., Cacciola, F., Salafia, F., Polkowska, Ż., Dugo, P., & Mondello, L. (2020). Concentration of potentially bioactive compounds in Italian extra virgin olive oils from various sources by using LC-MS and multivariate data analysis. Foods, 9(8), 1120.
PMID: 32823794 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466375/ PMC7466375] DOI: 10.3390/foods9081120</ref>

== Tomatoes in the Mediterranean Diet ==
Among the most consumed fruits and vegetables, tomatoes also deserve to be investigated as they are fundamental components of the Mediterranean diet, are available all year round, have an affordable price and have various benefits also in terms of cancer prevention.<ref>Shannon, O. M., Ashor, A. W., Scialo, F., Saretzki, G., Martin-Ruiz, C., Lara, J., ... & Mathers, J. C. (2021). Mediterranean diet and the hallmarks of ageing. European Journal of Clinical Nutrition, 75(8), 1176-1192. PMID: 33514872 DOI:[https://doi.org/10.1038/s41430-020-00841-x reference]</ref>

Tomatoes are a rich source of antioxidants, such as ascorbic acid, polyphenols, or carotenoids. Tomatoes contain minerals, vitamins, proteins, essential amino acids (leucine, threonine, valine, histidine, lysine, arginine), monounsaturated fatty acids (linoleic and linolenic acids), carotenoids (lycopene and β-carotenoids) and phytosterols (β-sitosterol, campesterol and stigmasterol). Lycopene is the main dietary carotenoid in tomato and tomato-based food products and '''lycopene consumption by humans has been reported to protect against [[Aging and cancer|cancer]], cardiovascular diseases, [[Aging and neurodegeneration|cognitive function]] and osteoporosis'''.<ref>Imran, M., Ghorat, F., Ul-Haq, I., Ur-Rehman, H., Aslam, F., Heydari, M., ... & Rebezov, M. (2020). Lycopene as a natural antioxidant used to prevent human health disorders. Antioxidants, 9(8), 706. PMID: 32759751 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464847 reference] DOI: 10.3390/antiox9080706</ref> Among the phenolic compounds present in tomato, '''[[quercetin]], kaempferol, naringenin, caffeic acid and lutein''' are the most common. Many of these compounds have antioxidant activities and are effective in protecting the human body against various oxidative stress-related diseases.<ref>Ali, M. Y., Sina, A. A. I., Khandker, S. S., Neesa, L., Tanvir, E. M., Kabir, A., ... & Gan, S. H. (2020). Nutritional Composition and Bioactive Compounds in Tomatoes and Their Impact on Human Health and Disease: A Review. Foods (Basel, Switzerland), 10(1), 45. PMID: 33375293 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823427 reference] DOI: 10.3390/foods10010045</ref><ref>Yang, Z., Li, W., Li, D., & Chan, A. S. (2023). Evaluation of Nutritional Compositions, Bioactive Components, and Antioxidant Activity of Three Cherry Tomato Varieties. Agronomy, 13(3), 637. https://doi.org/10.3390/agronomy13030637</ref>

The '''anti-inflammatory and anti-allergic active''' compound, which strongly inhibited histamine release in tomato skin has been identified as '''naringenin''' chalcone (trans-2'4'6'4-tetrahydroxychalcone).<ref>Yamamoto, T., Yoshimura, M., Yamaguchi, F., Kouchi, T., Tsuji, R., Saito, M., ... & Kikuchi, M. (2004). Anti-allergic activity of naringenin chalcone from a tomato skin extract. Bioscience, biotechnology, and biochemistry, 68(8), 1706-1711. PMID: 15322354 DOI:[https://doi.org/10.1271/bbb.68.1706 reference]</ref><ref>Escribano-Ferrer, E., Queralt Regue, J., Garcia-Sala, X., Boix Montanes, A., & Lamuela-Raventos, R. M. (2019). In vivo anti-inflammatory and antiallergic activity of pure naringenin, naringenin chalcone, and quercetin in mice. Journal of natural products, 82(2), 177-182. PMID: 30688453 DOI:[https://doi.org/10.1021/acs.jnatprod.8b00366 reference]</ref> Naringenin chalcone is bioavailable in humans from cherry tomatoes as a dietary source.<ref>Kolot, C., Rodriguez-Mateos, A., Feliciano, R., Bottermann, K., & Stahl, W. (2019). Bioavailability of naringenin chalcone in humans after ingestion of cherry tomatoes. International Journal for Vitamin and Nutrition Research. PMID: 30961461 DOI:[https://doi.org/10.1024/0300-9831/a000574 reference]</ref>

Naringenin can suppress cancer development in various body parts, alleviating the conditions of cancer patients by acting as effective alternative supplementary remedies. Their anticancer activities are pleiotropic, and they can modulate different cellular signaling pathways, suppress cytokine and growth factor production and arrest the cell cycle.<ref>Stabrauskiene, J., Kopustinskiene, D. M., Lazauskas, R., & Bernatoniene, J. (2022). Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines, 10(7), 1686. PMID: 35884991 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313440 reference] DOI: 10.3390/biomedicines10071686</ref> Naringenin improved memory and learning ability in aging mice by influencing TNF-α, which is involved in aging-associated cognitive impairment, protected cardiac muscle from aging. Naringenin promotes the synthesis of the [[extracellular matrix]] (ECM) in cartilage and, in turn, improves aging in both lipopolysaccharide- and reactive oxygen species (ROS)-induced skin [[Cellular senescence|senescence]]. This appears to occur through the [[Sirtuins|sirtuin]] SIRT1-mediated inhibition of [[NF-κΒ]], NADPH oxidase, and matrix metalloproteinases (MMPs) as seen in human dermal fibroblasts, suggesting a regenerative and anti-aging effect on the dermal cell structure.<ref>Lim, K. H., & Kim, G. R. (2018). Inhibitory effect of naringenin on LPS-induced skin senescence by SIRT1 regulation in HDFs. Biomedical Dermatology, 2(1), 26-34. doi: 10.1186/s41702-018-0035-6.</ref>

Like [[metformin]], naringenin displays in vitro and in vivo antidiabetic effects by sensitizing [[FOXO longevity genes|insulin signaling]] in insulin-sensitive cells and tissues, inhibiting gluconeogenesis in hepatocytes, suppressing adipocyte proliferation and adipogenesis, and protecting pancreas β-cells from apoptosis.<ref>Nyane, N. A., Tlaila, T. B., Malefane, T. G., Ndwandwe, D. E., & Owira, P. M. O. (2017). Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights. European Journal of Pharmacology, 803, 103-111. PMID: 28322845 DOI:[https://doi.org/10.1016/j.ejphar.2017.03.042 reference]</ref> Antioxidant activity of naringenin may be related to its upregulation through a transcriptional mechanism of intracellular [[Heat-shock response|heat shock]] protein 70 (HSP70), by which '''naringenin improves diabetic- or hyperglycemia-induced impairment of endothelial function'''.<ref>Zhang, Z., Liu, H., Hu, X., He, Y., Li, L., Yang, X., ... & Tao, S. (2022). Heat Shock Protein 70 Mediates the Protective Effect of Naringenin on High-Glucose-Induced Alterations of Endothelial Function. International Journal of Endocrinology, 2022:7275765 PMID: 35958293 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359828 reference] DOI: 10.1155/2022/7275765</ref>

== The Mediterranean Lifestyle ==
There is already robust evidence supporting the cardiometabolic health benefits of the traditional Mediterranean diet, rich in colourful fruits, vegetables, olive oil, edible wild greens, whole grains, seafood, and protein such as, fermented dairy products; whereas less information is available on the potential synergistic effects of a general healthy lifestyle.<ref>Christodoulou, E., Deligiannidou, G. E., Kontogiorgis, C., Giaginis, C., & Koutelidakis, A. E. (2023). Natural Functional Foods as a Part of the Mediterranean Lifestyle and Their Association with Psychological Resilience and Other Health-Related Parameters. Applied Sciences, 13(7), 4076. https://doi.org/10.3390/app13074076</ref> Other individual components such as for example, reducing sedentary behavior and increasing physical activity, sleep duration, taking naps, regular cheerful connection and communication with people, limiting salt and sugar intake—are also known to have positive effects on cardiometabolic health.<ref>Romero‐Cabrera, J. L., García‐Ríos, A., Sotos‐Prieto, M., Quintana‐Navarro, G., Alcalá‐Díaz, J. F., Martín‐Piedra, L., ... & Pérez‐Martínez, P. (2023). Adherence to a Mediterranean lifestyle improves metabolic status in coronary heart disease patients: A prospective analysis from the CORDIOPREV study. Journal of Internal Medicine, 293(5), 574-588. PMID: 36585892 DOI: 10.1111/joim.13602</ref><ref>Maroto-Rodriguez, J., Delgado-Velandia, M., Ortolá, R., Perez-Cornago, A., Kales, S. N., Rodríguez-Artalejo, F., & Sotos-Prieto, M. (2023, August). Association of a Mediterranean Lifestyle With All-Cause and Cause-Specific Mortality: A Prospective Study from the UK Biobank. In Mayo Clinic Proceedings. Elsevier. https://doi.org/10.1016/j.mayocp.2023.05.031</ref>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Lifespan interventions]]

Human Ageing Genomic Resources

2024-09-16T18:34:08Z

Dmitry Dzhagarov: /* THE REJUVENATION ROADMAP */

'''The Human Ageing Genomic Resources (HAGR)''' is a collection of databases and tools designed to help researchers study the genetics of human ageing using modern approaches such as functional genomics, network analyses, systems biology and evolutionary analyses.<ref>[https://genomics.senescence.info Human Ageing Genomic Resources]</ref>

== [https://ngdc.cncb.ac.cn/hall/index HALL: a comprehensive database for human aging and longevity studies] ==
Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.<ref>Li, H., Wu, S., Li, J., Xiong, Z., Yang, K., Ye, W., ... & Zhang, W. (2023). HALL: a comprehensive database for human aging and longevity studies. Nucleic Acids Research, gkad880. [https://doi.org/10.1093/nar/gkad880 DOI: 10.1093/nar/gkad880]</ref>

== [https://Bio-Learn.github.io/ Biolearn, an open-source library for biomarkers of aging] ==
Identifying and validating biomarkers of aging is pivotal for understanding the aging process and testing longevity interventions.
Biolearn is an open-source library (freely available at https://Bio-Learn.github.io/) dedicated to the implementation and application of aging biomarkers.<ref>Ying, K., Paulson, S., Perez-Guevara, M., Emamifar, M., Casas Martinez, M., Kwon, D., ... & Gladyshev, V. N. (2023). Biolearn, an open-source library for biomarkers of aging. bioRxiv, 2023-12. https://doi.org/10.1101/2023.12.02.569722</ref>

'''Biolearn facilitates''':

1. harmonization of existing aging biomarkers, while presenting a structured framework for novel biomarkers in standardized formats;

2. unification of public datasets, ensuring coherent structuring and formatting, thus simplifying cross-population validation studies; and

3. provision of computational methodologies to assess any harmonized biomarker against unified datasets.

== [https://doi.org/10.1101/2024.05.04.592445 A metabolic atlas of mouse aging] ==

<ref>Steven E Pilley, et al., (2024). A metabolic atlas of mouse aging. bioRxiv; doi: https://doi.org/10.1101/2024.05.04.592445</ref>

== [http://mengwanglab.org/atlas Cell Atlas of Worm Aging (CAWA)] ==

<ref>Gao, S.M., Qi, Y., Zhang, Q. et al. Aging atlas reveals cell-type-specific effects of pro-longevity strategies. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00631-1</ref>

== [https://db.cngb.org/cdcp/hlma/ Human Muscle Ageing Cell Atlas (HMA)] ==
The Human Muscle Ageing Cell Atlas provides a series of integrated cellular and molecular explanations for sarcopenia and frailty development in advanced ages.<ref>Lai, Y., Ramírez-Pardo, I., Isern, J. et al. (2024). Multimodal cell atlas of the ageing human skeletal muscle. Nature https://doi.org/10.1038/s41586-024-07348-6 </ref><ref>[https://db.cngb.org/cdcp/hlma/ Human Muscle Ageing Cell Atlas (HMA)]</ref>

== [http://www.thua45.cn/geredb-wp/ Gene Expression Regulation Database (GREDB)] ==
GereDB is an comprehensive cohort of gene expression regulation relationships curiated from published literatures. Geredb has been continually devepleted for more than 4 years, making it the one of the most trusted and complete collection of gene expression regulation database in the community.<ref>Huang, T., Huang, X., Shi, B. & Yao, M. (2019). GEREDB: Gene expression regulation database curated by mining abstracts from literature. Journal of Bioinformatics and Computational Biology 17, 1950024 https://www.ncbi.nlm.nih.gov/pubmed/31617460</ref>

== voyAGEr: free web interface for the analysis of age-related gene expression alterations in human tissues ==
'''voyAGEr''' is an online graphical interface to explore age-related gene expression alterations in 49 human tissues.<ref>Schneider A.L., Martins-Silva R., Kaizeler A., Saraiva-Agostinho N., Barbosa-Morais N. (2023). voyAGEr: free web interface for the analysis of age-related gene expression alterations in human tissues. bioRxiv, 521681. [https://doi.org/10.1101/2022.12.22.521681 doi: 10.1101/2022.12.22.521681]; eLife 12:RP88623. https://doi.org/10.7554/eLife.88623.3</ref>
voyAGEr was created to assist researchers with no expertise in bioinformatics, providing a supportive framework for elaborating, testing and refining their hypotheses on the molecular nature of human ageing and its association with pathologies, thereby also aiding in the discovery of novel therapeutic targets. voyAGEr is freely available at https://compbio.imm.medicina.ulisboa.pt/app/voyAGEr.
voyAGEr reveals transcriptomic signatures of the known asynchronous ageing between tissues, allowing the observation of tissue-specific age-periods of major transcriptional changes, associated with alterations in different biological pathways, cellular composition, and disease conditions.

== GenAge ==
A major resource in HAGR is GenAge,<ref>[https://genomics.senescence.info/genes/index.html GenAge Database of Ageing-Related Genes]</ref> which includes a curated database of over 300 genes related to human ageing and a database of over 2,000 ageing- and longevity-associated genes in model organisms.

=== Aging-related gene sets ===
Functions for aging-related gene sets. All included genes are collected from aging-related literature and manually annotated. All gene sets are divided into ten sub-categories. The species currently listed include humans and mice.<ref>[https://ngdc.cncb.ac.cn/aging/age_related_genes Aging-related gene sets]</ref>

== CodeKeeper™ ==
[https://bioviva-codekeeper.com '''CodeKeeper'''™] is BioViva's open access database for gene therapy. It is designed for anyone interested in what is happening in the gene therapy space. Advanced tools are available for universities, companies, independent researchers, and anyone else who is interested in understanding or contributing to the state-of-the-art.

=== Senescence promoting genes ===
=== Epigenomics ===
==== [http://www.bioapp.org/ewasdb/ EWASdb : epigenome-wide association study database] ====

=== Single-cell transcriptomics ===
<ref>Ma, S., Chi, X., Cai, Y., Ji, Z., Wang, S., Ren, J., & Liu, G. H. (2023). Decoding aging hallmarks at the single-cell level. Annual Review of Biomedical Data Science, 6. [https://doi.org/10.1146/annurev-biodatasci-020722-120642 DOI: 10.1146/annurev-biodatasci-020722-120642]</ref>
<ref>Cai, Y., Xiong, M., Xin, Z., Liu, C., Ren, J., Yang, X., ... & Liu, G. H. (2023). Decoding aging-dependent regenerative decline across tissues at single-cell resolution. Cell Stem Cell. PMID: 37898124 [https://doi.org/10.1016/j.stem.2023.09.014 DOI: 10.1016/j.stem.2023.09.014] </ref>

=== Proteomics ===

=== GenAge Human Genes ===
This section of GenAge features genes possibly related to human ageing. Briefly, genes were selected for inclusion based on findings in model organisms put in context of human biology plus the few genes directly related to ageing in humans. As such, genes should be seen as candidate human ageing-associated genes.<ref>[https://genomics.senescence.info/genes/human.html GenAge Human Genes]</ref>

==== [http://www.genemed.tech/gene4denovo/home Gene4Denovo: an integrated database and analytic platform for de novo mutations in humans] ====

=== GenAge Model Organisms ===
Ageing and/or longevity in model organisms<ref>[https://genomics.senescence.info/genes/models.html GenAge Model Organisms]</ref>

== AnAge ==
Another major database in HAGR is AnAge.<ref>[https://genomics.senescence.info/species/index.html AnAge Database of Animal Ageing and Longevity]</ref> Featuring over 4,000 species, AnAge provides a compilation of data on ageing, longevity, and life history that is ideal for the comparative biology of ageing.

== DrugAge ==
DrugAge provides data on over 500 ageing-related drugs across model organisms.<ref>[https://genomics.senescence.info/drugs/ DrugAge Database of Anti-Ageing Drugs]</ref>

=== [https://drugcentral.org DrugCentral] ===
DrugCentral, accessible at https://drugcentral.org , is an open-access online drug information repository. It covers over 4950 drugs, incorporating structural, physicochemical, and pharmacological details to support drug discovery, development, and repositioning.<ref>Halip, L., Avram, S., Curpan, R., Borota, A., Bora, A., Bologa, C., & Oprea, T. I. (2023). Exploring DrugCentral: from molecular structures to clinical effects. Journal of Computer-Aided Molecular Design, 1-14. PMID: 37707619 DOI: 10.1007/s10822-023-00529-x</ref>

=== Pharmacogenomics ===

== [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ THE REJUVENATION ROADMAP] ==

== The cell rejuvenation atlas ==
'''SINGULAR (Single-cell RNA-seq Investigation of Rejuvenation Agents and Longevity)''', a cell rejuvenation atlas that provides a unified system biology analysis of diverse rejuvenation strategies across multiple organs at single-cell resolution.<ref>Hodar, J. A., Jung, S., Soudy, M., Barvaux, S., & Del Sol, A. (2024). The cell rejuvenation atlas: leveraging network biology to identify master regulators of rejuvenation strategies. Aging. 16(17), 12168—12190 PMID: 39264584 [https://doi.org/10.18632/aging.206105 DOI: 10.18632/aging.206105]</ref>

Code for the processing pipeline and auxiliary functions in the workflow is available at https://github.com/jarcoshodar/singularsource.

SINGULAR is available as a publicly available interactive database at https://singular.lcsb.uni.lu/. Source code for a local install and exploration of the data is available at https://git-r3lab.uni.lu/mohamed.soudy/singular.

== References ==
<references />
[[Category:Longevity genes]]
[[Category:Drugs]]
[[Category:Tools to study aging]]
[[Category:Main list]]
[[Category:Drafts]]
[[Category:Database]]

FOXO longevity genes

2024-09-14T08:24:43Z

Dmitry Dzhagarov: /* OSER1 gene */

FOXO proteins are a family of transcription factors specially known for their role in longevity and for being a central component of the insulin signalling pathway. The insulin/IGF-1 signalling (IIS) pathway senses insulin and other insulin-like peptides (ILPs) and activates a signalling cascade which connects nutrient levels to metabolism, growth, reproduction, development and aging.

The activity of FOXO antagonises that of insulin: when insulin binds to the insulin receptor, FOXO is sequestered in the cytoplasm and is not able to activate downstream target genes. On the contrary, when insulin levels are low, FOXO translocates to the nucleus and acts on a wide range of cytoprotective and stress-response genes that eventually extend lifespan.

==== FOXO function ====
FOXO transcription factors are homeostasis regulators and are particularly important for responding to cellular stresses such as heat-shock, oxidation or metabolic stress.<ref name=":0">Eijkelenboom, A., & Burgering, B. (2013). FOXOs: signalling integrators for homeostasis maintenance. ''Nature Reviews Molecular Cell Biology'', ''14''(2), 83-97. doi: 10.1038/nrm3507</ref> They are also involved in a variety of other processes including glucose and lipid metabolism, [[autophagy]], cell cycle control, DNA repair and inflammation. FOXO proteins can also act as tumour suppressors.<ref name=":0" /><ref>Dansen, T., & Burgering, B. (2008). Unravelling the tumor-suppressive functions of FOXO proteins. ''Trends In Cell Biology'', ''18''(9), 421-429. doi: 10.1016/j.tcb.2008.07.004</ref>

In addition, FOXO is required for the striking lifespan extension (of 60%) of insulin-signalling mutants.<ref>Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. ''Nature'', ''366''(6454), 461-464. doi: 10.1038/366461a0</ref>

==== FOXO isoforms and orthologs ====
In humans, the family of Forkhead box O (FOXO) proteins consists of four members (known as “isoforms”): FOXO1, FOXO3, FOXO4 and FOXO6.<ref name=":1">Burgering, B. (2008). A brief introduction to FOXOlogy. ''Oncogene'', ''27''(16), [tel:2258-2262 2258-2262]. doi: 10.1038/onc.2008.29</ref> Whilst expressed ubiquitously in all tissues, FOXO1 is more highly expressed in adipocytes, FOXO3 in the liver, FOXO4 in muscle cells and FOXO6 in the nervous system.<ref name=":1" /> In invertebrates there is only one FOXO gene counterpart or “ortholog”, known as daf-16 in C. ''elegans'' nematodes'','' or dFOXO in ''Drosophila'' flies.

=== FOXO in aging and longevity ===
FOXO proteins are nowadays well established as longevity genes, especially FOXO3.<ref>Morris, B., Willcox, D., Donlon, T., & Willcox, B. (2015). A Major Gene for Human Longevity - A Mini-Review. ''Gerontology'', ''61''(6), 515-525. doi: 10.1159/000375235</ref> They are believed to protect cells from damage and to remove or repair already existing cellular damage.

Genetic association studies of single nucleotide polymorphisms (SNPs) have shown that FOXO3 consistently associates with centenarians of diverse human populations.<ref>Willcox, B., Donlon, T., He, Q., Chen, R., Grove, J., & Yano, K. et al. (2008). FOXO3A genotype is strongly associated with human longevity. ''Proceedings Of The National Academy Of Sciences'', ''105''(37), [tel:13987-13992 13987-13992]. doi: 10.1073/pnas.0801030105</ref> In humans, to date only two genes have shown to be consistently associated with extreme old age across human populations: FOXO3 and APOE (the latter coding for the protein apolipoprotein E, a subtype of which is well known for being a risk-factor gene to [[Aging and Neurodegeneration|Alzheimer’s Disease]]).<ref>Broer, L., Buchman, A., Deelen, J., Evans, D., Faul, J., & Lunetta, K. et al. (2014). GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy. ''The Journals Of Gerontology: Series A'', ''70''(1), 110-118. doi: 10.1093/gerona/glu166</ref>

Interestingly, the ''Hydra'', an invertebrate species considered to be biologically immortal, requires the FOXO transcription factor to maintain its capacity for cellular self-renewal and thus its immortality.<ref>Bridge, D., Theofiles, A., Holler, R., Marcinkevicius, E., Steele, R., & Martínez, D. (2010). FoxO and Stress Responses in the Cnidarian Hydra vulgaris. ''Plos ONE'', ''5''(7), e11686. doi: 10.1371/journal.pone.0011686</ref>

Deregulation of FOXOs has also been associated with several diseases such as cancer, neurological diseases, diabetes and cardiovascular disease.<ref>Calissi, G., Lam, E., & Link, W. (2020). Therapeutic strategies targeting FOXO transcription factors. ''Nature Reviews Drug Discovery'', ''20''(1), 21-38. doi: 10.1038/s41573-020-0088-2</ref>

==== [[OSER1 gene]] ====

<references />
[[Category:Main list]]
[[Category:Longevity genes]]

FOXO longevity genes

2024-09-14T08:24:16Z

Dmitry Dzhagarov: /* FOXO in aging and longevity */

FOXO proteins are a family of transcription factors specially known for their role in longevity and for being a central component of the insulin signalling pathway. The insulin/IGF-1 signalling (IIS) pathway senses insulin and other insulin-like peptides (ILPs) and activates a signalling cascade which connects nutrient levels to metabolism, growth, reproduction, development and aging.

The activity of FOXO antagonises that of insulin: when insulin binds to the insulin receptor, FOXO is sequestered in the cytoplasm and is not able to activate downstream target genes. On the contrary, when insulin levels are low, FOXO translocates to the nucleus and acts on a wide range of cytoprotective and stress-response genes that eventually extend lifespan.

==== FOXO function ====
FOXO transcription factors are homeostasis regulators and are particularly important for responding to cellular stresses such as heat-shock, oxidation or metabolic stress.<ref name=":0">Eijkelenboom, A., & Burgering, B. (2013). FOXOs: signalling integrators for homeostasis maintenance. ''Nature Reviews Molecular Cell Biology'', ''14''(2), 83-97. doi: 10.1038/nrm3507</ref> They are also involved in a variety of other processes including glucose and lipid metabolism, [[autophagy]], cell cycle control, DNA repair and inflammation. FOXO proteins can also act as tumour suppressors.<ref name=":0" /><ref>Dansen, T., & Burgering, B. (2008). Unravelling the tumor-suppressive functions of FOXO proteins. ''Trends In Cell Biology'', ''18''(9), 421-429. doi: 10.1016/j.tcb.2008.07.004</ref>

In addition, FOXO is required for the striking lifespan extension (of 60%) of insulin-signalling mutants.<ref>Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. ''Nature'', ''366''(6454), 461-464. doi: 10.1038/366461a0</ref>

==== FOXO isoforms and orthologs ====
In humans, the family of Forkhead box O (FOXO) proteins consists of four members (known as “isoforms”): FOXO1, FOXO3, FOXO4 and FOXO6.<ref name=":1">Burgering, B. (2008). A brief introduction to FOXOlogy. ''Oncogene'', ''27''(16), [tel:2258-2262 2258-2262]. doi: 10.1038/onc.2008.29</ref> Whilst expressed ubiquitously in all tissues, FOXO1 is more highly expressed in adipocytes, FOXO3 in the liver, FOXO4 in muscle cells and FOXO6 in the nervous system.<ref name=":1" /> In invertebrates there is only one FOXO gene counterpart or “ortholog”, known as daf-16 in C. ''elegans'' nematodes'','' or dFOXO in ''Drosophila'' flies.

=== FOXO in aging and longevity ===
FOXO proteins are nowadays well established as longevity genes, especially FOXO3.<ref>Morris, B., Willcox, D., Donlon, T., & Willcox, B. (2015). A Major Gene for Human Longevity - A Mini-Review. ''Gerontology'', ''61''(6), 515-525. doi: 10.1159/000375235</ref> They are believed to protect cells from damage and to remove or repair already existing cellular damage.

Genetic association studies of single nucleotide polymorphisms (SNPs) have shown that FOXO3 consistently associates with centenarians of diverse human populations.<ref>Willcox, B., Donlon, T., He, Q., Chen, R., Grove, J., & Yano, K. et al. (2008). FOXO3A genotype is strongly associated with human longevity. ''Proceedings Of The National Academy Of Sciences'', ''105''(37), [tel:13987-13992 13987-13992]. doi: 10.1073/pnas.0801030105</ref> In humans, to date only two genes have shown to be consistently associated with extreme old age across human populations: FOXO3 and APOE (the latter coding for the protein apolipoprotein E, a subtype of which is well known for being a risk-factor gene to [[Aging and Neurodegeneration|Alzheimer’s Disease]]).<ref>Broer, L., Buchman, A., Deelen, J., Evans, D., Faul, J., & Lunetta, K. et al. (2014). GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy. ''The Journals Of Gerontology: Series A'', ''70''(1), 110-118. doi: 10.1093/gerona/glu166</ref>

Interestingly, the ''Hydra'', an invertebrate species considered to be biologically immortal, requires the FOXO transcription factor to maintain its capacity for cellular self-renewal and thus its immortality.<ref>Bridge, D., Theofiles, A., Holler, R., Marcinkevicius, E., Steele, R., & Martínez, D. (2010). FoxO and Stress Responses in the Cnidarian Hydra vulgaris. ''Plos ONE'', ''5''(7), e11686. doi: 10.1371/journal.pone.0011686</ref>

Deregulation of FOXOs has also been associated with several diseases such as cancer, neurological diseases, diabetes and cardiovascular disease.<ref>Calissi, G., Lam, E., & Link, W. (2020). Therapeutic strategies targeting FOXO transcription factors. ''Nature Reviews Drug Discovery'', ''20''(1), 21-38. doi: 10.1038/s41573-020-0088-2</ref>

=== [[OSER1 gene]] ===

<references />
[[Category:Main list]]
[[Category:Longevity genes]]

FOXO longevity genes

2024-09-14T08:22:42Z

Dmitry Dzhagarov: /* OSER1 gene */

FOXO proteins are a family of transcription factors specially known for their role in longevity and for being a central component of the insulin signalling pathway. The insulin/IGF-1 signalling (IIS) pathway senses insulin and other insulin-like peptides (ILPs) and activates a signalling cascade which connects nutrient levels to metabolism, growth, reproduction, development and aging.

The activity of FOXO antagonises that of insulin: when insulin binds to the insulin receptor, FOXO is sequestered in the cytoplasm and is not able to activate downstream target genes. On the contrary, when insulin levels are low, FOXO translocates to the nucleus and acts on a wide range of cytoprotective and stress-response genes that eventually extend lifespan.

==== FOXO function ====
FOXO transcription factors are homeostasis regulators and are particularly important for responding to cellular stresses such as heat-shock, oxidation or metabolic stress.<ref name=":0">Eijkelenboom, A., & Burgering, B. (2013). FOXOs: signalling integrators for homeostasis maintenance. ''Nature Reviews Molecular Cell Biology'', ''14''(2), 83-97. doi: 10.1038/nrm3507</ref> They are also involved in a variety of other processes including glucose and lipid metabolism, [[autophagy]], cell cycle control, DNA repair and inflammation. FOXO proteins can also act as tumour suppressors.<ref name=":0" /><ref>Dansen, T., & Burgering, B. (2008). Unravelling the tumor-suppressive functions of FOXO proteins. ''Trends In Cell Biology'', ''18''(9), 421-429. doi: 10.1016/j.tcb.2008.07.004</ref>

In addition, FOXO is required for the striking lifespan extension (of 60%) of insulin-signalling mutants.<ref>Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. ''Nature'', ''366''(6454), 461-464. doi: 10.1038/366461a0</ref>

==== FOXO isoforms and orthologs ====
In humans, the family of Forkhead box O (FOXO) proteins consists of four members (known as “isoforms”): FOXO1, FOXO3, FOXO4 and FOXO6.<ref name=":1">Burgering, B. (2008). A brief introduction to FOXOlogy. ''Oncogene'', ''27''(16), [tel:2258-2262 2258-2262]. doi: 10.1038/onc.2008.29</ref> Whilst expressed ubiquitously in all tissues, FOXO1 is more highly expressed in adipocytes, FOXO3 in the liver, FOXO4 in muscle cells and FOXO6 in the nervous system.<ref name=":1" /> In invertebrates there is only one FOXO gene counterpart or “ortholog”, known as daf-16 in C. ''elegans'' nematodes'','' or dFOXO in ''Drosophila'' flies.

==== FOXO in aging and longevity ====
FOXO proteins are nowadays well established as longevity genes, especially FOXO3.<ref>Morris, B., Willcox, D., Donlon, T., & Willcox, B. (2015). A Major Gene for Human Longevity - A Mini-Review. ''Gerontology'', ''61''(6), 515-525. doi: 10.1159/000375235</ref> They are believed to protect cells from damage and to remove or repair already existing cellular damage.

Genetic association studies of single nucleotide polymorphisms (SNPs) have shown that FOXO3 consistently associates with centenarians of diverse human populations.<ref>Willcox, B., Donlon, T., He, Q., Chen, R., Grove, J., & Yano, K. et al. (2008). FOXO3A genotype is strongly associated with human longevity. ''Proceedings Of The National Academy Of Sciences'', ''105''(37), [tel:13987-13992 13987-13992]. doi: 10.1073/pnas.0801030105</ref> In humans, to date only two genes have shown to be consistently associated with extreme old age across human populations: FOXO3 and APOE (the latter coding for the protein apolipoprotein E, a subtype of which is well known for being a risk-factor gene to [[Aging and Neurodegeneration|Alzheimer’s Disease]]).<ref>Broer, L., Buchman, A., Deelen, J., Evans, D., Faul, J., & Lunetta, K. et al. (2014). GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy. ''The Journals Of Gerontology: Series A'', ''70''(1), 110-118. doi: 10.1093/gerona/glu166</ref>

Interestingly, the ''Hydra'', an invertebrate species considered to be biologically immortal, requires the FOXO transcription factor to maintain its capacity for cellular self-renewal and thus its immortality.<ref>Bridge, D., Theofiles, A., Holler, R., Marcinkevicius, E., Steele, R., & Martínez, D. (2010). FoxO and Stress Responses in the Cnidarian Hydra vulgaris. ''Plos ONE'', ''5''(7), e11686. doi: 10.1371/journal.pone.0011686</ref>

Deregulation of FOXOs has also been associated with several diseases such as cancer, neurological diseases, diabetes and cardiovascular disease.<ref>Calissi, G., Lam, E., & Link, W. (2020). Therapeutic strategies targeting FOXO transcription factors. ''Nature Reviews Drug Discovery'', ''20''(1), 21-38. doi: 10.1038/s41573-020-0088-2</ref>

=== [[OSER1 gene]] ===

<references />
[[Category:Main list]]
[[Category:Longevity genes]]

Telomeres

2024-09-14T08:18:53Z

Dmitry Dzhagarov: /* GV1001 */

A telomere is a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular [[Hallmarks of Aging|hallmarks of ageing]].

== History ==
In the 1930s Barbara McClintock and Herman Muller inferred the existence of unique structures at the end of chromosomes in corn and fruit fly.<ref>Creighton, H. B., & McClintock, B. (1931). A correlation of cytological and genetical crossing-over in Zea mays. ''Proceedings of the National Academy of Sciences'', ''17''(8), 492-497.</ref><ref>MULLER, H. J. (1938). The remaking of chromosomes. ''Collecting net'', ''13'', 181-198.</ref> They hypothesised that these structures were essential for chromosome stability and prevention of chromosome fusions. The name “telomere” was coined - from the Greek ''telos'' meaning “end” and ''meros'' meaning “part". In 1978 Elizabeth Blackburn sequenced telomeric DNA of a protozoan ''Tetrahymena thermophila'' and revealed it is composed of tandem repeats of hexanucleotide sequences. <ref>Blackburn, E. H., & Gall, J. G. (1978). A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. ''Journal of molecular biology'', ''120''(1), 33-53.</ref> In 1982, together with Jack Szostak, she experimentally confirmed the protective role of telomeres. <ref>Szostak, J. W., & Blackburn, E. H. (1982). Cloning yeast telomeres on linear plasmid vectors. ''Cell'', ''29''(1), 245-255.</ref> In 1985 Blackburn and Carol Greider discovered a novel enzyme, telomerase, capable of extending telomere length. <ref>Greider, C. W., & Blackburn, E. H. (1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. ''cell'', ''43''(2), 405-413.</ref> Blackburn, Szostak and Greider were awarded a Nobel Prize in Physiology or Medicine in 2009 “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”.<ref>Summary. NobelPrize.org. Nobel Prize Outreach AB 2022. Mon. 25 Jul 2022. <<nowiki>https://www.nobelprize.org/prizes/medicine/2009/press-release/</nowiki>></ref>

== Telomere function and structure ==
Telomeres are DNA fragments that cap the ends of linear chromosomes and protect them from erosion and end-to-end fusions.<ref>de Lange, Titia. ”How Telomeres Solve the End-Protection Problem”. ''Science'', vol. 326, nr 5955, november 2009, s. 948–52. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1126/science.1170633</nowiki>.</ref> The terminal ends of linear chromosomes cannot be fully replicated, and as a result telomeres shorten at each mitotic cycle. As telomeres reach a critical length, they cannot longer fully maintain their protective functions, which triggers a DNA damage response and arrests cell proliferation.<ref>Cesare, Anthony J., och Jan Karlseder. ”A Three-State Model of Telomere Control over Human Proliferative Boundaries”. ''Current Opinion in Cell Biology'', vol. 24, nr 6, december 2012, s. 731–38. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1016/j.ceb.2012.08.007</nowiki>.</ref> As DNA breaks in telomeres are irreparable, cell senescence can be triggered even when telomere lenght is not critically short. <ref>Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J. M., ... & d’Adda di Fagagna, F. (2012). Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. ''Nature cell biology'', ''14''(4), 355-365.</ref>

Telomeric DNA is made of tandem repeats of nucleotide sequences, and does not code for proteins. Sequence of telomeres is well-conserved among humans and other vertebrates and consists of “TTAGGG” repeats.<ref>Meyne, J., m.fl. ”Conservation of the Human Telomere Sequence (TTAGGG)n among Vertebrates.” ''Proceedings of the National Academy of Sciences'', vol. 86, nr 18, september 1989, s. 7049–53. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1073/pnas.86.18.7049</nowiki>.</ref><ref name=":0">Oeseburg, Hisko, m.fl. ”Telomere Biology in Healthy Aging and Disease”. ''Pflügers Archiv - European Journal of Physiology'', vol. 459, nr 2, januari 2010, s. 259–68. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1007/s00424-009-0728-1</nowiki>.</ref> As opposed to the sequence, telomere length varies widely among and within species, within an organism, and even between chromosomes.<ref name=":0" /> In humans, telomere length has been shown to vary between 5 and 15 thousand base pairs.<ref>Takubo, Kaiyo, m.fl. ”Telomere Lengths Are Characteristic in Each Human Individual”. ''Experimental Gerontology'', vol. 37, nr 4, april 2002, s. 523–31. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1016/S0531-5565(01)00218-2</nowiki>.</ref> The telomere is cloaked in a specialised six-protein complex, called shelterin, which ensures protection of chromosome ends and distinguishes telomeres from sites of DNA damage.<ref>de Lange, Titia. ”Shelterin: The Protein Complex That Shapes and Safeguards Human Telomeres”. ''Genes & Development'', vol. 19, nr 18, september 2005, s. 2100–10. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1101/gad.1346005</nowiki>.</ref>

== Telomerase ==
Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. <ref>Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. ''Microbiology and Molecular Biology Reviews'', vol. 66, nr 3, september 2002, s. 407–25. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1128/MMBR.66.3.407-425.2002</nowiki>.</ref>

==== GV1001 ====
'''GV1001''' is a small peptide containing 16 amino acids that mimics a fragment of the active catalytic site of human telomerase reverse transcriptase (hTERT).<ref>Park, H. H., Lee, K. Y., Kim, S., Lee, J. W., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2014). The novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiology of aging, 35(6), 1255-1274. PMID: 24439482 DOI: 10.1016/j.neurobiolaging.2013.12.015</ref> GV1001 peptide can be recognized by the immune system that reacts by killing the telomerase-active cells.<ref>Tian, X., Chen, B., & Liu, X. (2010). Telomere and telomerase as targets for cancer therapy. Applied biochemistry and biotechnology, 160(5), 1460-1472. PMID: 19412578 DOI: 10.1007/s12010-009-8633-9</ref><ref>Inderberg-Suso, E. M., Trachsel, S., Lislerud, K., Rasmussen, A. M., & Gaudernack, G. (2012). Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology, 1(5), 670-686. PMID: 22934259 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429571/ PMC3429571] DOI: 10.4161/onci.20426</ref> GV1001 has antioxidant and neuroprotective effects in neural stem cells, which appear to be mediated by scavenging free radicals, increasing survival signals and decreasing death signals.<ref>Park, H. H., Yu, H. J., Kim, S., Kim, G., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2016). Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals. Neurotoxicology, 55, 131-141. PMID: 27265016 DOI: 10.1016/j.neuro.2016.05.022</ref>

GV1001 was used for the treatment of Alzheimer's disease patients with moderate to severe dementia and confirmed that, compared to those in the placebo, GV1001 significantly improved the Alzheimer's disease patient’s cognitive function.<ref>Koh, S. H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., ... & Lee, K. Y. (2021). Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer’s disease already receiving donepezil: A phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimer's research & therapy, 13, 1-11. PMID: 33771205 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995588/ PMC7995588] DOI: 10.1186/s13195-021-00803-w</ref>
According to the hypothesis (Park H. et al., 2024) GV1001 binds to GnRHRs and activates downstream signaling pathways, increasing cAMP levels. This pathway might affect the degradation of Aβ peptides, reduction of p-tau, modulation of neuroinflammation (i.e., reducing pro-inflammatory and increasing anti-inflammatory microglia and astrocytes), and suppression of neuronal loss.<ref>Park, H., Kwon, H. S., Lee, K. Y., Kim, Y. E., Son, J. W., Choi, N. Y., ... & Koh, S. H. (2024). GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model. Brain, Behavior, and Immunity, 115, 295-307. PMID: 37884161 [https://doi.org/10.1016/j.bbi.2023.10.021 DOI: 10.1016/j.bbi.2023.10.021]</ref>

==== [[TERT activator compound (TAC)]] ====

== Telomeres in aging and age-related diseases ==
Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref> Telomere maintenance is a crucial aspect of cellular biology, influencing aging and cancer development. Three major factors are collectively involved in this context: '''the shelterin complex''',<ref>Wolf, S. E., & Shalev, I. (2023). The shelterin protein expansion of telomere dynamics: Linking early life adversity, life history, and the hallmarks of aging. Neuroscience & Biobehavioral Reviews, 152, 105261. PMID: 37268182 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527177/ PMC10527177] DOI: 10.1016/j.neubiorev.2023.105261</ref> the '''CTC1-STN1-TEN1 (CST) complex''',<ref>Cai, S. W., & de Lange, T. (2023). CST–Polα/Primase: the second telomere maintenance machine. Genes & Development, 37(13-14), 555-569. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10499019/ PMC10499019] DOI: 10.1101/gad.350479.123</ref> and '''telomerase'''.<ref>Boccardi, V., & Marano, L. (2024). Aging, Cancer, and Inflammation: The Telomerase Connection. International Journal of Molecular Sciences, 25(15), 8542. PMID: 39126110 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11313618/ PMC11313618] DOI: 10.3390/ijms25158542</ref>

The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.<ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.<ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.<ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.<ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

== Telomeres and telomerase in cancer and other diseases ==
Increased levels of telomerase have been found in the vast majority of human cancers, whereas mutations decreasing telomerase function cause a range of genetic disorders, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure.<ref>Roake, C. M., & Artandi, S. E. (2020). Regulation of human telomerase in homeostasis and disease. ''Nature reviews Molecular cell biology'', ''21''(7), 384-397.</ref> Longer telomere lenghts have been associated with higher risk of melanoma, lung cancer, prostate cancer, and chronic lymphocytic leukemia. <ref name=":2" />

== Telomeres and telomerase in anti-aging therapies ==
=== Age-reversing telomerase mRNA therapeutics ===
A dogma arose in the 1990s that telomerase causes cancer. This is wrong and set back the field by decades. The reality is that permanent telomerase supports cancer, whereas healthy stem cells frequently turn on telomerase transiently throughout our lives to stave off the devastating effects of short telomeres.<ref>[https://longevity.technology/news/telomere-boosting-mrna-therapeutic-turns-back-the-aging-clock/ Rejuvenation Technologies is targeting longevity and age-related disease with telomerase-based mRNA therapies]</ref> A single dose of '''telomerase mRNA delivered in vivo using lipid nanoparticles''' reverses years of telomere shortening in hours.<ref>[https://longevity.technology/news/rejuvenation-technologies-exits-stealth-with-10-6m-for-age-reversing-mrna-therapeutics/ Rejuvenation Technologies exits stealth with $10.6m for age-reversing mRNA therapeutics]</ref>

==== Mice ====
Mice engineered with much longer telomeres than those of the natural species showed improved mitochondrial function, improved metabolic parameters, decreased cancer, and increased longevity (12.75% increase in median longevity). <ref name=":3">Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref><ref>CNIO researchers obtain the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification - CNIO, accessed 05 Aug 2022</ref> Due to concerns related to the association between telomerase expression and cancer, this was an important finding that suggests that telomere length per se does not increase cancer risk in mice.<ref name=":3" />

Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref name=":4">Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.<ref name=":3" /><ref name=":4" />

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]

Telomeres

2024-09-14T08:12:02Z

Dmitry Dzhagarov: /* Telomeres in aging and age-related diseases */

A telomere is a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular [[Hallmarks of Aging|hallmarks of ageing]].

== History ==
In the 1930s Barbara McClintock and Herman Muller inferred the existence of unique structures at the end of chromosomes in corn and fruit fly.<ref>Creighton, H. B., & McClintock, B. (1931). A correlation of cytological and genetical crossing-over in Zea mays. ''Proceedings of the National Academy of Sciences'', ''17''(8), 492-497.</ref><ref>MULLER, H. J. (1938). The remaking of chromosomes. ''Collecting net'', ''13'', 181-198.</ref> They hypothesised that these structures were essential for chromosome stability and prevention of chromosome fusions. The name “telomere” was coined - from the Greek ''telos'' meaning “end” and ''meros'' meaning “part". In 1978 Elizabeth Blackburn sequenced telomeric DNA of a protozoan ''Tetrahymena thermophila'' and revealed it is composed of tandem repeats of hexanucleotide sequences. <ref>Blackburn, E. H., & Gall, J. G. (1978). A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. ''Journal of molecular biology'', ''120''(1), 33-53.</ref> In 1982, together with Jack Szostak, she experimentally confirmed the protective role of telomeres. <ref>Szostak, J. W., & Blackburn, E. H. (1982). Cloning yeast telomeres on linear plasmid vectors. ''Cell'', ''29''(1), 245-255.</ref> In 1985 Blackburn and Carol Greider discovered a novel enzyme, telomerase, capable of extending telomere length. <ref>Greider, C. W., & Blackburn, E. H. (1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. ''cell'', ''43''(2), 405-413.</ref> Blackburn, Szostak and Greider were awarded a Nobel Prize in Physiology or Medicine in 2009 “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”.<ref>Summary. NobelPrize.org. Nobel Prize Outreach AB 2022. Mon. 25 Jul 2022. <<nowiki>https://www.nobelprize.org/prizes/medicine/2009/press-release/</nowiki>></ref>

== Telomere function and structure ==
Telomeres are DNA fragments that cap the ends of linear chromosomes and protect them from erosion and end-to-end fusions.<ref>de Lange, Titia. ”How Telomeres Solve the End-Protection Problem”. ''Science'', vol. 326, nr 5955, november 2009, s. 948–52. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1126/science.1170633</nowiki>.</ref> The terminal ends of linear chromosomes cannot be fully replicated, and as a result telomeres shorten at each mitotic cycle. As telomeres reach a critical length, they cannot longer fully maintain their protective functions, which triggers a DNA damage response and arrests cell proliferation.<ref>Cesare, Anthony J., och Jan Karlseder. ”A Three-State Model of Telomere Control over Human Proliferative Boundaries”. ''Current Opinion in Cell Biology'', vol. 24, nr 6, december 2012, s. 731–38. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1016/j.ceb.2012.08.007</nowiki>.</ref> As DNA breaks in telomeres are irreparable, cell senescence can be triggered even when telomere lenght is not critically short. <ref>Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J. M., ... & d’Adda di Fagagna, F. (2012). Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. ''Nature cell biology'', ''14''(4), 355-365.</ref>

Telomeric DNA is made of tandem repeats of nucleotide sequences, and does not code for proteins. Sequence of telomeres is well-conserved among humans and other vertebrates and consists of “TTAGGG” repeats.<ref>Meyne, J., m.fl. ”Conservation of the Human Telomere Sequence (TTAGGG)n among Vertebrates.” ''Proceedings of the National Academy of Sciences'', vol. 86, nr 18, september 1989, s. 7049–53. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1073/pnas.86.18.7049</nowiki>.</ref><ref name=":0">Oeseburg, Hisko, m.fl. ”Telomere Biology in Healthy Aging and Disease”. ''Pflügers Archiv - European Journal of Physiology'', vol. 459, nr 2, januari 2010, s. 259–68. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1007/s00424-009-0728-1</nowiki>.</ref> As opposed to the sequence, telomere length varies widely among and within species, within an organism, and even between chromosomes.<ref name=":0" /> In humans, telomere length has been shown to vary between 5 and 15 thousand base pairs.<ref>Takubo, Kaiyo, m.fl. ”Telomere Lengths Are Characteristic in Each Human Individual”. ''Experimental Gerontology'', vol. 37, nr 4, april 2002, s. 523–31. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1016/S0531-5565(01)00218-2</nowiki>.</ref> The telomere is cloaked in a specialised six-protein complex, called shelterin, which ensures protection of chromosome ends and distinguishes telomeres from sites of DNA damage.<ref>de Lange, Titia. ”Shelterin: The Protein Complex That Shapes and Safeguards Human Telomeres”. ''Genes & Development'', vol. 19, nr 18, september 2005, s. 2100–10. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1101/gad.1346005</nowiki>.</ref>

== Telomerase ==
Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. <ref>Cong, Yu-Sheng, m.fl. ”Human Telomerase and Its Regulation”. ''Microbiology and Molecular Biology Reviews'', vol. 66, nr 3, september 2002, s. 407–25. ''DOI.org (Crossref)'', <nowiki>https://doi.org/10.1128/MMBR.66.3.407-425.2002</nowiki>.</ref>

==== GV1001 ====
'''GV1001''' is a small peptide containing 16 amino acids that mimics a fragment of the active catalytic site of human telomerase reverse transcriptase (hTERT).<ref>Park, H. H., Lee, K. Y., Kim, S., Lee, J. W., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2014). The novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiology of aging, 35(6), 1255-1274. PMID: 24439482 DOI: 10.1016/j.neurobiolaging.2013.12.015</ref> GV1001 peptide can be recognized by the immune system that reacts by killing the telomerase-active cells.<ref>Tian, X., Chen, B., & Liu, X. (2010). Telomere and telomerase as targets for cancer therapy. Applied biochemistry and biotechnology, 160(5), 1460-1472. PMID: 19412578 DOI: 10.1007/s12010-009-8633-9</ref><ref>Inderberg-Suso, E. M., Trachsel, S., Lislerud, K., Rasmussen, A. M., & Gaudernack, G. (2012). Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001. Oncoimmunology, 1(5), 670-686. PMID: 22934259 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429571/ PMC3429571] DOI: 10.4161/onci.20426</ref> GV1001 has antioxidant and neuroprotective effects in neural stem cells, which appear to be mediated by scavenging free radicals, increasing survival signals and decreasing death signals.<ref>Park, H. H., Yu, H. J., Kim, S., Kim, G., Choi, N. Y., Lee, E. H., ... & Koh, S. H. (2016). Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals. Neurotoxicology, 55, 131-141. PMID: 27265016 DOI: 10.1016/j.neuro.2016.05.022</ref>

GV1001 was used for the treatment of Alzheimer's disease patients with moderate to severe dementia and confirmed that, compared to those in the placebo, GV1001 significantly improved the Alzheimer's disease patient’s cognitive function.<ref>Koh, S. H., Kwon, H. S., Choi, S. H., Jeong, J. H., Na, H. R., Lee, C. N., ... & Lee, K. Y. (2021). Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer’s disease already receiving donepezil: A phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. Alzheimer's research & therapy, 13, 1-11. PMID: 33771205 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995588/ PMC7995588] DOI: 10.1186/s13195-021-00803-w</ref>
According to the hypothesis (Park H. et al., 2024) GV1001 binds to GnRHRs and activates downstream signaling pathways, increasing cAMP levels. This pathway might affect the degradation of Aβ peptides, reduction of p-tau, modulation of neuroinflammation (i.e., reducing pro-inflammatory and increasing anti-inflammatory microglia and astrocytes), and suppression of neuronal loss.<ref>Park, H., Kwon, H. S., Lee, K. Y., Kim, Y. E., Son, J. W., Choi, N. Y., ... & Koh, S. H. (2024). GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model. Brain, Behavior, and Immunity, 115, 295-307. PMID: 37884161 [https://doi.org/10.1016/j.bbi.2023.10.021 DOI: 10.1016/j.bbi.2023.10.021]</ref>

== Telomeres in aging and age-related diseases ==
Telomere dysfunction has been described as one of the 9 [[Hallmarks of Aging]], as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.<ref>Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., ... & Pierce, B. L. (2020). Determinants of telomere length across human tissues. ''Science'', ''369''(6509), eaaz6876.</ref><ref name=":1">Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref> Telomere maintenance is a crucial aspect of cellular biology, influencing aging and cancer development. Three major factors are collectively involved in this context: '''the shelterin complex''',<ref>Wolf, S. E., & Shalev, I. (2023). The shelterin protein expansion of telomere dynamics: Linking early life adversity, life history, and the hallmarks of aging. Neuroscience & Biobehavioral Reviews, 152, 105261. PMID: 37268182 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527177/ PMC10527177] DOI: 10.1016/j.neubiorev.2023.105261</ref> the '''CTC1-STN1-TEN1 (CST) complex''',<ref>Cai, S. W., & de Lange, T. (2023). CST–Polα/Primase: the second telomere maintenance machine. Genes & Development, 37(13-14), 555-569. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10499019/ PMC10499019] DOI: 10.1101/gad.350479.123</ref> and '''telomerase'''.<ref>Boccardi, V., & Marano, L. (2024). Aging, Cancer, and Inflammation: The Telomerase Connection. International Journal of Molecular Sciences, 25(15), 8542. PMID: 39126110 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11313618/ PMC11313618] DOI: 10.3390/ijms25158542</ref>

The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.<ref>Frenck Jr, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. ''Proceedings of the National Academy of Sciences'', ''95''(10), 5607-5610.</ref> On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.<ref>Calado, R. T., & Dumitriu, B. (2013, April). Telomere dynamics in mice and humans. In ''Seminars in hematology'' (Vol. 50, No. 2, pp. 165-174). WB Saunders.</ref> Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.<ref name=":2">Steenstrup, T., Kark, J. D., Verhulst, S., Thinggaard, M., Hjelmborg, J. V., Dalgård, C., ... & Aviv, A. (2017). Telomeres and the natural lifespan limit in humans. ''Aging (Albany NY)'', ''9''(4), 1130.</ref> Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.<ref>Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022). Telomere dysfunction in ageing and age-related diseases. ''Nature cell biology'', ''24''(2), 135-147.</ref> However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.<ref name=":1" /> There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.<ref>Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. ''Frontiers in Genetics'', ''11'', 630186.</ref>

== Telomeres and telomerase in cancer and other diseases ==
Increased levels of telomerase have been found in the vast majority of human cancers, whereas mutations decreasing telomerase function cause a range of genetic disorders, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure.<ref>Roake, C. M., & Artandi, S. E. (2020). Regulation of human telomerase in homeostasis and disease. ''Nature reviews Molecular cell biology'', ''21''(7), 384-397.</ref> Longer telomere lenghts have been associated with higher risk of melanoma, lung cancer, prostate cancer, and chronic lymphocytic leukemia. <ref name=":2" />

== Telomeres and telomerase in anti-aging therapies ==
=== Age-reversing telomerase mRNA therapeutics ===
A dogma arose in the 1990s that telomerase causes cancer. This is wrong and set back the field by decades. The reality is that permanent telomerase supports cancer, whereas healthy stem cells frequently turn on telomerase transiently throughout our lives to stave off the devastating effects of short telomeres.<ref>[https://longevity.technology/news/telomere-boosting-mrna-therapeutic-turns-back-the-aging-clock/ Rejuvenation Technologies is targeting longevity and age-related disease with telomerase-based mRNA therapies]</ref> A single dose of '''telomerase mRNA delivered in vivo using lipid nanoparticles''' reverses years of telomere shortening in hours.<ref>[https://longevity.technology/news/rejuvenation-technologies-exits-stealth-with-10-6m-for-age-reversing-mrna-therapeutics/ Rejuvenation Technologies exits stealth with $10.6m for age-reversing mRNA therapeutics]</ref>

==== Mice ====
Mice engineered with much longer telomeres than those of the natural species showed improved mitochondrial function, improved metabolic parameters, decreased cancer, and increased longevity (12.75% increase in median longevity). <ref name=":3">Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref><ref>CNIO researchers obtain the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification - CNIO, accessed 05 Aug 2022</ref> Due to concerns related to the association between telomerase expression and cancer, this was an important finding that suggests that telomere length per se does not increase cancer risk in mice.<ref name=":3" />

Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.<ref>Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. ''EMBO molecular medicine'', ''4''(8), 691-704.</ref> Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.<ref name=":4">Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., ... & Zhu, H. (2022). New intranasal and injectable gene therapy for healthy life extension. ''Proceedings of the National Academy of Sciences'', ''119''(20), e2121499119.</ref><ref>https://www.chemistryworld.com/news/gene-therapy-showcases-technique-to-extend-life-in-mice/4015718.article?utm_campaign=cw_shared&utm_medium=post&utm_source=navigator accessed 05 Aug 2022</ref> Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.<ref name=":3" /><ref name=":4" />

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]

OSER1 gene

2024-09-13T18:57:13Z

Dmitry Dzhagarov: Created page with "'''OSER1 (Oxidative stress-responsive serine-rich protein 1)''' is an evolutionarily conserved '''FOXO-regulated protein''' that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. OSER1 overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. Human proteomic analysis suggests that OSER1 plays roles in o..."

'''OSER1 (Oxidative stress-responsive serine-rich protein 1)''' is an evolutionarily conserved '''[[FOXO longevity genes|FOXO-regulated protein]]''' that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. OSER1 overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity.<ref>Song, J., Li, Z., Zhou, L. et al. FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species. Nat Commun 15, 7144 (2024). https://doi.org/10.1038/s41467-024-51542-z</ref>

<references />
[[Category:Longevity genes]]
[[Category:Main list]]
[[Category:Glossary]]

FOXO longevity genes

2024-09-13T18:56:02Z

Dmitry Dzhagarov: /* FOXO in aging and longevity */

FOXO proteins are a family of transcription factors specially known for their role in longevity and for being a central component of the insulin signalling pathway. The insulin/IGF-1 signalling (IIS) pathway senses insulin and other insulin-like peptides (ILPs) and activates a signalling cascade which connects nutrient levels to metabolism, growth, reproduction, development and aging.

The activity of FOXO antagonises that of insulin: when insulin binds to the insulin receptor, FOXO is sequestered in the cytoplasm and is not able to activate downstream target genes. On the contrary, when insulin levels are low, FOXO translocates to the nucleus and acts on a wide range of cytoprotective and stress-response genes that eventually extend lifespan.

==== FOXO function ====
FOXO transcription factors are homeostasis regulators and are particularly important for responding to cellular stresses such as heat-shock, oxidation or metabolic stress.<ref name=":0">Eijkelenboom, A., & Burgering, B. (2013). FOXOs: signalling integrators for homeostasis maintenance. ''Nature Reviews Molecular Cell Biology'', ''14''(2), 83-97. doi: 10.1038/nrm3507</ref> They are also involved in a variety of other processes including glucose and lipid metabolism, [[autophagy]], cell cycle control, DNA repair and inflammation. FOXO proteins can also act as tumour suppressors.<ref name=":0" /><ref>Dansen, T., & Burgering, B. (2008). Unravelling the tumor-suppressive functions of FOXO proteins. ''Trends In Cell Biology'', ''18''(9), 421-429. doi: 10.1016/j.tcb.2008.07.004</ref>

In addition, FOXO is required for the striking lifespan extension (of 60%) of insulin-signalling mutants.<ref>Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. ''Nature'', ''366''(6454), 461-464. doi: 10.1038/366461a0</ref>

==== FOXO isoforms and orthologs ====
In humans, the family of Forkhead box O (FOXO) proteins consists of four members (known as “isoforms”): FOXO1, FOXO3, FOXO4 and FOXO6.<ref name=":1">Burgering, B. (2008). A brief introduction to FOXOlogy. ''Oncogene'', ''27''(16), [tel:2258-2262 2258-2262]. doi: 10.1038/onc.2008.29</ref> Whilst expressed ubiquitously in all tissues, FOXO1 is more highly expressed in adipocytes, FOXO3 in the liver, FOXO4 in muscle cells and FOXO6 in the nervous system.<ref name=":1" /> In invertebrates there is only one FOXO gene counterpart or “ortholog”, known as daf-16 in C. ''elegans'' nematodes'','' or dFOXO in ''Drosophila'' flies.

==== FOXO in aging and longevity ====
FOXO proteins are nowadays well established as longevity genes, especially FOXO3.<ref>Morris, B., Willcox, D., Donlon, T., & Willcox, B. (2015). A Major Gene for Human Longevity - A Mini-Review. ''Gerontology'', ''61''(6), 515-525. doi: 10.1159/000375235</ref> They are believed to protect cells from damage and to remove or repair already existing cellular damage.

Genetic association studies of single nucleotide polymorphisms (SNPs) have shown that FOXO3 consistently associates with centenarians of diverse human populations.<ref>Willcox, B., Donlon, T., He, Q., Chen, R., Grove, J., & Yano, K. et al. (2008). FOXO3A genotype is strongly associated with human longevity. ''Proceedings Of The National Academy Of Sciences'', ''105''(37), [tel:13987-13992 13987-13992]. doi: 10.1073/pnas.0801030105</ref> In humans, to date only two genes have shown to be consistently associated with extreme old age across human populations: FOXO3 and APOE (the latter coding for the protein apolipoprotein E, a subtype of which is well known for being a risk-factor gene to [[Aging and Neurodegeneration|Alzheimer’s Disease]]).<ref>Broer, L., Buchman, A., Deelen, J., Evans, D., Faul, J., & Lunetta, K. et al. (2014). GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy. ''The Journals Of Gerontology: Series A'', ''70''(1), 110-118. doi: 10.1093/gerona/glu166</ref>

Interestingly, the ''Hydra'', an invertebrate species considered to be biologically immortal, requires the FOXO transcription factor to maintain its capacity for cellular self-renewal and thus its immortality.<ref>Bridge, D., Theofiles, A., Holler, R., Marcinkevicius, E., Steele, R., & Martínez, D. (2010). FoxO and Stress Responses in the Cnidarian Hydra vulgaris. ''Plos ONE'', ''5''(7), e11686. doi: 10.1371/journal.pone.0011686</ref>

Deregulation of FOXOs has also been associated with several diseases such as cancer, neurological diseases, diabetes and cardiovascular disease.<ref>Calissi, G., Lam, E., & Link, W. (2020). Therapeutic strategies targeting FOXO transcription factors. ''Nature Reviews Drug Discovery'', ''20''(1), 21-38. doi: 10.1038/s41573-020-0088-2</ref>

== [[OSER1 gene]] ==

<references />
[[Category:Main list]]
[[Category:Longevity genes]]

Why does green tea seem to improve longevity?

2024-09-03T17:08:36Z

Dmitry Dzhagarov: /* Cinnamoylated flavoalkaloid */

'''Green tea''' comes from the plant ''Camellia sinensis'', and is made from unfermented leaves. Freshly harvested tea leaves are immediately steamed to prevent fermentation and destroy enzymes.<ref>Ali, R. B., & Almokhtar, M. N. (2023). Camellia Sinensis (Green Tea) Health Benefits. Journal of Medical Sciences, 18(2), 1-7. https://doi.org/10.51984/joms.v18i2.2784</ref> This helps to preserve the natural polyphenols in green tea, which contribute to many health-promoting properties. Unlike black tea, which is oxidized and contains 50 mg of caffeine/cup, which is twice the caffeine content of green tea, green tea has slightly different types of flavonoids.

Studies have found that those who drink at least 5 cups of green tea per day are 76% less likely to die from all causes and cardiovascular disease (CVD) when compared to those who didn’t.<ref>Shin, S., Lee, J. E., Loftfield, E., Shu, X. O., Abe, S. K., Rahman, M. S., ... & Sinha, R. (2022). Coffee and tea consumption and mortality from all causes, cardiovascular disease and cancer: A pooled analysis of prospective studies from the Asia Cohort Consortium. International journal of epidemiology, 51(2), 626-640. PMID: 34468722 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308394/ PMC9308394] DOI: 10.1093/ije/dyab161</ref>

Supplementation with green tea derived natural products, may assist in the growth or maintenance of skeletal muscle and subsequently delay the onset of age-related metabolic diseases in older adults.<ref>Liu, H. W., & Chang, S. J. (2023). Effects of green tea–derived natural products on resistance exercise training in sarcopenia: A retrospective narrative mini-review. Journal of Food and Drug Analysis, 31(3), 381-386. https://doi.org/10.38212/2224-6614.3470</ref>

== Green Tea Polyphenol (‒)-Epigallocatechin-3-Gallate (EGCG) ==
The most abundant component of green tea is (−)-epigallocatechin-3-gallate (EGCG), which has been the focus of many clinical trials, revealing that EGCG possesses antiproliferative, antimutagenic, antioxidant, antibacterial, antiviral and chemopreventive effects.<ref>Wan, C. C., Hu, X., Li, M., Rengasamy, K. R., Cai, Y., & Liu, Z. (2023). Potential protective function of green tea polyphenol EGCG against high glucose-induced cardiac injury and aging. Journal of Functional Foods, 104, 105506. https://doi.org/10.1016/j.jff.2023.105506</ref><ref>Machin, A., & Putri, W. S. (2023). Green Tea with Its Active Compound EGCG for Acute Ischemic Stroke Treatment. In Recent Advances in the Health Benefits of Tea. IntechOpen. https://www.intechopen.com/chapters/83613</ref>

== Cinnamoylated flavoalkaloid ==
Green tea and especially loose leaf tea of the cultivar mountain shēng (raw) pu'er “Yiwu” prolonged lifespan the longest. ETCs (7 ester-type flavoalkaloids) are the major anti-aging components, among which CFs (4 cinnamoylated flavoalkaloids) is the strongest one with a '''73% lifespan extension''' in ''Caenorhabditis elegans''. The addition of ETCs confers lifespan and healthspan improvement via multiple mechanisms including the conserved metabolic pathway (the insulin/IGF-1 signaling (IIS) and dietary restriction (DR) mimetic pathways), glucocorticoid-inducible kinase-1 (SKN-1) and heat shock factor 1 (HSF 1) stress resistance pathway, and AAK-2 (the AMPK catalytic subunit)-NAD + -SIR 2.1 energy sensors pathway.<ref>Ke, J. P., Li, J. Y., Yang, Z., Wu, H. Y., Yu, J. Y., Yang, Y., ... & Bao, G. H. (2024). Unraveling anti-aging mystery of green tea in C. elegans: Chemical truth and multiple mechanisms. Food Chemistry, 460, 140510. PMID: 39033639 [https://doi.org/10.1016/j.foodchem.2024.140510 DOI: 10.1016/j.foodchem.2024.140510]</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Why does green tea seem to improve longevity?

2024-09-03T17:04:13Z

Dmitry Dzhagarov: /* Green Tea Polyphenol (‒)-Epigallocatechin-3-Gallate (EGCG) */

'''Green tea''' comes from the plant ''Camellia sinensis'', and is made from unfermented leaves. Freshly harvested tea leaves are immediately steamed to prevent fermentation and destroy enzymes.<ref>Ali, R. B., & Almokhtar, M. N. (2023). Camellia Sinensis (Green Tea) Health Benefits. Journal of Medical Sciences, 18(2), 1-7. https://doi.org/10.51984/joms.v18i2.2784</ref> This helps to preserve the natural polyphenols in green tea, which contribute to many health-promoting properties. Unlike black tea, which is oxidized and contains 50 mg of caffeine/cup, which is twice the caffeine content of green tea, green tea has slightly different types of flavonoids.

Studies have found that those who drink at least 5 cups of green tea per day are 76% less likely to die from all causes and cardiovascular disease (CVD) when compared to those who didn’t.<ref>Shin, S., Lee, J. E., Loftfield, E., Shu, X. O., Abe, S. K., Rahman, M. S., ... & Sinha, R. (2022). Coffee and tea consumption and mortality from all causes, cardiovascular disease and cancer: A pooled analysis of prospective studies from the Asia Cohort Consortium. International journal of epidemiology, 51(2), 626-640. PMID: 34468722 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308394/ PMC9308394] DOI: 10.1093/ije/dyab161</ref>

Supplementation with green tea derived natural products, may assist in the growth or maintenance of skeletal muscle and subsequently delay the onset of age-related metabolic diseases in older adults.<ref>Liu, H. W., & Chang, S. J. (2023). Effects of green tea–derived natural products on resistance exercise training in sarcopenia: A retrospective narrative mini-review. Journal of Food and Drug Analysis, 31(3), 381-386. https://doi.org/10.38212/2224-6614.3470</ref>

== Green Tea Polyphenol (‒)-Epigallocatechin-3-Gallate (EGCG) ==
The most abundant component of green tea is (−)-epigallocatechin-3-gallate (EGCG), which has been the focus of many clinical trials, revealing that EGCG possesses antiproliferative, antimutagenic, antioxidant, antibacterial, antiviral and chemopreventive effects.<ref>Wan, C. C., Hu, X., Li, M., Rengasamy, K. R., Cai, Y., & Liu, Z. (2023). Potential protective function of green tea polyphenol EGCG against high glucose-induced cardiac injury and aging. Journal of Functional Foods, 104, 105506. https://doi.org/10.1016/j.jff.2023.105506</ref><ref>Machin, A., & Putri, W. S. (2023). Green Tea with Its Active Compound EGCG for Acute Ischemic Stroke Treatment. In Recent Advances in the Health Benefits of Tea. IntechOpen. https://www.intechopen.com/chapters/83613</ref>

== Cinnamoylated flavoalkaloid ==
Green tea and especially loose leaf tea of the cultivar mountain shēng (raw) pu'er “Yiwu” prolonged lifespan the longest. ETCs (7 ester-type flavoalkaloids) are the major anti-aging components, among which CFs (4 cinnamoylated flavoalkaloids) is the strongest one with a '''73% lifespan extension'''. The addition of ETCs confers lifespan and healthspan improvement via multiple mechanisms including the conserved metabolic pathway (the insulin/IGF-1 signaling (IIS) and dietary restriction (DR) mimetic pathways), glucocorticoid-inducible kinase-1 (SKN-1) and heat shock factor 1 (HSF 1) stress resistance pathway, and AAK-2 (the AMPK catalytic subunit)-NAD + -SIR 2.1 energy sensors pathway.<ref>Ke, J. P., Li, J. Y., Yang, Z., Wu, H. Y., Yu, J. Y., Yang, Y., ... & Bao, G. H. (2024). Unraveling anti-aging mystery of green tea in C. elegans: Chemical truth and multiple mechanisms. Food Chemistry, 460, 140510. PMID: 39033639 [https://doi.org/10.1016/j.foodchem.2024.140510 DOI: 10.1016/j.foodchem.2024.140510]</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Preventing muscle loss

2024-09-01T18:11:12Z

Dmitry Dzhagarov:

'''Preventing muscle loss'''
'''Sarcopenia''' - an age-related disease characterized by loss of muscle strength, mass and performance is frequently associated with aging and plays a major role in the development of frailty syndrome.<ref>Damanti, S., Citterio, L., Zagato, L., Brioni, E., Magnaghi, C., Simonini, M., ... & Querini, P. R. (2024). Sarcopenic obesity and pre-sarcopenia contribute to frailty in community-dwelling Italian older people: data from the FRASNET study. BMC geriatrics, 24(1), 638. PMID: 39085777 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290298/ PMC11290298] DOI: 10.1186/s12877-024-05216-6</ref><ref>Heng, M. W. Y., Chan, A. W., Man, R. E., Fenwick, E. K., Chew, S. T., Tay, L., ... & Lamoureux, E. L. (2023). Individual and combined associations of sarcopenia, osteoporosis and obesity with frailty in a multi-ethnic asian older adult population. BMC geriatrics, 23(1), 802.</ref>
Skeletal muscle atrophy is characterized by weakening, shrinking, and decreasing muscle mass and fiber cross-sectional area at the histological level. It manifests as a reduction in force production, easy fatigue and decreased exercise capability, along with a lower quality of life.
'''Exercise''' with protein supplementation is widely acknowledged as '''the most effective therapy for skeletal muscle atrophy''';<ref>Yamada, M., Kimura, Y., Ishiyama, D., Nishio, N., Otobe, Y., Tanaka, T., ... & Arai, H. (2019). Synergistic effect of bodyweight resistance exercise and protein supplementation on skeletal muscle in sarcopenic or dynapenic older adults. Geriatrics & gerontology international, 19(5), 429-437. PMID: 30864254 DOI: 10.1111/ggi.13643</ref><ref>Liao, C. D., Huang, S. W., Chen, H. C., Huang, M. H., Liou, T. H., & Lin, C. L. (2024). Comparative Efficacy of Different Protein Supplements on Muscle Mass, Strength, and Physical Indices of Sarcopenia among Community-Dwelling, Hospitalized or Institutionalized Older Adults Undergoing Resistance Training: A Network Meta-Analysis of Randomized Controlled Trials. Nutrients, 16(7), 941. PMID: 38612975 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11013298/ PMC11013298] DOI: 10.3390/nu16070941</ref> unfortunately, it is not applicable for all patients. Several active substances for skeletal muscle atrophy have been discovered and evaluated in clinical trials, however, they have not been marketed to date.<ref>Najm, A., Niculescu, A. G., Grumezescu, A. M., & Beuran, M. (2024). Emerging Therapeutic Strategies in Sarcopenia: An Updated Review on Pathogenesis and Treatment Advances. International Journal of Molecular Sciences, 25(8), 4300. PMID: 38673885 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11050002/ PMC11050002] DOI: 10.3390/ijms25084300</ref>
Nutritional supplements play a pivotal role in the current management of sarcopenia. The leucine metabolite '''β-hydroxy-β-methylbutyric acid (HMB)''' supplement is one of the most extensively studied interventions for attenuating the progression of sarcopenia.

== Plant-derived bioactive compounds beneficial in preventing muscle loss and restoring muscle function ==

# '''myricanol''' <ref>Shen, S., Liao, Q., Lyu, P., Wang, J., & Lin, L. (2024). Myricanol prevents aging‐related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5. MedComm, 5(6), e566. PMID: 38868327 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167181/ PMC11167181] DOI: 10.1002/mco2.566</ref>
# '''tomatidine''' <ref>Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., ... & Adams, C. M. (2014). Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. Journal of Biological Chemistry, 289(21), 14913-14924. PMID: 24719321 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031541/ PMC4031541] DOI: 10.1074/jbc.M114.556241</ref>
# '''carnosol''' <ref>Lu, S., Li, Y., Shen, Q., Zhang, W., Gu, X., Ma, M., ... & Zhang, X. (2021). Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia. Journal of cachexia, sarcopenia and muscle, 12(3), 779-795. </ref> exhibited anticachexia effects mainly by inhibiting TNF-α/NF-κB pathway and decreasing muscle and adipose tissue loss. Carnosol might also ameliorate cancer cachexia-associated myotube atrophy by targeting P5CS (Delta-1-pyrroline-5-carboxylate synthase) and its downstream pathways.<ref>Fang, Q. Y., Wang, Y. P., Zhang, R. Q., Fan, M., Feng, L. X., Guo, X. D., ... & Liu, X. (2024). Carnosol ameliorated cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways. Frontiers in Pharmacology, 14, 1291194. PMID: 38249348 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10799341/ PMC10799341] DOI: 10.3389/fphar.2023.1291194</ref>
# '''handelin''' <ref>Zhang, H. J., Wang, B. H., Wang, X., Huang, C. P., Xu, S. M., Wang, J. L., ... & Xiang, Y. (2024). Handelin alleviates cachexia‐and aging‐induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation. Journal of Cachexia, Sarcopenia and Muscle, 15(1), 173-188. PMID: 38009816 PMC10834327 DOI: 10.1002/jcsm.13381</ref>

Preventing muscle loss

2024-09-01T13:01:58Z

Dmitry Dzhagarov: /* Plant-derived bioactive compounds beneficial in preventing muscle loss and restoring muscle function */

'''Preventing muscle loss'''

Skeletal muscle atrophy is characterized by weakening, shrinking, and decreasing muscle mass and fiber cross-sectional area at the histological level. It manifests as a reduction in force production, easy fatigue and decreased exercise capability, along with a lower quality of life.
'''Exercise''' is widely acknowledged as '''the most effective therapy for skeletal muscle atrophy'''; unfortunately, it is not applicable for all patients. Several active substances for skeletal muscle atrophy have been discovered and evaluated in clinical trials, however, they have not been marketed to date.

== Plant-derived bioactive compounds beneficial in preventing muscle loss and restoring muscle function ==
# '''triptolide''' <ref>Fang, W. Y., Tseng, Y. T., Lee, T. Y., Fu, Y. C., Chang, W. H., Lo, W. W., ... & Lo, Y. C. (2021). Triptolide prevents LPS‐induced skeletal muscle atrophy via inhibiting NF‐κB/TNF‐α and regulating protein synthesis/degradation pathway. British Journal of Pharmacology, 178(15), 2998-3016. PMID: 33788266 DOI: 10.1111/bph.15472</ref>
# '''myricanol''' <ref>Shen, S., Liao, Q., Lyu, P., Wang, J., & Lin, L. (2024). Myricanol prevents aging‐related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5. MedComm, 5(6), e566. PMID: 38868327 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167181/ PMC11167181] DOI: 10.1002/mco2.566</ref>
# '''tomatidine''' <ref>Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., ... & Adams, C. M. (2014). Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. Journal of Biological Chemistry, 289(21), 14913-14924. PMID: 24719321 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031541/ PMC4031541] DOI: 10.1074/jbc.M114.556241</ref>
# '''carnosol''' <ref>Lu, S., Li, Y., Shen, Q., Zhang, W., Gu, X., Ma, M., ... & Zhang, X. (2021). Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia. Journal of cachexia, sarcopenia and muscle, 12(3), 779-795. </ref> exhibited anticachexia effects mainly by inhibiting TNF-α/NF-κB pathway and decreasing muscle and adipose tissue loss. Carnosol might also ameliorate cancer cachexia-associated myotube atrophy by targeting P5CS (Delta-1-pyrroline-5-carboxylate synthase) and its downstream pathways.<ref>Fang, Q. Y., Wang, Y. P., Zhang, R. Q., Fan, M., Feng, L. X., Guo, X. D., ... & Liu, X. (2024). Carnosol ameliorated cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways. Frontiers in Pharmacology, 14, 1291194. PMID: 38249348 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10799341/ PMC10799341] DOI: 10.3389/fphar.2023.1291194</ref>
# '''handelin''' <ref>Zhang, H. J., Wang, B. H., Wang, X., Huang, C. P., Xu, S. M., Wang, J. L., ... & Xiang, Y. (2024). Handelin alleviates cachexia‐and aging‐induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation. Journal of Cachexia, Sarcopenia and Muscle, 15(1), 173-188. PMID: 38009816 PMC10834327 DOI: 10.1002/jcsm.13381</ref>

Preventing muscle loss

2024-09-01T12:59:25Z

Dmitry Dzhagarov: Created page with "'''Preventing muscle loss''' Skeletal muscle atrophy is characterized by weakening, shrinking, and decreasing muscle mass and fiber cross-sectional area at the histological level. It manifests as a reduction in force production, easy fatigue and decreased exercise capability, along with a lower quality of life. '''Exercise''' is widely acknowledged as '''the most effective therapy for skeletal muscle atrophy'''; unfortunately, it is not applicable for all patients. Sev..."

'''Preventing muscle loss'''

Skeletal muscle atrophy is characterized by weakening, shrinking, and decreasing muscle mass and fiber cross-sectional area at the histological level. It manifests as a reduction in force production, easy fatigue and decreased exercise capability, along with a lower quality of life.
'''Exercise''' is widely acknowledged as '''the most effective therapy for skeletal muscle atrophy'''; unfortunately, it is not applicable for all patients. Several active substances for skeletal muscle atrophy have been discovered and evaluated in clinical trials, however, they have not been marketed to date.

== Plant-derived bioactive compounds beneficial in preventing muscle loss and restoring muscle function ==
# triptolide <ref>Fang, W. Y., Tseng, Y. T., Lee, T. Y., Fu, Y. C., Chang, W. H., Lo, W. W., ... & Lo, Y. C. (2021). Triptolide prevents LPS‐induced skeletal muscle atrophy via inhibiting NF‐κB/TNF‐α and regulating protein synthesis/degradation pathway. British Journal of Pharmacology, 178(15), 2998-3016. PMID: 33788266 DOI: 10.1111/bph.15472</ref>
# myricanol <ref>Shen, S., Liao, Q., Lyu, P., Wang, J., & Lin, L. (2024). Myricanol prevents aging‐related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5. MedComm, 5(6), e566. PMID: 38868327 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167181/ PMC11167181] DOI: 10.1002/mco2.566</ref>
# tomatidine <ref>Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., ... & Adams, C. M. (2014). Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. Journal of Biological Chemistry, 289(21), 14913-14924. PMID: 24719321 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031541/ PMC4031541] DOI: 10.1074/jbc.M114.556241</ref>
# carnosol <ref>Lu, S., Li, Y., Shen, Q., Zhang, W., Gu, X., Ma, M., ... & Zhang, X. (2021). Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia. Journal of cachexia, sarcopenia and muscle, 12(3), 779-795. </ref> exhibited anticachexia effects mainly by inhibiting TNF-α/NF-κB pathway and decreasing muscle and adipose tissue loss. Carnosol might also ameliorate cancer cachexia-associated myotube atrophy by targeting P5CS (Delta-1-pyrroline-5-carboxylate synthase) and its downstream pathways.<ref>Fang, Q. Y., Wang, Y. P., Zhang, R. Q., Fan, M., Feng, L. X., Guo, X. D., ... & Liu, X. (2024). Carnosol ameliorated cancer cachexia-associated myotube atrophy by targeting P5CS and its downstream pathways. Frontiers in Pharmacology, 14, 1291194. PMID: 38249348 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10799341/ PMC10799341] DOI: 10.3389/fphar.2023.1291194</ref>
# handelin <ref>Zhang, H. J., Wang, B. H., Wang, X., Huang, C. P., Xu, S. M., Wang, J. L., ... & Xiang, Y. (2024). Handelin alleviates cachexia‐and aging‐induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation. Journal of Cachexia, Sarcopenia and Muscle, 15(1), 173-188. PMID: 38009816 PMC10834327 DOI: 10.1002/jcsm.13381</ref>

Calcium channel blockers (CCBs)

2024-08-28T21:01:47Z

Dmitry Dzhagarov:

'''Calcium channel blockers (CCBs)''' use was associated with a 70% lower risk for frailty (95%CI = 0.09 to 0.77).<ref>Chuang, S. Y., Pan, W. H., Chang, H. Y., Wu, C. I., Chen, C. Y., & Hsu, C. C. (2016). Protective effect of calcium channel blockers against frailty in older adults with hypertension. Journal of the American Geriatrics Society, 64(6), 1356-1358.</ref> The use of CCBs in 75+ y.o. patients with renovascular disease. was associated with a significant reduction in overall mortality and cardiovascular death.<ref>Deshmukh, H., Barker, E., Anbarasan, T., Levin, D., Bell, S., Witham, M. D., & George, J. (2018). Calcium channel blockers are associated with improved survival and lower cardiovascular mortality in patients with renovascular disease. Cardiovascular Therapeutics, 36(6), e12474. PMID: 30372589 DOI: 10.1111/1755-5922.12474</ref>

The point estimates for calcium channel blockers (CCBs) indicated a decrease in seven [[Epigenetic clock|DNAmAges]] (a decrease of 0.57 to 1.74 years in five PCDNAmAges, a 0.03-year decrease of aging rate in DunedinPACE, and an elongation of 0.01 in PCDNAmTL), among which the estimates for PCHorvathAge (beta = − 1.28, 95%CI = − 2.34 to − 0.21), PCSkin&bloodAge (beta = − 1.34, 95%CI = − 2.61 to − 0.07), PCPhenoAge (beta = − 1.74, 95%CI = − 2.58 to − 0.89), and PCGrimAge (beta = − 0.57, 95%CI = − 0.96 to − 0.17) excluded the null. In addition to DNAmAges, CCBs was also associated with decreased functional biological ages, shown in FAI (beta = − 2.18, 95%CI = − 3.65 to − 0.71) and FI (beta = − 1.31, 95%CI = − 2.43 to − 0.18).<ref>Tang, B., Li, X., Wang, Y., Sjölander, A., Johnell, K., Thambisetty, M., ... & Hägg, S. (2023). Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging. GeroScience, 45(3), 2065-2078. PMID: 37032369 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400489/ PMC10400489] DOI: 10.1007/s11357-023-00784-8</ref>

Patients with hypertension who were treated with calcium channel blocker (CCB), but not in diuretics demonstrated an association between telomere attrition rate and the differences in antihypertensive treatment response - their analyzes showed that the increase of leukocyte telomere length is associated with the decrease of systolic blood pressure and pulse pressure.<ref>Zhang, S. Y., Li, R. X., Yang, Y. Y., Chen, Y., Yang, S. J., Li, J., ... & Zhang, W. L. (2019). P1693 The longitudinal associations between telomere attrition and the effects of blood pressure lowering and antihypertensive treatment. European Heart Journal, 40(Supplement_1), ehz748-0448. https://doi.org/10.1093/eurheartj/ehz748.0448</ref>

CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients.

== Classes ==

=== Dihydropyridine calcium channel blockers (dipines) ===
Dihydropyridine (DHP) calcium channel blockers are derived from the molecule dihydropyridine and often used to reduce systemic vascular resistance and arterial pressure.

* Amlodipine (Norvasc)
* Aranidipine (Sapresta)
* Azelnidipine (Calblock)
* Barnidipine (HypoCa)
* Benidipine (Coniel)
* Cilnidipine (Atelec, Cinalong, Siscard) Not available in US
* Clevidipine (Cleviprex)
* Efonidipine (Landel)
* Felodipine (Plendil)
* Isradipine (DynaCirc, Prescal)
* Lacidipine (Motens, Lacipil)
* Lercanidipine (Zanidip)
* Manidipine (Calslot, Madipine)
* Nicardipine (Cardene, Carden SR)
* Nifedipine (Procardia, Adalat)
* Nilvadipine (Nivadil)
* Nimodipine (Nimotop) This substance can pass the blood-brain barrier and is used to prevent cerebral vasospasm.
* Nisoldipine (Baymycard, Sular, Syscor)
* Nitrendipine (Cardif, Nitrepin, Baylotensin)
* Pranidipine (Acalas)

=== Non-dihydropyridine ===
Fendiline
Gallopamil
Verapamil (Calan, Isoptin)
Diltiazem (Cardizem)
Gabapentin
Pregabalin
Ziconotide

'''Magnesium''' have also been shown to act as calcium channel blocker when administered orally.

'''Ethanol''' also inhibits L-type calcium channel.<ref>Uhrig, S., Vandael, D., Marcantoni, A., Dedic, N., Bilbao, A., Vogt, M. A., ... & Hansson, A. C. (2017). Differential roles for L-type calcium channel subtypes in alcohol dependence. Neuropsychopharmacology, 42(5), 1058-1069. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506795/ PMC5506795] DOI: 10.1038/npp.2016.266
</ref>

== Verapamil ==
(also: nifedipine, amlodipine, lacidipine, nicardipine)
Verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity.<ref>Liu, W., Lin, H., Mao, Z., Zhang, L., Bao, K., Jiang, B., ... & Li, J. (2020). Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy. Aging (Albany NY), 12(6), 5300. PMID: 32208362 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138547 PMC7138547] DOI: 10.18632/aging.102951</ref>

== Cinnarizine ==
Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome, also as a nootropic drug (memory and cognitive function enhancer) and as adjunct therapy for peripheral arterial disease.<ref>Kirtane, M. V., Bhandari, A., Narang, P., & Santani, R. (2019). Cinnarizine: a contemporary review. Indian Journal of Otolaryngology and Head & Neck Surgery, 71, 1060-1068. PMID: 31750127 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841794/ PMC6841794] DOI: 10.1007/s12070-017-1120-7</ref> As a selective calcium channel blocker (SCCB), it reduces the entry of Ca2+ ions into cells and decreases their concentration in the plasma membrane depot, reduces the tone of the smooth muscles of arterioles, and enhances the vasodilating effect of carbon dioxide.
Сinnarizine dose-dependently inhibits the mammalian target of rapamycin (mTOR), and selectively mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2), which allows cinnarizine to be classified as an mTOR inhibitor (rapalog) that is a geroprotector.<ref>Allen, S. A., Tomilov, A., & Cortopassi, G. A. (2018). Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochemical pharmacology, 155, 298-304. PMID 30028993 doi:10.1016/j.bcp.2018.07.013</ref><ref>Dumas, S. N., & Lamming, D. W. (2020). Next generation strategies for geroprotection via mTORC1 inhibition. The Journals of Gerontology: Series A, 75(1), 14-23. PMID 30794726 PMC 6909887 doi:10.1093/gerona/glz056</ref>

Chronic administration of the calcium channel blocker cinnarizine to senescent animals with significant aging-induced decreased density of dopamine D2 and especially D1 receptors, regain these pathological disorders.<ref>Camps, M., Ambrosio, S., Reiriz, J., Ballarin, M., Cutillas, B., & Mahy, N. (1993). Effect of age and cinnarizine treatment on brain dopamine receptors. Pharmacology, 46(1), 9-12. PMID: 8434032 DOI: 10.1159/000139023</ref>

== Fasudil ==
The small molecule fasudil, formerly known as HA1077 or AT‐877, is the ROCK inhibitor that has been used in Japan and China since 1995 for the treatment of vasospasms following subarachnoid haemorrhage, as well as to prevent the loss of intelligence and memory observed in stroke patients and the elderly.<ref>Suzuki, Y., Shibuya, M., Satoh, S. I., Sugimoto, Y., & Takakura, K. (2007). A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surgical neurology, 68(2), 126-131. PMID: 17586012 DOI: 10.1016/j.surneu.2006.10.037</ref> Fasudil also could ameliorate impairments in skeletal muscle blood flow observed in older adults<ref>Darvish, S., Coppock, M. E., & Murray, K. O. (2022). Age-related impairments in ATP release by red blood cells as an important contributor to declines in skeletal muscle blood flow in older adults. The Journal of physiology, 600(16), 3643. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378623/ PMC9378623]</ref> It is marketed under the name ERIL®. It was initially characterized as a calcium antagonist, different from previously known calcium channel blockers such as verapamil, diltiazem and nicardipine in that it could prevent arterial contraction in conditions where other calcium channel blockers had failed.<ref>Asano, T. O., Ikegaki, I. C., Satoh, S.,et al., & Hidaka, H. (1987). Mechanism of action of a novel antivasospasm drug, HA1077. Journal of Pharmacology and Experimental Therapeutics, 241(3), 1033-1040. PMID 3598899</ref>

Despite its successful introduction into clinical practice in Japan and China for almost 30 years, the use of fasudil in other countries faces certain limitations. Although fasudil inhibits both ROCK isoforms (ROCK1 and ROCK2) more potently than other kinases, some of its side effects, including hypotension, skin reactions and reversible renal dysfunction, are major barriers to its widespread use.<ref>Wolff, A. W., Peine, J., Höfler, J., Zurek, G., Hemker, C., & Lingor, P. (2024). SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants. CNS drugs, 38(4), 291-302. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980656/ PMC10980656]</ref>

== References ==
<references />

[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Main list]]

Granzyme B

2024-08-25T19:35:28Z

Dmitry Dzhagarov:

'''Granzymes''', a family of serine proteases with intracellular cytotoxic and/or proinflammatory functions, are increasingly recognized for their emerging roles in biological aging and disease.
Widely recognized as intracellular mediators of cell death, granzymes, particularly '''granzyme B (GzmB)''' is observed in numerous age-related conditions, also accumulate in the extracellular milieu of tissues with age, contributing to chronic tissue injury, inflammation, and impaired healing. Genetic deletion and/or pharmacological inhibition of granzyme B reduces premature aging and/or disease phenotypes in animal models.<ref>Richardson, K. C., Jung, K., Matsubara, J. A., Choy, J. C., & Granville, D. J. (2024). Granzyme B in aging and age-related pathologies. Trends in Molecular Medicine. https://doi.org/10.1016/j.molmed.2024.07.010</ref>

== VTI-1002, a small molecule, specific inhibitor against GzmB ==
<ref>Shen, Y., Zeglinski, M. R., Turner, C. T., Raithatha, S. A., Wu, Z., Russo, V., ... & Granville, D. J. (2018). Topical small molecule granzyme B inhibitor improves remodeling in a murine model of impaired burn wound healing. Experimental & molecular medicine, 50(5), 1-11. PMID: 29849046 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976625/ PMC5976625] DOI: 10.1038/s12276-018-0095-0</ref>

[[Category:Aging pathways and hallmarks]]
[[Category:Drafts]]
[[Category:Drugs]]
[[Category:Glossary]]

Granzyme B

2024-08-25T19:22:09Z

Dmitry Dzhagarov:

Granzyme B

2024-08-25T19:21:04Z

Dmitry Dzhagarov: Created page with "'''Granzymes''', a family of serine proteases with intracellular cytotoxic and/or proinflammatory functions, are increasingly recognized for their emerging roles in biological aging and disease. Widely recognized as intracellular mediators of cell death, granzymes, particularly '''granzyme B (GzmB)''' is observed in numerous age-related conditions, also accumulate in the extracellular milieu of tissues with age, contributing to chronic tissue injury, inflammation, and i..."

Small nucleoli as a visible cellular hallmark of longevity and metabolic health

2024-08-25T18:28:13Z

Dmitry Dzhagarov: /* SNORA13 */

The nucleolus is a nuclear subcompartment where ribosomal RNA is synthesized and assembled into ribosomal subunits. It is a dynamic organelle subject to inputs from growth signalling pathways, nutrients, and stress, whose size correlates with rRNA synthesis.<ref>Guarente, L. (1997). Link between aging and the nucleolus. Genes & development, 11(19), 2449-2455. PMID: 9334311 [https://genesdev.cshlp.org/content/11/19/2449.long DOI: 10.1101/gad.11.19.2449]</ref><ref>Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M., & Lamond, A. I. (2010). The nucleolus under stress. Molecular cell, 40(2), 216-227. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987465/ PMC2987465/] doi: 10.1016/j.molcel.2010.09.024</ref> The nucleolus is also a production site for other ribonucleoprotein particles, including various splicing factors, the signal recognition particle, stress granules and the siRNA machinery. The expression of nucleolar genes is an excellent predictor of a proliferation index (PRI).<ref>Wang, M., & Lemos, B. (2017). Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation. PLoS genetics, 13(9), e1006994. PMID: 28880866 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605086/ PMC5605086] DOI: 10.1371/journal.pgen.1006994</ref>

'''Despite not being included as one of the “[[hallmarks of aging]]”, numerous evidences indicate a role for nucleoli in ageing'''.<ref>Kasselimi, E., Pefani, D. E., Taraviras, S., & Lygerou, Z. (2022). Ribosomal DNA and the nucleolus at the heart of aging. Trends in Biochemical Sciences, 47(4), 328-341. PMID: 35063340 [https://doi.org/10.1016/j.tibs.2021.12.007 DOI: 10.1016/j.tibs.2021.12.007]</ref> Studies reveal that multiple longevity pathways strikingly reduce nucleolar size, and diminish expression of the nucleolar protein FIB-1, ribosomal RNA, and ribosomal proteins across different species.<ref>Yi, Y. H., Ma, T. H., Lee, L. W., Chiou, P. T., Chen, P. H., Lee, C. M., ... & Lo, S. J. (2015). A Genetic Cascade of let-7-ncl-1-fib-1 Modulates Nucleolar Size and rRNA Pool in Caenorhabditis elegans. PLoS genetics, 11(10), e1005580. PMID: 26492166 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619655/ PMC4619655] DOI: 10.1371/journal.pgen.1005580</ref><ref name="premature" >Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 328. PMID: 28855503 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577202/ PMC5577202] DOI: 10.1038/s41467-017-00322-z</ref><ref name="hallmark" >Tiku, V., Jain, C., Raz, Y., Nakamura, S., Heestand, B., Liu, W., ... & Antebi, A. (2017). Small nucleoli are a cellular hallmark of longevity. Nature communications, 8(1), 16083. PMID: 28853436 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582349/ PMC5582349] DOI: 10.1038/ncomms16083</ref> A significant correlation between aging and nucleolar size in healthy individuals was also found; specifically, cells derived from individuals with a premature ageing disorder Hutchinson–Gilford progeria syndrome (HGPS) exhibited large nucleoli, which were comparable in size to those of old healthy individuals.<ref name="premature" /><ref>Zlotorynski, E. (2017). Live longer with small nucleoli. Nat Rev Mol Cell Biol 18, 651 https://doi.org/10.1038/nrm.2017.100</ref>

It was assumed that expansion and fragmentation of the nucleolus are the result of the massive accumulation of extrachromosomal ribosomal DNA circles (ERCs) occupying more space and recruiting more ribosome biogenesis factors.<ref>Li, Y., Jiang, Y., Paxman, J., O’Laughlin, R., Klepin, S., Zhu, Y., ... & Hao, N. (2020). A programmable fate decision landscape underlies single-cell aging in yeast. Science, 369(6501), 325-329. PMID: 32675375 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437498/ PMC7437498] DOI: 10.1126/science.aax9552</ref> However, it was discovered that nucleolar expansion occurs independently of ERCs so cannot be taken as evidence of a contribution of ERCs alone to senescence - nucleolar enlargement also occurs in cells lacking ERCs.<ref name="rather" >Zylstra, A., Hadj-Moussa, H., Horkai, D., Whale, A. J., Piguet, B., & Houseley, J. (2023). Senescence in yeast is associated with amplified linear fragments of chromosome XII rather than ribosomal DNA circle accumulation. PLoS Biology, 21(8), e3002250. PMID: 37643194 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464983/ PMC10464983] DOI: 10.1371/journal.pbio.3002250</ref>

The senescence entry point (SEP) represents an abrupt transition in ageing at which yeast cells cease to divide rapidly and the cell cycle becomes slow and heterogeneous.<ref>Fehrmann, S., Paoletti, C., Goulev, Y., Ungureanu, A., Aguilaniu, H., & Charvin, G. (2013). Aging yeast cells undergo a sharp entry into senescence unrelated to the loss of mitochondrial membrane potential. Cell reports, 5(6), 1589-1599.</ref> Cells passed the SEP irrespective of ERCs, while at least in yeast, the SEP across a wide range of conditions and mutants is obviously tightly associated with copy number amplification of a region of chromosome XII between the rDNA and the telomere (ChrXIIr) forming linear fragments up to approximately 1.8 Mb size, which arises in aged cells through a different mechanism to ERCs.<ref name="rather" />

<ref>Sharifi, S., Chaudhari, P., Martirosyan, A., Eberhardt, A. O., Witt, F., Gollowitzer, A., ... & Ermolaeva, M. (2024). Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans. Nature Communications, 15(1), 1702. PMID: 38402241 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10894287/ PMC10894287] DOI: 10.1038/s41467-024-46037-w</ref>

Nucleolar stress induced by arginine-rich peptides leads to a generalized accumulation of orphan ribosomal proteins, which is toxic in cells and drives accelerated aging in mice. The toxicity of arginine-rich peptides is alleviated by targeting ribosome biogenesis pathways such as mTOR or MYC.<ref>Sirozh, O., Jung, B., Sanchez-Burgos, L., Ventoso, I., Lafarga, V., & Fernandez-Capetillo, O. (2024). Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice. bioRxiv, 2023-08. Molecular Cell https://doi.org/10.1016/j.molcel.2024.02.031
</ref>
<ref>Cockrell, A. J., & Gerton, J. L. (2022). Nucleolar organizer regions as transcription-based scaffolds of nucleolar structure and function. In Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine (pp. 551-580). Cham: Springer International Publishing. PMID: 36348121 DOI: 10.1007/978-3-031-06573-6_19</ref>

<ref name="hallmark" />

== Ribosome biogenesis ==
Eukaryotes partition many of the complex, essential process of ribosome biogenesis (RB) steps into the nucleolus, a phase-separated membraneless organelle within the enveloped nucleus. In human cells, three of the four mature ribosomal RNAs (rRNAs), the 18S, 5.8S and 28S rRNAs, are synthesized in the nucleolus as components of the polycistronic 47S primary pre-rRNA precursor transcript from tandem ribosomal DNA (rDNA) repeats by RNA Polymerase 1 (RNAP1). The 5S rRNA is separately transcribed in the nucleus by RNA Polymerase 3 (RNAP3). A myriad of ribosome assembly factors (AFs) execute endo- and exonucleolytic pre-rRNA processing and modification events to liberate the mature rRNAs from the 47S transcript, forming the small 40S and large 60S ribosomal subunits. AFs also facilitate the binding of structurally-constitutive ribosomal proteins (RPs) and the folding of the maturing subunits at the macromolecular scale. Defects in RB can trigger the nucleolar stress response during which labile members of the 5S RNP including RPL5 (uL18) or RPL11 (uL5) bind and sequester the TP53-specific E3 ligase MDM2, effectively stabilizing TP53 levels and leading to CDKN1A (p21) induction, cell cycle arrest, and apoptosis. In aging, there is a decrease in the cellular rate of ribosome synthesis, which includes reduced expression of both rRNA and r-proteins, and an associated decrease in nucleolar size.<ref>Correll, C. C., Bartek, J., & Dundr, M. (2019). The nucleolus: a multiphase condensate balancing ribosome synthesis and translational capacity in health, aging and ribosomopathies. Cells, 8(8), 869. PMID: 31405125 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721831/ PMC6721831] DOI: 10.3390/cells8080869</ref> <ref name="repressors" >Bryant, C. J., McCool, M. A., Rosado González, G. T., Abriola, L., Surovtseva, Y. V., & Baserga, S. J. (2024). Discovery of novel microRNA mimic repressors of ribosome biogenesis. Nucleic Acids Research, 52(4), 1988-2011. PMID: 38197221 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10899765/ PMC10899765] DOI: 10.1093/nar/gkad1235</ref><ref>Ganley, A. R., & Kobayashi, T. (2014). Ribosomal DNA and cellular senescence: new evidence supporting the connection between rDNA and aging. FEMS yeast research, 14(1), 49-59. PMID: 24373458 DOI: 10.1111/1567-1364.12133</ref><ref>Wang, M., & Lemos, B. (2019). Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome research, 29(3), 325-333. PMID: 30765617 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396418/ PMC6396418] DOI: 10.1101/gr.241745.118</ref>

== Small nucleolar RNAs ==
Small nucleolar RNAs (snoRNAs) are a large class of small noncoding RNAs present in all eukaryotes. They have been characterized as playing a central role in ribosome biogenesis, guiding either the sequence-specific chemical modification of pre-rRNA (ribosomal RNA) or its processing.<ref>Dupuis-Sandoval, F., Poirier, M., & Scott, M. S. (2015). The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdisciplinary Reviews: RNA, 6(4), 381-397. https://doi.org/10.1002/wrna.1284</ref><ref>Piñeiro Ugalde, A., Roiz del Valle, D., Moledo Nodar, L., Menéndez Caravia, X., Pérez Freije, J. M., & López Otín, C. (2024). Non-coding RNA contribution to aging and lifespan. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 79(4), glae058, https://doi.org/10.1093/gerona/glae058</ref>
Small nucleolar RNAs (snoRNAs) regulate cardiac-relevant signaling pathways, oxidative and metabolic cellular stress, gene expression, and intercellular communication.<ref name="snoRNAs" >Chabronova, A., Holmes, T. L., Hoang, D. M., Denning, C., James, V., Smith, J. G., & Peffers, M. J. (2024). SnoRNAs in cardiovascular development, function, and disease. Trends in Molecular Medicine. https://doi.org/10.1016/j.molmed.2024.03.004</ref> An association between levels of circulating snoRNAs and myocardial infarction and heart failure has been found, indicating the potential of these snoRNAs as biomarkers.<ref name="snoRNAs" />

The MIR-28 family members, '''hsa-miR-28-5p''' and '''hsa-miR-708-5p''', are strong inhibitors of pre-18S pre-rRNA processing (a key step in ribosome biogenesis) by way of potent downregulation of the levels of the mRNA of the ribosomal protein S28 (RPS28, a ribosomal protein component of the 40S ribosomal subunit.<ref name="repressors" /> <ref>Gawade, K., & Raczynska, K. D. (2024). Imprinted small nucleolar RNAs: Missing link in development and disease?. Wiley Interdisciplinary Reviews: RNA, 15(1), e1818. PMID: 37722601 DOI: 10.1002/wrna.1818</ref>

=== SNORA13 ===
SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13, a highly conserved H/ACA box snoRNA, is essential for multiple forms of senescence in human cells and in mice.<ref>Cheng, Y., Wang, S., Zhang, H., Lee, J. S., Ni, C., Guo, J., ... & Mendell, J. T. (2024). A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence. Cell. 187(17), 4770-4789.e23 PMID: 38981482 [https://doi.org/10.1016/j.cell.2024.06.019 DOI: 10.1016/j.cell.2024.06.019]</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Stub]]
[[Category:Drafts]]
[[Category:Aging pathways and hallmarks]]
[[Category:Fundamentals]]

Senolytics

2024-08-24T15:28:24Z

Dmitry Dzhagarov: /* Senescent cells as a factor of aging and age-associated diseases */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]] (due to [[Autophagy#Mitophagy|mitophagy]]), remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref>João Pedro de Magalhães (2024). [https://www.science.org/doi/10.1126/science.adj7050 Cellular senescence in normal physiology].Science, 384, 1300-1301. DOI:10.1126/science.adj7050</ref><ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.<ref>Lemaitre, J. M. (2024). Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin. Journal of the European Academy of Dermatology and Venereology, 38, 5-14.https://doi.org/10.1111/jdv.19820</ref>
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.<ref>Yusupova, M., Ankawa, R., Yosefzon, Y., Meiri, D., Bachelet, I., & Fuchs, Y. (2023). Apoptotic dysregulation mediates stem cell competition and tissue regeneration. Nature Communications, 14(1), 7547. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10662150/ PMC10662150] PMID:37985759 DOI:10.1038/s41467-023-41684-x</ref>

==== Markers of cellular senescence ====
The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21CIP1/WAF1,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16INK4a, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the de-repression of the '''p16INK4a''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been shown that the removal of senescent p16INK4a-positive cells can slow the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> However, whether cells that express '''p16INK4a''' are actually 'senescent cells', and if removal of such cells could cause harm in specific contexts has been questioned by more recent work.<ref name=":1" /> Moreover, a limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations of the genome. It can instead be easier to use small molecule senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics are thought to start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells, such as by differentiation of resident stem cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Notably, this is dependent on the availability of stem cell pools which are known to decline with aging, and this has been identified as a theoretical limitation of senolytics, if the lack of such stem cells means new tissue is not formed. It has also been speculated that '''if''' '''the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
Therapeutics for killing senescent cells could take the form of senolytic small molecules or immune-based clearance (antibodies or cytotoxic T cells).<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref> Senescent cells rely on prosurvival stress response adaptations to avoid apoptosis. This suggests that an attractive senescent cell killing approach would be to use small-molecule inhibitors to block cell death-resistance pathways, thereby using the endogenous stress to drive these cells into apoptosis. Existing inhibitors of prosurvival pathways used in cancer therapy may have utility for senescent cell killing, and could be even more effective for this use given that senescent cells, unlike cancer, do not proliferate.
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

Long-term study of the intermittent dasatinib plus quercetin (5 mg/kg + 50 mg/kg) exposure (two consecutive days monthly for 6 months) on aging outcomes and inflammation in nonhuman primates resulted in significant positive body composition changes with improvement in immune cell profiles and reduced glycosylated hemoglobin A1c.<ref>Ruggiero AD, Vemuri R, Blawas M et al (2023) Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design. Geroscience. https://doi.org/10.1007/s11357-023-00830-5</ref>

A computer-assisted expression analysis study suggested that '''piperlongumine''' (a known natural senolytic found in long pepper ''Piper longum''<ref>Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., ... & Zheng, G. (2016). Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY), 8(11), 2915. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191878/ PMC5191878] DOI: 10.18632/aging.101100</ref>) combination with quercetin (“P+Q”) may be a natural-compound alternative to the combination of dasatinib and quercetin (“D+Q”).<ref>Meiners, F., Secci, R., Sueto, S., Fuellen, G., & Barrantes, I. (2022). Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. bioRxiv, 2022-05. https://doi.org/10.1101/2022.05.26.492763</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Flavonoid 4,4′-dimethoxychalcone ===
The flavonoid 4,4′-dimethoxychalcone (DMC) is particularly abundant in the plant ''Angelica keiskei koidzumi'', which has been used in Asian traditional medicine, and was documented for its ability to promote autophagy-dependent longevity and health.<ref>Carmona-Gutierrez, D., Zimmermann, A., Kainz, K., Pietrocola, F., Chen, G., Maglioni, S., ... & Madeo, F. (2019). The flavonoid 4, 4′-dimethoxychalcone promotes autophagy-dependent longevity across species. Nature communications, 10(1), 651. PMID: 30783116 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180/ PMC6381180] DOI: 10.1038/s41467-019-08555-w</ref> By inhibiting the enzymatic activity of a metalloenzyme ferrochelatase, DMC induces iron accumulation and further ferroptosis.<ref>Yang, C., Wang, T., Zhao, Y., Meng, X., Ding, W., Wang, Q., ... & Deng, H. (2022). Flavonoid 4, 4′-dimethoxychalcone induced ferroptosis in cancer cells by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH. Free Radical Biology and Medicine, 188, 14-23. PMID: 35697292 [https://doi.org/10.1016/j.freeradbiomed.2022.06.010 DOI: 10.1016/j.freeradbiomed.2022.06.010]</ref> Since ferrochelatase was highly expressed in senescent cells compared to non-senescent cells DMC inhibited ferrochelatase and induced ferritinophagy, which led to an increase of labile iron pool, triggering ferroptosis of senescent cells.<ref>Wang, T., Yang, C., Li, Z., Li, T., Zhang, R., Zhao, Y., ... & Deng, H. (2024). Flavonoid 4, 4′-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy. Redox Biology, 69, 103017. PMID: 38176315 [https://doi.org/10.1016/j.redox.2023.103017 DOI: 10.1016/j.redox.2023.103017] </ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Supramolecular senolytics ===
Supramolecular senolytics is organic molecules that selectively target receptors overexpressed in the membranes of aging cells. By leveraging the higher levels of reactive oxygen species (ROS) found in aging cells, these molecules promote the formation of disulfide bonds and create oligomers that bind together. Self-assembly of these oligomers '''occurred only inside the mitochondria of senescent cells''' due to selective localization of the peptides by cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells.<ref>Kim, S., Chae, J. B., Kim, D., Park, C. W., Sim, Y., Lee, H., ... & Ryu, J. H. (2023). Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells. Journal of the American Chemical Society. PMID: 37664981 [https://doi.org/10.1021/jacs.3c06898 DOI: 10.1021/jacs.3c06898]</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== Salvestrols ===
Salvestrol (lat. ''salvus'' - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens.
Under the influence of the '''cytochrome P450 enzyme CYP1B1''', which was reported to be involved in performance of two important factors of aging: mitochondrial function and reactive oxygen species (ROS) production,<ref>Lu, Y., Nanayakkara, G., Sun, Y., Liu, L., Xu, K., Drummer IV, C., ... & Yang, X. (2021). Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation. Redox Biology, 47, 102142. PMID: 34598017 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487079/ PMC8487079] DOI: 10.1016/j.redox.2021.102142 </ref> and which is expressed in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence,<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref><ref>Huynh, D. T. M., Hai, H. T., Hau, N. M., Lan, H. K., Vinh, T. P., De Tran, V., & Pham, D. T. (2023). Preparations and characterizations of effervescent granules containing azithromycin solid dispersion for children and elder: Solubility enhancement, taste-masking, and digestive acidic protection. Heliyon, 9(6). e16592 PMID: 37292293 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245243/ PMC10245243] DOI: 10.1016/j.heliyon.2023.e16592</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== BET degraders as senolytic drugs ====
[[File:Super-enhancer-associated oncogenes.jpg|thumb|Super-enhancers activate gene transcription and induce tumorigenesis using densely bound proteins BRD4 and master transcription factors (according to Qian, H et al., 2023).<ref name="Super" >Qian, H., Zhu, M., Tan, X., Zhang, Y., Liu, X., & Yang, L. (2023). Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets. Cell Death Discovery, 9(1), 470. PMID: 38135679 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10746725/ PMC10746725] DOI: 10.1038/s41420-023-01775-6</ref>]]
'''Super-enhancers''' are large clusters of enhancers that are in close genomic proximity, are densely bound by the '''BET bromodomain protein BRD4''' and master transcription factors, and are characterized by massive H3K27ac and H3K4me signals in '''ChIP sequencing (Chromatin immunoprecipitation followed by sequencing)'''.<ref>Blayney, J. W., Francis, H., Rampasekova, A., Camellato, B., Mitchell, L., Stolper, R., ... & Kassouf, M. (2023). Super-enhancers include classical enhancers and facilitators to fully activate gene expression. Cell, 186(26), 5826-5839. PMID: 38101409 [https://doi.org/10.1016/j.cell.2023.11.030 DOI: 10.1016/j.cell.2023.11.030]</ref>
Super-enhancers and their reader BRD4 are critical tumorigenic drivers.<ref name="Super" />

Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, '''ARV-825''', that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref> In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment.<ref>Sato, S., Koyama, K., Ogawa, H., Murakami, K., Imakura, T., Yamashita, Y., ... & Nishioka, Y. (2023). A novel BRD4 degrader, ARV-825, attenuates lung fibrosis through senolysis and antifibrotic effect. Respiratory Investigation, 61(6), 781-792. PMID: 37741093 DOI: 10.1016/j.resinv.2023.08.003</ref>

'''BETd-246''', a BRD degrader belonging to the second generation, exhibits favorable selectivity and anti-neoplastic properties. BETd-246 exhibits significant therapeutic efficacy against lung cancer and hematological cancer.<ref>Zhang, M., Li, Y., Zhang, Z., Zhang, X., Wang, W., Song, X., & Zhang, D. (2023). BRD4 Protein as a Target for Lung Cancer and Hematological Cancer Therapy: A Review. Current Drug Targets, 24(14), 1079-1092. https://doi.org/10.2174/0113894501269090231012090351</ref>
BRD4 is also a repressor in cardiac reprogramming, acting primarily through cytokine oncostatin-M, and transient, but not permanent, degradation of BRD4 by a BET degrader, senolytic BETd-246 treatment can enhance cardiac-reprogramming-based regeneration in vivo.<ref>Liu, L., Guo, Y., Tian, S., Lei, I., Gao, W., Li, Z., ... & Wang, Z. (2024). Transient BRD4 degradation improves cardiac reprogramming by inhibiting macrophage/Oncostatin M induced JAK/STAT pathway. bioRxiv, 2023-12. https://doi.org/10.1101/2023.12.31.573781</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

Garcia H. et al., describe a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with Proteo-Lipid Vehicles (PLVs). These PLVs employ fusion-associated small transmembrane (FAST) proteins that can efficiently transduce a wide range of cells in vivo. Selective ablation of target cells is then achieved through the expression of a potent pro-apoptotic transgene driven by a specific senescence-associated promoter such as p16Ink4A or p53. Aged mice treated with '''FAST-PLV senolytic''' showed significantly reduced senescent cell burden. Mice treated with senolytic PLVs had an increased median post-treatment survival of 160%, lower clinical frailty,
and improved physical and heart function. Spontaneous tumor burden in these mice was reduced.<ref>Garcia H. et al., & Lewis J.D. (2023). SYSTEMIC SENOLYSIS USING A GENETIC MEDICINE IMPROVES HEALTHSPAN IN NATURALLY AGED MICE. Abstracts of 13TH INTERNATIONAL CONFERENCE ON FRAILTY & SARCOPENIA RESEARCH (ICFSR)</ref>

==== Senolytic CAR T cells and natural killer (NK) cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>
Diminished Natural killer (NK) cells activity in elderly individuals is associated with disorders such as atherosclerosis, the development of hypertension<ref>Delaney, J. A., Olson, N. C., Sitlani, C. M., Fohner, A. E., Huber, S. A., Landay, A. L., ... & Doyle, M. F. (2021). Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA). BMC Cardiovascular Disorders, 21, 1-9. PMID: 33482725 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821496/ PMC7821496] DOI: 10.1186/s12872-021-01857-2</ref><ref>Lee, Y. K., Suh, E., Oh, H., Haam, J. H., & Kim, Y. S. (2024). Decreased natural killer cell activity as a potential predictor of hypertensive incidence. Frontiers in Immunology, 15, 1376421. PMID: 38715619 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074345/ PMC11074345] DOI: 10.3389/fimmu.2024.1376421</ref> and an elevated risk of mortality.<ref>Cho, A. R., Suh, E., Oh, H., Cho, B. H., Gil, M., & Lee, Y. K. (2023). Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. International Journal of Molecular Sciences, 24(15), 12505. PMID: 37569879 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419953/ PMC10419953] DOI: 10.3390/ijms241512505</ref><ref>Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., & Nomura, T. (1997). Natural killer cells in the late decades of human life. Clinical Immunology and Immunopathology, 84(3), 269-275. PMID: 9281385 DOI: 10.1006/clin.1997.4401</ref><ref>Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., ... & Dan, K. (2001). Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology, 124(3), 392-397. PMID: 11472399 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906081/ PMC1906081] DOI: 10.1046/j.1365-2249.2001.01571.x</ref>

Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or p16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

Senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the '''senescence-associated protein urokinase plasminogen activator receptor (uPAR)''' can safely eliminate uPAR-positive senescent cells that accumulate during aging.<ref name="uPAR" /> Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.<ref>Amor, C., Fernández-Maestre, I., Chowdhury, S. et al. (2024). Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging https://doi.org/10.1038/s43587-023-00560-5
PMID: 37841853 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571605/ PMC10571605] DOI: 10.21203/rs.3.rs-3385749/v1</ref>

Alternatively, NK-cell-based therapies show promise in rejuvenating immunosenescence, eliminating senescent cells and alleviating SASPs, that lead to aging-associated diseases.<ref>Qi, C., & Liu, Q. (2023). Natural killer cells in aging and age-related diseases. Neurobiology of Disease, 183, 106156. PMID: 37209924 DOI: 10.1016/j.nbd.2023.106156</ref> The rapid development of inexpensive and accessible non-viral methods for engineering immune cells makes this approach a promising way to combat diseases of aging.<ref>Bexte, T., & Ullrich, E. (2024). Empowering virus-free CAR immune cell therapies. Molecular Therapy. 32(6), P1609-1611 PMID 38795701 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184381 PMC 11184381] doi:10.1016/j.ymthe.2024.05.023</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
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[[Category:Main list]]
[[Category:Drugs]]
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Seno-protective benefits of tropoelastin

2024-08-15T17:39:54Z

Dmitry Dzhagarov: Created page with "Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases.<ref>Shek, N., Choy, A. M., Lang, C. C., Miller, B. E., Tal-Singer, R., Bolton, C. E., ... & Huang, J. T. (2024). Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases. npj Aging, 10(1), 15. PMID: 38413600 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10899634/ PMC10899634] DOI: 10.1038/s41514-024-00143-7</ref> "... Ultra-..."

Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases.<ref>Shek, N., Choy, A. M., Lang, C. C., Miller, B. E., Tal-Singer, R., Bolton, C. E., ... & Huang, J. T. (2024). Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases. npj Aging, 10(1), 15. PMID: 38413600 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10899634/ PMC10899634] DOI: 10.1038/s41514-024-00143-7</ref>
"... Ultra-long lived proteins such as elastin, collagen, and eye lens crystalline have been considered as the Achilles heel of the aging proteome as their damages and losses are not easily repaired. Among them, elastin is unique in providing the characteristics of elasticity, resilience, and deformability of tissues such as the aorta, lung, and skin etc, and its fragmentation and degradation represents an important feature of normal aging. Elastin is a crosslinked polymeric network of '''tropoelastin monomers''' catalysed by lysine oxidase during development. In adult tissues, elastin has an extremely low turnover rate with a half-life of ~74 years under normal conditions in contrast to minutes to days for most intracellular proteins. In general, adult tissues lack the capability of regenerating functional elastic fibre. These two unique properties imply that '''an increased turnover of this ultra-long-lived protein in adult tissues could result in irreversible changes to elastin-rich tissues'''. ..."

Despite the above mentioned, evidence has emerged that to some extent this elastin network is still being renewed. Moreover, ''in vitro'' experiments have even demonstrated that the addition of endogenous tropoelastin (the soluble monomer of elastin) prolongs mesenchymal stromal/stem cells (MSCs) vitality and delays senescence during replicative aging.<ref>Lee, S. S., Al Halawani, A., Teo, J. D., Weiss, A. S., & Yeo, G. C. (2024). The Matrix Protein Tropoelastin Prolongs Mesenchymal Stromal Cell Vitality and Delays Senescence During Replicative Aging. Advanced Science, 2402168. https://doi.org/10.1002/advs.202402168</ref>

[[Category:Drugs]]
[[Category:Drafts]]
[[Category:Stub]]

Calcium channel blockers (CCBs)

2024-08-15T16:14:36Z

Dmitry Dzhagarov: /* Cinnarizine */

'''Calcium channel blockers (CCBs)''' use was associated with a 70% lower risk for frailty (95%CI = 0.09 to 0.77).<ref>Chuang, S. Y., Pan, W. H., Chang, H. Y., Wu, C. I., Chen, C. Y., & Hsu, C. C. (2016). Protective effect of calcium channel blockers against frailty in older adults with hypertension. Journal of the American Geriatrics Society, 64(6), 1356-1358.</ref>

The point estimates for calcium channel blockers (CCBs) indicated a decrease in seven [[Epigenetic clock|DNAmAges]] (a decrease of 0.57 to 1.74 years in five PCDNAmAges, a 0.03-year decrease of aging rate in DunedinPACE, and an elongation of 0.01 in PCDNAmTL), among which the estimates for PCHorvathAge (beta = − 1.28, 95%CI = − 2.34 to − 0.21), PCSkin&bloodAge (beta = − 1.34, 95%CI = − 2.61 to − 0.07), PCPhenoAge (beta = − 1.74, 95%CI = − 2.58 to − 0.89), and PCGrimAge (beta = − 0.57, 95%CI = − 0.96 to − 0.17) excluded the null. In addition to DNAmAges, CCBs was also associated with decreased functional biological ages, shown in FAI (beta = − 2.18, 95%CI = − 3.65 to − 0.71) and FI (beta = − 1.31, 95%CI = − 2.43 to − 0.18).<ref>Tang, B., Li, X., Wang, Y., Sjölander, A., Johnell, K., Thambisetty, M., ... & Hägg, S. (2023). Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging. GeroScience, 45(3), 2065-2078. PMID: 37032369 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400489/ PMC10400489] DOI: 10.1007/s11357-023-00784-8</ref>

Patients with hypertension who were treated with calcium channel blocker (CCB), but not in diuretics demonstrated an association between telomere attrition rate and the differences in antihypertensive treatment response - their analyzes showed that the increase of leukocyte telomere length is associated with the decrease of systolic blood pressure and pulse pressure.<ref>Zhang, S. Y., Li, R. X., Yang, Y. Y., Chen, Y., Yang, S. J., Li, J., ... & Zhang, W. L. (2019). P1693 The longitudinal associations between telomere attrition and the effects of blood pressure lowering and antihypertensive treatment. European Heart Journal, 40(Supplement_1), ehz748-0448. https://doi.org/10.1093/eurheartj/ehz748.0448</ref>

== Verapamil ==
(also: nifedipine, amlodipine, lacidipine, nicardipine)
Verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity.<ref>Liu, W., Lin, H., Mao, Z., Zhang, L., Bao, K., Jiang, B., ... & Li, J. (2020). Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy. Aging (Albany NY), 12(6), 5300. PMID: 32208362 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138547 PMC7138547] DOI: 10.18632/aging.102951</ref>

== Cinnarizine ==
Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome, also as a nootropic drug (memory and cognitive function enhancer) and as adjunct therapy for peripheral arterial disease.<ref>Kirtane, M. V., Bhandari, A., Narang, P., & Santani, R. (2019). Cinnarizine: a contemporary review. Indian Journal of Otolaryngology and Head & Neck Surgery, 71, 1060-1068. PMID: 31750127 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841794/ PMC6841794] DOI: 10.1007/s12070-017-1120-7</ref> As a selective calcium channel blocker (SCCB), it reduces the entry of Ca2+ ions into cells and decreases their concentration in the plasma membrane depot, reduces the tone of the smooth muscles of arterioles, and enhances the vasodilating effect of carbon dioxide.
Сinnarizine dose-dependently inhibits the mammalian target of rapamycin (mTOR), and selectively mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2), which allows cinnarizine to be classified as an mTOR inhibitor (rapalog) that is a geroprotector.<ref>Allen, S. A., Tomilov, A., & Cortopassi, G. A. (2018). Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochemical pharmacology, 155, 298-304. PMID 30028993 doi:10.1016/j.bcp.2018.07.013</ref><ref>Dumas, S. N., & Lamming, D. W. (2020). Next generation strategies for geroprotection via mTORC1 inhibition. The Journals of Gerontology: Series A, 75(1), 14-23. PMID 30794726 PMC 6909887 doi:10.1093/gerona/glz056</ref>

Chronic administration of the calcium channel blocker cinnarizine to senescent animals with significant aging-induced decreased density of dopamine D2 and especially D1 receptors, regain these pathological disorders.<ref>Camps, M., Ambrosio, S., Reiriz, J., Ballarin, M., Cutillas, B., & Mahy, N. (1993). Effect of age and cinnarizine treatment on brain dopamine receptors. Pharmacology, 46(1), 9-12. PMID: 8434032 DOI: 10.1159/000139023</ref>

== Fasudil ==
The small molecule fasudil, formerly known as HA1077 or AT‐877, is the ROCK inhibitor that has been used in Japan and China since 1995 for the treatment of vasospasms following subarachnoid haemorrhage, as well as to prevent the loss of intelligence and memory observed in stroke patients and the elderly.<ref>Suzuki, Y., Shibuya, M., Satoh, S. I., Sugimoto, Y., & Takakura, K. (2007). A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surgical neurology, 68(2), 126-131. PMID: 17586012 DOI: 10.1016/j.surneu.2006.10.037</ref> Fasudil also could ameliorate impairments in skeletal muscle blood flow observed in older adults<ref>Darvish, S., Coppock, M. E., & Murray, K. O. (2022). Age-related impairments in ATP release by red blood cells as an important contributor to declines in skeletal muscle blood flow in older adults. The Journal of physiology, 600(16), 3643. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378623/ PMC9378623]</ref> It is marketed under the name ERIL®. It was initially characterized as a calcium antagonist, different from previously known calcium channel blockers such as verapamil, diltiazem and nicardipine in that it could prevent arterial contraction in conditions where other calcium channel blockers had failed.<ref>Asano, T. O., Ikegaki, I. C., Satoh, S.,et al., & Hidaka, H. (1987). Mechanism of action of a novel antivasospasm drug, HA1077. Journal of Pharmacology and Experimental Therapeutics, 241(3), 1033-1040. PMID 3598899</ref>

Despite its successful introduction into clinical practice in Japan and China for almost 30 years, the use of fasudil in other countries faces certain limitations. Although fasudil inhibits both ROCK isoforms (ROCK1 and ROCK2) more potently than other kinases, some of its side effects, including hypotension, skin reactions and reversible renal dysfunction, are major barriers to its widespread use.<ref>Wolff, A. W., Peine, J., Höfler, J., Zurek, G., Hemker, C., & Lingor, P. (2024). SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants. CNS drugs, 38(4), 291-302. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980656/ PMC10980656]</ref>

== References ==
<references />

[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Main list]]

Calcium channel blockers (CCBs)

2024-08-15T13:38:15Z

Dmitry Dzhagarov: /* Cinnarizine */

'''Calcium channel blockers (CCBs)''' use was associated with a 70% lower risk for frailty (95%CI = 0.09 to 0.77).<ref>Chuang, S. Y., Pan, W. H., Chang, H. Y., Wu, C. I., Chen, C. Y., & Hsu, C. C. (2016). Protective effect of calcium channel blockers against frailty in older adults with hypertension. Journal of the American Geriatrics Society, 64(6), 1356-1358.</ref>

The point estimates for calcium channel blockers (CCBs) indicated a decrease in seven [[Epigenetic clock|DNAmAges]] (a decrease of 0.57 to 1.74 years in five PCDNAmAges, a 0.03-year decrease of aging rate in DunedinPACE, and an elongation of 0.01 in PCDNAmTL), among which the estimates for PCHorvathAge (beta = − 1.28, 95%CI = − 2.34 to − 0.21), PCSkin&bloodAge (beta = − 1.34, 95%CI = − 2.61 to − 0.07), PCPhenoAge (beta = − 1.74, 95%CI = − 2.58 to − 0.89), and PCGrimAge (beta = − 0.57, 95%CI = − 0.96 to − 0.17) excluded the null. In addition to DNAmAges, CCBs was also associated with decreased functional biological ages, shown in FAI (beta = − 2.18, 95%CI = − 3.65 to − 0.71) and FI (beta = − 1.31, 95%CI = − 2.43 to − 0.18).<ref>Tang, B., Li, X., Wang, Y., Sjölander, A., Johnell, K., Thambisetty, M., ... & Hägg, S. (2023). Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging. GeroScience, 45(3), 2065-2078. PMID: 37032369 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400489/ PMC10400489] DOI: 10.1007/s11357-023-00784-8</ref>

Patients with hypertension who were treated with calcium channel blocker (CCB), but not in diuretics demonstrated an association between telomere attrition rate and the differences in antihypertensive treatment response - their analyzes showed that the increase of leukocyte telomere length is associated with the decrease of systolic blood pressure and pulse pressure.<ref>Zhang, S. Y., Li, R. X., Yang, Y. Y., Chen, Y., Yang, S. J., Li, J., ... & Zhang, W. L. (2019). P1693 The longitudinal associations between telomere attrition and the effects of blood pressure lowering and antihypertensive treatment. European Heart Journal, 40(Supplement_1), ehz748-0448. https://doi.org/10.1093/eurheartj/ehz748.0448</ref>

== Verapamil ==
(also: nifedipine, amlodipine, lacidipine, nicardipine)
Verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity.<ref>Liu, W., Lin, H., Mao, Z., Zhang, L., Bao, K., Jiang, B., ... & Li, J. (2020). Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy. Aging (Albany NY), 12(6), 5300. PMID: 32208362 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138547 PMC7138547] DOI: 10.18632/aging.102951</ref>

== Cinnarizine ==
Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. Cinnarizine is predominantly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménière's disease, or Cogan's syndrome. As a selective calcium channel blocker (SCCB), it reduces the entry of Ca2+ ions into cells and decreases their concentration in the plasma membrane depot, reduces the tone of the smooth muscles of arterioles, and enhances the vasodilating effect of carbon dioxide.
Сinnarizine dose-dependently inhibits the mammalian target of rapamycin (mTOR), and selectively mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2), which allows cinnarizine to be classified as an mTOR inhibitor (rapalog) that is a geroprotector.<ref>Allen, S. A., Tomilov, A., & Cortopassi, G. A. (2018). Small molecules bind human mTOR protein and inhibit mTORC1 specifically. Biochemical pharmacology, 155, 298-304. PMID 30028993 doi:10.1016/j.bcp.2018.07.013</ref><ref>Dumas, S. N., & Lamming, D. W. (2020). Next generation strategies for geroprotection via mTORC1 inhibition. The Journals of Gerontology: Series A, 75(1), 14-23. PMID 30794726 PMC 6909887 doi:10.1093/gerona/glz056</ref>

Chronic administration of the calcium channel blocker cinnarizine to senescent animals with significant aging-induced decreased density of dopamine D2 and especially D1 receptors, regain these pathological disorders.<ref>Camps, M., Ambrosio, S., Reiriz, J., Ballarin, M., Cutillas, B., & Mahy, N. (1993). Effect of age and cinnarizine treatment on brain dopamine receptors. Pharmacology, 46(1), 9-12. PMID: 8434032 DOI: 10.1159/000139023</ref>

== Fasudil ==
The small molecule fasudil, formerly known as HA1077 or AT‐877, is the ROCK inhibitor that has been used in Japan and China since 1995 for the treatment of vasospasms following subarachnoid haemorrhage, as well as to prevent the loss of intelligence and memory observed in stroke patients and the elderly.<ref>Suzuki, Y., Shibuya, M., Satoh, S. I., Sugimoto, Y., & Takakura, K. (2007). A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surgical neurology, 68(2), 126-131. PMID: 17586012 DOI: 10.1016/j.surneu.2006.10.037</ref> Fasudil also could ameliorate impairments in skeletal muscle blood flow observed in older adults<ref>Darvish, S., Coppock, M. E., & Murray, K. O. (2022). Age-related impairments in ATP release by red blood cells as an important contributor to declines in skeletal muscle blood flow in older adults. The Journal of physiology, 600(16), 3643. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378623/ PMC9378623]</ref> It is marketed under the name ERIL®. It was initially characterized as a calcium antagonist, different from previously known calcium channel blockers such as verapamil, diltiazem and nicardipine in that it could prevent arterial contraction in conditions where other calcium channel blockers had failed.<ref>Asano, T. O., Ikegaki, I. C., Satoh, S.,et al., & Hidaka, H. (1987). Mechanism of action of a novel antivasospasm drug, HA1077. Journal of Pharmacology and Experimental Therapeutics, 241(3), 1033-1040. PMID 3598899</ref>

Despite its successful introduction into clinical practice in Japan and China for almost 30 years, the use of fasudil in other countries faces certain limitations. Although fasudil inhibits both ROCK isoforms (ROCK1 and ROCK2) more potently than other kinases, some of its side effects, including hypotension, skin reactions and reversible renal dysfunction, are major barriers to its widespread use.<ref>Wolff, A. W., Peine, J., Höfler, J., Zurek, G., Hemker, C., & Lingor, P. (2024). SAFE-ROCK: A Phase I Trial of an Oral Application of the ROCK Inhibitor Fasudil to Assess Bioavailability, Safety, and Tolerability in Healthy Participants. CNS drugs, 38(4), 291-302. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10980656/ PMC10980656]</ref>

== References ==
<references />

[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Main list]]

Pentadecanoic Acid (C15: 0)

2024-08-13T19:13:35Z

Dmitry Dzhagarov: /* References */

{| class="wikitable"
|+ Molar mass 242.403 g·mol−1
|-
! Pentadecanoic Acid (C15: 0) C15H30O2
|-
| [[File:Pentadecanoic acid (C15-0).jpg|250px]]
|-
| CASNo = 1002-84-2
|-
| PubChem = 13849
|}
'''Pentadecanoic Acid (C15: 0)''', also known as '''pentadecylic acid''', is a fatty acid, like omega-3 and omega-6, but unlike them, pentadecanoic acid (C15: 0) has no double bonds in its main chain, making it a resilient molecule that is resistant to oxidation.<ref name="resistant" >Venn-Watson, S. K., & Butterworth, C. N. (2022). Broader and safer clinically-relevant activities of pentadecanoic acid compared to omega-3: Evaluation of an emerging essential fatty acid across twelve primary human cell-based disease systems. PloS one, 17(5), e0268778. PMID: 35617322 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135213/ PMC9135213] DOI: 10.1371/journal.pone.0268778</ref><ref name="Leading" >Venn-Watson, S., & Schork, N. J. (2023). Pentadecanoic Acid (C15: 0), an Essential Fatty Acid, Shares Clinically Relevant Cell-Based Activities with Leading Longevity-Enhancing Compounds. Nutrients, 15(21), 4607. https://doi.org/10.3390/nu15214607</ref>
Pentadecylic acid occurs in hydrogenated mutton fat, ruminant meat, some types of fish, milk fat from cows and some plants.<ref name="dietary" >Venn-Watson, S., Lumpkin, R., & Dennis, E. A. (2020). Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential?. Scientific reports, 10(1), 8161. PMID: 32424181 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235264/ PMC7235264] DOI: 10.1038/s41598-020-64960-y</ref><ref>Jenkins, B., West, J. A., & Koulman, A. (2015). A review of odd-chain fatty acid metabolism and the role of pentadecanoic acid (C15: 0) and heptadecanoic acid (C17: 0) in health and disease. Molecules, 20(2), 2425-2444. PMID: 25647578 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272531 PMC6272531] DOI: 10.3390/molecules20022425</ref>

In 2005, Hulbert<ref name="Hulbert" >Hulbert, A. J. , Pamplona, R. , Buffenstein, R. , & Buttemer, W. A. (2007). Life and death: Metabolic rate, membrane composition, and life span of animals. Physiological Reviews, 87, 1175–1213. PMID: 17928583 DOI: 10.1152/physrev.00047.2006</ref> proposed the membrane pacemaker theory of aging. This theory emphasizes that the fatty acid composition of membranes is a critical factor in lipid peroxidation and consequently in the rate of aging and determination of lifespan. Indeed, it has been suggested that the specific acyl composition of membranes works as a timer to determinate longevity in different species. Long-lived animals have a low degree of fatty acid unsaturation in cell membranes due to decreases in PUFAs and higher levels of less unsaturated fatty acids,<ref name="Hulbert" /> changes that make them more resistant to lipid peroxidation in vivo.<ref>Pamplona, R., & Barja, G. (2007). Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. Ageing research reviews, 6(3), 189-210. PMID: 17702671 DOI: 10.1016/j.arr.2007.06.002</ref><ref>Martín, M. G., & Dotti, C. G. (2022). Plasma membrane and brain dysfunction of the old: Do we age from our membranes?. Frontiers in cell and developmental biology, 10, 1031007. PMID: 36274849 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582647 PMC9582647] DOI: 10.3389/fcell.2022.1031007</ref>

<ref>Venn-Watson SK, Butterworth CN (2022) Broader and safer clinically-relevant activities of pentadecanoic acid compared to omega-3: Evaluation of an emerging essential fatty acid across twelve primary human cell-based disease systems. PLoS ONE 17(5): e0268778. https://doi.org/10.1371/journal.pone.0268778</ref>

=== See also: ===
[https://longevity.technology/news/c150-combats-cellular-fragility-syndrome-obesity-and-aging/ Raising levels of fatty acid C15:0 through supplementation can improve metabolic health and combat cellular aging.]

== References ==
<references />
[[Category:Lifespan interventions]]
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Drafts]]

Small ncRNAs influencing ageing and lifespan

2024-08-13T16:46:40Z

Dmitry Dzhagarov: /* miR-130b-5p */

A '''non-coding RNA (ncRNA)''' is a functional RNA molecule that is not translated into a protein. Non-coding RNAs are endogenous transcripts that govern gene regulatory networks, thus impacting both physiological and pathological events. Non-coding RNAs constitute the majority of endogenous transcripts in the cells since human genome consists of only 3% protein-coding genes and most of the genome is transcribed to produce non-coding RNAs. ncRNA comprise numerous RNA species grouped in different classes, based on their different lengths and activities. Among these molecules, microRNAs, [[Long non-coding RNAs in aging and aging-associated diseases|long non-coding RNAs]], and more recently [[Circular RNAs (CircRNAs)|circular RNAs]] are considered crucial mediators of almost all cellular processes.<ref>Zhang, P., Wu, W., Chen, Q., & Chen, M. (2019). Non-coding RNAs and their integrated networks. Journal of integrative bioinformatics, 16(3). PMID: 31301674 PMCID: PMC6798851 DOI: 10.1515/jib-2019-0027</ref><ref>Varghese, L. N., Schwenke, D. O., & Katare, R. (2023). Role of noncoding RNAs in cardiac ageing. Frontiers in Cardiovascular Medicine, 10. PMID: 37034355 PMCID: PMC10073704 DOI: 10.3389/fcvm.2023.1142575</ref>

== MicroRNAs ==
[[File:Some of the most important microRNA pathways in cellular aging.jpg|thumb|Some of the most important microRNA pathways in cellular aging according to Liangge He et al. 2023<ref>He, L., Li, M., Liu, Z., Padhiar, A. A., & Zhou, G. (2023). Senescence of mesenchymal stem cells: implications in extracellular vesicles, miRNAs and their functional and therapeutic potentials. Aging Pathobiology and Therapeutics, 03-17. DOI: 10.31491/APT.2023.03.107</ref>]]
MicroRNAs (miRNAs) are endogenous small (∼22–25 nucleotides long) noncoding RNAs that control the expression of target mRNA by translational repression or mRNA degradation.<ref>Bushati, N., & Cohen, S. M. (2007). microRNA functions. Annu. Rev. Cell Dev. Biol., 23, 175-205. PMID: 17506695 DOI: 10.1146/annurev.cellbio.23.090506.123406</ref> They are involved in many biological processes such as developmental timing, differentiation, cell death, stem cell proliferation and differentiation, immune response, aging and cancer. That's why miRNAs are the best characterized small non-coding RNAs influencing ageing and lifespan. Multiple miRNAs, including miRNA-1, miRNA-21, miRNA-22, miRNA-34a, miRNA-17, miRNA-145, miRNA-140, miRNA-106b, and miRNA-449a, are widely considered as critical regulators for cell senescence.<ref>Kinser, H. E., & Pincus, Z. (2020). MicroRNAs as modulators of longevity and the aging process. Human genetics, 139(3), 291-308. PMID: 31297598 PMCID: PMC6954352 DOI: 10.1007/s00439-019-02046-0</ref><ref>Zia, A., Farkhondeh, T., Sahebdel, F., Pourbagher-Shahri, A. M., & Samarghandian, S. (2022). Key miRNAs in Modulating Aging and Longevity: A Focus on Signaling Pathways and Cellular Targets. Current Molecular Pharmacology, 15(5), 736-762. PMID: 34533452 DOI: 10.2174/1874467214666210917141541</ref><ref>Ma, X., Zheng, Q., Zhao, G., Yuan, W., & Liu, W. (2020). Regulation of cellular senescence by microRNAs. Mechanisms of Ageing and Development, 189, 111264. PMID: 32450085 DOI: 10.1016/j.mad.2020.111264</ref><ref>Azizidoost, S., Nasrolahi, A., Sheykhi-Sabzehpoush, M., Akiash, N., Assareh, A. R., Anbiyaee, O., ... & Kempisty, B. (2023). Potential roles of endothelial cells-related non-coding RNAs in cardiovascular diseases. Pathology-Research and Practice, 154330. https://doi.org/10.1016/j.prp.2023.154330</ref><ref>Ortiz, G. G. R., Mohammadi, Y., Nazari, A., Ataeinaeini, M., Kazemi, P., Yasamineh, S., ... & Gholizadeh, O. (2023). A state-of-the-art review on the MicroRNAs roles in hematopoietic stem cell aging and longevity. Cell Communication and Signaling, 21(1), 1-16. PMID: 37095512 PMCID: PMC10123996 DOI: 10.1186/s12964-023-01117-0</ref><ref>Chen, Z., Li, C., Huang, H., Shi, Y. L., & Wang, X. (2023). Research progress of aging-related microRNAs. Current Stem Cell Research & Therapy. PMID: 36892029 DOI: 10.2174/1574888X18666230308111043</ref>

=== Let-7 as a promising target in aging and aging-related diseases ===
Let-7, one of the first miRNAs discovered, was initially shown to control developmental timing in ''Caenorhabditis elegans''<ref>Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C., Rougvie, A. E., ... & Ruvkun, G. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. nature, 403(6772), 901-906. PMID: 10706289 DOI: 10.1038/35002607</ref> In mice, 12 genes encode members of the Let-7 family, which includes nine slightly different miRNAs [Let-7a, Let-c, Let-7f (all encoded by two genes), and Let-7b, Let-7d, Let-7e, Let-7g, Let-7i, and miR-98 (all encoded by one gene)]. Processing of Let-7 can be inhibited by an RNA-binding protein LIN28, that is highly expressed in embryonic stem cells.<ref>Newman, M. A., & Hammond, S. M. (2010). Lin-28: an early embryonic sentinel that blocks Let-7 biogenesis. The international journal of biochemistry & cell biology, 42(8), 1330-1333. PMID: 20619222 DOI: 10.1016/j.biocel.2009.02.023</ref> Interestingly, Lin-28 can be used to
achieve [[epigenetic reprogramming]] of human somatic cells into iPSC, even from centenarians fibroblasts.<ref>Lapasset, L., Milhavet, O., Prieur, A., Besnard, E., Babled, A., Aït-Hamou, N., ... & Lemaitre, J. M. (2011). Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & development, 25(21), 2248-2253. PMID: 22056670 PMCID: PMC3219229 DOI: 10.1101/gad.173922.111</ref>
Ectopic global LIN28a overexpression in mice was found to result in increased body size and crown–rump length, as well as increased glucose metabolism and [[insulin sensitivity]].<ref>Zhu, H., Shah, S., Shyh-Chang, N., Shinoda, G., Einhorn, W. S., Viswanathan, S. R., ... & Daley, G. Q. (2010). Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nature genetics, 42(7), 626-630. PMID: 20512147 PMCID: PMC3069638 DOI: 10.1038/ng.593</ref> LIN28A expression ends after development in most of tissues, and its re-expression in adult transgenic mice has been reported to enhance the regeneration of various somatic tissues by acting on somatic stem cells harbored within those tissues.<ref>Shyh-Chang, N., Zhu, H., De Soysa, T. Y., Shinoda, G., Seligson, M. T., Tsanov, K. M., ... & Daley, G. Q. (2013). Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell, 155(4), 778-792. PMID: 24209617 PMCID: PMC3917449 DOI: 10.1016/j.cell.2013.09.059</ref><ref>Pieknell, K., Sulistio, Y. A., Wulansari, N., Darsono, W. H. W., Chang, M. Y., Ko, J. Y., ... & Lee, S. H. (2022). LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming. Cell Death & Differentiation, 29(3), 540-555. PMID: 34556809 PMCID: PMC8901931 DOI: 10.1038/s41418-021-00873-1</ref> Knockout of Let-7 with a locked nucleic acid (LNA)-modified antimiR, that could inhibit Let-7 function in the whole body of mice, can reverse the glucose tolerance of diet-induced obese mice.<ref>Frost, R. J., & Olson, E. N. (2011). Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proceedings of the National Academy of Sciences, 108(52), 21075-21080. PMID: 22160727 PMCID: PMC3248488 DOI: 10.1073/pnas.1118922109</ref>

Preliminary evidence suggests that beneficial effects of [[metformin]] may be due to regulation of let-7 expression, since "metformin no longer has potent antidiabetic actions in a liver-specific let-7 loss-of-function mouse model".<ref>Xie, D., Chen, F., Zhang, Y., Shi, B., Song, J., Chaudhari, K., ... & Huang, Y. (2022). Let-7 underlies metformin-induced inhibition of hepatic glucose production. Proceedings of the National Academy of Sciences, 119(14), e2122217119. PMID: 35344434 PMCID: PMC9169108 DOI: 10.1073/pnas.2122217119</ref><ref>Zhu, H., Jia, Z., Li, Y. R., & Danelisen, I. (2023). Molecular mechanisms of action of metformin: latest advances and therapeutic implications. Clinical and Experimental Medicine, 1-11. PMID: 37016064 PMCID: PMC10072049 DOI: 10.1007/s10238-023-01051-y</ref>

<ref>Frost, R. J., & Olson, E. N. (2011). Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proceedings of the National Academy of Sciences, 108(52), 21075-21080. PMID: 22160727 PMCID: PMC3248488 DOI: 10.1073/pnas.1118922109</ref>
<ref>Thornton, J. E., & Gregory, R. I. (2012). How does Lin28 let-7 control development and disease?. Trends in cell biology, 22(9), 474-482. PMID: 22784697 PMCID: PMC3432650 DOI: 10.1016/j.tcb.2012.06.001</ref>
<ref>Wang, Y., Zhao, J., Chen, S., Li, D., Yang, J., Zhao, X., ... & Xu, L. (2022). Let-7 as a promising target in aging and aging-related diseases: a promise or a pledge. Biomolecules, 12(8), 1070. PMID: 36008964 PMCID: PMC9406090 DOI: 10.3390/biom12081070</ref>
<ref>Cappelletti, C., Galbardi, B., Bruttini, M., Salerno, F., Canioni, E., Pasanisi, M. B., ... & Mantegazza, R. (2019). Aging‐associated genes and let‐7 microRNAs: a contribution to myogenic program dysregulation in oculopharyngeal muscular dystrophy. The FASEB Journal, 33(6), 7155-7167. PMID: 30860873 DOI: 10.1096/fj.201801577RR</ref>

=== MicroRNA-141-3p ===
Emerging evidence shows that the microRNA-141-3p is involved in various age-related pathologies. The mitochondria-related miR-141-3p might '''promote the pro-inflammatory cytokine (IL-6) expression''', inducing the inflammatory response and contributing to the development of obesity. miR-141-3p over-expression reduced the tumor suppressor gene PTEN expression and promoted ATP production, oxidative stress, and '''the reduction of antioxidant capacity'''.<ref>Ji, J., Qin, Y., Ren, J., Lu, C., Wang, R., Dai, X., ... & Wang, X. (2015). Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD-induced obesity by inhibiting PTEN. Scientific reports, 5(1), 1-12. PMID: 26548909 PMCID: PMC4637860 DOI: 10.1038/srep16262</ref> As a regulator of PPARγ (Peroxisome proliferator- activated receptor gamma), miR-143a-3p play an important role in adipogenesis via regulating MAPK7 (Mitogen-activated protein kinase 7) and fatty acid.<ref>Zhang, P., Du, J., Wang, L., Niu, L., Zhao, Y., Tang, G., ... & Zhu, L. (2018). MicroRNA-143a-3p modulates preadipocyte proliferation and differentiation by targeting MAPK7. Biomedicine & Pharmacotherapy, 108, 531-539. PMID: 30243086 DOI: 10.1016/j.biopha.2018.09.080</ref>

Inhibiting miR-141-3p for three months with twice-weekly subcutaneous injections of '''Anti-miR-141-3p''' treatment improves musculoskeletal health with improving bone microstructure and muscle fiber size in aged mice. Molecular analysis revealed that miR-141-3p regulates the expression of AU-rich RNA-binding factor 1 (AUF1) and promotes the expression of the known muscle wasting transcription factor FOXO-1 (Forkhead transcription factor 1). It also promotes
senescence (p21, p16) and pro-inflammatory (TNF-α, IL-1β, IFN-γ) environment whereas inhibiting miR-141-3p prevents these effects.<ref>Sagar Vyavahare , Sandeep Kumar , Kathryn Smith , Bharati Mendhe , Roger Zhong , Marion A. Cooley , Babak Baban , Carlos M. Isales , Mark Hamrick , William D Hill , Sadanand Fulzele. (2023). Inhibiting MicroRNA-141-3p Improves Musculoskeletal Health in Aged Mice. Aging and disease. 2023 https://doi.org/10.14336/AD.2023.0310-1</ref>

=== miR-214-3p ===
miR-214-3p was downregulated in aged adipose stem cells (ASC)s, and its overexpression rejuvenated aged adipose stem cell (ASC).<ref name="RASSF5" >Ren, S., Li, C., Xiong, H., Wu, Q., Wu, X., Xiong, Z., ... & Chen, J. (2024). The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis. Stem Cells Translational Medicine, szae015.</ref>
A [[Long non-coding RNAs in aging and aging-associated diseases|long non-coding RNA]] named double homeobox A pseudogene 10 ('''DUXAP10''') located in the cytoplasm and functioned as a '''decoy for miR-214-3p''' is significantly accumulated in aged ASCs.<ref name="RASSF5" /> Knocking down DUXAP10 promoted stem cell proliferation and migration and halted cell senescence and the secretion of proinflammatory cytokines. Ras Association Domain Family Member 5 ('''RASSF5''') was the target of miR-214-3p and was upregulated in aged ASCs. Overexpressing DUXAP10 and inhibiting miR-214-3p both enhanced RASSF5 content in ASCs, while DUXAP10 knockdown promoted the therapeutic ability of aged ASCs for skin wound healing.<ref name="RASSF5" />

=== miRNA-34a ===
miR-34a has been implicated in cardiovascular fibrosis, dysfunction and related cardiovascular disorders as an essential regulator. There is a pivotal link among miR-34a, cardiovascular fibrosis, and Smad4/TGF-β1 signaling.
miR-34a plays the critical roles in cardiovascular apoptosis, autophagy, inflammation, senescence and remodeling by modulating multifunctional signaling pathways.<ref>Hua, C. C., Liu, X. M., Liang, L. R., Wang, L. F., & Zhong, J. C. (2022). Targeting the microRNA-34a as a novel therapeutic strategy for cardiovascular diseases. Frontiers in Cardiovascular Medicine, 8, 2243. PMID: 35155600 PMCID: PMC8828972 DOI: 10.3389/fcvm.2021.784044</ref>
MiR-34a accelerated the progression of atherosclerosis by regulating [[FOXO longevity genes|FOXO3]] expression. It was reported that FOXO3 plays a critical role in restraining oxidative damage in ox-LDL-induced endothelial cell injury via the miR-34a/SIRT1/FOXO3 signaling pathway.<ref>Zhang, H., Zhao, Z., Pang, X., Yang, J., Yu, H., Zhang, Y., ... & Zhao, J. (2017). MiR-34a/sirtuin-1/foxo3a is involved in genistein protecting against ox-LDL-induced oxidative damage in HUVECs. Toxicology Letters, 277, 115-122. PMID: 28688900 DOI: 10.1016/j.toxlet.2017.07.216</ref><ref>Raucci, A., Macrì, F., Castiglione, S., Badi, I., Vinci, M. C., & Zuccolo, E. (2021). MicroRNA-34a: the bad guy in age-related vascular diseases. Cellular and Molecular Life Sciences, 1-24. PMID: 34698884 PMCID: PMC8629897 DOI: 10.1007/s00018-021-03979-4</ref>
The expression of miR-34a increased in senescent MSCs cell culture with continuous passage.<ref>Mokhberian, N., Bolandi, Z., Eftekhary, M., Hashemi, S. M., Jajarmi, V., Sharifi, K., & Ghanbarian, H. (2020). Inhibition of miR-34a reduces cellular senescence in human adipose tissue-derived mesenchymal stem cells through the activation of SIRT1. Life Sciences, 257, 118055. PMID: 32634429 DOI: 10.1016/j.lfs.2020.118055</ref><ref>Badi, I., Mancinelli, L., Polizzotto, A., Ferri, D., Zeni, F., Burba, I., et al. (2018). miR34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase). Atvb 38 (9), 2079–2090. doi:10.1161/atvbaha.118.311298</ref> MiR34a significantly reduced [[Sirtuins|SIRT1]] activity, [[NAD+]] content, and NAD+/NADH ratio by targeting nicotinamide phosphoribosyl-transferase ([[NAD+#NAMPT|NAMPT]]).<ref>Pi, C., Ma, C., Wang, H., Sun, H., Yu, X., Gao, X., ... & He, X. (2021). MiR-34a suppression targets Nampt to ameliorate bone marrow mesenchymal stem cell senescence by regulating NAD+-Sirt1 pathway. Stem Cell Research & Therapy, 12(1), 271. PMID: 33957971 PMCID: PMC8101138 DOI: 10.1186/s13287-021-02339-0</ref>

The expression of miR-34a was strongly correlated with HbA1c level, suggesting that increased miR-34a expression is related to high glucose.<ref>Boon, R. A., Iekushi, K., Lechner, S., Seeger, T., Fischer, A., Heydt, S., ... & Dimmeler, S. (2013). MicroRNA-34a regulates cardiac ageing and function. Nature, 495(7439), 107-110. PMID: 23426265 DOI: 10.1038/nature11919</ref><ref>Fomison-Nurse, I., Saw, E. E. L., Gandhi, S., Munasinghe, P. E., Van Hout, I., Williams, M. J. A., ... & Katare, R. (2018). Diabetes induces the activation of pro-ageing miR-34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells. Cell Death & Differentiation, 25(7), 1336-1349. PMID: 29302057 PMCID: PMC6030067 DOI: 10.1038/s41418-017-0047-6</ref>

<ref>Raucci, A., Macrì, F., Castiglione, S., Badi, I., Vinci, M. C., & Zuccolo, E. (2021). MicroRNA-34a: the bad guy in age-related vascular diseases. Cellular and Molecular Life Sciences, 1-24. PMID: 34698884 PMCID: PMC8629897 DOI: 10.1007/s00018-021-03979-4</ref>

=== miR-130b-5p ===
Patients with coronary artery disease (CAD) have high levels of miR-130b-5p in peripheral blood that correlated with severity of coronary artery disease.<ref>Coban, N., Ozuynuk, A. S., Erkan, A. F., Guclu-Geyik, F., & Ekici, B. (2021). Levels of miR-130b-5p in peripheral blood are associated with severity of coronary artery disease. Molecular Biology Reports, 48, 7719-7732. PMID: 34689283 DOI: 10.1007/s11033-021-06780-5</ref>
Mechanistic studies revealed that miR-130b-5p mainly promoted the cardiomyocyte proliferation through the MAPK-ERK signaling pathway, and the dual-specific phosphatase 6 (Dusp6), a negative regulator of the MAPK-ERK signaling, was the direct target of miR-130b-5p. Moreover, overexpression of miR-130b-5p could promote the proliferation of cardiomyocytes and improve cardiac function in mice after myocardial infarction (MI).<ref>Feng, K., Wu, Y., Li, J., Sun, Q., Ye, Z., Li, X., ... & Kang, J. (2024). Critical Role of miR-130b-5p in Cardiomyocyte Proliferation and Cardiac Repair in Mice After Myocardial Infarction. Stem Cells, 42(1), 29-41. PMID: 37933895 [https://doi.org/10.1093/stmcls/sxad080 DOI: 10.1093/stmcls/sxad080]</ref>

Human miR-130b-5p exhibited an impact upon the mRNA levels of a '''negative modulator of aging, Sprr1a''' when expressed in human primary dermal
fibroblasts (HDFs), and induced cellular senescence.<ref>Hong, J. Y., Nam, H. J., Ji, H., Kim, Y. Y., Hyun, M., Park, H. J., ... & McCrea, P. D. (2023). Sprr1 and miR-130b contribute to the senescence-like phenotype in aging. bioRxiv, 2023-10. PMID: 37961492 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634805/ PMC10634805] DOI: 10.1101/2023.10.25.563779</ref>

=== miR-200c-3p ===
Some studies have shown that the expression levels of '''miR-31-5p, miR-141-3p,''' and '''miR-200c-3p''' are elevated with age.<ref>Capri, M., Olivieri, F., Lanzarini, C., Remondini, D., Borelli, V., Lazzarini, R., ... & Grazi, G. L. (2017). Identification of miR‐31‐5p, miR‐141‐3p, miR‐200c‐3p, and GLT 1 as human liver aging markers sensitive to donor–recipient age‐mismatch in transplants. Aging cell, 16(2), 262-272. PMID: 27995756 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334540/ PMC5334540] DOI: 10.1111/acel.12549</ref> It was discovered that miR-200c-3p promoted the proliferation of adipose-derived MSCs and delayed cellular senescence.<ref>Anastasiadou, E., Ceccarelli, S., Messina, E., Gerini, G., Megiorni, F., Pontecorvi, P., ... & Marchese, C. (2021). MiR-200c-3p maintains stemness and proliferative potential in adipose-derived stem cells by counteracting senescence mechanisms. PLoS One, 16(9), e0257070. PMID: 34534238 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448302/ PMC8448302] DOI: 10.1371/journal.pone.0257070</ref>
miR-200c-3p can target and negatively regulate stearoyl-CoA desaturase 2 (SCD2) by binding to the 3′-UTR of SCD2 mRNA to restrain lipid synthesis in MSCs and thus reverse the inhibitory effect of SCD2 over-expression on MSC senescence.<ref>Yu, X., Zhang, C., Ma, Q., Gao, X., Sun, H., Sun, Y., ... & He, X. (2024). SCD2 Regulation Targeted by miR-200c-3p on Lipogenesis Alleviates Mesenchymal Stromal Cell Senescence. International Journal of Molecular Sciences, 25(15), 8538. PMID: 39126105 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11313047/ PMC11313047] DOI: 10.3390/ijms25158538</ref>

== Small nuclear RNAs ==

== Piwi-interacting RNA ==

== References ==
<references />
[[Category:Main list]]
[[Category:Fundamentals]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Aging pathways and hallmarks]]
[[Category:Stub]]
[[Category:Drafts]]

Calcium channel blockers (CCBs)

2024-08-11T13:28:49Z

Dmitry Dzhagarov: /* Verapamil */

Epigenetic clock

2024-08-09T04:01:00Z

Dmitry Dzhagarov: /* Epigenetic clocks and aging */

{{DISPLAYTITLE:Epigenetic clocks}}

Epigenetic clocks are based on an individuals's DNA methylation (DNAm) status, referred to as ''DNAm age'' or ''epigenetic age''. They can be used to estimate chronological age and might potentially measure some aspects of [[biological age]]. Some studies argue that epigenetic clocks can predict all-cause mortality better than chronological age and other traditional risk factors.<ref name=":22">[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref> However, there is currently no definitive evidence that epigenetic clocks can predict remaining lifespan and future health status at the individual level (but can be useful at the population level).

It is worth noting that epigenetic clocks have not offered a causal explanation of aging. They represent a tool to measure biological age status and, in a way, they show us what we already knew: there is a change in tissue composition over time across different cell types, with cells accumulating a number of [[Hallmarks of Aging|hallmarks of aging]], specially “inflammaging”.<ref name=":32">Horvath, S. (2013). DNA methylation age of human tissues and cell types. ''Genome Biology'', ''14''(10), 3156. https://doi.org/10.1186/gb-2013-14-10-r115</ref><ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref> Nonetheless, epigenetic clocks might be useful in providing a solid framework to test rejuvenating interventions, such as [[epigenetic reprogramming]].<ref>Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., & Wang, C. et al. (2020). Reprogramming to recover youthful epigenetic information and restore vision. ''Nature'', ''588''(7836), 124-129. doi: 10.1038/s41586-020-2975-4</ref>

A variety of other aging clocks exist based on parameters other than the methylation status. These include transcriptomics clocks,<ref>Holzscheck, N., Falckenhayn, C., Söhle, J., Kristof, B., Siegner, R., & Werner, A. et al. (2021). Modeling transcriptomic age using knowledge-primed artificial neural networks. ''Npj Aging And Mechanisms Of Disease'', ''7''(1). doi: 10.1038/s41514-021-00068-5</ref><ref>Mamoshina, P., Volosnikova, M., Ozerov, I., Putin, E., Skibina, E., Cortese, F., & Zhavoronkov, A. (2018). Machine Learning on Human Muscle Transcriptomic Data for Biomarker Discovery and Tissue-Specific Drug Target Identification. ''Frontiers In Genetics'', ''9''. doi: 10.3389/fgene.2018.00242</ref> glycation clocks,<ref>Severin, F., Feniouk, B., & Skulachev, V. (2013). Advanced glycation of cellular proteins as a possible basic component of the “master biological clock”. ''Biochemistry (Moscow)'', ''78''(9), 1043-1047. doi: 10.1134/s0006297913090101</ref> telomere clocks,<ref>Harley, C. (1991). Telomere loss: mitotic clock or genetic time bomb?. ''Mutation Research/Dnaging'', ''256''(2-6), 271-282. doi: 10.1016/0921-8734(91)90018-7</ref> microbiome clocks,<ref>Galkin, F., Mamoshina, P., Aliper, A., Putin, E., Moskalev, V., Gladyshev, V., & Zhavoronkov, A. (2020). Human Gut Microbiome Aging Clock Based on Taxonomic Profiling and Deep Learning. ''Iscience'', ''23''(6), 101199. doi: 10.1016/j.isci.2020.101199</ref><ref>Gopu, V., Cai, Y., Krishnan, S., Rajagopal, S., Camacho, F., & Toma, R. et al. (2020). An accurate aging clock developed from the largest dataset of microbial and human gene expression reveals molecular mechanisms of aging. doi: 10.1101/2020.09.17.301887</ref> or more recently the DNAm PhenoAge,<ref>Levine, M., Lu, A., Quach, A., Chen, B., Assimes, T., & Bandinelli, S. et al. (2018). An epigenetic biomarker of aging for lifespan and healthspan. ''Aging'', ''10''(4), 573-591. doi: 10.18632/aging.101414</ref> which combines epigenetic clocks with several measurements of functional performance.
== General purpose of epigenetic clocks ==
People vary significantly in how they age, with various factors leading to accelerated aging. Some examples include depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref name=":2">[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]]</ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.]</ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]]</ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref> By measuring biological age, researchers could identify people who exhibit accelerated aging or vice versa slow aging.<ref>Dec, E., Clement, J., Cheng, K., Church, G. M., Fossel, M. B., Rehkopf, D. H., ... & Horvath, S. (2023). Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity. GeroScience, 1-19. PMID: 36964402 DOI: 10.1007/s11357-023-00731-7</ref><ref>Daunay, A., Hardy, L., Bouyacoub, Y., Sahbatou, M., Touvier, M., Blanché, H., ... & How-Kit, A. (2022). Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites. Aging, 14(19), 7718-7733. PMID: 36202132 PMC9596211 DOI: 10.18632/aging.204316</ref> This would determine who might benefit the most from an anti-aging drug, and perhaps be used as a surrogate marker for more quickly identifying if an aging intervention slows or even reverses aging.<ref>Ferrucci, L., Gonzalez-Freire, M., Fabbri, E., Simonsick, E., Tanaka, T., Moore, Z., Salimi, S., Sierra, F., & Cabo, R. de. (2020). Measuring biological aging in humans: A quest. ''Aging Cell'', ''19''(2), e13080. https://doi.org/https://doi.org/10.1111/acel.13080</ref>

Quantifying biological age is considered important for longevity research, as running clinical trials over several decades to show whether human life has been extended is unrealistic. Instead, it might be more practical to use biological aging clocks to predict if a therapy is likely to extend healthspan and lifespan within a shorter timeframe.

== Mechanism ==
The epigenetic clock works by measuring DNA methylation levels, i.e., the number and distribution of methyl groups attached to the DNA molecule. These ‘tags’ signal genes to be turned on or off.

Epigenetic clocks appear to measure a universal feature of aging across species. The same algorithm, based on the same set of biomarkers (DNAm) has been shown to strongly predict chronological age in hundreds of animals, including mice, bats, and humans. Notably, the residual or unexplained variance of epigenetic clocks (such as GrimAge) for prediction of chronological age appears to further capture biological age.<ref name=":0">Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., Hou, L., Baccarelli, A. A., Li, Y., Stewart, J. D., Whitsel, E. A., Assimes, T. L., Ferrucci, L., & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. ''Aging'', ''11''(2), 303–327. https://doi.org/10.18632/aging.101684</ref> For GrimAge, this aspect is referred to as AgeAccelGrim, where the regression of DNA GrimAge on chronological age predicts whether biological age is greater or lesser than chronological age.<ref name=":0" /> In other words, epigenetic clocks accurately predict one's age based on various DNAm biomarkers, but the error in prediction reflects the differences in rates of biological aging between individuals.

[[wikipedia:DNA_methylation|DNA methylation]] is the attachment of a methyl group to one of the “links” in the DNA strain (specifically, cytosine nucleotide). This does not affect the content of the DNA itself, but it does affect how it is read and used by the cell. This is one of the group of changes called epigenetics – changes in the organism's physical function which do not alter the DNA sequence itself, but can be inherited under certain conditions.

There have been a number of studies showing that as humans (and other mammals) age, patterns of methylation in their DNA change in certain ways.<ref>Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E., & Ryan, J. (2019). The epigenetic clock as a predictor of disease and mortality risk: A systematic review and meta-analysis. ''Clinical Epigenetics'', ''11''(1), 62. https://doi.org/10.1186/s13148-019-0656-7</ref> The exact patterns of change are quite complex and not yet fully described, but broadly, two tendencies have been detected. First, the global level of methylation decreases, unequally in different tissues (for example, in mice, methylation levels decreased in the brain, heart, and spleen, but not in the lungs or liver). Secondly, the local methylation levels increase in certain locations: CpG islands (regions on a DNA strain where the sequence cytosine-guanine occurs with high frequency) and bivalent chromatin domain promoters (a promoter is a DNA sequence which initiates the transcription of the gene following it).

These changes can be used to estimate the biological age of the organism, and there are a [[wikipedia:Epigenetic_clock#Other_age_estimators_based_on_DNA_methylation_levels|number of approaches]] to achieving this measurement, the most common being the Horvath’s clock, developed by Horvath et al. in 2013.<ref>Bocklandt, S., Lin, W., Sehl, M. E., Sánchez, F. J., Sinsheimer, J. S., Horvath, S., & Vilain, E. (2011). Epigenetic predictor of age. ''PLOS ONE'', ''6''(6), e14821. https://doi.org/10.1371/journal.pone.0014821</ref> They used publicly available datasets of methylation data collected on [[wikipedia:Illumina,_Inc.|Illumina]] chips, and analyzed 21,369 CpG sites available on both 27k and 450k chips (the number referring to the total number of sites that the chip analyzes). The team then used a penalized regression model (elastic net regularization, which is essentially a linear combination of lasso and ridge regularization penalties, which thus drives the model to have both smaller coefficients and fewer of them) to identify 353 sites providing the most signals, of which 193 correlated with age positively, and the remaining 160 negatively. The clock then applies a calibration function to the weighted average of these 353 sites methylation levels to determine the biological age.

=== Methylation marker genes associated with aging ===
Regarding the definition of the markers, many candidate loci have been proposed, such as ELOVL2 (cg16867657),<ref>Manco, L., & Dias, H. C. (2022). DNA methylation analysis of ELOVL2 gene using droplet digital PCR for age estimation purposes. Forensic Science International, 333, 111206. PMID 35131731 doi:10.1016/j.forsciint.2022.111206</ref> EDARADD,<ref>Ni, X. L., Yuan, H. P., Jiao, J., Wang, Z. P., Su, H. B., Lyu, Y., ... & Yang, Z. (2022). An epigenetic clock model for assessing the human biological age of healthy aging. Zhonghua yi xue za zhi, 102(2), 119-124. PMID 35012300 doi:10.3760/cma.j.cn112137-20210817-01862</ref><ref>Daunay, A., Hardy, L. M., Bouyacoub, Y., Sahbatou, M., Touvier, M., Blanché, H., ... & How-Kit, A. (2022). Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites. Aging, 14(19), 7718—7733. PMID 36202132 doi:10.18632/aging.204316</ref> C1orf132 (cg10501210),<ref>Spólnicka, M., Pośpiech, E., Pepłońska, B., Zbieć-Piekarska, R., Makowska, Ż., Pięta, A., ... & Branicki, W. (2018). DNA methylation in ELOVL2 and C1orf132 correctly predicted chronological age of individuals from three disease groups. International journal of legal medicine, 132(1), 1-11. PMID 28725932 PMC 5748441 doi:10.1007/s00414-017-1636-0</ref> TRIM59, FHL2, KLF14, PDE4C, FHL2 (cg22454769), OTUD7A (cg04875128), CCDC102B (cg19283806),<ref>Fleckhaus, J., & Schneider, P. M. (2020). Novel multiplex strategy for DNA methylation-based age prediction from small amounts of DNA via Pyrosequencing. Forensic Science International: Genetics, 44, 102189. PMID: 31648151 DOI: 10.1016/j.fsigen.2019.102189</ref> ASPA, and PENK.<ref>Fan, H., Xie, Q., Zhang, Z., Wang, J., Chen, X., & Qiu, P. (2022). Chronological age prediction: developmental evaluation of DNA methylation-based machine learning models. Frontiers in Bioengineering and Biotechnology, 9, 1462. PMID: 35141217 PMCID: PMC8819006 DOI: 10.3389/fbioe.2021.819991</ref><ref>Varshavsky, M., Harari, G., Glaser, B., Dor, Y., Shemer, R., & Kaplan, T. (2023). Accurate age prediction from blood using of small set of DNA methylation sites and a cohort-based machine learning algorithm. bioRxiv, 2023-01. https://doi.org/10.1101/2023.01.20.524874</ref><ref>Jung, S. E., Lim, S. M., Hong, S. R., Lee, E. H., Shin, K. J., & Lee, H. Y. (2019). DNA methylation of the ELOVL2, FHL2, KLF14, C1orf132/MIR29B2C, and TRIM59 genes for age prediction from blood, saliva, and buccal swab samples. Forensic Science International: Genetics, 38, 1-8. PMID: 30300865 DOI: 10.1016/j.fsigen.2018.09.010</ref>

==== ELOVL2 ====
Elongase of very long chain fatty acids 2 (ELOVL2) represents a robust candidate gene as (i) its epigenetic variability is highly correlated with age predictions, (ii) it is included in most current age prediction models, and (iii) it does not show tissue-specificity, as observed for most of the epigenetic markers identified so far.<ref>Slieker, R. C., Relton, C. L., Gaunt, T. R., Slagboom, P. E., & Heijmans, B. T. (2018). Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception. Epigenetics & chromatin, 11, 1-11. PMID: 29848354 PMCID: PMC5975493 DOI: 10.1186/s13072-018-0191-3</ref><ref>Paparazzo, E., Lagani, V., Geracitano, S., Citrigno, L., Aceto, M. A., Malvaso, A., ... & Montesanto, A. (2023). An ELOVL2-Based Epigenetic Clock for Forensic Age Prediction: A Systematic Review. International Journal of Molecular Sciences, 24(3), 2254. PMID: 36768576 PMCID: PMC9916975 DOI: 10.3390/ijms24032254</ref><ref>Sukawutthiya, P., Sathirapatya, T., & Vongpaisarnsin, K. (2021). A minimal number CpGs of ELOVL2 gene for a chronological age estimation using pyrosequencing. Forensic Science International, 318, 110631. PMID: 33279766 DOI: 10.1016/j.forsciint.2020.110631</ref>
Functionally, Elovl2 plays an irreplaceable role in the synthesis of poly unsaturated fatty acids (PUFA)s, which are critical for a range of biological processes. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum (ER) stress and mitochondrial dysfunction, leading to key aging phenotypes at both cellular and physiological level. Elovl2 deficiency induced a switch in metabolism from the tri-carboxylic acid cycle to glycolysis, an effect which produces more reactive oxidative species (ROS), causes oxidative stress in cells, tissues, and organs, and also act as a messenger for inflammatory responses. In addition, PUFAs are essential in the resolution of inflammation. In addition to that, there was a dramatic accumulation of fatty acids upon Elovl2 knockout, including arachidonic acid. As accumulation of arachidonic acid might also contribute to inflammation for its being used for Prostaglandin E2 (PGE2) generation, PGE2 may be involved in inflammation upon Elovl2 knockout.<ref>Li, X., Wang, J., Wang, L., Gao, Y., Feng, G., Li, G., ... & Zhang, K. (2022). Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging. Signal Transduction and Targeted Therapy, 7(1), 162. PMID: 35610223 PMC9130224 DOI: 10.1038/s41392-022-00964-6</ref> The accumulation of free fatty acids in the ER would damage ER function, resulting in an increased incidence of unfolded or misfolded protein load and chronic ER stress.<ref>Siddiqui, A. J., Jahan, S., Chaturvedi, S., Siddiqui, M. A., Alshahrani, M. M., Abdelgadir, A., ... & Adnan, M. (2023). Therapeutic Role of ELOVL in Neurological Diseases. ACS omega. 8(11), 9764–9774 PMID: 36969404 PMC10034982 DOI: 10.1021/acsomega.3c00056</ref>

== Discovery ==
Changes in methylation levels with aging have been observed for some time.<ref>Romanov, G. A., & Vaniushin, B. F. (1980). Intragenomic specificity of DNA methylation in animals. Qualitative differences in tissues and '''changes in methylation of repeating sequences during aging''', carcinogenesis and hormonal induction. [Article in Russian]. Molekuliarnaia Biologiia, 14(2), 357-368. PMID: 7383031</ref> The first work using epigenetic changes as a basis for biological clocks was published in 2009 by Schumacher.<ref>Schumacher, A. (2009). ''An epigenetic clock: Anticorrelation & DNA methylation as biomarker for aging.'' https://doi.org/10.13140/RG.2.2.12457.83042</ref> In 2013, the labs of Trey Ideker and Kang Zhang at the University of California, San Diego published the Hannum epigenetic clock, which consisted of 71 markers which accurately estimate age based on blood methylation levels.<ref>Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.-B., Gao, Y., Deconde, R., Chen, M., Rajapakse, I., Friend, S., Ideker, T., & Zhang, K. (2013). Genome-wide methylation profiles reveal quantitative views of human aging rates. ''Molecular Cell'', ''49''(2), 359–367. https://doi.org/10.1016/j.molcel.2012.10.016</ref> In the same year, the first multi-tissue epigenetic clock was developed by Steve Horvath, a professor of human genetics and of biostatistics at UCLA.<ref name=":3">Horvath, S. (2013). DNA methylation age of human tissues and cell types. ''Genome Biology'', ''14''(10), 3156. https://doi.org/10.1186/gb-2013-14-10-r115</ref> Horvath’s clock allows the measurement of the age of different tissues of the same organism with the same clock, so it is the most widely used in aging research today.

== Epigenetic clocks and aging ==

=== Retroelement-based epigenetic clocks ===
Emerging evidence suggests a correlation between aging, chronic diseases, and the reactivation of specific retroelements, primarily LINEs and HERV-K-derived retrovirus like particles (RVLPs). These findings highlight the potential of DNA methylation states of specific retroelements as reliable predictors of chronical and potentially biological aging, complementing existing epigenetic clocks and offering an additional mechanism to consider in epigenetic clock signals. This permits the construction of retroelement-based epigenetic clocks to support the hypothesis of dysregulation of endogenous retroelements as a potential contributor to the biological hallmarks of aging and suggest that therapeutic interventions modifying the epigenetic states of specific retroelements in the human genome could have beneficial effects against a root cause of aging and disease.<ref>Ndhlovu, L. C., Bendall, M. L., Dwaraka, V., Pang, A. P., Dopkins, N., Carreras, N., ... & Corley, M. J. (2024). Retro‐age: A unique epigenetic biomarker of aging captured by DNA methylation states of retroelements. Aging Cell, e14288. https://doi.org/10.1111/acel.14288</ref><ref>Ndhlovu, L. C., Bendall, M. L., Dwaraka, V., Pang, A. P., Dopkins, N., Carreras, N., ... & Corley, M. J. (2023). Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states. bioRxiv. PMID: 38106164 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10723416/ PMC10723416] DOI: 10.1101/2023.12.06.570422</ref>

It is not yet known whether epigenetic changes are a cause or consequence of other biological aging mechanisms. Epigenetic clocks have been used in some clinical trials of longevity drugs in an attempt to measure biological age. However, to enable its use as a surrogate marker, validation of various epigenetic clocks will require large-scale randomized clinical trials.

Several theories have been proposed, and are discussed below:

=== Link with Hallmarks of Aging ===
There is evidence that changed methylation patterns can be linked to some of the [[Hallmarks of Aging|hallmarks of aging]]: loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and immunosenescence.<ref>Jiang, S., & Guo, Y. (2020, July 8). ''Epigenetic clock: DNA methylation in aging'' [Review Article]. Stem Cells International. https://doi.org/https://doi.org/10.1155/2020/1047896</ref> Lu, Yuancheng, et al. were able to reverse age-induced loss of sight from glaucoma, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1">Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M. S., Yang, J.-H., Zhou, S., Hoffmann, E. M., Karg, M. M., Schultz, M. B., Kane, A. E., Davidsohn, N., Korobkina, E., Chwalek, K., … Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. ''Nature'', ''588''(7836), 124–129. https://doi.org/10.1038/s41586-020-2975-4</ref> They used three out of the four so-called 'Yamanaka factors', which are proteins necessary for reprogramming adult somatic cells back to pluripotent stem cells. Using the factors in live organisms for prolonged periods of time is known to cause cancer by boosting up cell division. But, with the exclusion of one of these factors (c-Myc), that is known to be oncogenic. The other three factors were kept active in mice for over a year without inducing any tumors.

The induction of these factors allowed the mice to regrow a mechanically damaged optic nerve. Normally, a mouse's optic nerve can regrow during early development, but then loses this ability a few days after birth. In this experiment, adult mice were able to re-obtain a similar regenerative ability and regained around half of their lost visual acuity.

Another result achieved using the Yamanaka factors was the restoration of the vision of healthy, middle-aged (one-year-old) mice. Before treatment, these mice scored worse than the younger mice on tests of visual acuity, but one month after treatment, they had similar results

=== Information Theory of Aging ===
Another theory, popularised by Professor David Sinclair, is that epigenetic changes might be the master regulator of aging - known as [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/ the information theory of aging].

Since DNA is identical in every somatic cell, each cell needs to “know” which genes to read in order to differentiate itself from a stem cell and perform its function. For example, a neuron cell only expresses (i.e. uses) genes relevant for being a neuron, and not a muscle cell or a skin cell. This is achieved through methylation and other epigenetic mechanisms.

The theory goes that aging is fundamentally caused by the accumulation of the effects of errors in this process, eventually causing a cell to stop functioning normally and either become cancerous or die.

== Relevance for longevity research ==
For discussion see Fig. 2 from.<ref>Noroozi, R., Rudnicka, J., Pisarek, A., Wysocka, B., Masny, A., Boroń, M., ... & Pośpiech, E. (2024). Analysis of epigenetic clocks links yoga, sleep, education, reduced meat intake, coffee, and a SOCS2 gene variant to slower epigenetic aging. GeroScience, 46(2), 2583-2604. PMID: 38103096 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10828238/ PMC10828238] DOI: 10.1007/s11357-023-01029-4</ref>
=== Smoking ===
Research shows that smoking increases epigenetic age of buccal cells, airway cells, esophagus tissue, and lung tissue. Quitting smoking causes the epigenetic age acceleration in airway cells (but not in lung tissue) to revert to the level of non-smokers.<ref>Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. ''Clinical Epigenetics'', ''11''(1), 183. https://doi.org/10.1186/s13148-019-0777-z</ref>

=== Obesity ===
Obesity (defined as increased BMI) has been shown to correlate with increased epigenetic age in a number of tissues. For liver tissue, one study found an average increase of approximately 2.2 years of epigenetic age for each 10 BMI units.<ref>Horvath, S., Erhart, W., Brosch, M., Ammerpohl, O., von Schönfels, W., Ahrens, M., Heits, N., Bell, J. T., Tsai, P.-C., Spector, T. D., Deloukas, P., Siebert, R., Sipos, B., Becker, T., Röcken, C., Schafmayer, C., & Hampe, J. (2014). Obesity accelerates epigenetic aging of human liver. ''Proceedings of the National Academy of Sciences'', ''111''(43), 15538–15543. https://doi.org/10.1073/pnas.1412759111</ref> There was no correlation for blood cells, however. Another study found an increase of approximately 2.3 years per 10 BMI points for visceral adipose tissue (visceral fat).<ref>de Toro-Martín, J., Guénard, F., Tchernof, A., Hould, F.-S., Lebel, S., Julien, F., Marceau, S., & Vohl, M.-C. (2019). Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity. ''Clinical Epigenetics'', ''11''(1), 172. https://doi.org/10.1186/s13148-019-0754-6</ref>

=== Depression ===
Major depressive disorder (MDD) was also found to be associated with increased epigenetic age. One study found increased epigenetic age in blood cells associated with symptoms of MDD and childhood trauma scores.<ref>Han, L. K. M., Aghajani, M., Clark, S. L., Chan, R. F., Hattab, M. W., Shabalin, A. A., Zhao, M., Kumar, G., Xie, L. Y., Jansen, R., Milaneschi, Y., Dean, B., Aberg, K. A., van den Oord, E. J. C. G., & Penninx, B. W. J. H. (2018). Epigenetic aging in major depressive disorder. ''American Journal of Psychiatry'', ''175''(8), 774–782. https://doi.org/10.1176/appi.ajp.2018.17060595</ref> They also analyzed brain cells (collected post mortem) and found that increased epigenetic age correlated with MDD symptoms.

=== Centenarians ===
Those who live past the age of 100 have reduced DNAm levels, with a pattern of methylation that appears to correlate less in neighboring [[wikipedia:CpG_site|cytosine-phosphate-guanine (CpG) sites]] of the DNA of newborns, which were more homogenous.<ref>Heyn, H., Li, N., Ferreira, H. J., Moran, S., Pisano, D. G., Gomez, A., Diez, J., Sanchez-Mut, J. V., Setien, F., Carmona, F. J., Puca, A. A., Sayols, S., Pujana, M. A., Serra-Musach, J., Iglesias-Platas, I., Formiga, F., Fernandez, A. F., Fraga, M. F., Heath, S. C., … Esteller, M. (2012). Distinct DNA methylomes of newborns and centenarians. ''Proceedings of the National Academy of Sciences'', ''109''(26), 10522–10527. https://doi.org/10.1073/pnas.1120658109</ref>

=== Partial epigenetic reprogramming ===
YuanCheng Lu and colleagues were able to reverse loss of sight in age-related and glaucoma induced retinal ganglion cell loss, and even regenerate a mechanically damaged eye nerve. This was achieved by manipulating methylation patterns in mice, using partial epigenetic reprogramming delivered via viral gene therapy.<ref name=":1" /> Epigenetic clocks in this study demonstrated an apparent reversal of epigenetic age in mice treated with epigenetic reprogramming.<ref name=":1" />

== Other uses ==
[[File:CAGE.jpg|thumb|Predictors (cAge, ZhangAge, HannumAge, and HorvathAge) performance in the GSE55763 dataset in accordance with Bernabeu et al. 2022.<ref>Bernabeu, E., McCartney, D. L., Gadd, D. A., Hillary, R. F., Lu, A. T., Murphy, L., ... & Marioni, R. E. (2023). Refining epigenetic prediction of chronological and biological age. Genome Med 15, 12 https://doi.org/10.1186/s13073-023-01161-y</ref> Pearson correlation (r), root mean squared error (RMSE), and median absolute error (MAE)]]
Epigenetic clock also has many other [[wikipedia:Epigenetic_clock#Motivation_for_biological_clocks|applications]]:

* Testing the validity of various theories of biological aging
* Diagnosing various age related diseases and for defining cancer subtypes
* Predicting/prognosticating the onset of various diseases
* Serving as surrogate markers for evaluating therapeutic interventions including rejuvenation approaches,
* Studying developmental biology and cell differentiation
* Forensic applications, e.g. to estimate the age of a suspect based on blood left at a crime scene

== References ==
<references />
{{DEFAULTSORT:Epigenetic_clocks}}
[[Category:Main list]]
[[Category:Longevity concepts]]

Resveratrol

2024-08-07T18:16:28Z

Dmitry Dzhagarov: /* Derivatives of resveratrol and drug development attempts */

[[File:Resveratrol.png|thumb|200x200px|The chemical structure of trans-resveratrol.]]
Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a compound produced naturally by various plants in response to injury or microbial infection. Its main dietary sources include grapes, blueberry, cranberry, peanuts, and legumes.<ref>Tian, B., & Liu, J. (2020). Resveratrol: A review of plant sources, synthesis, stability, modification and food application. ''Journal of the Science of Food and Agriculture'', ''100''(4), 1392-1404. https://doi.org/10.1002/jsfa.10152</ref> Resveratrol has gained widespread attention, in part due to reports of its lifespan extension properties in a range of model organisms.<ref>Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1852''(6), 1209-1218. https://doi.org/10.1016/j.bbadis.2015.01.012</ref> However, there has also been significant controversy and criticism.<ref name=":6">Kaeberlein, M. (2010). Resveratrol and rapamycin: are they anti‐aging drugs?. ''Bioessays'', ''32''(2), 96-99.</ref> Resveratrol is currently considered a dietary supplement and is not an approved medicine.

As of today, resveratrol is known to have widespread effects in physiology but is not considered to be a lifespan extending agent.<ref>Pearson, K., Baur, J., Lewis, K., Peshkin, L., Price, N., & Labinskyy, N. et al. (2008). Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. ''Cell Metabolism'', ''8''(2), 157-168. doi: 10.1016/j.cmet.2008.06.011</ref> Additionally, despite years of widespread misinformation resveratrol has been debunked as a specific ''in vivo'' activator of the [[Sirtuins|sirtuin]] protein SIR2.<ref name=":7">Beher, D., Wu, J., Cumine, S., Kim, K., Lu, S., Atangan, L., & Wang, M. (2009). Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity. ''Chemical Biology &Amp; Drug Design'', ''74''(6), 619-624. doi: 10.1111/j.1747-0285.2009.00901.x</ref><ref name=":8">Pacholec, M., Bleasdale, J., Chrunyk, B., Cunningham, D., Flynn, D., & Garofalo, R. et al. (2010). SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1. ''Journal Of Biological Chemistry'', ''285''(11), [tel:8340-8351 8340-8351]. doi: 10.1074/jbc.m109.088682</ref>

== Evidence of lifespan extension ==
Resveratrol has been shown to extend healthy lifespan in yeast, worms, fruit flies, bees, and fish by 10-70% <ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196. https://doi.org/10.1038/nature01960</ref><ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689. https://doi.org/10.1038/nature02789</ref><ref>Rascón, B., Hubbard, B. P., Sinclair, D. A., & Amdam, G. V. (2012). The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. ''Aging (Albany NY)'', ''4''(7), 499. https://doi.org/10.18632/aging.100474</ref><ref>Valenzano, D. R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., & Cellerino, A. (2006). Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. ''Current biology'', ''16''(3), 296-300. https://doi.org/10.1016/j.cub.2005.12.038</ref><ref>Yu, X., & Li, G. (2012). Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. ''Experimental gerontology'', ''47''(12), 940-949. https://doi.org/10.1016/j.exger.2012.08.009</ref> In mice on a high-calorie diet, resveratrol reduced the risk of death from the diet by 31%.<ref>Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., ... & Sinclair, D. A. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. ''Nature'', ''444''(7117), 337-342. https://dx.doi.org/10.1038/nature05354</ref> However, many of these studies come from Sinclair's lab, which in the past had conflicting monetary interests given he was the founder of the company Sirtris Pharmaceuticals, a biotechnology company focused on using resveratrol and other potential [[Sirtuins|sirtuin]] activators to extend human lifespan.<ref>https://www.sec.gov/Archives/edgar/data/1388775/000104746907001505/a2176355zs-1.htm</ref>

Independent laboratories demonstrated there is no lifespan extension in healthy mice and rats.<ref>Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., ... & de Cabo, R. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. ''Cell metabolism'', ''8''(2), 157-168. https://doi.org/10.1016/j.cmet.2008.06.011</ref><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., De Cabo, R., ... & Strong, R. (2011). Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. ''The Journals of Gerontology: Series A'', ''66''(2), 191-201. https://doi.org/10.1093/gerona/glq178</ref><ref>Strong, R., Miller, R. A., Astle, C. M., Baur, J. A., De Cabo, R., Fernandez, E., ... & Harrison, D. E. (2013). Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''68''(1), 6-16. https://dx.doi.org/10.1093/gerona/gls070</ref><ref name=":4">da Luz, P. L., Tanaka, L., Brum, P. C., Dourado, P. M. M., Favarato, D., Krieger, J. E., & Laurindo, F. R. M. (2012). Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. ''Atherosclerosis'', ''224''(1), 136-142. https://doi.org/10.1016/j.atherosclerosis.2012.06.007</ref> Resveratrol has been shown to delay aspects of vascular aging in rodents, improving aging-impaired cognitive function.<ref name=":4" /><ref>Gocmez, S. S., Gacar, N., Utkan, T., Gacar, G., Scarpace, P. J., & Tumer, N. (2016). Protective effects of resveratrol on aging-induced cognitive impairment in rats. ''Neurobiology of learning and memory'', ''131'', 131-136. https://doi.org/10.1016/j.nlm.2016.03.022</ref> However given the lack of evidence of resveratrol to extend lifespan in rodent models, it does not appear likely to produce meaningful benefit for human aging.

Currently, it is unclear whether resveratrol will exert meaningful biological effects in humans.<ref name=":6" /> This is an ongoing area of research, but evidence for human lifespan extension will need to be shown in large, randomized controlled trials.

== Human clinical trials ==
A range of clinical trials investigating the health benefits of resveratrol supplementation has been performed, some carrying conflicting results.<ref name=":0" /><ref name=":1" /> Resveratrol has been shown to improve glucose control and insulin sensitivity in persons with type 2 diabetes, and modulate some cancer-related genes.<ref>Liu, K., Zhou, R., Wang, B., & Mi, M. T. (2014). Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. ''The American journal of clinical nutrition'', ''99''(6), 1510-1519. https://doi.org/10.3945/ajcn.113.082024</ref><ref>Zhu, X., Wu, C., Qiu, S., Yuan, X., & Li, L. (2017). Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: Systematic review and meta-analysis. ''Nutrition & metabolism'', ''14''(1), 1-10. https://doi.org/10.1186/s12986-017-0217-z</ref><ref>Ko, J. H., Sethi, G., Um, J. Y., Shanmugam, M. K., Arfuso, F., Kumar, A. P., ... & Ahn, K. S. (2017). The role of resveratrol in cancer therapy. ''International journal of molecular sciences'', ''18''(12), 2589. https://dx.doi.org/10.3390/ijms18122589</ref> Resveratrol supplementation in postmenopausal women (150 mg per day for 12 months) resulted in improvement of overall cognitive performance.<ref>Zaw, J. J. T., Howe, P. R., & Wong, R. H. (2020). Sustained cerebrovascular and cognitive benefits of resveratrol in postmenopausal women. ''Nutrients'', ''12''(3), 828. https://doi.org/10.3390/nu12030828</ref> The study suggested that resveratrol supplementation could potentially reverse cognitive ageing by up to 10 years.

The ¨Invecchiare in Chianti (InCHIANTI) Study¨ (literally meaning “Aging in the Chianti Region”), conducted a prospective cohort study of 783 people over the age of 65 in the Chianti region of Italy, and demonstrated that urinary concentration of resveratrol metabolite was not associated to age-related diseases nor was predictive of all-cause mortality.<ref>Semba, R., Ferrucci, L., Bartali, B., Urpí-Sarda, M., Zamora-Ros, R., & Sun, K. et al. (2014). Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults. ''JAMA Internal Medicine'', ''174''(7), 1077. doi: 10.1001/jamainternmed.2014.1582</ref> Therefore, they concluded that resveratrol had no significant influence on healthspan nor lifespan of the individuals in the study.

== Safety and bioavailability ==
It has been shown that resveratrol is generally safe in humans.<ref name=":0">Singh, A. P., Singh, R., Verma, S. S., Rai, V., Kaschula, C. H., Maiti, P., & Gupta, S. C. (2019). Health benefits of resveratrol: Evidence from clinical studies. ''Medicinal research reviews'', ''39''(5), 1851-1891. https://doi.org/10.1002/med.21565</ref><ref name=":1">Bitterman, J. L., & Chung, J. H. (2015). Metabolic effects of resveratrol: addressing the controversies. ''Cellular and Molecular Life Sciences'', ''72''(8), 1473-1488. https://doi.org/10.1007/s00018-014-1808-8</ref> Mild adverse effects such as nausea, diarrhea, and abdominal pain have been reported with doses of 1 g per day and higher.<ref>Brown, V. A., Patel, K. R., Viskaduraki, M., Crowell, J. A., Perloff, M., Booth, T. D., ... & Brenner, D. E. (2010). Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. ''Cancer research'', ''70''(22), [tel:9003-9011 9003-9011]. https://doi.org/10.1158/0008-5472.can-10-2364</ref><ref>Patel, K. R., Scott, E., Brown, V. A., Gescher, A. J., Steward, W. P., & Brown, K. (2011). Clinical trials of resveratrol. ''Annals of the New York Academy of Sciences'', ''1215''(1), 161-169. https://doi.org/10.1111/j.1749-6632.2010.05853.x</ref>

Resveratrol is quickly metabolized and is poorly absorbed in the human body, which limits its potential for clinical use in humans.<ref name=":0" />

== Mechanism ==
[[File:SIRT1.png|alt=|thumb|400x400px|'''SIRT1 is proposed to be the main molecular target through which resveratrol delivers its health benefits.''' AMPK, 5′‐AMP‐activated protein kinase; SIRT1, sirtuin type 1; PGC‐1α, peroxisome proliferator‐activated receptor‐γ coactivator 1α; eNOS, endothelial nitric oxide synthase 3; NF‐κb, nuclear factor‐κB; FOXO, forkhead box O; Nrf2, nuclear factor erythroid 2 like 2. Scheme adapted from <ref name=":2">Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1852''(6), 1209-1218. https://doi.org/10.1016/j.bbadis.2015.01.012</ref><ref name=":3">Kulkarni, S. S., & Cantó, C. (2015). The molecular targets of resveratrol. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1852''(6), 1114-1123. https://doi.org/10.1016/j.bbadis.2014.10.005</ref>]]
Resveratrol had been proposed to act via [[sirtuins]] to multiple downstream cellular targets involved in regulating aging. Silent Information Regulator 1 (SIRT1) protein was initially suggested as its main target in mammals,<ref name=":0" /> whilst SIR2 was proposed to be the main resveratrol target in yeast.<ref>Howitz, K., Bitterman, K., Cohen, H., Lamming, D., Lavu, S., & Wood, J. et al. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196. doi: 10.1038/nature01960</ref>

Resveratrol was hypothesised to induce SIRT1 either directly or through phosphorylation of AMP-activated protein kinase (AMPK). Upon induction, SIRT1 has been shown to modulate activity of molecules taking part in stimulating mitochondrial biogenesis, vasodilation, antioxidant defence, glucose and lipid homeostasis, as well as those inhibiting inflammation.<ref name=":2" /><ref name=":3" /> Alternative modes of action for resveratrol have been suggested, such as introduction of replicative stress in the cell.<ref name=":5">Benslimane, Y., Bertomeu, T., Coulombe-Huntington, J., McQuaid, M., Sánchez-Osuna, M., Papadopoli, D., ... & Harrington, L. (2020). Genome-wide screens reveal that resveratrol induces replicative stress in human cells. ''Molecular Cell'', ''79''(5), 846-856. https://doi.org/10.1016/j.molcel.2020.07.010</ref>

Whether resveratrol directly activates SIRT1 is controversial, with a number of studies failing to observe activation or interaction between the two molecules. <ref name=":7" /><ref name=":8" /> It is now generally considered that resveratrol does not activate sirtuins ''in vivo.'' Studies ''in vitro'' had apparently used a modified peptide on resveratrol which changed its conformation and allowed it to bind SIR2 and SIRT1.<ref name=":7" />

This story is somewhat reminiscent of experiments in which [[sirtuins]] had been reported to extend lifespan in C. ''elegans'' by 50%''.''<ref>Tissenbaum, H., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. ''Nature'', ''410''(6825), 227-230. doi: 10.1038/35065638</ref> When independent scientists failed to recapitulate such findings, it came to light that the original experiments had been performed in an animal with a sensory neuronal background mutation previously linked to longevity, whilst it had no sifnificant effect in wild-type strains.<ref>Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., & Piper, M. et al. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. ''Nature'', ''477''(7365), 482-485. doi: 10.1038/nature10296</ref> Therefore sirtuins have similarly been debunked as longevity genes.

== Derivatives of resveratrol and drug development attempts ==
In 2004 a company called Sirtris Pharmaceuticals, Inc. was conceived to study potential of resveratrol as a drug for type 2 diabetes, cancer, and other diseases. The company's initial product was called SRT501, and was a formulation of reservatrol. In 2008 Sirtris was purchased by the pharma giant GlaxoSmithKline (GSK).<ref>http://blogs.nature.com/news/2013/03/gsk-absorbs-controversial-longevity-company.html</ref> Further development of SRT501 were terminated in 2010, in part due to its side effects and lack of specificity to SIRT1, followed by shutdown of Sirtis in 2013. <ref>Popat, R., Plesner, T., Davies, F., Cook, G., Cook, M., Elliott, P., ... & Cavenagh, J. (2012). A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. ''British journal of haematology'', ''160''(5), 714-717. https://doi.org/10.1111/bjh.12154 </ref>

== Resveratrol Discussion - Is It Really Good For You? ==
Since ancient times, red wine has been prescribed by all doctors as a means of strengthening the body and promoting longevity. Flavonoids from wine and purple berries, as well as purple sweet potatoes, have been repeatedly shown to have beneficial effects. Similarly, the positive effects of niacin in the elderly have been repeatedly confirmed. But is this related to resveratrol?<ref>[https://youtu.be/Xn0EJQPyxkA?si=w5SS2Hdn-dxGBasF The David Sinclair $720,000,000 Train Wreck!]</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Drugs]]

Aging-related epigenetic changes

2024-08-07T16:34:52Z

Dmitry Dzhagarov: /* Aging-related epigenetic changes, their impacts on gene expression, and the functional consequences thereof */

Epigenetics, a rapidly evolving field, refers to the study of modifications to gene expression that does not alter the DNA sequence. Epigenetic dysregulation is both a hallmark and a driver of aging and restoring epigenetic integrity can reverse aging phenotypes.<ref>Pereira, B., Correia, F. P., Alves, I. A., Costa, M., Gameiro, M., Martins, A. P., & Saraiva, J. A. (2024). Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity. Ageing Research Reviews, 102204. PMID: 38272265 [https://doi.org/10.1016/j.arr.2024.102204 DOI: 10.1016/j.arr.2024.102204]</ref>
== Aging-related epigenetic changes, their impacts on gene expression, and the functional consequences thereof ==
(According to Wu et al., 2024<ref>Wu, Z., Zhang, W., Qu, J., & Liu, G. H. (2024). Emerging epigenetic insights into aging mechanisms and interventions. Trends in Pharmacological Sciences. PMID: 38216430 [https://doi.org/10.1016/j.tips.2023.12.002 DOI: 10.1016/j.tips.2023.12.002]</ref>)
{| class="wikitable"
|+ Abbreviations: Aβ, amyloid β; APP, amyloid precursor protein; BACE1, beta-site APP cleaving enzyme 1; cGAS, cyclic GMP-AMP synthase; CYP1B1, cytochrome P450 family 1 subfamily B member 1; ERK, extracellular signal-regulated kinase; ERV, endogenous retrovirus; FASN, fatty acid synthase; IFN, interferon; LAD, lamina-associated domain; LINE-1, long-interspersed element-1; MAPK, mitogen-activated protein kinase; MMP13, matrix metalloproteinase 13; MSC, mesenchymal stem cell; OA, osteoarthritis; PSG, pregnancy-specific beta-1 glycoprotein; SASP, senescence-associated secretory phenotype; STING, stimulator of interferon genes.
|-
! '''Epigenetic change''' !! Gene expression!! Functional consequence !! Refs
|-
| || || ||
|-
| Decreased DNA 5mC || Upregulated ''CDKN2A'' (p16) || Accelerated senescence of human cancer cells || <ref>Wang L.
et al.
Exploiting senescence for the treatment of cancer.
Nat. Rev. Cancer. 2022; 22: 340-355</ref>
|-
| || Upregulated APP and BACE1 ||Increased Aβ production in human neuroblastoma cells || <ref>Wu Z.
et al.
Stress, epigenetics, and aging: unraveling the intricate crosstalk.
Mol. Cell. 2023; 84: 34-54</ref>
|-
| || || ||
|-
| Decreased DNA 5mC and H3K9me3, increased H3K36me3 || Upregulated endogenous retrovirus (ERV) || Accelerated human MSC senescence || <ref>Liu X. et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell. 2023; 186: 287-304</ref>
|-
| || || ||
|-
| Decreased DNA 5mC, H3K9me3 and H4K20me3, increased H3K27ac and H3K4me1 || Upregulated PSG genes || Accelerated human MSC senescence || <ref>Liu Z.
et al.
Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging.
Dev. Cell. 2022; 57: 1347-1368</ref>
|-
| || || ||
|-
| Decreased H3K9 and H3K36 methylation || Upregulated SASP factors, p16, and CDKN1A (p21) || Bleomycin-induced senescence of human prostate stromal cells || <ref>Zhang B.
et al.
KDM4 orchestrates epigenomic remodeling of senescent cells and potentiates the senescence-associated secretory phenotype.
Nat. Aging. 2021; 1: 454-472</ref>
|-
| || || ||
|-
| Decreased H3K9me3 and H3K27me3 || Upregulated LINE-1 || Accelerated senescence of primary fibroblasts derived from patients with progeroid syndromes ||<ref>Della Valle F. et al. LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes. Sci. Transl. Med. 2022; 14eabl6057</ref>
|-
| || || ||
|-
| Decreased heterochromatin and LAD, increased chromatin accessibility || Upregulated LINE-1 || Accelerated human MSC senescence || <ref>Bi S.
et al.
SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer.
Protein Cell. 2020; 11: 483-504</ref>
|-
| || || ||
|-
| Decreased RNA m6A || Downregulated MIS12 || Accelerated human MSC senescence || <ref>Wu Z.
et al. METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic Acids Res. 2020; 48: 11083-11096</ref>
|-
| || Downregulated NPNT || Accelerated human myotube senescence || <ref>Wu Z. et al. m6A epitranscriptomic regulation of tissue homeostasis during primate aging. Nat. Aging. 2023; 3: 705-721</ref>
|-
| || || ||
|-
| Increased circRREB1 || Upregulated FASN, MMP13, p16, p21, and TP53 (p53) || Progression of chondrocyte senescence and OA pathogenesis in mice || <ref>Gong Z. et al. CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications. Nat. Commun. 2023; 14: 5242</ref>
|-
| || || ||
|-
| Increased DNA 5mC || Downregulated ELOVL2 || Aging of human fibroblasts || <ref>Li X. et al. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging. Signal Transduct. Target. Ther. 2022; 7: 162</ref>
|-
| || || ||
|-
| Increased DNA 6mA || Upregulated heat stress response genes || Transgenerational longevity of Caenorhabditis elegans induced by heat shock || <ref>Wan Q.L. et al. N(6)-methyldeoxyadenine and histone methylation mediate transgenerational survival advantages induced by hormetic heat stress. Sci. Adv. 2021; 7eabc3026</ref>
|-
| || || ||
|-
| Increased H3K14ac || Upregulated CDKN2B (p15) || Accelerated human MSC senescence || <ref>Wang W. et al. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence. Sci. Transl. Med. 2021; 13eabd2655</ref>
|-
| || || ||
|-
| Increased H3K27ac and H3K4me1 || Upregulated HMGB2 || Rejuvenation of senescent human MSCs and alleviation of OA in aged mice || <ref>Jing Y.
et al. Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation. Cell Stem Cell. 2023; 30: 1452-1471</ref>
|-
| || || ||
|-
| Increased H3K27ac and H3K9ac || Upregulated Aβ || Progression of AD-related degeneration || <ref>Nativio R. et al.An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease. Nat. Genet. 2020; 52: 1024-1035</ref>
|-
| || || ||
|-
| Increased H3K4me3 || Upregulated p21 || Accelerated human MSC senescence || <ref>Yan K. et al. SGF29 nuclear condensates reinforce cellular aging. Cell Discov. 2023; 9: 110</ref>
|-
| || || ||
|-
| Increased histone acetylation || Upregulated p16 and p53 || Accelerated senescence of human cancer cells || <ref>Wang L. et al. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer. 2022; 22: 340-355</ref>
|-
| || || ||
|-
| Increased miR-145 || Downregulated semaphorin-3A || Alleviation of heart aging || <ref>Wagner J.U.G.et al.Aging impairs the neurovascular interface in the heart. Science. 2023; 381: 897-906</ref>
|-
| || || ||
|-
| Increased miR-31 || Repression of CLOCK and activation of MAPK/ERK signaling || Accelerated skin aging || <ref>Yu Y.et al. A stress-induced miR-31-CLOCK-ERK pathway is a key driver and therapeutic target for skin aging. Nat. Aging. 2021; 1: 795-809</ref>
|-
| || || ||
|-
| Increased RNA m5C || Repressed cGAS-STING activity || Decreased IFN-β || <ref>Chen T. et al. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab. 2023; 35: 1782-1798</ref>
|-
| || || ||
|-
| Increased RNA m6A || Downregulated CDKN1C (p57) || Alleviated MSC senescence, improved MSC survival and angiogenesis, and enhanced cardioprotective effect against myocardial infarction in mice || <ref>Gao X. et al. Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction. FASEB J. 2023; 37e23294</ref>
|-
| || Upregulated CYP1B1 || Accelerated human MSC aging and onset of OA in mice || <ref>Ye G.et al. ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Exp. Mol. Med. 2023; 55: 1743-1756</ref>
|-
| || || ||
|-
| Increased RNA m6A and m5C || Upregulated p21 || Oxidative stress-induced senescence of human cancer cells || <ref>Li Q.
et al. NSUN2-mediated m5C methylation and METTL3/METTL14-mediated m6A methylation cooperatively enhance p21 translation. J. Cell. Biochem. 2017; 118: 2587-2598</ref>
|-
|}

== Six drivers of aging identified among genes differentially expressed with age ==
(According to '''preliminary results''' of Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller and Roberto Civitell.<ref>Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller, Roberto Civitelli (2024). Six drivers of aging identified among genes differentially expressed with age. bioRxiv 2024.08.02.606402; doi: https://doi.org/10.1101/2024.08.02.606402</ref> available under a CC-BY-NC 4.0 International license.

Therapeutic directions cannot be extrapolated from purely observational gene expression data, where drivers of aging cannot be distinguished from compensatory protective responses and irrelevant downstream effects.

The top '''age-upregulated genes''' were '''TMEM176A, EFEMP1, CP,''' and '''HLA-A''';

the top '''age-downregulated genes''' were '''CA4, SIAH, SPARC,''' and '''UQCR10'''.

* EFEMP1, also known as fibulin-3, is an extracellular matrix glycoprotein strongly associated with aging pathologies: overexpression contributes to age-related macular degeneration, high plasma levels are associated with signs of brain aging and higher risk of dementia, and upregulation of this gene is associated with Werner syndrome, a premature aging
condition.
* CP, or ceruloplasmin, is a copper-binding glycoprotein involved in iron metabolism and defense against oxidative stress; decreased CP activity is associated with advanced age and age-related diseases, such as Parkinson’s and Alzheimer’s disease

Out of 10 age-upregulated and 9 age-downregulated genes that were tested, '''six genes were with evolutionarily conserved, causal roles
in the aging process:'''

two '''age-upregulated''' genes ('''csp-3/CASP1''' and '''spch-2/RSRC1''') and

four '''age-downregulated''' genes ('''C42C1.8/DIRC2, ost-1/SPARC, fzy-1/CDC20,''' and '''cah-3/CA4''') produced significant and reproducible lifespan extension when knocked down in ''C. elegans''.

== References ==
<references />
[[Category:Main list]]
[[Category:Drafts]]
[[Category:Aging pathways and hallmarks]]

P53 protein involvement in Longevity

2024-08-07T15:18:15Z

Dmitry Dzhagarov: /* For further reading */

The p53 protein, encoded by TP53 gene, is a specific transcription factor consisting of 393 amino acids with 7 functional domains from N‐terminal to C‐terminal, transactivation domain (TAD)‐1, TAD‐2, proline‐rich domain (PRD), DNA‐binding domain (DBD), hinge domain (HD), oligomerization domain (OD), and C‐terminal regulatory domain (CTR). It is a tumor suppressor that is coded by the most often mutated gene in human cancers.<ref name="Targeting" >Shen, J., Wang, Q., Mao, Y., Gao, W., & Duan, S. (2023). Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies. MedComm, 4(3), e288. PMID: 37256211 PMCID: PMC10225743 DOI: 10.1002/mco2.288 </ref> The human gene encoding the p53 protein is called ''TP53'' (italics indicate that this is the name of a gene, not a protein), and includes 11 exons and 10 introns. In humans, this gene is located on chromosome 17 (17p13.1). P53 helps regulate cell growth and repair, and its loss of function is associated with negative outcomes in cancer patients. Activation of p53 is mediated by multiple stress signals, including DNA damage, hypoxia and strong proliferative signals.<ref name="Targeting" /> Depending on the type of stress, p53 can either temporarily halt cell growth and initiate repair or permanently stop cell proliferation.<ref>Hafner, A., Bulyk, M. L., Jambhekar, A., & Lahav, G. (2019). The multiple mechanisms that regulate p53 activity and cell fate. Nature reviews Molecular cell biology, 20(4), 199-210. PMID: 30824861 DOI: 10.1038/s41580-019-0110-x</ref>
[[File:P53 Isoforms.jpg|thumb|'''p53 Isoforms'''. Functional domains: TAD1 (residues 1−39) & TAD2 (residues 40–61) transactivation domains 1 and 2 (acidic); PRD - proline-rich domain (residues 62–93); DBD - DNA binding domain (residues 94–290); HD - the hinge domain (residues 291–324);At its carboxyl terminus, p53 comprises an oligomerization domain (OD) (residues 325–356) and a negative regulation domain (α) (residues 357–393). ]]

== p53 isoforms ==
Twelve protein isoforms have been shown to be produced through alternative mRNA translation initiation (p53/47) or splicing (full-length p53 or FLp53, p53β, p53γ, Δ40p53α, Δ40p53β, Δ40p53γ, Δ133p53α, Δ133p53β, Δ133p53γ, Δ160p53α, Δ160p53β, Δ160p53γ).<ref>Wylie, A., Jones, A. E., Das, S., Lu, W. J., & Abrams, J. M. (2022). Distinct p53 isoforms code for opposing transcriptional outcomes. Developmental cell, 57(15), 1833-1846. PMID: 35820415 PMC9378576 (available on 2023-08-08) DOI: 10.1016/j.devcel.2022.06.015</ref><ref>Joruiz, S. M., & Bourdon, J. C. (2016). p53 isoforms: key regulators of the cell fate decision. Cold Spring Harbor perspectives in medicine, 6(8), a026039. PMID: 26801896 PMC4968168 DOI: 10.1101/cshperspect.a026039</ref><ref>Anbarasan, T., & Bourdon, J. C. (2019). The emerging landscape of p53 isoforms in physiology, cancer and degenerative diseases. International journal of molecular sciences, 20(24), 6257. PMID: 31835844 PMC6941119 DOI: 10.3390/ijms20246257</ref>

== Hypothesis of Bartas et al. ==
According to the hypothesis of Bartas et al. specific p53 variations are associated with longevity.<ref name="kingdom" >Bartas, M., Brázda, V., Volná, A., Červeň, J., Pečinka, P., & Zawacka-Pankau, J. E. (2021). The changes in the P53 protein across the animal kingdom point to its involvement in longevity. International Journal of Molecular Sciences, 22(16), 8512. PMID: 34445220 PMCID: PMC8395165 DOI: 10.3390/ijms22168512</ref> In support of the hypothesis, the following arguments are given in particular:
# Bowhead whales had a significantly longer lifespan (about four times longer) compared with other whales. In contrast to other Cetacea, Balaena mysticetus had a unique leucine substitution in the proline-rich region, corresponding to amino acid residue 77 in human p53.
# The olm (Proteus anguinus, Batrachia, Amphibians) has a maximal documented lifespan of 102 years (whereas most amphibian species live for less than 30 years). The p53 protein from this species had additional serine and arginine residues in the core domain (corresponding to an insertion after amino acid L188 in human p53), which had a deleterious effect on p53 functionality.
# Myotis brandtii and Myotis lucifugus are very small bats (max 8 g body weight) and provide a significant exception from Max Kleiber’s law (mouse-to-elephant curve) since their lifespan is extremely long in relation to their small body size. These two species share a unique arrangement in the p53 DNA-binding region, with the insertion of seven amino acid residues in the central DNA-binding region (following amino acid 295 in the human p53 canonical sequence).
The abovementioned analysis and some other facts of long-lived organisms in various animal groups led to conclusion that the amino acid sequence of p53 is associated with organismal lifespan.<ref name="kingdom" />

== TP53 gene copy numbers ==
Although it is logical to assume that cell divisions increases the chance of mutation accumulation and, consequently, the chance for malignancies, in practice, [[Aging and cancer#Peto's paradox|Peto's paradox]] is observed: larger animals despite their large body size, a significantly greater number of cells and their long life span not develop cancer more often than much smaller animals with short life span.<ref>Tollis, M., Boddy, A. M., & Maley, C. C. (2017). Peto’s Paradox: how has evolution solved the problem of cancer prevention?. BMC biology, 15, 1-5. PMID: 28705195 PMC5513346 DOI: 10.1186/s12915-017-0401-7</ref><ref>Perillo, M., Silla, A., Punzo, A., Caliceti, C., Kriete, A., Sell, C., & Lorenzini, A. (2023). Peto’s paradox: nature has used multiple strategies to keep cancer at bay while evolving long lifespans and large body masses. A systematic mini-review. Biomedical Journal, 100654. https://doi.org/10.1016/j.bj.2023.100654</ref> For example, the cancer mortality rate for elephants was found to be less than 5% compared with a cancer mortality rate for humans of 11% to 25%. This may be due to the fact that elephants contain 20 copies of p53, making apoptosis much more likely, whereas humans only possess one copy of p53 in their genetic code, which means that human cells are less likely to trigger apoptosis upon DNA damage, increasing the likelihood of cancer.<ref>Voskarides, K., & Giannopoulou, N. (2023). The role of TP53 in adaptation and evolution. Cells, 12(3), 512. PMID: 36766853 PMCID: PMC9914165 DOI: 10.3390/cells12030512</ref>

== For further reading ==
* Sheekey, E., & Narita, M. (2023). p53 in senescence–it's a marathon, not a sprint. The FEBS journal, 290(5), 1212-1220. https://doi.org/10.1111/febs.16325
* Reinhardt, L. S., Groen, K., Newton, C., & Avery-Kiejda, K. A. (2023). The role of truncated p53 isoforms in the DNA damage response. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 188882. PMID: 36977456 [https://doi.org/10.1016/j.bbcan.2023.188882 DOI: 10.1016/j.bbcan.2023.188882]
* Romani Osbourne, Kelly M. Thayer (2024). Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. bioRxiv 2024.08.05.606567; doi: https://doi.org/10.1101/2024.08.05.606567

== References ==
<references />

[[Category:Longevity genes]]
[[Category:Drafts]]
[[Category:Stub]]
[[Category:Main list]]

G-quadruplex (G4)-driven epigenomic aging

2024-08-07T15:03:28Z

Dmitry Dzhagarov: /* Small molecules targeting G4 */

Nucleic acid sequences rich in guanine are capable of forming '''four-stranded structures called G-quadruplexes(G4)''', stabilized by hydrogen bonding between a tetrad of guanine bases<ref>Sen D, Gilbert W (1988). Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature. 334 (6180): 364–6. Bibcode:1988Natur.334..364S. doi:10.1038/334364a0. PMID 3393228</ref> and it generally extends over the C-rich strand forming a 3′ overhang reaching approximately 50–300 nucleotides in mammals.<ref>Chai, W., Du, Q., Shay, J. W., & Wright, W. E. (2006). Human telomeres have different overhang sizes at leading versus lagging strands. Molecular cell, 21(3), 427-435. PMID: 16455497 DOI: 10.1016/j.molcel.2005.12.004</ref> Endogenous G4 (eG4), with its unique secondary structure, is involved in a variety of important biological processes such as gene transcription, translation regulation, telomere extension, and chromatin modification. <ref name="In vivo" >Zhang, Z. H., Qian, S. H., Wei, D., & Chen, Z. X. (2023). In vivo dynamics and regulation of DNA G-quadruplex structures in mammals. Cell & Bioscience, 13(1), 117. PMID: 37381029 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10303365 PMC10303365] DOI: 10.1186/s13578-023-01074-8</ref>

The structures of eG4s are affected by interacting proteins in vivo. During DNA replication, double-stranded (dsDNA) is unwound into single-stranded DNA (ssDNA) by helicases<ref>Mendoza, O., Bourdoncle, A., Boulé, J. B., Brosh Jr, R. M., & Mergny, J. L. (2016). G-quadruplexes and helicases. Nucleic acids research, 44(5), 1989-2006.</ref> and stabilized by ssDNA-binding proteins. During transcription, the promoter TATA box interacts with TFIIH to melt the promoter. As a kind of nucleic acid structures, eG4s will inevitably be regulated by interacting proteins. The proteins that can interact with eG4s can be divided into two types according to their functions: one is the protein that can unfold eG4s (such as G4 helicase), and the other is the protein that can bind and stabilize eG4s. These two types of proteins together regulate the dynamics of eG4s in vivo.<ref name="In vivo" />

Transcription of the C-rich telomeric strand generates a class of telomeric repeat-containing RNAs called TERRA (TElomere Repeat-containing RNA) with distinct subtelomeric sequences at their 5′ end and '''the same G-rich telomeric sequence at their 3′ end'''. These features are shared by TERRA molecules expressed by all the organisms studied to date.<ref>Barral, A., & Déjardin, J. (2020). Telomeric chromatin and TERRA. Journal of molecular biology, 432(15), 4244-4256. PMID: 32151584 DOI: 10.1016/j.jmb.2020.03.003</ref> Recent evidence indicates that aging is a condition which results in upregulation of TERRA in different cellular settings.<ref>Rivosecchi, J., & Cusanelli, E. (2023). TERRA beyond cancer: the biology of telomeric repeat‐containing RNAs in somatic and germ cells. Frontiers in Aging, 4. PMID: 37636218 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448526/ PMC10448526] DOI: 10.3389/fragi.2023.1224225</ref><ref>Canale, P., Campolo, J., Borghini, A., & Andreassi, M. G. (2023). Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease. Biomedicines, 11(12), 3211. PMID: 38137431 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10740775/ PMC10740775] DOI: 10.3390/biomedicines11123211</ref> The G-quadruplex structure of TERRA is an important recognition element for the TRF2 shelterin subunit and physically interacts with it to bind to telomeric DNA and also with TRF1 to preserve the telomere’s structural stability.<ref>Abreu, P. L., Lee, Y. W., & Azzalin, C. M. (2022). In Vitro Characterization of the Physical Interactions between the Long Noncoding RNA TERRA and the Telomeric Proteins TRF1 and TRF2. International Journal of Molecular Sciences, 23(18), 10463. PMID: 36142374 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500956 PMC9500956] DOI: 10.3390/ijms231810463</ref><ref>Rivosecchi, J., Jurikova, K., & Cusanelli, E. (2024). Telomere-specific regulation of TERRA and its impact on telomere stability. In Seminars in Cell & Developmental Biology (Vol. 157, pp. 3-23). Academic Press.</ref>

The formation of telomeric quadruplexes has been shown to decrease the activity of the enzyme telomerase, which is responsible for elongating telomeres.<ref>De Cian, A., Cristofari, G., Reichenbach, P., De Lemos, E., Monchaud, D., Teulade-Fichou, M. P., ... & Mergny, J. L. (2007). Reevaluation of telomerase inhibition by quadruplex ligands and their mechanisms of action. Proceedings of the National Academy of Sciences, 104(44), 17347-17352.</ref><ref>Fletcher, T. M., Sun, D., Salazar, M., & Hurley, L. H. (1998). Effect of DNA secondary structure on human telomerase activity. Biochemistry, 37(16), 5536-5541. PMID: 9548937 DOI: 10.1021/bi972681p</ref><ref>Bryan, T. M. (2020). G-quadruplexes at telomeres: friend or foe?. Molecules, 25(16), 3686. PMID: 32823549 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464828/ PMC7464828] DOI: 10.3390/molecules25163686</ref>

High occurrences of oxidized guanines in G4 structures due to the oxidative stress occurring under the influence of the reactive oxygen species (ROS) affects the genome stability and promotes mutagenesis, that can destabilize the stacking of guanin, senescence, and other age-related diseases.<ref>Bielskutė, S., Plavec, J., & Podbevšek, P. (2019). Impact of oxidative lesions on the human telomeric G-quadruplex. Journal of the American Chemical Society, 141(6), 2594-2603. PMID: 30657306 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727377 PMC6727377] DOI: 10.1021/jacs.8b12748</ref><ref>Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., ... & Abete, P. (2018). Oxidative stress, aging, and diseases. Clinical interventions in aging, 757-772. PMID: 29731617 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927356 PMC5927356] DOI: 10.2147/CIA.S158513</ref> G4s in CDS (the coding sequence, that codes for a protein) and CpG regions (that contain several CpG methylated sequences of DNA) are the least likely regions to be affected by mutations, while enhancers and intergenic G4s are prone to higher variant-induced stabilization and destabilization due to the single-nucleotide variants.<ref>Neupane, A., Chariker, J. H., & Rouchka, E. C. (2023). Analysis of nucleotide variations in human g-quadruplex forming regions associated with disease states. Genes, 14(12), 2125. PMID: 36778288 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915501 PMC9915501] DOI: 10.1101/2023.01.30.526341</ref>

== Small molecules targeting G4 ==
Small molecules targeting G-quadruplexes are also important as potent drugs for therapy of cancer and other diseases.<ref>Cao, S., Su, Q., Chen, Y. H., Wang, M. L., Xu, Y., Wang, L. H., ... & Wang, Z. G. (2024). Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides. International Journal of Molecular Sciences, 25(1), 623. https://doi.org/10.3390/ijms25010623</ref><ref>Monsen, R.C. (2023). Higher-order G-quadruplexes in promoters are untapped drug targets. Front. Chem., 11, 1211512.</ref><ref>Wang, K.B.; Elsayed, M.S.A.; Wu, G.; et al. (2019). Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. J. Am. Chem. Soc., 141, 11059–11070.</ref><ref>Shu, H.; Zhang, R.; Xiao, K.; et al. (2022). G-Quadruplex-Binding Proteins: Promising Targets for Drug Design. Biomolecules, 12, 648.</ref><ref>Kosiol, N.; Juranek, S.; Brossart, P.; et al. (2021). G-quadruplexes: A promising target for cancer therapy. Mol. Cancer, 20, 40.</ref><ref>Teng, F.Y.; Jiang, Z.Z.; Guo, M.; et al. (2021). G-quadruplex DNA: A novel target for drug design. Cell. Mol. Life Sci., 78, 6557–6583.</ref><ref>Zou, M.; Li, J.Y.; Zhang, M.J.; et al. (2021). G-quadruplex binder pyridostatin as an effective multi-target ZIKV inhibitor. Int. J. Biol. Macromol., 190, 178–188.</ref><ref>Hu, X.X.; Wang, S.Q.; Gan, S.Q.; et al. (2021). A Small Ligand That Selectively Binds to the G-quadruplex at the Human Vascular Endothelial Growth Factor Internal Ribosomal Entry Site and Represses the Translation. Front. Chem., 9, 781198.</ref><ref>Miglietta, G.; Marinello, J.; Russo, M.; Capranico, G. (2019). Ligands stimulating antitumour immunity as the next G-quadruplex challenge. Mol. Cancer 2022, 21, 180.</ref><ref>Dhamodharan, V.; Pradeepkumar, P.I. Specific Recognition of Promoter G-Quadruplex DNAs by Small Molecule Ligands and Light-up Probes. ACS Chem. Biol., 14, 2102–2114.</ref><ref>Yang, D.; Okamoto, K. (2010). Structural Insights into G-Quadruplexes: Towards New Anticancer Drugs. Future Med. Chem., 2, 619–646.</ref><ref>Neidle, S.; Parkinson, G. (2002). Telomere Maintenance as a Target for Anticancer Drug Discovery. Nat. Rev. Drug Discov., 1, 383–393. </ref><ref>Sun, D.; Thompson, B.; Cathers, B.E. et al. (1997). Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound. J. Med. Chem., 40, 2113–2116.</ref><ref>Merlino, F., Marzano, S., Zizza, P., D’Aria, F., Grasso, N., Carachino, A., ... & Pagano, B. (2024). Unlocking the potential of protein-derived peptides to target G-quadruplex DNA: from recognition to anticancer activity. Nucleic Acids Research, 52(12), 6748–6762, https://doi.org/10.1093/nar/gkae471</ref>

<ref>Routh ED, Creacy SD, Beerbower PE, Akman SA, Vaughn JP, Smaldino PJ (2017). A G-quadruplex DNA-affinity Approach for Purification of Enzymaticacvly Active G4 Resolvase1. Journal of Visualized Experiments. 121 (121). doi:10.3791/55496. PMC 5409278. PMID 28362374</ref>
<ref>Varshney, D., Spiegel, J., Zyner, K., Tannahill, D. & Balasubramanian, S. (2020). The regulation and functions of DNA and RNA G-quadruplexes. Nat Rev Mol Cell Biol 21, 459-474</ref>
<ref>Huppert, J. L., & Balasubramanian, S. (2005). Prevalence of quadruplexes in the human genome. Nucleic acids research, 33(9), 2908-2916. PMID: 15914667 PMCID: PMC1140081 DOI: 10.1093/nar/gki609</ref>
<ref>Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. (2013). Quantitative visualization of DNA G-quadruplex structures in human cells. Nat Chem 5, 182-186</ref>
<ref>Hansel-Hertsch, R. et al. (2016). G-quadruplex structures mark human regulatory chromatin. Nature genetics 48, 1267-1272</ref>
<ref>Hansel-Hertsch, R., Spiegel, J., Marsico, G., Tannahill, D. & Balasubramanian, S. (2018). Genome-wide mapping of endogenous G-quadruplex DNA structures by chromatin immunoprecipitation and high-throughput sequencing. Nat Protoc 13, 551-564</ref>
<ref>Lyu, J., Shao, R., Kwong Yung, P. Y. & Elsasser, S. J. (2022). Genome-wide mapping of G766 quadruplex structures with CUT&Tag. Nucleic acids research 50, e13 (2022).</ref>
<ref>Muller, S., Kumari, S., Rodriguez, R. & Balasubramanian, S. (2010). Small-molecule-mediated G768 quadruplex isolation from human cells. Nat Chem 2, 1095-1098</ref>
<ref>Zhang, X., Spiegel, J., Martinez Cuesta, S., Adhikari, S. & Balasubramanian, S. (2021). Chemical profiling of DNA G-quadruplex-interacting proteins in live cells. Nat Chem 13, 626-633</ref>
<ref>Sergeev, A. V., Loiko, A. G., Genatullina, A. I., Petrov, A. S., Kubareva, E. A., Dolinnaya, N. G., & Gromova, E. S. (2023). Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter. International Journal of Molecular Sciences, 25(1), 45. https://doi.org/10.3390/ijms25010045</ref>
<ref>Soriano-Lerma, A., Sanchez-Martin, V., Murciano-Calles, J., Ortiz-Gonzalez, M., Tello-Lopez, M. J., Perez-Carrasco, V., ... & Garcia-Salcedo, J. A. (2024). Resveratrol targets G-quadruplexes to exert its pharmacological effects. bioRxiv, 2024-07. https://doi.org/10.1101/2024.07.29.605564</ref>

== G4 may participate in non-genetic mechanisms driving aging ==
G4s accumulate at specific genomic loci during aging and the coefficient of variation of the G4 signal increased with cell age.<ref name="universal" >Jin, W., Zheng, J., Xiao, Y., Ju, L., Chen, F., Fu, J., ... & Zhang, Y. (2024). A universal molecular mechanism driving aging. bioRxiv, 2024-01. https://doi.org/10.1101/2024.01.06.574476</ref> This G4 accumulation drives clock-like chromatin opening, since G4 formation drives aging-associated, clock like chromatin opening.<ref name="universal" />
It was shown that delayed genome replication is a general feature of aging loci and that G4 stimulates local transcription replication interaction to delay genome replication.<ref name="universal" /> The authors of the article also hypothesized that G4 stability might also regulate age-associated DNA hypomethylation.<ref name="universal" /> The authors also suggest that "perturbing G4 formation might be of particular interest for modulating natural and pathological aging".<ref name="universal" />
== References ==
<references />

[[Category:Main list]]
[[Category:Drafts]]

Interleukin-11 (IL-11)

2024-08-02T11:54:40Z

Dmitry Dzhagarov: /* IL11 can cause senescence */

'''Interleukin-11 (IL-11)''' is a pleiotropic cytokine that belongs to glycoprotein 130 (gp130) family.<ref>Cook, S. A., & Schafer, S. (2020). Hiding in plain sight: interleukin-11 emerges as a master regulator of fibrosis, tissue integrity, and stromal inflammation. Annual Review of Medicine, 71, 263-276. PMID: 31986085 [https://doi.org/10.1146/annurev-med-041818-011649 DOI: 10.1146/annurev-med-041818-011649]</ref> Due to this, it has much in common with the proteins of the IL-6 family of cytokines.<ref>Metcalfe, R. D., Putoczki, T. L., & Griffin, M. D. (2020). Structural understanding of interleukin 6 family cytokine signaling and targeted therapies: focus on interleukin 11. Frontiers in Immunology, 11, 1424. PMID: 32765502 PMC7378365 DOI: 10.3389/fimmu.2020.01424</ref> However, IL-6 family cytokines signal predominantly via JAK/STAT, whereas IL-11 has been shown to activate ERK in fibroblasts without a detectable transcriptional (STAT-mediated) response.<ref>Garbers, C., & Scheller, J. (2013). Interleukin-6 and interleukin-11: same same but different. Biological chemistry, 394(9), 1145-1161. PMID: 23740659 DOI: 10.1515/hsz-2013-0166</ref>

== IL-11 in Hematopoiesis ==
Interleukin-11 plays a significant role in the synthesis and maturation of hematopoietic cells, inhibition of adipogenesis, regulation of embryo implantation, and trophoblasts invasion. IL-11 is a potent hematopoietic stimulator following radiation therapy and chemotherapy, and markedly increases platelet counts. Recombinant IL-11 (Oprelvekin, trade name Neumega) is approved by the FDA to treat thrombocytopenia following radiation treatment in humans.<ref>Wilde, M. I., & Faulds, D. (1998). Oprelvekin: a review of its pharmacology and therapeutic potential in chemotherapy-induced thrombocytopenia. BioDrugs, 10(2), 159-171. PMID: 18020592 DOI: 10.2165/00063030-199810020-00006</ref>

== Inhibition of IL-11 may be a potent contraceptive ==
<ref>Menkhorst, E., Salamonsen, L., Robb, L., & Dimitriadis, E. (2009). IL11 antagonist inhibits uterine stromal differentiation, causing pregnancy failure in mice. Biology of reproduction, 80(5), 920-927. PMID: 19144959 PMC2849829 DOI: 10.1095/biolreprod.108.073601</ref>

== IL-11 in the lung ==
IL-11 plays a role in viral airway disorders; human stromal cells stimulated with respiratory syncytial virus, rhinovirus, and parainfluenza virus type 3 secrete high levels of IL-11. However, IL-11 activity does not alter the initial immune responses and bacterial clearance in the context of acute respiratory infections.<ref>Einarsson, O., Geba, G. P., Zhu, Z., Landry, M., & Elias, J. A. (1996). Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness. The Journal of clinical investigation, 97(4), 915-924. PMID: 8613544 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC507136/ PMC507136] DOI: 10.1172/JCI118514</ref>
Interleukin-11 (IL-11) is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung.<ref>Ng, B., Dong, J., D’Agostino, G., Viswanathan, S., Widjaja, A. A., Lim, W. W., ... & Cook, S. A. (2019). Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Science Translational Medicine, 11(511), eaaw1237.PMID: 37228276 PMC10204861 DOI: 10.1183/23120541.00679-2022</ref> IL-11 and and its cognate receptor IL-11Rα are overexpressed in pulmonary arteries of pulmonary hypertension associated to IPF patients, and contributes to pulmonary artery remodeling and pulmonary hypertension.<ref>Milara, J., Roger, I., Montero, P., Artigues, E., Escrivá, J., & Cortijo, J. (2022). IL-11 system participates in pulmonary artery remodeling and hypertension in pulmonary fibrosis. Respiratory Research, 23(1), 1-18. PMID: 36376885 PMC9664718 DOI: 10.1186/s12931-022-02241-0</ref><ref>Ng, B., Dong, J., D’Agostino, G., Viswanathan, S., Widjaja, A. A., Lim, W. W., ... & Cook, S. A. (2019). Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Science Translational Medicine, 11(511), eaaw1237. PMID: 31554736 DOI: 10.1126/scitranslmed.aaw1237</ref> Interleukin-11 negatively impacts lung epithelial regeneration by inhibiting progenitor cell activation and suppressing alveolar differentiation.<ref>Kortekaas, R. K., Geillinger-Kästle, K. E., Borghuis, T., Belharch, K., Webster, M., Timens, W., ... & Gosens, R. (2023). Interleukin-11 disrupts alveolar epithelial progenitor function. ERJ Open Research, 9(3). PMID: 37228276 PMC10204861 DOI: 10.1183/23120541.00679-2022</ref>
Arachidonic acid (AA) increased mRNA expression and secretion of IL-11 in lung fibroblasts in a dose-dependent manner that was dependent on the activation of the p38 or ERK MAPK signaling pathways.<ref>Sasaki, K., Komamura, S., & Matsuda, K. (2023). Extracellular stimulation of lung fibroblasts with arachidonic acid increases interleukin 11 expression through p38 and ERK signaling. Biological Chemistry, 404(1), 59-69. PMID: 36268909 DOI: 10.1515/hsz-2022-0218</ref>

IL‐11 is highly expressed in the prematurely aged lung tissues of mice,<ref name="senescence"> Chen, H., Chen, H., Liang, J., Gu, X., Zhou, J., Xie, C., ... & Jin, J. (2020). TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency. Experimental & Molecular Medicine, 52(1), 130-151. PMID: 31959867 PMC7000795 DOI: 10.1038/s12276-019-0371-7</ref> while the expression of Sirt1 diminishes with physiological aging in mice. Sirt1 overexpression reduced signs of aging, in particular decreased pulmonary SA-β-gal and p16- and p53-positive cells, as well as expression of p16, p19, p21, and p53; improved pulmonary dysfunction, DNA damage, senescence‐associated secretory phenotype, and fibrosis through downregulating TGF‐β1/IL‐11/MEK/ERK signaling.<ref name="Sirt1"> Zhou, J., Chen, H., Wang, Q., Chen, S., Wang, R., Wang, Z., ... & Jin, J. (2022). Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription. Aging Cell, 21(8), e13680.</ref>

== IL-11 is a crucial determinant of cardiovascular fibrosis ==
In the heart, IL-11 has been identified as a key fibrotic factor, acting downstream of the main fibrotic factor TGFβ1, driving fibrotic protein synthesis.<ref>Schafer, S., Viswanathan, S., Widjaja, A. A., Lim, W. W., Moreno-Moral, A., DeLaughter, D. M., ... & Cook, S. A. (2017). IL-11 is a crucial determinant of cardiovascular fibrosis. Nature, 552(7683), 110-115. PMID: 29160304 PMC5807082 DOI: 10.1038/nature24676</ref>
<ref>Wu, J., Ma, W., Qiu, Z., & Zhou, Z. (2023). Roles and mechanism of IL-11 in vascular diseases. Frontiers in cardiovascular medicine, 10, 1171697. PMID: 37304948 PMC10250654 DOI: 10.3389/fcvm.2023.1171697</ref>
IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes that establish IL11 as a disease factor. As compared to wild-type controls, Il11 expressing mouse hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells.<ref>Sweeney, M. D., O'Fee, K., Villanueva-Hayes, C., Rahman, E., Lee, M., Andrew, I., ... & Cook, S. A. (2023). Cardiomyocyte-restricted expression of IL11 causes cardiac fibrosis, inflammation, and dysfunction. bioRxiv, 2023-05. https://doi.org/10.1101/2023.05.23.541928</ref>

== Interleukin-11 in Pathologies of the Nervous System ==
<ref>Seyedsadr, M., Wang, Y., Elzoheiry, M., Shree Gopal, S., Jang, S., Duran, G., ... & Markovic-Plese, S. (2023). IL-11 induces NLRP3 inflammasome activation in monocytes and inflammatory cell migration to the central nervous system. Proceedings of the National Academy of Sciences, 120(26), e2221007120. PMID: 37339207 PMC10293805 (available on 2023-12-20) DOI: 10.1073/pnas.2221007120</ref>
<ref>Airapetov, M. I., Eresko, S. O., Ignatova, P. D., Lebedev, A. A., Bychkov, E. R., & Shabanov, P. D. (2023). Interleukin-11 in Pathologies of the Nervous System. Molecular Biology, 57(1), 1-6. PMID: 37016665 PMCID: PMC10062686 DOI: 10.1134/S0026893323010028</ref>
<ref>Airapetov, M., Eresko, S., Ignatova, P., Lebedev, A., Bychkov, E., & Shabanov, P. (2022). A brief summary regarding the roles of interleukin-11 in neurological diseases. BioScience Trends, 16(5), 367-370. PMID: 36261332 DOI: 10.5582/bst.2022.01331</ref>

== IL-11 can increase the tumorigenic capacity of cells ==

== IL11 can cause senescence ==
[[File:Female Il11-deleted mice are protected from age-associated obesity, frailty, and metabolic decline.jpg|thumb|Female Il11-deleted mice are protected from age-associated obesity, frailty, and metabolic decline.<ref name="Cook"> Widjaja, A. A., Lim, W. W., Viswanathan, S., Chothani, S., Corden, B., Goh, J. W. T., ... & Cook, S. A. (2023). Inhibition of an immunometabolic axis of mTORC1 activation extends mammalian healthspan. bioRxiv, 2023-07. https://doi.org/10.1101/2023.07.09.548250</ref>]]
As mice age, IL11 is progressively upregulated in liver, skeletal muscle, and fat to stimulate an ERK/AMPK/mTORC1 axis of cellular, tissue- and organismal-level ageing pathologies. In old mice, deletion of Il11 or Il11ra1 protects against metabolic multi-morbidity, sarcopenia, and frailty. Administration of anti-IL11 therapy to elderly mice for six months reactivates an age-repressed program of white fat beiging, reverses metabolic dysfunction, restores muscle function, and reduces frailty. Across studies, inhibition of IL11 lowers epigenetic age, reduces telomere attrition, and preserves mitochondrial function.<ref name="Cook" /> Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%.<ref>Widjaja, A.A., Lim, WW., Viswanathan, S. et al. (2024). Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature. 632, 157–165 https://doi.org/10.1038/s41586-024-07701-9</ref>

== Small moleculas and inhibitors ==
Blockage of sgp130Fc (by TJ301 (sgp130Fc)) or inhibition of the JAK2/STAT3 pathway (by WP1066 (a JAK2/STAT3 inhibitor)) could ameliorate the profibrotic effect of IL-11.<ref>Ye, W., Wang, Q., Zhao, L., Wang, C., Zhang, D., Zhou, M., ... & Xue, Y. (2023). Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11. Immunological Investigations, 52(6), 703-716. PMID: 37401665 DOI: 10.1080/08820139.2023.2222746</ref>

Current IL-11 signalling inhibitors include antibodies against either IL-11 or IL-11Rα and IL-11 mutants, especially a cytokine variant, '''IL-11 Mutein''', which potently inhibits IL-11 signaling in human cells.<ref>Metcalfe, R. D., Hanssen, E., Fung, K. Y., Aizel, K., Kosasih, C. C., Zlatic, C. O., ... & Griffin, M. D. (2023). Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant. Nature Communications, 14(1), 7543. PMID: 37985757 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10662374/ PMC10662374] DOI: 10.1038/s41467-023-42754-w</ref>

One important next step would be to test candidate IL-11 drugs in mice with diverse genetic backgrounds and in multiple laboratories to be sure that the results are reproducible. Beyond that, determining the effect of anti-IL-11 drug candidates on longevity in people could be a challenge. Instead researchers might do well to focus on a specific condition associated with ageing.<ref>Ledford H. (2024). [https://doi.org/10.1038/d41586-024-02298-5 Mice live longer when inflammation-boosting protein is blocked. Humans also have the protein, called IL-11, offering hope for a future longevity treatment]. Nature (News)</ref>

== Understanding interleukin 11 as a disease gene and therapeutic target ==
<ref>Cook, S. A. (2023). Understanding interleukin 11 as a disease gene and therapeutic target. Biochemical journal, 480(23), 1987-2008. PMID: 38054591 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10754292/ '''PMC10754292'''] DOI: 10.1042/BCJ20220160</ref>

Also see video from The Aging and Drug Discovery Conference (ARDD) 2022. Stuart Cook's report: [https://youtu.be/oNc5MxkWrms '''The IL-11/ERK/mTOR axis is a target for extending mammalian healthspan'''] and from AnaBios [https://youtu.be/niJO_S16epQ Antibody Mediated Blockade of Interleukin-11 Signaling for IPF & Other Fibrotic Diseases]

== References ==
<references />
[[Category:Drafts]]
[[Category:Lifespan interventions]]
[[Category:Age-related diseases]]
[[Category:Aging pathways and hallmarks]]
[[Category:Main list]]

Hallmarks of aging

2024-08-01T17:21:40Z

Dmitry Dzhagarov: /* 10. Cell size */

[[Biological age|Biological aging]] is not regarded as a single process, but rather as a complex group of interconnected cellular and molecular mechanisms. It is also worth noting that within the field of aging research there is also disagreement as to the actual concept of aging.<ref>Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.</ref>

The ¨Hallmarks of Aging¨ describe the basic processes thought to underlie aging in different organisms. These hallmarks are thought to be fundamental mechanisms shared across multiple major age-related diseases such as cancer, diabetes, cardiovascular disorders and neurodegenerative diseases. In a now widely-cited [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ 2013 research paper], nine tentative hallmarks of aging were proposed.<ref name=":0">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell'', ''153''(6), 1194-1217.</ref>

It is important to note that these hallmarks only offer a phenotypic observation of features associated with aging, but may fail to provide a ''causal'' explanation of aging (see section ´''[https://en.longevitywiki.org/wiki/Hallmarks_of_Aging#Critical_Review Critical Review]´'').

A decade after the original review, the "Hallmarks of Aging" has been updated and 3 new hallmarks have been added: [[Autophagy|disabled macroautophagy]], [[Inflammaging|chronic inflammation]] and dysbiosis.<ref>López-Otín, C. ''et al.'' (2023) “Hallmarks of aging: An expanding universe,” ''Cell'', 186(2), pp. 243–278. Available at: <nowiki>https://doi.org/10.1016/j.cell.2022.11.001</nowiki>. </ref>
== Criteria for the Hallmarks of Aging ==
López-Otín et al.<ref name=":0" /> proposed in 2013 nine candidate aging traits thought to contribute to the aging phenotype and determine lifespan. These candidates arise from previous findings in research literature, with special focus on mammalian aging but also including key insights from simpler model organisms such as C. ''elegans''.<ref>Kenyon, C. (2010). The genetics of ageing. ''Nature'', ''464''(7288), 504-512. doi: 10.1038/nature08980</ref><ref>Gems, D., & Partridge, L. (2013). Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. ''Annual Review Of Physiology'', ''75''(1), 621-644. doi: 10.1146/annurev-physiol-030212-183712</ref>

The '''criteria''' that each hallmark should, ideally, fulfil in order to be considered as an aging hallmark are:

# The hallmark should not only appear in a given mutant, but should in fact be present in wild-type aging models.
# Increasing the incidence of a hallmark (or degree to which is present) should lead to accelerated aging and shorter lifespan.
# Decreasing the incidence of a hallmark should lead to a decreased rate of aging and longer lifespan.

The authors of the study acknowledge that all three criteria are not met in many hallmarks, specially regarding criterion #3. They argue that complex relationships and interconnectedness between all hallmarks impedes observing beneficial lifespan effects when modifying just one aspect of aging. Furthermore, the lack of knowledge regarding how to experimentally ameliorate some hallmarks adds difficulty into validating this criterion.

== Categories of the Hallmarks of Aging ==
The proposed Hallmarks of Aging are grouped into three main categories according to their hierarchy.[[File:The categories of the Hallmarks of Aging.jpg|thumb|The categories of the Hallmarks of Aging and their functional hierarchy.<ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref>|350x350px]]
'''Primary hallmarks''' - defined as negative traits and sources of damage, which unequivocally lead to decreased health. This category includes:

* Genomic instability
* Telomere attrition
* Epigenetic alterations
* Loss of Proteostasiss

'''Antagonist hallmarks''' - defined as traits resulting from response to damage, and with varying effects on health depending on the intensity of their activity. For instance, low levels of cellular senescence might lead to health benefits, whilst high levels of cellular senesce might, in the opposite way, cause accelerated aging. This includes:

* Deregulated nutrient sensing
* Mitochondrial dysfunction
* Cellular senescence

'''Integrative hallmarks''' - defined as traits resulting from dysfunctional damage responses and considered to be the "culprits" of the aging phenotypes, given their direct negative effect on tissue homeostasis and function. This comprises:

* Stem cell exhaustion
* Altered intercellular communication

== The 9 Hallmarks of Aging ==
[[File:Scheme of the 9 Hallmarks of Aging.jpg|thumb|Graphic of the nine proposed hallmarks of aging, as described on López-Otín et al. 2013 Review on ''Cell''.<ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref> These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.]]

=== 1. Genomic instability ===
''See the full article on [[DNA damage and repair]]''

The genome is the total sum of DNA in our body and becomes damaged over time, with genomic instability leading to various age-related health problems.<ref name=":0" /> DNA carries the information to make proteins that make up cells and tissues in living organisms.

DNA damage may be caused by UV radiation, X-ray radiation, chemical toxins such as tobacco.<ref name=":2">Rastogi, R. P., Kumar, A., Tyagi, M. B., & Sinha, R. P. (2010). Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair. ''Journal of nucleic acids'', ''2010''.</ref> The damage can also occur due to normal chemical reactions in our body, known as metabolism, and create byproducts (reactive oxygen species) that damage the DNA.<ref name=":2" />

As detailed in a review article, some scientists regard DNA damage as a unifying cause of the aging process, with causative interactions with all the so-called hallmarks of aging.<ref>Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. (2021). The central role of DNA damage in the ageing process. ''Nature'', ''592''(7856), 695-703.</ref>

The body has evolved repair systems to deal with the DNA damage as it arises and special proteins (enzymes) detect and repair broken strands of the DNA. However, the DNA repair processes are not perfect and errors in the DNA (mutations) arise over time. The body generally deals with these cells with too many mutations, through a kind of programmed cell suicide known as apoptosis. Alternatively, cells can undergo cellular senescence, a state of permanent cell cycle arrest that prevents further cell division. These senescent cells accumulate with aging and have been causatively linked to various age-related diseases and functional decline in mice.<ref>Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019). Cellular senescence: aging, cancer, and injury. ''Physiological reviews'', ''99''(2), 1047-1078.</ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. ''Nature'', ''479''(7372), 232-236.</ref>

=== 2. Telomere attrition ===
''See the full article on [[telomeres]].''

[[Telomeres]] are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. They protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the ends of the DNA strand for a double strand break.

Telomere shortening is associated with aging, mortality and aging-related diseases.<ref name=":0" /> Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging.<ref>Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref> Leonard Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase.<ref>Hayflick, L. (1965). The limited in vitro lifetime of human diploid cell strains. ''Experimental cell research'', ''37''(3), 614-636.</ref> Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. This is useful when uncontrolled cell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary.

An enzyme called telomerase elongates [[telomeres]] in gametes (reproductive cells) and embryonic stem cells. Telomerase deficiency in humans has been linked to several aging-related diseases related to loss of regenerative capacity of tissues.<ref>de Jesus, B. B., & Blasco, M. A. (2013). Telomerase at the intersection of cancer and aging. ''Trends in genetics'', ''29''(9), 513-520.</ref> It has also been shown that premature aging in telomerase-deficient mice is reverted when telomerase is reactivated.<ref>Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., ... & DePinho, R. A. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. ''Nature'', ''469''(7328), 102-106.</ref>

=== 3. Epigenetic alterations ===
''Learn about [[Epigenetic clock|epigenetic clocks]].''

Out of all the genes that make up a genome, only a subset are expressed at any given time. The functioning of a genome depends both on the specific order of its nucleotides (genomic factors), and also on which sections of the DNA chain are spooled tightly on histones and thus rendered inaccessible, and which ones are unspooled and available for transcription (epigenomic factors). Depending on the needs of the specific tissue type and environment that a given cell is in, histones can be modified to turn specific genes on or off as needed. The profile of where, when and to what extent these modifications occur (the epigenetic profile) changes with aging, turning useful genes off and unnecessary ones on, disrupting the normal functioning of the cell.

As an example, [[sirtuins]] are a type of protein deacetylase that promotes the binding of DNA onto histones and thus controls gene expression by turning them of or off. These enzymes use [[NAD+|NAD]] as a cofactor. As we age, the level of [[NAD+|NAD]] in our cells decreases and so does the ability of certain sirtuins to turn off unneeded genes at the right time. Decreasing the activity of certain sirtuins has been associated with accelerated aging and increasing their activity has been shown to stave off several age-related diseases.

=== 4. Loss of proteostasis ===
''See the full article on [[proteostasis]].''

[[Proteostasis]] is the homeostatic process of maintaining all the proteins necessary for the functioning of the cell in their proper shape, structure and abundance.<ref name=":0" /> Protein misfolding, oxidation, abnormal cleavage or undesired post-translational modification can create dysfunctional or even toxic proteins or protein aggregates that hinder the normal functioning of the cell. Though these proteins are continually removed and recycled, formation of damaged or aggregated proteins increases with age, leading to a gradual loss of proteostasis. Based on animal studies, this can be slowed or suppressed by caloric restriction or by administration of rapamycin, which is partly mediated through inhibiting the mTOR pathway.

Loss of [[proteostasis]] has been linked to various age-related diseases. [[Aging and neurodegeneration|Neurodegenerative]] diseases are prominent examples of this, for example, Alzheimer's is associated with the accumulation of proteins that are regarded as toxic to brain neurons, such as amyloid beta and tau.<ref>Kaeberlein, M., & Galvan, V. (2019). Rapamycin and Alzheimer’s disease: time for a clinical trial?. ''Science translational medicine'', ''11''(476).</ref><ref name=":1">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> The role of aging in the loss of proteostasis has been shown to improve diseases such as Alzheimer's and Parkinson's, via investigating rapamycin or chaperone-mediated autophagy.<ref name=":1" /><ref>[https://link.springer.com/article/10.1007/s11064-012-0909-8 Yao, R. Q., Qi, D. S., Yu, H. L., Liu, J., Yang, L. H., & Wu, X. X. (2012). Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF–TrkB–PI3K/Akt signaling pathway. ''Neurochemical research'', ''37''(12), 2777-2786.]</ref><ref>Pupyshev, A. B., Tikhonova, M. A., Akopyan, A. A., Tenditnik, M. V., Dubrovina, N. I., & Korolenko, T. A. (2019). Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease. ''Pharmacology Biochemistry and Behavior'', ''177'', 1-11.</ref>

=== 5. Deregulated nutrient-sensing ===
''See the full article on [[metabolic flexibility]].''

Nutrient sensing is a cell's ability to recognize, and respond to, changes in the concentration of macronutrients such as glucose, fatty acids and amino acids. In times of abundance, anabolism is induced through various pathways, the most well-studied among them the [[mTOR]] pathway. When energy and nutrients are scarce, proteins such as the AMPK receptor senses this and turns down mTOR to conserve resources.

In a growing organism, growth and cell proliferation are important and thus mTOR is upregulated. In a fully grown organism, mTOR-activating signals naturally decline during aging. It has been found that forcibly overactivating these pathways in grown mice leads to accelerated aging and increased incidence of cancer. mTOR inhibition methods like [[Calorie restriction|dietary restriction]] or [[rapamycin]] have been shown to be one of the most robust methods of increasing healthy lifespan in worms, flies and mice.

[[Metabolic flexibility]] is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states. This has shown to be dependent on functional mitochondrial dynamics.<ref name=":3">Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metabolism, 26(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref> Loss of [[metabolic flexibility]] (or the proper activation/suppression of the AMPK and mTOR pathways) during aging has been proposed as the main [[risk factor]] for the onset of age-related diseases.<ref name=":3" />

=== 6. Mitochondrial dysfunction ===
''See the full article on [[Mitochondrial Dysfunction|mitochondrial dysfunction]].''

The [[mitochondria]] is the powerhouse of the cell. Different human cells can contain up to thousands of mitochondria, each one converting carbon (in the form of acetyl-CoA) and oxygen into energy (in the form of ATP) and carbon dioxide during cellular respiration.

During aging, the efficiency of mitochondria tends to decrease. The reasons for this are still quite unclear, but several mechanisms are suspected - reduced biogenesis, accumulation of damage and mutations in mitochondrial DNA, oxidation of mitochondrial proteins, and defective quality control by mitophagy. [[Mitochondrial Dysfunction|Dysfunctional mitochondria]] contribute to aging through interfering with intercellular signalling and triggering inflammatory reactions.

[[Mitochondria]] are highly dynamic organelles that undergo coordinated cycles of fission and fusion in order to maintain their shape, distribution and size, as shown by imaging studies in live cells. Functional mitochondrial dynamics are key for regulating organismal homeostasis and are required to maintain appropriate [[metabolic flexibility]].

=== 7. Cellular senescence ===
''See the full article on [[cellular senescence]].''

Under certain conditions, a cell will exit the cell cycle without dying, instead becoming dormant and ceasing its normal function. This is called cellular senescence. Senescence can be induced by several factors, including telomere shortening, DNA damage and stress. Since the immune system is programmed to seek out and eliminate senescent cells, it might be that senescence is one way for the body to rid itself of cells damaged beyond repair. Compounds targeting the removal of senescent cells are known as [[senolytics]].

The links between cell senescence and aging are several:

* The proportion of senescent cells increases with age.
* Senescent cells secrete inflammatory markers which may contribute to aging.
* Clearance of senescent cells has been found to delay the onset of age-related disorders.

=== 8. Stem cell exhaustion ===
Stem cells are undifferentiated or partially differentiated cells that can proliferate indefinitely. For the first few days after fertilization, the embryo consists almost entirely of stem cells. As the fetus grows, the cells multiply, differentiate and assume their appropriate function within the organism. In adults, stem cells are mostly located in areas that undergo gradual wear (intestine, lung, mucosa, skin) or need continuous replenishment (red blood cells, immune cells, sperm cells, hair follicles).

Loss of regenerative ability is one of the most obvious consequences of aging. This is largely because the proportion of stem cells and the speed of their division gradually lowers over time. It has been found that stem cell rejuvenation can reverse some of the effects of aging at the organismal level.

=== 9. Altered intercellular communication ===
Different tissues and the cells they consist of need to orchestrate their work in a tightly controlled manner so that the organism as a whole can function. One of the main ways this is achieved is through excreting signal molecules into the blood where they make their way to other tissues, affecting their behavior. The profile of these molecules changes as we age.

One of the most prominent changes in cell signaling biomarkers is "[[inflammaging]]", the development of a chronic low-grade inflammation throughout the body with advanced age. The normal role of inflammation is to recruit the body's immune system and repair mechanisms to a specific damaged area for as long as the damage and threat are present. The constant presence of inflammation markers throughout the body wears out the immune system and damages healthy tissue.

It's also been found that senescent cells excrete a specific set of molecules called the [[Cellular_senescence#SASP|'''SASP''']] (Senescence-Associated Secretory Phenotype) which induce [[Cellular senescence|senescence]] in neighboring cells. Conversely, lifespan-extending manipulations targeting one tissue can slow the aging process in other tissues as well.

=== 10. Cell size ===
<ref>Lengefeld, J., Cheng, C. W., Maretich, P., Blair, M., Hagen, H., McReynolds, M. R., ... & Amon, A. (2021). Cell size is a determinant of stem cell potential during aging. Science advances, 7(46), eabk0271.</ref>
<ref>Biran, A., Zada, L., Abou Karam, P., Vadai, E., Roitman, L., Ovadya, Y., ... & Krizhanovsky, V. (2017). Quantitative identification of senescent cells in aging and disease. Aging cell, 16(4), 661-671. PMID: 28455874 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506427/ PMC5506427] DOI: 10.1111/acel.12592</ref>
<ref>Vidal, P. J., Pérez, A. P., Yahya, G., & Aldea, M. (2024). Transcriptomic balance and optimal growth are determined by cell size. Molecular Cell. https://doi.org/10.1016/j.molcel.2024.07.005</ref>
<ref>Pérez-Ortín, J. E., García-Marcelo, M. J., Delgado-Román, I., Muñoz-Centeno, M. C., & Chávez, S. (2024). Influence of cell volume on the gene transcription rate. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 195008. PMID: 38246270 DOI: 10.1016/j.bbagrm.2024.195008</ref>
<ref>Lanz, M. C., Zatulovskiy, E., Swaffer, M. P., Zhang, L., Ilerten, I., Zhang, S., ... & Skotheim, J. M. (2022). Increasing cell size remodels the proteome and promotes senescence. Molecular cell, 82(17), 3255-3269. PMID: 35987199 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9444988/ PMC9444988] DOI: 10.1016/j.molcel.2022.07.017</ref>
<ref>Manohar, S., & Neurohr, G. E. (2024). Too big not to fail: emerging evidence for size‐induced senescence. The FEBS Journal, 291(11), 2291-2305. PMID: 37986656 DOI: 10.1111/febs.16983</ref>
<ref>Khurana, A., Chadha, Y., & Schmoller, K. M. (2023). Too big not to fail: Different paths lead to senescence of enlarged cells. Molecular Cell, 83(22), 3946-3947. DOI:https://doi.org/10.1016/j.molcel.2023.10.024</ref>

==== [[Small nucleoli as a visible cellular hallmark of longevity and metabolic health|Correlation between aging and nucleolar size]] ====

== Critical Review ==
While the nine proposed Hallmarks of Aging are believed to each contribute to the aging process itself, definitive evidence is missing. As mentioned previously, many of the hallmarks fail to fulfil the three criteria by which they were selected for. Scientists are, therefore, not yet able to confirm whether ameliorating these hallmarks would indeed lead to a decelerated aging phenotype and increased lifespan, which would provide evidence that these hallmarks are upstream of the aging process.

Consequently, these hallmarks do not offer a ''causal'' explanation as to ''why'' we age, and could potentially just offer a phenotypic observation of associated aging features. In other words, these observed hallmarks might be a result of an upstream unknown aging process, similar to how the appearance of wrinkles or white hairs is known to be associated to older individuals.

Another important aspect of the Hallmarks of Aging by López-Otín et al., is the limitation of its scope to a whole-organism level. The latest high-throughout RNA-seq studies, including from the longevity-research giant [https://www.calicolabs.com Calico], have demonstrated that aging is largely regulated in a tissue-specific manner and that age-dependent changes vary enormously according to cell type.<ref name=":4">Roux, A., Yuan, H., Podshivalova, K., Hendrickson, D., Kerr, R., Kenyon, C., & Kelley, D. (2022). The complete cell atlas of an aging multicellular organism. doi: 10.1101/2022.06.15.496201</ref><ref>Wang, X., Jiang, Q., Song, Y., He, Z., Zhang, H., & Song, M. et al. (2022). Ageing induces tissue‐specific transcriptomic changes in ''Caenorhabditis elegans''. ''The EMBO Journal'', ''41''(8). doi: 10.15252/embj.2021109633</ref> In fact, down-regulation of energy metabolism pathways during aging is the only universal change observed across all cell types.<ref name=":4" /> This highlights the importance of building a more comprehensive tissue-specific reference, for the hallmarks of aging, as it has already been explored in the context of [[Aging and Neurodegeneration|neurodegenerative diseases.]]<ref>Mattson, M., & Arumugam, T. (2018). Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. ''Cell Metabolism'', ''27''(6), 1176-1199. doi: 10.1016/j.cmet.2018.05.011</ref>

'''PanSci''', a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes allowed to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Including aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes.<ref>Zhang, Z., Schaefer, C., Jiang, W., Lu, Z., Lee, J., Sziraki, A., ... & Cao, J. (2024). A Panoramic View of Cell Population Dynamics in Mammalian Aging. bioRxiv, 2024-03. https://doi.org/10.1101/2024.03.01.583001</ref>

Nonetheless, and similarly to the case of [[Epigenetic clock|epigenetic clocks]], the Hallmarks of Aging might provide a useful framework to examine the effect of rejuvenating interventions, until more exhaustive studies of the hallmarks of aging are available at the tissue level.

=== Biomarkers of aging ===
<ref>Aging Biomarker Consortium., Bao, H., Cao, J. et al. (2023). [https://www.researchgate.net/profile/Ruici-Yang/publication/370003516_Biomarkers_of_aging/links/6438fa43168a0b54ecca954a/Biomarkers-of-aging.pdf Biomarkers of aging.] Sci. China Life Sci. https://doi.org/10.1007/s11427-023-2305-0</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Fundamentals]]
[[Category:Database]]

Hallmarks of aging

2024-08-01T17:07:09Z

Dmitry Dzhagarov: /* Cell size */

[[Biological age|Biological aging]] is not regarded as a single process, but rather as a complex group of interconnected cellular and molecular mechanisms. It is also worth noting that within the field of aging research there is also disagreement as to the actual concept of aging.<ref>Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.</ref>

The ¨Hallmarks of Aging¨ describe the basic processes thought to underlie aging in different organisms. These hallmarks are thought to be fundamental mechanisms shared across multiple major age-related diseases such as cancer, diabetes, cardiovascular disorders and neurodegenerative diseases. In a now widely-cited [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ 2013 research paper], nine tentative hallmarks of aging were proposed.<ref name=":0">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell'', ''153''(6), 1194-1217.</ref>

It is important to note that these hallmarks only offer a phenotypic observation of features associated with aging, but may fail to provide a ''causal'' explanation of aging (see section ´''[https://en.longevitywiki.org/wiki/Hallmarks_of_Aging#Critical_Review Critical Review]´'').

A decade after the original review, the "Hallmarks of Aging" has been updated and 3 new hallmarks have been added: [[Autophagy|disabled macroautophagy]], [[Inflammaging|chronic inflammation]] and dysbiosis.<ref>López-Otín, C. ''et al.'' (2023) “Hallmarks of aging: An expanding universe,” ''Cell'', 186(2), pp. 243–278. Available at: <nowiki>https://doi.org/10.1016/j.cell.2022.11.001</nowiki>. </ref>
== Criteria for the Hallmarks of Aging ==
López-Otín et al.<ref name=":0" /> proposed in 2013 nine candidate aging traits thought to contribute to the aging phenotype and determine lifespan. These candidates arise from previous findings in research literature, with special focus on mammalian aging but also including key insights from simpler model organisms such as C. ''elegans''.<ref>Kenyon, C. (2010). The genetics of ageing. ''Nature'', ''464''(7288), 504-512. doi: 10.1038/nature08980</ref><ref>Gems, D., & Partridge, L. (2013). Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. ''Annual Review Of Physiology'', ''75''(1), 621-644. doi: 10.1146/annurev-physiol-030212-183712</ref>

The '''criteria''' that each hallmark should, ideally, fulfil in order to be considered as an aging hallmark are:

# The hallmark should not only appear in a given mutant, but should in fact be present in wild-type aging models.
# Increasing the incidence of a hallmark (or degree to which is present) should lead to accelerated aging and shorter lifespan.
# Decreasing the incidence of a hallmark should lead to a decreased rate of aging and longer lifespan.

The authors of the study acknowledge that all three criteria are not met in many hallmarks, specially regarding criterion #3. They argue that complex relationships and interconnectedness between all hallmarks impedes observing beneficial lifespan effects when modifying just one aspect of aging. Furthermore, the lack of knowledge regarding how to experimentally ameliorate some hallmarks adds difficulty into validating this criterion.

== Categories of the Hallmarks of Aging ==
The proposed Hallmarks of Aging are grouped into three main categories according to their hierarchy.[[File:The categories of the Hallmarks of Aging.jpg|thumb|The categories of the Hallmarks of Aging and their functional hierarchy.<ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref>|350x350px]]
'''Primary hallmarks''' - defined as negative traits and sources of damage, which unequivocally lead to decreased health. This category includes:

* Genomic instability
* Telomere attrition
* Epigenetic alterations
* Loss of Proteostasiss

'''Antagonist hallmarks''' - defined as traits resulting from response to damage, and with varying effects on health depending on the intensity of their activity. For instance, low levels of cellular senescence might lead to health benefits, whilst high levels of cellular senesce might, in the opposite way, cause accelerated aging. This includes:

* Deregulated nutrient sensing
* Mitochondrial dysfunction
* Cellular senescence

'''Integrative hallmarks''' - defined as traits resulting from dysfunctional damage responses and considered to be the "culprits" of the aging phenotypes, given their direct negative effect on tissue homeostasis and function. This comprises:

* Stem cell exhaustion
* Altered intercellular communication

== The 9 Hallmarks of Aging ==
[[File:Scheme of the 9 Hallmarks of Aging.jpg|thumb|Graphic of the nine proposed hallmarks of aging, as described on López-Otín et al. 2013 Review on ''Cell''.<ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref> These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.]]

=== 1. Genomic instability ===
''See the full article on [[DNA damage and repair]]''

The genome is the total sum of DNA in our body and becomes damaged over time, with genomic instability leading to various age-related health problems.<ref name=":0" /> DNA carries the information to make proteins that make up cells and tissues in living organisms.

DNA damage may be caused by UV radiation, X-ray radiation, chemical toxins such as tobacco.<ref name=":2">Rastogi, R. P., Kumar, A., Tyagi, M. B., & Sinha, R. P. (2010). Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair. ''Journal of nucleic acids'', ''2010''.</ref> The damage can also occur due to normal chemical reactions in our body, known as metabolism, and create byproducts (reactive oxygen species) that damage the DNA.<ref name=":2" />

As detailed in a review article, some scientists regard DNA damage as a unifying cause of the aging process, with causative interactions with all the so-called hallmarks of aging.<ref>Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. (2021). The central role of DNA damage in the ageing process. ''Nature'', ''592''(7856), 695-703.</ref>

The body has evolved repair systems to deal with the DNA damage as it arises and special proteins (enzymes) detect and repair broken strands of the DNA. However, the DNA repair processes are not perfect and errors in the DNA (mutations) arise over time. The body generally deals with these cells with too many mutations, through a kind of programmed cell suicide known as apoptosis. Alternatively, cells can undergo cellular senescence, a state of permanent cell cycle arrest that prevents further cell division. These senescent cells accumulate with aging and have been causatively linked to various age-related diseases and functional decline in mice.<ref>Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019). Cellular senescence: aging, cancer, and injury. ''Physiological reviews'', ''99''(2), 1047-1078.</ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. ''Nature'', ''479''(7372), 232-236.</ref>

=== 2. Telomere attrition ===
''See the full article on [[telomeres]].''

[[Telomeres]] are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. They protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the ends of the DNA strand for a double strand break.

Telomere shortening is associated with aging, mortality and aging-related diseases.<ref name=":0" /> Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging.<ref>Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref> Leonard Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase.<ref>Hayflick, L. (1965). The limited in vitro lifetime of human diploid cell strains. ''Experimental cell research'', ''37''(3), 614-636.</ref> Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. This is useful when uncontrolled cell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary.

An enzyme called telomerase elongates [[telomeres]] in gametes (reproductive cells) and embryonic stem cells. Telomerase deficiency in humans has been linked to several aging-related diseases related to loss of regenerative capacity of tissues.<ref>de Jesus, B. B., & Blasco, M. A. (2013). Telomerase at the intersection of cancer and aging. ''Trends in genetics'', ''29''(9), 513-520.</ref> It has also been shown that premature aging in telomerase-deficient mice is reverted when telomerase is reactivated.<ref>Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., ... & DePinho, R. A. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. ''Nature'', ''469''(7328), 102-106.</ref>

=== 3. Epigenetic alterations ===
''Learn about [[Epigenetic clock|epigenetic clocks]].''

Out of all the genes that make up a genome, only a subset are expressed at any given time. The functioning of a genome depends both on the specific order of its nucleotides (genomic factors), and also on which sections of the DNA chain are spooled tightly on histones and thus rendered inaccessible, and which ones are unspooled and available for transcription (epigenomic factors). Depending on the needs of the specific tissue type and environment that a given cell is in, histones can be modified to turn specific genes on or off as needed. The profile of where, when and to what extent these modifications occur (the epigenetic profile) changes with aging, turning useful genes off and unnecessary ones on, disrupting the normal functioning of the cell.

As an example, [[sirtuins]] are a type of protein deacetylase that promotes the binding of DNA onto histones and thus controls gene expression by turning them of or off. These enzymes use [[NAD+|NAD]] as a cofactor. As we age, the level of [[NAD+|NAD]] in our cells decreases and so does the ability of certain sirtuins to turn off unneeded genes at the right time. Decreasing the activity of certain sirtuins has been associated with accelerated aging and increasing their activity has been shown to stave off several age-related diseases.

=== 4. Loss of proteostasis ===
''See the full article on [[proteostasis]].''

[[Proteostasis]] is the homeostatic process of maintaining all the proteins necessary for the functioning of the cell in their proper shape, structure and abundance.<ref name=":0" /> Protein misfolding, oxidation, abnormal cleavage or undesired post-translational modification can create dysfunctional or even toxic proteins or protein aggregates that hinder the normal functioning of the cell. Though these proteins are continually removed and recycled, formation of damaged or aggregated proteins increases with age, leading to a gradual loss of proteostasis. Based on animal studies, this can be slowed or suppressed by caloric restriction or by administration of rapamycin, which is partly mediated through inhibiting the mTOR pathway.

Loss of [[proteostasis]] has been linked to various age-related diseases. [[Aging and neurodegeneration|Neurodegenerative]] diseases are prominent examples of this, for example, Alzheimer's is associated with the accumulation of proteins that are regarded as toxic to brain neurons, such as amyloid beta and tau.<ref>Kaeberlein, M., & Galvan, V. (2019). Rapamycin and Alzheimer’s disease: time for a clinical trial?. ''Science translational medicine'', ''11''(476).</ref><ref name=":1">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> The role of aging in the loss of proteostasis has been shown to improve diseases such as Alzheimer's and Parkinson's, via investigating rapamycin or chaperone-mediated autophagy.<ref name=":1" /><ref>[https://link.springer.com/article/10.1007/s11064-012-0909-8 Yao, R. Q., Qi, D. S., Yu, H. L., Liu, J., Yang, L. H., & Wu, X. X. (2012). Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF–TrkB–PI3K/Akt signaling pathway. ''Neurochemical research'', ''37''(12), 2777-2786.]</ref><ref>Pupyshev, A. B., Tikhonova, M. A., Akopyan, A. A., Tenditnik, M. V., Dubrovina, N. I., & Korolenko, T. A. (2019). Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease. ''Pharmacology Biochemistry and Behavior'', ''177'', 1-11.</ref>

=== 5. Deregulated nutrient-sensing ===
''See the full article on [[metabolic flexibility]].''

Nutrient sensing is a cell's ability to recognize, and respond to, changes in the concentration of macronutrients such as glucose, fatty acids and amino acids. In times of abundance, anabolism is induced through various pathways, the most well-studied among them the [[mTOR]] pathway. When energy and nutrients are scarce, proteins such as the AMPK receptor senses this and turns down mTOR to conserve resources.

In a growing organism, growth and cell proliferation are important and thus mTOR is upregulated. In a fully grown organism, mTOR-activating signals naturally decline during aging. It has been found that forcibly overactivating these pathways in grown mice leads to accelerated aging and increased incidence of cancer. mTOR inhibition methods like [[Calorie restriction|dietary restriction]] or [[rapamycin]] have been shown to be one of the most robust methods of increasing healthy lifespan in worms, flies and mice.

[[Metabolic flexibility]] is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states. This has shown to be dependent on functional mitochondrial dynamics.<ref name=":3">Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metabolism, 26(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref> Loss of [[metabolic flexibility]] (or the proper activation/suppression of the AMPK and mTOR pathways) during aging has been proposed as the main [[risk factor]] for the onset of age-related diseases.<ref name=":3" />

=== 6. Mitochondrial dysfunction ===
''See the full article on [[Mitochondrial Dysfunction|mitochondrial dysfunction]].''

The [[mitochondria]] is the powerhouse of the cell. Different human cells can contain up to thousands of mitochondria, each one converting carbon (in the form of acetyl-CoA) and oxygen into energy (in the form of ATP) and carbon dioxide during cellular respiration.

During aging, the efficiency of mitochondria tends to decrease. The reasons for this are still quite unclear, but several mechanisms are suspected - reduced biogenesis, accumulation of damage and mutations in mitochondrial DNA, oxidation of mitochondrial proteins, and defective quality control by mitophagy. [[Mitochondrial Dysfunction|Dysfunctional mitochondria]] contribute to aging through interfering with intercellular signalling and triggering inflammatory reactions.

[[Mitochondria]] are highly dynamic organelles that undergo coordinated cycles of fission and fusion in order to maintain their shape, distribution and size, as shown by imaging studies in live cells. Functional mitochondrial dynamics are key for regulating organismal homeostasis and are required to maintain appropriate [[metabolic flexibility]].

=== 7. Cellular senescence ===
''See the full article on [[cellular senescence]].''

Under certain conditions, a cell will exit the cell cycle without dying, instead becoming dormant and ceasing its normal function. This is called cellular senescence. Senescence can be induced by several factors, including telomere shortening, DNA damage and stress. Since the immune system is programmed to seek out and eliminate senescent cells, it might be that senescence is one way for the body to rid itself of cells damaged beyond repair. Compounds targeting the removal of senescent cells are known as [[senolytics]].

The links between cell senescence and aging are several:

* The proportion of senescent cells increases with age.
* Senescent cells secrete inflammatory markers which may contribute to aging.
* Clearance of senescent cells has been found to delay the onset of age-related disorders.

=== 8. Stem cell exhaustion ===
Stem cells are undifferentiated or partially differentiated cells that can proliferate indefinitely. For the first few days after fertilization, the embryo consists almost entirely of stem cells. As the fetus grows, the cells multiply, differentiate and assume their appropriate function within the organism. In adults, stem cells are mostly located in areas that undergo gradual wear (intestine, lung, mucosa, skin) or need continuous replenishment (red blood cells, immune cells, sperm cells, hair follicles).

Loss of regenerative ability is one of the most obvious consequences of aging. This is largely because the proportion of stem cells and the speed of their division gradually lowers over time. It has been found that stem cell rejuvenation can reverse some of the effects of aging at the organismal level.

=== 9. Altered intercellular communication ===
Different tissues and the cells they consist of need to orchestrate their work in a tightly controlled manner so that the organism as a whole can function. One of the main ways this is achieved is through excreting signal molecules into the blood where they make their way to other tissues, affecting their behavior. The profile of these molecules changes as we age.

One of the most prominent changes in cell signaling biomarkers is "[[inflammaging]]", the development of a chronic low-grade inflammation throughout the body with advanced age. The normal role of inflammation is to recruit the body's immune system and repair mechanisms to a specific damaged area for as long as the damage and threat are present. The constant presence of inflammation markers throughout the body wears out the immune system and damages healthy tissue.

It's also been found that senescent cells excrete a specific set of molecules called the [[Cellular_senescence#SASP|'''SASP''']] (Senescence-Associated Secretory Phenotype) which induce [[Cellular senescence|senescence]] in neighboring cells. Conversely, lifespan-extending manipulations targeting one tissue can slow the aging process in other tissues as well.

=== 10. Cell size ===
<ref>Lengefeld, J., Cheng, C. W., Maretich, P., Blair, M., Hagen, H., McReynolds, M. R., ... & Amon, A. (2021). Cell size is a determinant of stem cell potential during aging. Science advances, 7(46), eabk0271.</ref>
<ref>Biran, A., Zada, L., Abou Karam, P., Vadai, E., Roitman, L., Ovadya, Y., ... & Krizhanovsky, V. (2017). Quantitative identification of senescent cells in aging and disease. Aging cell, 16(4), 661-671. PMID: 28455874 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506427/ PMC5506427] DOI: 10.1111/acel.12592</ref>
<ref>Vidal, P. J., Pérez, A. P., Yahya, G., & Aldea, M. (2024). Transcriptomic balance and optimal growth are determined by cell size. Molecular Cell. https://doi.org/10.1016/j.molcel.2024.07.005</ref>
<ref>Pérez-Ortín, J. E., García-Marcelo, M. J., Delgado-Román, I., Muñoz-Centeno, M. C., & Chávez, S. (2024). Influence of cell volume on the gene transcription rate. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 195008. PMID: 38246270 DOI: 10.1016/j.bbagrm.2024.195008</ref>
<ref>Lanz, M. C., Zatulovskiy, E., Swaffer, M. P., Zhang, L., Ilerten, I., Zhang, S., ... & Skotheim, J. M. (2022). Increasing cell size remodels the proteome and promotes senescence. Molecular cell, 82(17), 3255-3269. PMID: 35987199 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9444988/ PMC9444988] DOI: 10.1016/j.molcel.2022.07.017</ref>
<ref>Manohar, S., & Neurohr, G. E. (2024). Too big not to fail: emerging evidence for size‐induced senescence. The FEBS Journal, 291(11), 2291-2305. PMID: 37986656 DOI: 10.1111/febs.16983</ref>
<ref>Khurana, A., Chadha, Y., & Schmoller, K. M. (2023). Too big not to fail: Different paths lead to senescence of enlarged cells. Molecular Cell, 83(22), 3946-3947. DOI:https://doi.org/10.1016/j.molcel.2023.10.024</ref>

== Critical Review ==
While the nine proposed Hallmarks of Aging are believed to each contribute to the aging process itself, definitive evidence is missing. As mentioned previously, many of the hallmarks fail to fulfil the three criteria by which they were selected for. Scientists are, therefore, not yet able to confirm whether ameliorating these hallmarks would indeed lead to a decelerated aging phenotype and increased lifespan, which would provide evidence that these hallmarks are upstream of the aging process.

Consequently, these hallmarks do not offer a ''causal'' explanation as to ''why'' we age, and could potentially just offer a phenotypic observation of associated aging features. In other words, these observed hallmarks might be a result of an upstream unknown aging process, similar to how the appearance of wrinkles or white hairs is known to be associated to older individuals.

Another important aspect of the Hallmarks of Aging by López-Otín et al., is the limitation of its scope to a whole-organism level. The latest high-throughout RNA-seq studies, including from the longevity-research giant [https://www.calicolabs.com Calico], have demonstrated that aging is largely regulated in a tissue-specific manner and that age-dependent changes vary enormously according to cell type.<ref name=":4">Roux, A., Yuan, H., Podshivalova, K., Hendrickson, D., Kerr, R., Kenyon, C., & Kelley, D. (2022). The complete cell atlas of an aging multicellular organism. doi: 10.1101/2022.06.15.496201</ref><ref>Wang, X., Jiang, Q., Song, Y., He, Z., Zhang, H., & Song, M. et al. (2022). Ageing induces tissue‐specific transcriptomic changes in ''Caenorhabditis elegans''. ''The EMBO Journal'', ''41''(8). doi: 10.15252/embj.2021109633</ref> In fact, down-regulation of energy metabolism pathways during aging is the only universal change observed across all cell types.<ref name=":4" /> This highlights the importance of building a more comprehensive tissue-specific reference, for the hallmarks of aging, as it has already been explored in the context of [[Aging and Neurodegeneration|neurodegenerative diseases.]]<ref>Mattson, M., & Arumugam, T. (2018). Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. ''Cell Metabolism'', ''27''(6), 1176-1199. doi: 10.1016/j.cmet.2018.05.011</ref>

'''PanSci''', a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes allowed to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Including aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes.<ref>Zhang, Z., Schaefer, C., Jiang, W., Lu, Z., Lee, J., Sziraki, A., ... & Cao, J. (2024). A Panoramic View of Cell Population Dynamics in Mammalian Aging. bioRxiv, 2024-03. https://doi.org/10.1101/2024.03.01.583001</ref>

Nonetheless, and similarly to the case of [[Epigenetic clock|epigenetic clocks]], the Hallmarks of Aging might provide a useful framework to examine the effect of rejuvenating interventions, until more exhaustive studies of the hallmarks of aging are available at the tissue level.

=== Biomarkers of aging ===
<ref>Aging Biomarker Consortium., Bao, H., Cao, J. et al. (2023). [https://www.researchgate.net/profile/Ruici-Yang/publication/370003516_Biomarkers_of_aging/links/6438fa43168a0b54ecca954a/Biomarkers-of-aging.pdf Biomarkers of aging.] Sci. China Life Sci. https://doi.org/10.1007/s11427-023-2305-0</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Fundamentals]]
[[Category:Database]]

Hallmarks of aging

2024-08-01T16:20:26Z

Dmitry Dzhagarov: /* 9. Altered intercellular communication */

[[Biological age|Biological aging]] is not regarded as a single process, but rather as a complex group of interconnected cellular and molecular mechanisms. It is also worth noting that within the field of aging research there is also disagreement as to the actual concept of aging.<ref>Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.</ref>

The ¨Hallmarks of Aging¨ describe the basic processes thought to underlie aging in different organisms. These hallmarks are thought to be fundamental mechanisms shared across multiple major age-related diseases such as cancer, diabetes, cardiovascular disorders and neurodegenerative diseases. In a now widely-cited [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ 2013 research paper], nine tentative hallmarks of aging were proposed.<ref name=":0">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell'', ''153''(6), 1194-1217.</ref>

It is important to note that these hallmarks only offer a phenotypic observation of features associated with aging, but may fail to provide a ''causal'' explanation of aging (see section ´''[https://en.longevitywiki.org/wiki/Hallmarks_of_Aging#Critical_Review Critical Review]´'').

A decade after the original review, the "Hallmarks of Aging" has been updated and 3 new hallmarks have been added: [[Autophagy|disabled macroautophagy]], [[Inflammaging|chronic inflammation]] and dysbiosis.<ref>López-Otín, C. ''et al.'' (2023) “Hallmarks of aging: An expanding universe,” ''Cell'', 186(2), pp. 243–278. Available at: <nowiki>https://doi.org/10.1016/j.cell.2022.11.001</nowiki>. </ref>
== Criteria for the Hallmarks of Aging ==
López-Otín et al.<ref name=":0" /> proposed in 2013 nine candidate aging traits thought to contribute to the aging phenotype and determine lifespan. These candidates arise from previous findings in research literature, with special focus on mammalian aging but also including key insights from simpler model organisms such as C. ''elegans''.<ref>Kenyon, C. (2010). The genetics of ageing. ''Nature'', ''464''(7288), 504-512. doi: 10.1038/nature08980</ref><ref>Gems, D., & Partridge, L. (2013). Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. ''Annual Review Of Physiology'', ''75''(1), 621-644. doi: 10.1146/annurev-physiol-030212-183712</ref>

The '''criteria''' that each hallmark should, ideally, fulfil in order to be considered as an aging hallmark are:

# The hallmark should not only appear in a given mutant, but should in fact be present in wild-type aging models.
# Increasing the incidence of a hallmark (or degree to which is present) should lead to accelerated aging and shorter lifespan.
# Decreasing the incidence of a hallmark should lead to a decreased rate of aging and longer lifespan.

The authors of the study acknowledge that all three criteria are not met in many hallmarks, specially regarding criterion #3. They argue that complex relationships and interconnectedness between all hallmarks impedes observing beneficial lifespan effects when modifying just one aspect of aging. Furthermore, the lack of knowledge regarding how to experimentally ameliorate some hallmarks adds difficulty into validating this criterion.

== Categories of the Hallmarks of Aging ==
The proposed Hallmarks of Aging are grouped into three main categories according to their hierarchy.[[File:The categories of the Hallmarks of Aging.jpg|thumb|The categories of the Hallmarks of Aging and their functional hierarchy.<ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref>|350x350px]]
'''Primary hallmarks''' - defined as negative traits and sources of damage, which unequivocally lead to decreased health. This category includes:

* Genomic instability
* Telomere attrition
* Epigenetic alterations
* Loss of Proteostasiss

'''Antagonist hallmarks''' - defined as traits resulting from response to damage, and with varying effects on health depending on the intensity of their activity. For instance, low levels of cellular senescence might lead to health benefits, whilst high levels of cellular senesce might, in the opposite way, cause accelerated aging. This includes:

* Deregulated nutrient sensing
* Mitochondrial dysfunction
* Cellular senescence

'''Integrative hallmarks''' - defined as traits resulting from dysfunctional damage responses and considered to be the "culprits" of the aging phenotypes, given their direct negative effect on tissue homeostasis and function. This comprises:

* Stem cell exhaustion
* Altered intercellular communication

== The 9 Hallmarks of Aging ==
[[File:Scheme of the 9 Hallmarks of Aging.jpg|thumb|Graphic of the nine proposed hallmarks of aging, as described on López-Otín et al. 2013 Review on ''Cell''.<ref>López-Otín, C., Blasco, M., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. ''Cell'', ''153''(6), 1194-1217. doi: 10.1016/j.cell.2013.05.039</ref> These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.]]

=== 1. Genomic instability ===
''See the full article on [[DNA damage and repair]]''

The genome is the total sum of DNA in our body and becomes damaged over time, with genomic instability leading to various age-related health problems.<ref name=":0" /> DNA carries the information to make proteins that make up cells and tissues in living organisms.

DNA damage may be caused by UV radiation, X-ray radiation, chemical toxins such as tobacco.<ref name=":2">Rastogi, R. P., Kumar, A., Tyagi, M. B., & Sinha, R. P. (2010). Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair. ''Journal of nucleic acids'', ''2010''.</ref> The damage can also occur due to normal chemical reactions in our body, known as metabolism, and create byproducts (reactive oxygen species) that damage the DNA.<ref name=":2" />

As detailed in a review article, some scientists regard DNA damage as a unifying cause of the aging process, with causative interactions with all the so-called hallmarks of aging.<ref>Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. (2021). The central role of DNA damage in the ageing process. ''Nature'', ''592''(7856), 695-703.</ref>

The body has evolved repair systems to deal with the DNA damage as it arises and special proteins (enzymes) detect and repair broken strands of the DNA. However, the DNA repair processes are not perfect and errors in the DNA (mutations) arise over time. The body generally deals with these cells with too many mutations, through a kind of programmed cell suicide known as apoptosis. Alternatively, cells can undergo cellular senescence, a state of permanent cell cycle arrest that prevents further cell division. These senescent cells accumulate with aging and have been causatively linked to various age-related diseases and functional decline in mice.<ref>Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019). Cellular senescence: aging, cancer, and injury. ''Physiological reviews'', ''99''(2), 1047-1078.</ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. ''Nature'', ''479''(7372), 232-236.</ref>

=== 2. Telomere attrition ===
''See the full article on [[telomeres]].''

[[Telomeres]] are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. They protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the ends of the DNA strand for a double strand break.

Telomere shortening is associated with aging, mortality and aging-related diseases.<ref name=":0" /> Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging.<ref>Muñoz-Lorente, M. A., Cano-Martin, A. C., & Blasco, M. A. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. ''Nature communications'', ''10''(1), 1-14.</ref> Leonard Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase.<ref>Hayflick, L. (1965). The limited in vitro lifetime of human diploid cell strains. ''Experimental cell research'', ''37''(3), 614-636.</ref> Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. This is useful when uncontrolled cell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary.

An enzyme called telomerase elongates [[telomeres]] in gametes (reproductive cells) and embryonic stem cells. Telomerase deficiency in humans has been linked to several aging-related diseases related to loss of regenerative capacity of tissues.<ref>de Jesus, B. B., & Blasco, M. A. (2013). Telomerase at the intersection of cancer and aging. ''Trends in genetics'', ''29''(9), 513-520.</ref> It has also been shown that premature aging in telomerase-deficient mice is reverted when telomerase is reactivated.<ref>Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., ... & DePinho, R. A. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. ''Nature'', ''469''(7328), 102-106.</ref>

=== 3. Epigenetic alterations ===
''Learn about [[Epigenetic clock|epigenetic clocks]].''

Out of all the genes that make up a genome, only a subset are expressed at any given time. The functioning of a genome depends both on the specific order of its nucleotides (genomic factors), and also on which sections of the DNA chain are spooled tightly on histones and thus rendered inaccessible, and which ones are unspooled and available for transcription (epigenomic factors). Depending on the needs of the specific tissue type and environment that a given cell is in, histones can be modified to turn specific genes on or off as needed. The profile of where, when and to what extent these modifications occur (the epigenetic profile) changes with aging, turning useful genes off and unnecessary ones on, disrupting the normal functioning of the cell.

As an example, [[sirtuins]] are a type of protein deacetylase that promotes the binding of DNA onto histones and thus controls gene expression by turning them of or off. These enzymes use [[NAD+|NAD]] as a cofactor. As we age, the level of [[NAD+|NAD]] in our cells decreases and so does the ability of certain sirtuins to turn off unneeded genes at the right time. Decreasing the activity of certain sirtuins has been associated with accelerated aging and increasing their activity has been shown to stave off several age-related diseases.

=== 4. Loss of proteostasis ===
''See the full article on [[proteostasis]].''

[[Proteostasis]] is the homeostatic process of maintaining all the proteins necessary for the functioning of the cell in their proper shape, structure and abundance.<ref name=":0" /> Protein misfolding, oxidation, abnormal cleavage or undesired post-translational modification can create dysfunctional or even toxic proteins or protein aggregates that hinder the normal functioning of the cell. Though these proteins are continually removed and recycled, formation of damaged or aggregated proteins increases with age, leading to a gradual loss of proteostasis. Based on animal studies, this can be slowed or suppressed by caloric restriction or by administration of rapamycin, which is partly mediated through inhibiting the mTOR pathway.

Loss of [[proteostasis]] has been linked to various age-related diseases. [[Aging and neurodegeneration|Neurodegenerative]] diseases are prominent examples of this, for example, Alzheimer's is associated with the accumulation of proteins that are regarded as toxic to brain neurons, such as amyloid beta and tau.<ref>Kaeberlein, M., & Galvan, V. (2019). Rapamycin and Alzheimer’s disease: time for a clinical trial?. ''Science translational medicine'', ''11''(476).</ref><ref name=":1">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> The role of aging in the loss of proteostasis has been shown to improve diseases such as Alzheimer's and Parkinson's, via investigating rapamycin or chaperone-mediated autophagy.<ref name=":1" /><ref>[https://link.springer.com/article/10.1007/s11064-012-0909-8 Yao, R. Q., Qi, D. S., Yu, H. L., Liu, J., Yang, L. H., & Wu, X. X. (2012). Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF–TrkB–PI3K/Akt signaling pathway. ''Neurochemical research'', ''37''(12), 2777-2786.]</ref><ref>Pupyshev, A. B., Tikhonova, M. A., Akopyan, A. A., Tenditnik, M. V., Dubrovina, N. I., & Korolenko, T. A. (2019). Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease. ''Pharmacology Biochemistry and Behavior'', ''177'', 1-11.</ref>

=== 5. Deregulated nutrient-sensing ===
''See the full article on [[metabolic flexibility]].''

Nutrient sensing is a cell's ability to recognize, and respond to, changes in the concentration of macronutrients such as glucose, fatty acids and amino acids. In times of abundance, anabolism is induced through various pathways, the most well-studied among them the [[mTOR]] pathway. When energy and nutrients are scarce, proteins such as the AMPK receptor senses this and turns down mTOR to conserve resources.

In a growing organism, growth and cell proliferation are important and thus mTOR is upregulated. In a fully grown organism, mTOR-activating signals naturally decline during aging. It has been found that forcibly overactivating these pathways in grown mice leads to accelerated aging and increased incidence of cancer. mTOR inhibition methods like [[Calorie restriction|dietary restriction]] or [[rapamycin]] have been shown to be one of the most robust methods of increasing healthy lifespan in worms, flies and mice.

[[Metabolic flexibility]] is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states. This has shown to be dependent on functional mitochondrial dynamics.<ref name=":3">Weir, H., Yao, P., Huynh, F., Escoubas, C., Goncalves, R., & Burkewitz, K. et al. (2017). Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metabolism, 26(6), 884-896.e5. doi: 10.1016/j.cmet.2017.09.024</ref> Loss of [[metabolic flexibility]] (or the proper activation/suppression of the AMPK and mTOR pathways) during aging has been proposed as the main [[risk factor]] for the onset of age-related diseases.<ref name=":3" />

=== 6. Mitochondrial dysfunction ===
''See the full article on [[Mitochondrial Dysfunction|mitochondrial dysfunction]].''

The [[mitochondria]] is the powerhouse of the cell. Different human cells can contain up to thousands of mitochondria, each one converting carbon (in the form of acetyl-CoA) and oxygen into energy (in the form of ATP) and carbon dioxide during cellular respiration.

During aging, the efficiency of mitochondria tends to decrease. The reasons for this are still quite unclear, but several mechanisms are suspected - reduced biogenesis, accumulation of damage and mutations in mitochondrial DNA, oxidation of mitochondrial proteins, and defective quality control by mitophagy. [[Mitochondrial Dysfunction|Dysfunctional mitochondria]] contribute to aging through interfering with intercellular signalling and triggering inflammatory reactions.

[[Mitochondria]] are highly dynamic organelles that undergo coordinated cycles of fission and fusion in order to maintain their shape, distribution and size, as shown by imaging studies in live cells. Functional mitochondrial dynamics are key for regulating organismal homeostasis and are required to maintain appropriate [[metabolic flexibility]].

=== 7. Cellular senescence ===
''See the full article on [[cellular senescence]].''

Under certain conditions, a cell will exit the cell cycle without dying, instead becoming dormant and ceasing its normal function. This is called cellular senescence. Senescence can be induced by several factors, including telomere shortening, DNA damage and stress. Since the immune system is programmed to seek out and eliminate senescent cells, it might be that senescence is one way for the body to rid itself of cells damaged beyond repair. Compounds targeting the removal of senescent cells are known as [[senolytics]].

The links between cell senescence and aging are several:

* The proportion of senescent cells increases with age.
* Senescent cells secrete inflammatory markers which may contribute to aging.
* Clearance of senescent cells has been found to delay the onset of age-related disorders.

=== 8. Stem cell exhaustion ===
Stem cells are undifferentiated or partially differentiated cells that can proliferate indefinitely. For the first few days after fertilization, the embryo consists almost entirely of stem cells. As the fetus grows, the cells multiply, differentiate and assume their appropriate function within the organism. In adults, stem cells are mostly located in areas that undergo gradual wear (intestine, lung, mucosa, skin) or need continuous replenishment (red blood cells, immune cells, sperm cells, hair follicles).

Loss of regenerative ability is one of the most obvious consequences of aging. This is largely because the proportion of stem cells and the speed of their division gradually lowers over time. It has been found that stem cell rejuvenation can reverse some of the effects of aging at the organismal level.

=== 9. Altered intercellular communication ===
Different tissues and the cells they consist of need to orchestrate their work in a tightly controlled manner so that the organism as a whole can function. One of the main ways this is achieved is through excreting signal molecules into the blood where they make their way to other tissues, affecting their behavior. The profile of these molecules changes as we age.

One of the most prominent changes in cell signaling biomarkers is "[[inflammaging]]", the development of a chronic low-grade inflammation throughout the body with advanced age. The normal role of inflammation is to recruit the body's immune system and repair mechanisms to a specific damaged area for as long as the damage and threat are present. The constant presence of inflammation markers throughout the body wears out the immune system and damages healthy tissue.

It's also been found that senescent cells excrete a specific set of molecules called the [[Cellular_senescence#SASP|'''SASP''']] (Senescence-Associated Secretory Phenotype) which induce [[Cellular senescence|senescence]] in neighboring cells. Conversely, lifespan-extending manipulations targeting one tissue can slow the aging process in other tissues as well.

=== Cell size ===
<ref>Lengefeld, J., Cheng, C. W., Maretich, P., Blair, M., Hagen, H., McReynolds, M. R., ... & Amon, A. (2021). Cell size is a determinant of stem cell potential during aging. Science advances, 7(46), eabk0271.</ref>
<ref>Biran, A., Zada, L., Abou Karam, P., Vadai, E., Roitman, L., Ovadya, Y., ... & Krizhanovsky, V. (2017). Quantitative identification of senescent cells in aging and disease. Aging cell, 16(4), 661-671. PMID: 28455874 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506427/ PMC5506427] DOI: 10.1111/acel.12592</ref>
<ref>Vidal, P. J., Pérez, A. P., Yahya, G., & Aldea, M. (2024). Transcriptomic balance and optimal growth are determined by cell size. Molecular Cell. https://doi.org/10.1016/j.molcel.2024.07.005</ref>
<ref>Pérez-Ortín, J. E., García-Marcelo, M. J., Delgado-Román, I., Muñoz-Centeno, M. C., & Chávez, S. (2024). Influence of cell volume on the gene transcription rate. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 195008. PMID: 38246270 DOI: 10.1016/j.bbagrm.2024.195008</ref>

== Critical Review ==
While the nine proposed Hallmarks of Aging are believed to each contribute to the aging process itself, definitive evidence is missing. As mentioned previously, many of the hallmarks fail to fulfil the three criteria by which they were selected for. Scientists are, therefore, not yet able to confirm whether ameliorating these hallmarks would indeed lead to a decelerated aging phenotype and increased lifespan, which would provide evidence that these hallmarks are upstream of the aging process.

Consequently, these hallmarks do not offer a ''causal'' explanation as to ''why'' we age, and could potentially just offer a phenotypic observation of associated aging features. In other words, these observed hallmarks might be a result of an upstream unknown aging process, similar to how the appearance of wrinkles or white hairs is known to be associated to older individuals.

Another important aspect of the Hallmarks of Aging by López-Otín et al., is the limitation of its scope to a whole-organism level. The latest high-throughout RNA-seq studies, including from the longevity-research giant [https://www.calicolabs.com Calico], have demonstrated that aging is largely regulated in a tissue-specific manner and that age-dependent changes vary enormously according to cell type.<ref name=":4">Roux, A., Yuan, H., Podshivalova, K., Hendrickson, D., Kerr, R., Kenyon, C., & Kelley, D. (2022). The complete cell atlas of an aging multicellular organism. doi: 10.1101/2022.06.15.496201</ref><ref>Wang, X., Jiang, Q., Song, Y., He, Z., Zhang, H., & Song, M. et al. (2022). Ageing induces tissue‐specific transcriptomic changes in ''Caenorhabditis elegans''. ''The EMBO Journal'', ''41''(8). doi: 10.15252/embj.2021109633</ref> In fact, down-regulation of energy metabolism pathways during aging is the only universal change observed across all cell types.<ref name=":4" /> This highlights the importance of building a more comprehensive tissue-specific reference, for the hallmarks of aging, as it has already been explored in the context of [[Aging and Neurodegeneration|neurodegenerative diseases.]]<ref>Mattson, M., & Arumugam, T. (2018). Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. ''Cell Metabolism'', ''27''(6), 1176-1199. doi: 10.1016/j.cmet.2018.05.011</ref>

'''PanSci''', a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes allowed to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Including aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes.<ref>Zhang, Z., Schaefer, C., Jiang, W., Lu, Z., Lee, J., Sziraki, A., ... & Cao, J. (2024). A Panoramic View of Cell Population Dynamics in Mammalian Aging. bioRxiv, 2024-03. https://doi.org/10.1101/2024.03.01.583001</ref>

Nonetheless, and similarly to the case of [[Epigenetic clock|epigenetic clocks]], the Hallmarks of Aging might provide a useful framework to examine the effect of rejuvenating interventions, until more exhaustive studies of the hallmarks of aging are available at the tissue level.

=== Biomarkers of aging ===
<ref>Aging Biomarker Consortium., Bao, H., Cao, J. et al. (2023). [https://www.researchgate.net/profile/Ruici-Yang/publication/370003516_Biomarkers_of_aging/links/6438fa43168a0b54ecca954a/Biomarkers-of-aging.pdf Biomarkers of aging.] Sci. China Life Sci. https://doi.org/10.1007/s11427-023-2305-0</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Fundamentals]]
[[Category:Database]]

Lipofuscin

2024-08-01T11:35:57Z

Dmitry Dzhagarov: /* Remofuscin */

'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref> In motor neurons of centenarians, up to 75% of cell volume can be occupied by lipofuscin.<ref>Yin, D. (1996). Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radical Biology and Medicine, 21(6), 871-888. PMID: 8902532 DOI: 10.1016/0891-5849(96)00175-x</ref>
[[File:Lipofuscin.jpg|thumb|Lipofuscin spots on the upper surface of the hands.]]
Lipofuscin is proposed as a [[Cellular senescence|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>

Accumulation of lipofuscin or "aging pigment" is part of normal aging, and should be distinguished from accumulation of '''ceroid''' - autofluorescent storage material associated with disease and usually produced under various pathological conditions not necessarily related to aging.<ref>Seehafer, S. S., & Pearce, D. A. (2006). You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiology of aging, 27(4), 576-588. PMID: 16455164 DOI: 10.1016/j.neurobiolaging.2005.12.006</ref> Ceroid has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis.<ref>
Albaghdadi, M. S., Ikegami, R., Kassab, M. B., Gardecki, J. A., Kunio, M., Chowdhury, M. M., ... & Jaffer, F. A. (2021). Near-infrared autofluorescence in atherosclerosis associates with ceroid and is generated by oxidized lipid-induced oxidative stress. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(7), e385-e398. PMID: 34011166 PMC8222195 DOI: 10.1161/ATVBAHA.120.315612</ref>

== Detection of lipofuscin ==
During the process of aging, lipofuscin accumulates in a nearly linear way in postmitotic senescencent cells (cardiomyocytes, retinal epithelial pigment cells, hepatocytes, neurons and keratinocytes),<ref name="biomarker">Georgakopoulou, E. A., Tsimaratou, K., Evangelou, K., Fernandez, M. P., Zoumpourlis, V., Trougakos, I. P., ... & Gorgoulis, V. G. (2013). Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY), 5(1), 37. PMID: 23449538 PMCID: PMC3616230 DOI: 10.18632/aging.100527</ref> and has been proposed as a detectable "marker" to estimate aging. This approach is particularly used to determine the age of crabs and other crustaceans either by labor histological fluorescent-microscopy examinations<ref>Jung, T., Höhn, A., & Grune, T. (2010). Lipofuscin: detection and quantification by microscopic techniques. Advanced Protocols in Oxidative Stress II, 173-193. PMID: 20072918 DOI: 10.1007/978-1-60761-411-1_13</ref> or simply by extractable lipofuscin solvent fluorescence measurements.<ref>Pinchuk, A. I., Harvey, H. R., & Eckert, G. L. (2016). Development of biochemical measures of age in the Alaskan red king crab Paralithodes camtschaticus (Anomura): Validation, refinement and initial assessment. Fisheries Research, 183, 92-98.https://doi.org/10.1016/j.fishres.2016.05.019</ref>

Detection of lipofuscin content can be used as a biomarker of old lysosome accumulation, either by its typical autofluorescence properties and fluorescence-based methods, or by selective staining with Sudan black B, which stained lipofuscin granules, allowing for detection in cells, tissues and body fluids.<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMCID: PMC5242262 DOI: 10.1111/acel.12545</ref><ref>Salmonowicz, H., & Passos, J. F. (2017). Detecting senescence: a new method for an old pigment. Aging Cell, 16(3), 432-434. </ref><ref>Lozano‐Torres, B., Blandez, J. F., García‐Fernández, A., Sancenón, F., & Martínez‐Máñez, R. (2022). Lipofuscin labelling through biorthogonal strain‐promoted azide‐alkyne cycloaddition for the detection of senescent cells. The FEBS Journal. PMID: 35527516 DOI: 10.1111/febs.16477</ref><ref>Evangelou, K., & Gorgoulis, V. G. (2017). Sudan Black B, the specific histochemical stain for lipofuscin: a novel method to detect senescent cells. In Oncogene-Induced Senescence (pp. 111-119). Humana Press, New York, NY. PMID: 27812872 DOI: 10.1007/978-1-4939-6670-7_10</ref>

== Relation to aging diseases ==
Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[Advanced glycation end products (AGEs)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>

Isolated lipofuscin aggregates, as shown in vitro, were readily incorporated by fibroblasts and caused cell death at low concentrations (LC50 = 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity.<ref>Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. (2024). Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. bioRxiv .03.25.586520; doi: https://doi.org/10.1101/2024.03.25.586520</ref>

Lipofuscin granules accumulation can lead to pathology and accelerate the aging process.<ref>Feldman, T. B., Dontsov, A. E., Yakovleva, M. A., & Ostrovsky, M. A. (2022). Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age. Biophysical Reviews, 1-15. PMID: 36124271 PMCID: PMC9481861 (available on 2023-08-08) DOI: 10.1007/s12551-022-00989-9</ref> The rate of lipofuscin formation has been shown to be negatively correlated with the life expectancy of postmitotic cells, i.e., the higher the rate, the shorter the lifespan of the cell due to decrease of cellular adaptability.<ref>Jung, T., Bader, N., & Grune, T. (2007). Lipofuscin: formation, distribution, and metabolic consequences. Annals of the New York Academy of Sciences, 1119(1), 97-111. PMID: 18056959 DOI: 10.1196/annals.1404.008</ref> Therefore, progressive deposition of lipofuscin might promote the development of age-related pathologies, including macular degeneration, heart failure, and neuro-degenerative diseases.

=== Dry AMD ===
One of the diseases associated with the accumulation of lipofuscin is dry [[Aging and eye disease|age-related macular degeneration]] (dry AMD) – a disease often diagnosed in people over 70 years of age and a leading cause of rapid vision loss. Dry AMD is a slow-progressing disease in which yellow drusen containing lipofuscin are deposited between the retinal pigment epithelial (RPE) cell layer and Bruch’s membrane.<ref>Jhingan, M., Singh, S. R., Samanta, A., Arora, S., Tucci, D., Amarasekera, S., ... & Chhablani, J. (2021). Drusen ooze: predictor for progression of dry age-related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology, 259(9), [tel:2687-2694 2687-2694]. DOI:[https://doi.org/10.1007/s00417-021-05147-7 10.1007/s00417-021-05147-7]</ref> A phototoxic components of lipofuscin such as A2E (Bis-retinoid N-retinyl-N-retinylidene ethanolamine) that induces inflammation and apoptosis in RPE cells,<ref>Sparrow, J. R., & Boulton, M. (2005). RPE lipofuscin and its role in retinal pathobiology. Experimental eye research, 80(5), 595-606.</ref> are accumulated with age and mediate damage under blue light exposure.<ref>Brandstetter, C., Mohr, L. K., Latz, E., Holz, F. G., & Krohne, T. U. (2015). Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. Journal of Molecular Medicine, 93(8), 905-916. PMID: 25783493 PMC4510924 DOI: 10.1007/s00109-015-1275-1</ref><ref name="Light">Jin, H. L., & Jeong, K. W. (2022). Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells. Biomolecules & therapeutics, 30(3), 291. PMID: 35074938 PMCID: PMC9047491 DOI: 10.4062/biomolther.2021.155</ref> It has been reported that iron levels increase in RPE during ageing and this intracellular iron can interact with bisretinoid lipofuscin in RPE to promote cell damage.<ref>Zhao, T., Guo, X., & Sun, Y. (2021). Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging and disease, 12(2), 529. PMID: 33815881 PMCID: PMC7990372 DOI: 10.14336/AD.2020.0912</ref> Therefore, to alleviate the deteriorating effects of lipofuscin on age-related macular degeneration, iron chelation, either independently or in combination with bisretinoid inhibitors could potentially serve as AMD treatments.<ref>Ueda, K., Kim, H. J., Zhao, J., Song, Y., Dunaief, J. L., & Sparrow, J. R. (2018). Iron promotes oxidative cell death caused by bisretinoids of retina. Proceedings of the National Academy of Sciences, 115(19), [tel:4963-4968 4963-4968]. PMID: 29686088 PMCID: PMC5948992 DOI: 10.1073/pnas.1722601115</ref> To protect human RPE cells from oxidative damage, caused by reactive oxygen species generated by the photo-excited lipofuscin, also is able L‐Citrulline, a naturally occurring amino acid with known antioxidant properties<ref>Hassel, C., Couchet, M., Jacquemot, N., Blavignac, C., Loï, C., Moinard, C., & Cia, D. (2022). Citrulline protects human retinal pigment epithelium from hydrogen peroxide and iron/ascorbate induced damages. Journal of Cellular and Molecular Medicine, 26(10), [tel:2808-2818 2808-2818]. PMID: 35460170 PMCID: PMC9097847 DOI: 10.1111/jcmm.17294</ref> and the main active component of ''Spirulina maxima'' P-phycocyanin - pigment with anti-inflammatory and antioxidant activities.<ref>Cho, H. M., Jo, Y. D., & Choung, S. Y. (2022). Protective Effects of Spirulina maxima against Blue Light-Induced Retinal Damages in A2E-Laden ARPE-19 Cells and Balb/c Mice. Nutrients, 14(3), 401. PMID: 35276761 PMCID: PMC8840079 DOI: 10.3390/nu14030401</ref>

The drug Lysoclear is an enzyme developed to enter RPE cells and break down lipofuscin deposits in the lysosomes, a therapeutic approach that proposes to reverse dry age-related macular degeneration and Stargardt's macular degeneration.<ref>www.ichortherapeutics.com</ref> Phase 1 clinical trials started in 2018.

==== Zinc deficiency ====
Zinc-deficient animals showed a greater number of lipofuscin granules.<ref>Julien, S., Biesemeier, A., Kokkinou, D., Eibl, O., & Schraermeyer, U. (2011). Zinc deficiency leads to lipofuscin accumulation in the retinal pigment epithelium of pigmented rats. PLoS One, 6(12), e29245. PMID: 22216222 PMCID: PMC3245262 DOI: 10.1371/journal.pone.0029245</ref> The relationship between zinc deficiency and enhanced lipofuscin accumulation suggest that zinc deficiency may result in the accumulation of substrates for autophagy whereas low zinc does not stimulate autophagy.<ref>Blasiak, J., Pawlowska, E., Chojnacki, J., Szczepanska, J., Chojnacki, C., & Kaarniranta, K. (2020). Zinc and autophagy in age-related macular degeneration. International Journal of Molecular Sciences, 21(14), 4994. PMID: 32679798 PMCID: PMC7404247 DOI: 10.3390/ijms21144994</ref> Autophagy is also inhibited when A2E-treated RPE cells are exposed to blue light.<ref name="Light"/> Currently, the only intervention available for the treatment of dry AMD is Age-Related Eye Disease Supplement (AREDS), an oral supplement containing vitamin C, vitamin E, lutein/zeaxanthin, and '''zinc'''. It was shown that AREDS can reduce the risk of advanced AMD by about 25% over a 5-year period in patients with intermediate AMD.<ref>Age-Related Eye Disease Study Research Group. (2001). A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Archives of ophthalmology, 119(10), 1417-1436. PMID: 11594942 PMCID: PMC1462955 DOI: 10.1001/archopht.119.10.1417</ref>

=== Lipofuscin accumulation in aging heart ===
Lipofuscin granules are found abundantly in myocardial cells.<ref>Kakimoto, Y., Okada, C., Kawabe, N., Sasaki, A., Tsukamoto, H., Nagao, R., & Osawa, M. (2019). Myocardial lipofuscin accumulation in ageing and sudden cardiac death. Scientific reports, 9(1), 1-8. PMID: 30824797 PMCID: PMC6397159 DOI: 10.1038/s41598-019-40250-0</ref><ref>Li, W. W., Wang, H. J., Tan, Y. Z., Wang, Y. L., Yu, S. N., & Li, Z. H. (2021). Reducing lipofuscin accumulation and cardiomyocytic senescence of aging heart by enhancing autophagy. Experimental Cell Research, 403(1), 112585. PMID: 33811905 DOI: 10.1016/j.yexcr.2021.112585</ref><ref>Wang, L., Xiao, C. Y., Li, J. H., Tang, G. C., & Xiao, S. S. (2022). Transport and Possible Outcome of Lipofuscin in Mouse Myocardium. Advances in Gerontology, 12(3), 247-263. </ref> The myocardial tissues of mice have the ability to eliminate the lipofuscin produced in the cardiomyocytes into the myocardial blood circulation. It is mainly carried out of cardiomyocytes into the myocardial interstitium in the form of small lipofuscin granules, using capsule-like protrusions that are formed on the sarcolemma.<ref>Wang, L., Xiao, C. Y., Li, J. H., Tang, G. C., & Xiao, S. S. (2020). Observation of the Transport and Removal of Lipofuscin from the Mouse Myocardium using Transmission Electron Microscope. BioRxiv. https://doi.org/10.1101/2020.03.10.985507</ref>

=== Role of lipofuscin in age-related neurodegeneration ===
Lipofuscin aggregation represents a risk factor for [[Aging and neurodegeneration|neurodegeneration]].<ref>Moreno-García, A., Kun, A., Calero, O., Medina, M., & Calero, M. (2018). An overview of the role of lipofuscin in age-related neurodegeneration. Frontiers in Neuroscience, 12, 464. PMID: 30026686 PMCID: PMC6041410 DOI: 10.3389/fnins.2018.00464</ref>

Progranulin neurons that normally have high levels of progranulin expression are more susceptible to age-related pathology, such as neuronal lipofuscinosis, in GRN−/− mice.<ref>Ahmed, Z., Sheng, H., Xu, Y. F., Lin, W. L., Innes, A. E., Gass, J., ... & Lewis, J. (2010). Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. The American journal of pathology, 177(1), 311-324. PMID: 20522652 PMCID: PMC2893674 DOI: 10.2353/ajpath.2010.090915</ref>

[[File:Lipofuscin in aged (60y) human epidermis.jpg|thumb|Lipofuscin granules (brown) accumulation in aged (60y) human epidermis according to Rübe et al., & Scherthan (2021).<ref>Rübe, C. E., Bäumert, C., Schuler, N., Isermann, A., Schmal, Z., Glanemann, M., ... & Scherthan, H. (2021). Human skin aging is associated with increased expression of the histone variant H2A. J in the epidermis. npj Aging and Mechanisms of Disease, 7(1), 1-11 PMID:33795696 PMC8016850 DOI:10.1038/s41514-021-00060-z</ref>]]
=== Lipofuscin-accumulating in skin cells ===
Lipofuscin is an endogenous photosensitizer that efficiently absorbs ultraviolet radiation and visible light, forming electronic excited states that transfer energy to surrounding molecules. It is assumed, that photosensitized lipofuscin is cytotoxic because of its ability to incorporate redox-active transition metals (Fe+2), resulting in a redox-active surface, able to catalyze the Fenton reaction. Reactive oxygen and nitrogen species (ROS/RNS) generated by photosensitization of lipofuscin leads to DNA damage and strand breaks.<ref>Tonolli, P. N., Baptista, M. S., & Chiarelli-Neto, O. (2021). Melanin, lipofuscin and the effects of visible light in the skin. Journal of Photochemistry and Photobiology, 7, 100044. https://doi.org/10.1016/j.jpap.2021.100044</ref><ref>Skoczyńska, A., Budzisz, E., Trznadel-Grodzka, E., & Rotsztejn, H. (2017). Melanin and lipofuscin as hallmarks of skin aging. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 34(2), 97-103. PMID: 28507486 PMCID: PMC5420599 DOI: 10.5114/ada.2017.67070</ref> It was observed that application of vitamin E may reduce the level of lipofuscin in skin biopsies as well as lighten the skin (but not in very old ones).<ref>Monji, A., Morimoto, N., Okuyama, I., Yamashita, N., & Tashiro, N. (1994). Effect of dietary vitamin E on lipofuscin accumulation with age in the rat brain. Brain research, 634(1), 62-68. PMID: 8156392 DOI: 10.1016/0006-8993(94)90258-5</ref><ref name="biomarker"/> Light-induced skin damage can be protected by regulating the ROS-ER stress-[[autophagy]]-apoptosis axis with '''hydrogen sulfide''' ('''H2S''').<ref>Zhu, S., Li, X., Wu, F., Cao, X., Gou, K., Wang, C., & Lin, C. (2022). Blue light induces skin apoptosis and degeneration through activation of the endoplasmic reticulum stress-autophagy apoptosis axis: Protective role of hydrogen sulfide. Journal of Photochemistry and Photobiology B: Biology, 229, 112426. https://doi.org/10.1016/j.jphotobiol.2022.112426</ref>

== Inhibitors of lipofuscin accumulation ==
It was suggested that formation of A2E and other toxic lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridinephosphatidyl-ethanolamine) and atRALdi-PE (all-trans-retinal dimer phosphatidylethanolamine), occurs in the retina in a non-enzymatic manner and can be considered a by-product of a properly functioning visual cycle.<ref>Sparrow, J. R., Gregory-Roberts, E., Yamamoto, K., Blonska, A., Ghosh, S. K., Ueda, K., & Zhou, J. (2012). The bisretinoids of retinal pigment epithelium. Progress in retinal and eye research, 31(2), 121-135. PMID: 22209824 PMCID: PMC3288746 DOI: 10.1016/j.preteyeres.2011.12.001</ref> The formation of A2E was completely inhibited in total darkness, so, humans with retinal or macular degeneration may slow progression of their disease by limiting exposure to light.<ref>Mata, N. L., Weng, J., & Travis, G. H. (2000). Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proceedings of the National Academy of Sciences, 97(13), [tel:7154-7159 7154-7159]. PMID: 10852960 PMCID: PMC16515 DOI: 10.1073/pnas.130110497</ref>

==== Meclofenoxate ====
'''Meclofenoxate''' is a cholinergic nootropic also known as '''centrophenoxine'''. It is an ester of dimethylethanolamine ('''DMAE''') and 4-chlorophenoxyacetic acid (pCPA).
Meclofenoxate, as well as DMAE, have been found to increase the dissolution and removal of lipofuscin<ref>Hasan, M., Glees, P., & Spoerri, P. E. (1974). Dissolution and removal of neuronal lipofuscin following dimethylaminoethyl p-chlorophenoxyacetate administration to guinea pigs. Cell and Tissue Research, 150(3), 369-375. PMID: 4367734 DOI: 10.1007/BF00220143</ref><ref>Riga, S., & Riga, D. (1974). Effects of centrophenoxine on the lipofuscin pigments in the nervous system of old rats. Brain Research, 72(2), 265-275. PMID: 4151704 DOI: 10.1016/0006-8993(74)90864-6</ref><ref>Spoerri, P. E., Glees, P., & El Ghazzawi, E. (1974). Accumulation of lipofuscin in the myocardium of senile guinea pigs: dissolution and removal of lipofuscin following dimethylaminoethyl p-chlorophenoxyacetate administration. An electron microscopic study. Mechanisms of Ageing and Development, 3, 311-321. PMID: 4618294 DOI: 10.1016/0047-6374(74)90027-x</ref> '''leading to lifespan extension of mice'''.<ref>Hochschild, R. (1973). Effect of dimethylaminoethanol on the life span of senile male A/J mice. Experimental Gerontology, 8(4), 185-191. https://doi.org/10.1016/0531-5565(73)90025-9</ref><ref>Hochschild, R. (1973). Effect of dimethylaminoethyl p-chlorophenoxyacetate on the life span of male Swiss Webster albino mice. Experimental gerontology, 8(4), 177-183. DOI: 10.1016/0531-5565(73)90024-7</ref> As a result of meclophenoxate treatment, a gradual decrease in the myocardial volume occupied by the pigment was noted. After 4-6 weeks of treatment, the pigment bodies were found lodged into the capillary endothelium and the lumen, facilitating the removal of the pigment via blood stream.<ref>Patro, N. I. S. H. A., Sharma, S. P., & Patro, I. K. (1992). Lipofuscin accumulation in ageing myocardium & its removal by meclophenoxate. The Indian Journal of Medical Research, 96, 192-198. PMID:[https://pubmed.ncbi.nlm.nih.gov/1512044/ 1512044]</ref><ref>Hochschild, R. (1973). Effect of dimethylaminoethanol on the life span of senile male A/J mice. Experimental Gerontology, 8(4), 185-191.</ref>

=== Remofuscin ===
'''Remofuscin''', a small molecule belonging to the tetrahydropyridoether class of compounds is able to remove lipofuscin from the RPE by accumulation specifically in RPE pigments and thus stimulation of the exocytosis.<ref>Julien, S., & Schraermeyer, U. (2012). Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys. Neurobiology of aging, 33(10), [tel:2390-2397 2390-2397]. PMID: 22244091 DOI: 10.1016/j.neurobiolaging.2011.12.009</ref> Remofuscin formerly known as '''Soraprazan''' a potent and reversible selective inhibitor of gastric H,K-ATPase may be a promising drug candidate to manage neurodegenerative diseases related to lipofuscin accumulation.<ref>Julien‐Schraermeyer, S., Illing, B., Tschulakow, A., Taubitz, T., Guezguez, J., Burnet, M., & Schraermeyer, U. (2020). Penetration, distribution, and elimination of remofuscin/soraprazan in Stargardt mouse eyes following a single intravitreal injection using pharmacokinetics and transmission electron microscopic autoradiography: Implication for the local treatment of Stargardt’s disease and dry age‐related macular degeneration. Pharmacology Research & Perspectives, 8(6), e00683. PMID: 33164337 PMCID: PMC7649431 DOI: 10.1002/prp2.683</ref> Remofuscin reverses lipofuscin accumulation in aged primary human RPE cells and is non-cytotoxic in aged SD mouse RPE cells in vitro.<ref name="reactive">Fang, Y., Taubitz, T., Tschulakow, A. V., Heiduschka, P., Szewczyk, G., Burnet, M., ... & Julien-Schraermeyer, S. (2022). Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species. Free Radical Biology and Medicine, 182, 132-149. PMID: 35219849 DOI: 10.1016/j.freeradbiomed.2022.02.025</ref> Mechanism causing lipofuscinolysis may involve the reactive oxygen species generated via the presence of remofuscin. Remofuscin binds to lipofuscin and is a superoxide generator when illuminated with light. Superoxide might help to degrade the polymeric lipofuscin into smaller units which then are transported out of the lysosomes by exocytosis.<ref name="reactive"/><ref name="elegans">Oh, M., Yeom, J., Schraermeyer, U., Julien-Schraermeyer, S., & Lim, Y. H. (2022). Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan. Scientific reports, 12(1), 1-13. PMID: 35504961 PMCID: PMC9064964 DOI: 10.1038/s41598-022-11325-2</ref> Remofuscin reduces existing levels of lipofuscin in the RPE instead of merely slowing down accumulation of further toxic Vitamin A aggregates.<ref>Sears, A. E., Bernstein, P. S., Cideciyan, A. V., Hoyng, C., Issa, P. C., Palczewski, K., ... & Scholl, H. P. (2017). Towards treatment of Stargardt disease: workshop organized and sponsored by the Foundation Fighting Blindness. Translational vision science & technology, 6(5), 6-6.PMID: 28920007 PMCID: PMC5599228 DOI: 10.1167/tvst.6.5.6</ref><ref name="elegans"/>

Aging biomarkers were improved in remofuscin-treated ''Caenorhabditis elegans'' worms, resulting in '''a significant (p <0.05) increase in their lifespan'''.<ref name="elegans"/> The expression levels of genes related to lysosomes, a nuclear hormone receptor, fatty acid beta-oxidation, and xenobiotic detoxification were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. ''elegans'' with loss-of-function mutations of genes related to lysosomes and xenobiotic detoxification, suggesting that these genes are associated with lifespan extension in remofuscin-treated C. ''elegans''.<ref name="elegans"/>

=== Curcumin ===
Intestinal lipofuscin levels were reduced by 39.5% and 47.5%, respectively, in curcumin-treated adult ''C. elegans'' day-4 and -8 days of adulthood nematodes, compared to untreated controls.<ref>Liao, V. H. C., Yu, C. W., Chu, Y. J., Li, W. H., Hsieh, Y. C., & Wang, T. T. (2011). Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mechanisms of ageing and development, 132(10), 480-487. PMID: 21855561 DOI: 10.1016/j.mad.2011.07.008</ref> This ability of curcumin is apparently not related to its action as a [[senolytics]], since the potent senolytic fisetin, although it removed old cells, did not affect lipofuscin levels.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 </ref>

=== NMDA receptor antagonists ===
N-methyl-D-aspartate (NMDA) receptors signaling is a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. NMDA receptor antagonists, such as '''Ro 25-6981''', '''CP-101,606''' and '''AZD6765''', degrade lipofuscin via [[autophagy]] in human RPE cells.<ref>Lee, J. R., & Jeong, K. W. (2022). NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells. Medicina, 58(8), 1129. PMID: 36013596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415004 PMC9415004] DOI: 10.3390/medicina58081129</ref> Ro 25-6981 has not yet been approved for clinical use. Among the clinically approved NMDA antagonists, '''memantine''' and '''ifenprodil''' have been proposed as drug repositioning to remove N-retinylidene-N-retinylethanolamine (A2E), an intracellular lipofuscin component.<ref>Lee, J. R., & Jeong, K. W. (2023). N-retinylidene-N-retinylethanolamine degradation in human retinal pigment epithelial cells via memantine-and ifenprodil-mediated autophagy. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 27(5), 449. PMID: 37641807 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466070 PMC10466070] DOI: 10.4196/kjpp.2023.27.5.449</ref>

=== ATM inhibition ===
The increase in lipid peroxidation during oxidative stress increases the content of intra-lysosomal lipofuscins in fibroblasts during senescence.<ref>McHugh, D., & Gil, J. (2018). Senescence and aging: Causes, consequences, and therapeutic avenues. Journal of Cell Biology, 217(1), 65-77.</ref> Senescence amelioration in normal aging cells is mediated by the recovered mitochondrial function upon inhibition of a key mediator of DNA damage signaling and repair - Ataxia telangiectasia mutated (ATM).<ref>Khanna, K. K., Lavin, M. F., Jackson, S. P., & Mulhern, T. D. (2001). ATM, a central controller of cellular responses to DNA damage. Cell Death & Differentiation, 8(11), 1052-1065.</ref><ref>Kang, H. T., Park, J. T., Choi, K., Kim, Y., Choi, H. J. C., Jung, C. W., ... & Park, S. C. (2017). Chemical screening identifies ATM as a target for alleviating senescence. Nature chemical biology, 13(6), 616-623. PMID: 28346404 DOI: 10.1038/nchembio.2342</ref><ref>Song, S. B., & Hwang, E. S. (2020). High levels of ROS impair lysosomal acidity and autophagy flux in glucose-deprived fibroblasts by activating ATM and Erk pathways. Biomolecules, 10(5), 761. PMID: 32414146 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277562/ PMC7277562] DOI: 10.3390/biom10050761</ref>

ATM inhibitors '''KU-60019''', '''CP-466722''' or antioxidant '''N-acetyl-cysteine (NAC)''' significantly reduced lipofuscin accumulation.<ref>Song, S. B., Shim, W., & Hwang, E. S. (2023). Lipofuscin granule accumulation requires autophagy activation. Molecules and Cells, 46(8), 486-495. PMID: 37438887 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440269 PMC10440269] DOI: 10.14348/molcells.2023.0019</ref>

== See also ==
* Renteln, M. (2024). Toward systemic lipofuscin removal. Rejuvenation Research, (ja). https://doi.org/10.1089/rej.2024.0034
* Ilie, O. D., Ciobica, A., Riga, S., Dhunna, N., McKenna, J., Mavroudis, I., ... & Riga, D. (2020). Mini-review on lipofuscin and aging: focusing on the molecular interface, the biological recycling mechanism, oxidative stress, and the gut-brain axis functionality. Medicina, 56(11), 626. PMID: 33228124 PMCID: PMC7699382 DOI: 10.3390/medicina56110626
* Nasiri, L., Vaez-Mahdavi, M. R., Hassanpour, H., Ghazanfari, T., Ardestani, S. K., Askari, N., ... & Rahimlou, B. (2023). Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence. International Immunopharmacology, 114, 109549. https://doi.org/10.1016/j.intimp.2022.109549 Chronic oxidative stress and continuous inflammatory stimulation in veterans, due to mustard gas poisoning once in 1987, led to cells senescence with increased lipofuscin, and telomere shortening.
* Nociari, M. M., Lehmann, G. L., Perez Bay, A. E., Radu, R. A., Jiang, Z., Goicochea, S., ... & Rodriguez-Boulan, E. (2014). Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium. Proceedings of the National Academy of Sciences, 111(14), E1402-E1408. PMID: 24706818 PMCID: PMC3986126 DOI: 10.1073/pnas.1400530111

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Age-related diseases]]

Lipofuscin

2024-08-01T10:42:15Z

Dmitry Dzhagarov:

'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref> In motor neurons of centenarians, up to 75% of cell volume can be occupied by lipofuscin.<ref>Yin, D. (1996). Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radical Biology and Medicine, 21(6), 871-888. PMID: 8902532 DOI: 10.1016/0891-5849(96)00175-x</ref>
[[File:Lipofuscin.jpg|thumb|Lipofuscin spots on the upper surface of the hands.]]
Lipofuscin is proposed as a [[Cellular senescence|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>

Accumulation of lipofuscin or "aging pigment" is part of normal aging, and should be distinguished from accumulation of '''ceroid''' - autofluorescent storage material associated with disease and usually produced under various pathological conditions not necessarily related to aging.<ref>Seehafer, S. S., & Pearce, D. A. (2006). You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiology of aging, 27(4), 576-588. PMID: 16455164 DOI: 10.1016/j.neurobiolaging.2005.12.006</ref> Ceroid has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis.<ref>
Albaghdadi, M. S., Ikegami, R., Kassab, M. B., Gardecki, J. A., Kunio, M., Chowdhury, M. M., ... & Jaffer, F. A. (2021). Near-infrared autofluorescence in atherosclerosis associates with ceroid and is generated by oxidized lipid-induced oxidative stress. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(7), e385-e398. PMID: 34011166 PMC8222195 DOI: 10.1161/ATVBAHA.120.315612</ref>

== Detection of lipofuscin ==
During the process of aging, lipofuscin accumulates in a nearly linear way in postmitotic senescencent cells (cardiomyocytes, retinal epithelial pigment cells, hepatocytes, neurons and keratinocytes),<ref name="biomarker">Georgakopoulou, E. A., Tsimaratou, K., Evangelou, K., Fernandez, M. P., Zoumpourlis, V., Trougakos, I. P., ... & Gorgoulis, V. G. (2013). Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY), 5(1), 37. PMID: 23449538 PMCID: PMC3616230 DOI: 10.18632/aging.100527</ref> and has been proposed as a detectable "marker" to estimate aging. This approach is particularly used to determine the age of crabs and other crustaceans either by labor histological fluorescent-microscopy examinations<ref>Jung, T., Höhn, A., & Grune, T. (2010). Lipofuscin: detection and quantification by microscopic techniques. Advanced Protocols in Oxidative Stress II, 173-193. PMID: 20072918 DOI: 10.1007/978-1-60761-411-1_13</ref> or simply by extractable lipofuscin solvent fluorescence measurements.<ref>Pinchuk, A. I., Harvey, H. R., & Eckert, G. L. (2016). Development of biochemical measures of age in the Alaskan red king crab Paralithodes camtschaticus (Anomura): Validation, refinement and initial assessment. Fisheries Research, 183, 92-98.https://doi.org/10.1016/j.fishres.2016.05.019</ref>

Detection of lipofuscin content can be used as a biomarker of old lysosome accumulation, either by its typical autofluorescence properties and fluorescence-based methods, or by selective staining with Sudan black B, which stained lipofuscin granules, allowing for detection in cells, tissues and body fluids.<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMCID: PMC5242262 DOI: 10.1111/acel.12545</ref><ref>Salmonowicz, H., & Passos, J. F. (2017). Detecting senescence: a new method for an old pigment. Aging Cell, 16(3), 432-434. </ref><ref>Lozano‐Torres, B., Blandez, J. F., García‐Fernández, A., Sancenón, F., & Martínez‐Máñez, R. (2022). Lipofuscin labelling through biorthogonal strain‐promoted azide‐alkyne cycloaddition for the detection of senescent cells. The FEBS Journal. PMID: 35527516 DOI: 10.1111/febs.16477</ref><ref>Evangelou, K., & Gorgoulis, V. G. (2017). Sudan Black B, the specific histochemical stain for lipofuscin: a novel method to detect senescent cells. In Oncogene-Induced Senescence (pp. 111-119). Humana Press, New York, NY. PMID: 27812872 DOI: 10.1007/978-1-4939-6670-7_10</ref>

== Relation to aging diseases ==
Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[Advanced glycation end products (AGEs)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>

Isolated lipofuscin aggregates, as shown in vitro, were readily incorporated by fibroblasts and caused cell death at low concentrations (LC50 = 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity.<ref>Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. (2024). Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. bioRxiv .03.25.586520; doi: https://doi.org/10.1101/2024.03.25.586520</ref>

Lipofuscin granules accumulation can lead to pathology and accelerate the aging process.<ref>Feldman, T. B., Dontsov, A. E., Yakovleva, M. A., & Ostrovsky, M. A. (2022). Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age. Biophysical Reviews, 1-15. PMID: 36124271 PMCID: PMC9481861 (available on 2023-08-08) DOI: 10.1007/s12551-022-00989-9</ref> The rate of lipofuscin formation has been shown to be negatively correlated with the life expectancy of postmitotic cells, i.e., the higher the rate, the shorter the lifespan of the cell due to decrease of cellular adaptability.<ref>Jung, T., Bader, N., & Grune, T. (2007). Lipofuscin: formation, distribution, and metabolic consequences. Annals of the New York Academy of Sciences, 1119(1), 97-111. PMID: 18056959 DOI: 10.1196/annals.1404.008</ref> Therefore, progressive deposition of lipofuscin might promote the development of age-related pathologies, including macular degeneration, heart failure, and neuro-degenerative diseases.

=== Dry AMD ===
One of the diseases associated with the accumulation of lipofuscin is dry [[Aging and eye disease|age-related macular degeneration]] (dry AMD) – a disease often diagnosed in people over 70 years of age and a leading cause of rapid vision loss. Dry AMD is a slow-progressing disease in which yellow drusen containing lipofuscin are deposited between the retinal pigment epithelial (RPE) cell layer and Bruch’s membrane.<ref>Jhingan, M., Singh, S. R., Samanta, A., Arora, S., Tucci, D., Amarasekera, S., ... & Chhablani, J. (2021). Drusen ooze: predictor for progression of dry age-related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology, 259(9), [tel:2687-2694 2687-2694]. DOI:[https://doi.org/10.1007/s00417-021-05147-7 10.1007/s00417-021-05147-7]</ref> A phototoxic components of lipofuscin such as A2E (Bis-retinoid N-retinyl-N-retinylidene ethanolamine) that induces inflammation and apoptosis in RPE cells,<ref>Sparrow, J. R., & Boulton, M. (2005). RPE lipofuscin and its role in retinal pathobiology. Experimental eye research, 80(5), 595-606.</ref> are accumulated with age and mediate damage under blue light exposure.<ref>Brandstetter, C., Mohr, L. K., Latz, E., Holz, F. G., & Krohne, T. U. (2015). Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. Journal of Molecular Medicine, 93(8), 905-916. PMID: 25783493 PMC4510924 DOI: 10.1007/s00109-015-1275-1</ref><ref name="Light">Jin, H. L., & Jeong, K. W. (2022). Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells. Biomolecules & therapeutics, 30(3), 291. PMID: 35074938 PMCID: PMC9047491 DOI: 10.4062/biomolther.2021.155</ref> It has been reported that iron levels increase in RPE during ageing and this intracellular iron can interact with bisretinoid lipofuscin in RPE to promote cell damage.<ref>Zhao, T., Guo, X., & Sun, Y. (2021). Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging and disease, 12(2), 529. PMID: 33815881 PMCID: PMC7990372 DOI: 10.14336/AD.2020.0912</ref> Therefore, to alleviate the deteriorating effects of lipofuscin on age-related macular degeneration, iron chelation, either independently or in combination with bisretinoid inhibitors could potentially serve as AMD treatments.<ref>Ueda, K., Kim, H. J., Zhao, J., Song, Y., Dunaief, J. L., & Sparrow, J. R. (2018). Iron promotes oxidative cell death caused by bisretinoids of retina. Proceedings of the National Academy of Sciences, 115(19), [tel:4963-4968 4963-4968]. PMID: 29686088 PMCID: PMC5948992 DOI: 10.1073/pnas.1722601115</ref> To protect human RPE cells from oxidative damage, caused by reactive oxygen species generated by the photo-excited lipofuscin, also is able L‐Citrulline, a naturally occurring amino acid with known antioxidant properties<ref>Hassel, C., Couchet, M., Jacquemot, N., Blavignac, C., Loï, C., Moinard, C., & Cia, D. (2022). Citrulline protects human retinal pigment epithelium from hydrogen peroxide and iron/ascorbate induced damages. Journal of Cellular and Molecular Medicine, 26(10), [tel:2808-2818 2808-2818]. PMID: 35460170 PMCID: PMC9097847 DOI: 10.1111/jcmm.17294</ref> and the main active component of ''Spirulina maxima'' P-phycocyanin - pigment with anti-inflammatory and antioxidant activities.<ref>Cho, H. M., Jo, Y. D., & Choung, S. Y. (2022). Protective Effects of Spirulina maxima against Blue Light-Induced Retinal Damages in A2E-Laden ARPE-19 Cells and Balb/c Mice. Nutrients, 14(3), 401. PMID: 35276761 PMCID: PMC8840079 DOI: 10.3390/nu14030401</ref>

The drug Lysoclear is an enzyme developed to enter RPE cells and break down lipofuscin deposits in the lysosomes, a therapeutic approach that proposes to reverse dry age-related macular degeneration and Stargardt's macular degeneration.<ref>www.ichortherapeutics.com</ref> Phase 1 clinical trials started in 2018.

==== Zinc deficiency ====
Zinc-deficient animals showed a greater number of lipofuscin granules.<ref>Julien, S., Biesemeier, A., Kokkinou, D., Eibl, O., & Schraermeyer, U. (2011). Zinc deficiency leads to lipofuscin accumulation in the retinal pigment epithelium of pigmented rats. PLoS One, 6(12), e29245. PMID: 22216222 PMCID: PMC3245262 DOI: 10.1371/journal.pone.0029245</ref> The relationship between zinc deficiency and enhanced lipofuscin accumulation suggest that zinc deficiency may result in the accumulation of substrates for autophagy whereas low zinc does not stimulate autophagy.<ref>Blasiak, J., Pawlowska, E., Chojnacki, J., Szczepanska, J., Chojnacki, C., & Kaarniranta, K. (2020). Zinc and autophagy in age-related macular degeneration. International Journal of Molecular Sciences, 21(14), 4994. PMID: 32679798 PMCID: PMC7404247 DOI: 10.3390/ijms21144994</ref> Autophagy is also inhibited when A2E-treated RPE cells are exposed to blue light.<ref name="Light"/> Currently, the only intervention available for the treatment of dry AMD is Age-Related Eye Disease Supplement (AREDS), an oral supplement containing vitamin C, vitamin E, lutein/zeaxanthin, and '''zinc'''. It was shown that AREDS can reduce the risk of advanced AMD by about 25% over a 5-year period in patients with intermediate AMD.<ref>Age-Related Eye Disease Study Research Group. (2001). A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Archives of ophthalmology, 119(10), 1417-1436. PMID: 11594942 PMCID: PMC1462955 DOI: 10.1001/archopht.119.10.1417</ref>

=== Lipofuscin accumulation in aging heart ===
Lipofuscin granules are found abundantly in myocardial cells.<ref>Kakimoto, Y., Okada, C., Kawabe, N., Sasaki, A., Tsukamoto, H., Nagao, R., & Osawa, M. (2019). Myocardial lipofuscin accumulation in ageing and sudden cardiac death. Scientific reports, 9(1), 1-8. PMID: 30824797 PMCID: PMC6397159 DOI: 10.1038/s41598-019-40250-0</ref><ref>Li, W. W., Wang, H. J., Tan, Y. Z., Wang, Y. L., Yu, S. N., & Li, Z. H. (2021). Reducing lipofuscin accumulation and cardiomyocytic senescence of aging heart by enhancing autophagy. Experimental Cell Research, 403(1), 112585. PMID: 33811905 DOI: 10.1016/j.yexcr.2021.112585</ref><ref>Wang, L., Xiao, C. Y., Li, J. H., Tang, G. C., & Xiao, S. S. (2022). Transport and Possible Outcome of Lipofuscin in Mouse Myocardium. Advances in Gerontology, 12(3), 247-263. </ref> The myocardial tissues of mice have the ability to eliminate the lipofuscin produced in the cardiomyocytes into the myocardial blood circulation. It is mainly carried out of cardiomyocytes into the myocardial interstitium in the form of small lipofuscin granules, using capsule-like protrusions that are formed on the sarcolemma.<ref>Wang, L., Xiao, C. Y., Li, J. H., Tang, G. C., & Xiao, S. S. (2020). Observation of the Transport and Removal of Lipofuscin from the Mouse Myocardium using Transmission Electron Microscope. BioRxiv. https://doi.org/10.1101/2020.03.10.985507</ref>

=== Role of lipofuscin in age-related neurodegeneration ===
Lipofuscin aggregation represents a risk factor for [[Aging and neurodegeneration|neurodegeneration]].<ref>Moreno-García, A., Kun, A., Calero, O., Medina, M., & Calero, M. (2018). An overview of the role of lipofuscin in age-related neurodegeneration. Frontiers in Neuroscience, 12, 464. PMID: 30026686 PMCID: PMC6041410 DOI: 10.3389/fnins.2018.00464</ref>

Progranulin neurons that normally have high levels of progranulin expression are more susceptible to age-related pathology, such as neuronal lipofuscinosis, in GRN−/− mice.<ref>Ahmed, Z., Sheng, H., Xu, Y. F., Lin, W. L., Innes, A. E., Gass, J., ... & Lewis, J. (2010). Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. The American journal of pathology, 177(1), 311-324. PMID: 20522652 PMCID: PMC2893674 DOI: 10.2353/ajpath.2010.090915</ref>

[[File:Lipofuscin in aged (60y) human epidermis.jpg|thumb|Lipofuscin granules (brown) accumulation in aged (60y) human epidermis according to Rübe et al., & Scherthan (2021).<ref>Rübe, C. E., Bäumert, C., Schuler, N., Isermann, A., Schmal, Z., Glanemann, M., ... & Scherthan, H. (2021). Human skin aging is associated with increased expression of the histone variant H2A. J in the epidermis. npj Aging and Mechanisms of Disease, 7(1), 1-11 PMID:33795696 PMC8016850 DOI:10.1038/s41514-021-00060-z</ref>]]
=== Lipofuscin-accumulating in skin cells ===
Lipofuscin is an endogenous photosensitizer that efficiently absorbs ultraviolet radiation and visible light, forming electronic excited states that transfer energy to surrounding molecules. It is assumed, that photosensitized lipofuscin is cytotoxic because of its ability to incorporate redox-active transition metals (Fe+2), resulting in a redox-active surface, able to catalyze the Fenton reaction. Reactive oxygen and nitrogen species (ROS/RNS) generated by photosensitization of lipofuscin leads to DNA damage and strand breaks.<ref>Tonolli, P. N., Baptista, M. S., & Chiarelli-Neto, O. (2021). Melanin, lipofuscin and the effects of visible light in the skin. Journal of Photochemistry and Photobiology, 7, 100044. https://doi.org/10.1016/j.jpap.2021.100044</ref><ref>Skoczyńska, A., Budzisz, E., Trznadel-Grodzka, E., & Rotsztejn, H. (2017). Melanin and lipofuscin as hallmarks of skin aging. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 34(2), 97-103. PMID: 28507486 PMCID: PMC5420599 DOI: 10.5114/ada.2017.67070</ref> It was observed that application of vitamin E may reduce the level of lipofuscin in skin biopsies as well as lighten the skin (but not in very old ones).<ref>Monji, A., Morimoto, N., Okuyama, I., Yamashita, N., & Tashiro, N. (1994). Effect of dietary vitamin E on lipofuscin accumulation with age in the rat brain. Brain research, 634(1), 62-68. PMID: 8156392 DOI: 10.1016/0006-8993(94)90258-5</ref><ref name="biomarker"/> Light-induced skin damage can be protected by regulating the ROS-ER stress-[[autophagy]]-apoptosis axis with '''hydrogen sulfide''' ('''H2S''').<ref>Zhu, S., Li, X., Wu, F., Cao, X., Gou, K., Wang, C., & Lin, C. (2022). Blue light induces skin apoptosis and degeneration through activation of the endoplasmic reticulum stress-autophagy apoptosis axis: Protective role of hydrogen sulfide. Journal of Photochemistry and Photobiology B: Biology, 229, 112426. https://doi.org/10.1016/j.jphotobiol.2022.112426</ref>

== Inhibitors of lipofuscin accumulation ==
It was suggested that formation of A2E and other toxic lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridinephosphatidyl-ethanolamine) and atRALdi-PE (all-trans-retinal dimer phosphatidylethanolamine), occurs in the retina in a non-enzymatic manner and can be considered a by-product of a properly functioning visual cycle.<ref>Sparrow, J. R., Gregory-Roberts, E., Yamamoto, K., Blonska, A., Ghosh, S. K., Ueda, K., & Zhou, J. (2012). The bisretinoids of retinal pigment epithelium. Progress in retinal and eye research, 31(2), 121-135. PMID: 22209824 PMCID: PMC3288746 DOI: 10.1016/j.preteyeres.2011.12.001</ref> The formation of A2E was completely inhibited in total darkness, so, humans with retinal or macular degeneration may slow progression of their disease by limiting exposure to light.<ref>Mata, N. L., Weng, J., & Travis, G. H. (2000). Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proceedings of the National Academy of Sciences, 97(13), [tel:7154-7159 7154-7159]. PMID: 10852960 PMCID: PMC16515 DOI: 10.1073/pnas.130110497</ref>

==== Meclofenoxate ====
'''Meclofenoxate''' is a cholinergic nootropic also known as '''centrophenoxine'''. It is an ester of dimethylethanolamine ('''DMAE''') and 4-chlorophenoxyacetic acid (pCPA).
Meclofenoxate, as well as DMAE, have been found to increase the dissolution and removal of lipofuscin<ref>Hasan, M., Glees, P., & Spoerri, P. E. (1974). Dissolution and removal of neuronal lipofuscin following dimethylaminoethyl p-chlorophenoxyacetate administration to guinea pigs. Cell and Tissue Research, 150(3), 369-375. PMID: 4367734 DOI: 10.1007/BF00220143</ref><ref>Riga, S., & Riga, D. (1974). Effects of centrophenoxine on the lipofuscin pigments in the nervous system of old rats. Brain Research, 72(2), 265-275. PMID: 4151704 DOI: 10.1016/0006-8993(74)90864-6</ref><ref>Spoerri, P. E., Glees, P., & El Ghazzawi, E. (1974). Accumulation of lipofuscin in the myocardium of senile guinea pigs: dissolution and removal of lipofuscin following dimethylaminoethyl p-chlorophenoxyacetate administration. An electron microscopic study. Mechanisms of Ageing and Development, 3, 311-321. PMID: 4618294 DOI: 10.1016/0047-6374(74)90027-x</ref> '''leading to lifespan extension of mice'''.<ref>Hochschild, R. (1973). Effect of dimethylaminoethanol on the life span of senile male A/J mice. Experimental Gerontology, 8(4), 185-191. https://doi.org/10.1016/0531-5565(73)90025-9</ref><ref>Hochschild, R. (1973). Effect of dimethylaminoethyl p-chlorophenoxyacetate on the life span of male Swiss Webster albino mice. Experimental gerontology, 8(4), 177-183. DOI: 10.1016/0531-5565(73)90024-7</ref> As a result of meclophenoxate treatment, a gradual decrease in the myocardial volume occupied by the pigment was noted. After 4-6 weeks of treatment, the pigment bodies were found lodged into the capillary endothelium and the lumen, facilitating the removal of the pigment via blood stream.<ref>Patro, N. I. S. H. A., Sharma, S. P., & Patro, I. K. (1992). Lipofuscin accumulation in ageing myocardium & its removal by meclophenoxate. The Indian Journal of Medical Research, 96, 192-198. PMID:[https://pubmed.ncbi.nlm.nih.gov/1512044/ 1512044]</ref><ref>Hochschild, R. (1973). Effect of dimethylaminoethanol on the life span of senile male A/J mice. Experimental Gerontology, 8(4), 185-191.</ref>

=== Remofuscin ===
'''Remofuscin''', a small molecule belonging to the tetrahydropyridoether class of compounds is able to remove lipofuscin from the RPE by accumulation specifically in RPE pigments and thus stimulation of the exocytosis.<ref>Julien, S., & Schraermeyer, U. (2012). Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys. Neurobiology of aging, 33(10), [tel:2390-2397 2390-2397]. PMID: 22244091 DOI: 10.1016/j.neurobiolaging.2011.12.009</ref> Remofuscin formerly known as '''Soraprazan''' a potent and reversible selective inhibitor of gastric H,K-ATPase may be a promising drug candidate to manage neurodegenerative diseases related to lipofuscin accumulation.<ref>Julien‐Schraermeyer, S., Illing, B., Tschulakow, A., Taubitz, T., Guezguez, J., Burnet, M., & Schraermeyer, U. (2020). Penetration, distribution, and elimination of remofuscin/soraprazan in Stargardt mouse eyes following a single intravitreal injection using pharmacokinetics and transmission electron microscopic autoradiography: Implication for the local treatment of Stargardt’s disease and dry age‐related macular degeneration. Pharmacology Research & Perspectives, 8(6), e00683. PMID: 33164337 PMCID: PMC7649431 DOI: 10.1002/prp2.683</ref> Remofuscin reverses lipofuscin accumulation in aged primary human RPE cells and is non-cytotoxic in aged SD mouse RPE cells in vitro.<ref name="reactive">Fang, Y., Taubitz, T., Tschulakow, A. V., Heiduschka, P., Szewczyk, G., Burnet, M., ... & Julien-Schraermeyer, S. (2022). Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species. Free Radical Biology and Medicine, 182, 132-149. PMID: 35219849 DOI: 10.1016/j.freeradbiomed.2022.02.025</ref> Mechanism causing lipofuscinolysis may involve the reactive oxygen species generated via the presence of remofuscin. Remofuscin binds to lipofuscin and is a superoxide generator when illuminated with light. Superoxide might help to degrade the polymeric lipofuscin into smaller units which then are transported out of the lysosomes by exocytosis.<ref name="reactive"/><ref name="elegans">Oh, M., Yeom, J., Schraermeyer, U., Julien-Schraermeyer, S., & Lim, Y. H. (2022). Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan. Scientific reports, 12(1), 1-13. PMID: 35504961 PMCID: PMC9064964 DOI: 10.1038/s41598-022-11325-2</ref> Remofuscin reduces existing levels of lipofuscin in the RPE instead of merely slowing down accumulation of further toxic Vitamin A aggregates.<ref>Sears, A. E., Bernstein, P. S., Cideciyan, A. V., Hoyng, C., Issa, P. C., Palczewski, K., ... & Scholl, H. P. (2017). Towards treatment of Stargardt disease: workshop organized and sponsored by the Foundation Fighting Blindness. Translational vision science & technology, 6(5), 6-6.PMID: 28920007 PMCID: PMC5599228 DOI: 10.1167/tvst.6.5.6</ref><ref name="elegans"/>

Aging biomarkers were improved in remofuscin-treated ''Caenorhabditis elegans'' worms, resulting in '''a significant (p <0.05) increase in their lifespan'''.<ref name="elegans"/> The expression levels of genes related to lysosomes, a nuclear hormone receptor, fatty acid beta-oxidation, and xenobiotic detoxification were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. ''elegans'' with loss-of-function mutations of genes related to lysosomes and xenobiotic detoxification, suggesting that these genes are associated with lifespan extension in remofuscin-treated C. ''elegans''.<ref name="elegans"/>

=== NMDA receptor antagonists ===
N-methyl-D-aspartate (NMDA) receptors signaling is a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. NMDA receptor antagonists, such as '''Ro 25-6981''', '''CP-101,606''' and '''AZD6765''', degrade lipofuscin via [[autophagy]] in human RPE cells.<ref>Lee, J. R., & Jeong, K. W. (2022). NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells. Medicina, 58(8), 1129. PMID: 36013596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415004 PMC9415004] DOI: 10.3390/medicina58081129</ref> Ro 25-6981 has not yet been approved for clinical use. Among the clinically approved NMDA antagonists, '''memantine''' and '''ifenprodil''' have been proposed as drug repositioning to remove N-retinylidene-N-retinylethanolamine (A2E), an intracellular lipofuscin component.<ref>Lee, J. R., & Jeong, K. W. (2023). N-retinylidene-N-retinylethanolamine degradation in human retinal pigment epithelial cells via memantine-and ifenprodil-mediated autophagy. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 27(5), 449. PMID: 37641807 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466070 PMC10466070] DOI: 10.4196/kjpp.2023.27.5.449</ref>

=== ATM inhibition ===
The increase in lipid peroxidation during oxidative stress increases the content of intra-lysosomal lipofuscins in fibroblasts during senescence.<ref>McHugh, D., & Gil, J. (2018). Senescence and aging: Causes, consequences, and therapeutic avenues. Journal of Cell Biology, 217(1), 65-77.</ref> Senescence amelioration in normal aging cells is mediated by the recovered mitochondrial function upon inhibition of a key mediator of DNA damage signaling and repair - Ataxia telangiectasia mutated (ATM).<ref>Khanna, K. K., Lavin, M. F., Jackson, S. P., & Mulhern, T. D. (2001). ATM, a central controller of cellular responses to DNA damage. Cell Death & Differentiation, 8(11), 1052-1065.</ref><ref>Kang, H. T., Park, J. T., Choi, K., Kim, Y., Choi, H. J. C., Jung, C. W., ... & Park, S. C. (2017). Chemical screening identifies ATM as a target for alleviating senescence. Nature chemical biology, 13(6), 616-623. PMID: 28346404 DOI: 10.1038/nchembio.2342</ref><ref>Song, S. B., & Hwang, E. S. (2020). High levels of ROS impair lysosomal acidity and autophagy flux in glucose-deprived fibroblasts by activating ATM and Erk pathways. Biomolecules, 10(5), 761. PMID: 32414146 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277562/ PMC7277562] DOI: 10.3390/biom10050761</ref>

ATM inhibitors '''KU-60019''', '''CP-466722''' or antioxidant '''N-acetyl-cysteine (NAC)''' significantly reduced lipofuscin accumulation.<ref>Song, S. B., Shim, W., & Hwang, E. S. (2023). Lipofuscin granule accumulation requires autophagy activation. Molecules and Cells, 46(8), 486-495. PMID: 37438887 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440269 PMC10440269] DOI: 10.14348/molcells.2023.0019</ref>

== See also ==
* Renteln, M. (2024). Toward systemic lipofuscin removal. Rejuvenation Research, (ja). https://doi.org/10.1089/rej.2024.0034
* Ilie, O. D., Ciobica, A., Riga, S., Dhunna, N., McKenna, J., Mavroudis, I., ... & Riga, D. (2020). Mini-review on lipofuscin and aging: focusing on the molecular interface, the biological recycling mechanism, oxidative stress, and the gut-brain axis functionality. Medicina, 56(11), 626. PMID: 33228124 PMCID: PMC7699382 DOI: 10.3390/medicina56110626
* Nasiri, L., Vaez-Mahdavi, M. R., Hassanpour, H., Ghazanfari, T., Ardestani, S. K., Askari, N., ... & Rahimlou, B. (2023). Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence. International Immunopharmacology, 114, 109549. https://doi.org/10.1016/j.intimp.2022.109549 Chronic oxidative stress and continuous inflammatory stimulation in veterans, due to mustard gas poisoning once in 1987, led to cells senescence with increased lipofuscin, and telomere shortening.
* Nociari, M. M., Lehmann, G. L., Perez Bay, A. E., Radu, R. A., Jiang, Z., Goicochea, S., ... & Rodriguez-Boulan, E. (2014). Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium. Proceedings of the National Academy of Sciences, 111(14), E1402-E1408. PMID: 24706818 PMCID: PMC3986126 DOI: 10.1073/pnas.1400530111

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Age-related diseases]]

Human Ageing Genomic Resources

2024-08-01T10:36:23Z

Dmitry Dzhagarov: /* GenAge */

'''The Human Ageing Genomic Resources (HAGR)''' is a collection of databases and tools designed to help researchers study the genetics of human ageing using modern approaches such as functional genomics, network analyses, systems biology and evolutionary analyses.<ref>[https://genomics.senescence.info Human Ageing Genomic Resources]</ref>

== [https://ngdc.cncb.ac.cn/hall/index HALL: a comprehensive database for human aging and longevity studies] ==
Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.<ref>Li, H., Wu, S., Li, J., Xiong, Z., Yang, K., Ye, W., ... & Zhang, W. (2023). HALL: a comprehensive database for human aging and longevity studies. Nucleic Acids Research, gkad880. [https://doi.org/10.1093/nar/gkad880 DOI: 10.1093/nar/gkad880]</ref>

== [https://Bio-Learn.github.io/ Biolearn, an open-source library for biomarkers of aging] ==
Identifying and validating biomarkers of aging is pivotal for understanding the aging process and testing longevity interventions.
Biolearn is an open-source library (freely available at https://Bio-Learn.github.io/) dedicated to the implementation and application of aging biomarkers.<ref>Ying, K., Paulson, S., Perez-Guevara, M., Emamifar, M., Casas Martinez, M., Kwon, D., ... & Gladyshev, V. N. (2023). Biolearn, an open-source library for biomarkers of aging. bioRxiv, 2023-12. https://doi.org/10.1101/2023.12.02.569722</ref>

'''Biolearn facilitates''':

1. harmonization of existing aging biomarkers, while presenting a structured framework for novel biomarkers in standardized formats;

2. unification of public datasets, ensuring coherent structuring and formatting, thus simplifying cross-population validation studies; and

3. provision of computational methodologies to assess any harmonized biomarker against unified datasets.

== [https://doi.org/10.1101/2024.05.04.592445 A metabolic atlas of mouse aging] ==

<ref>Steven E Pilley, et al., (2024). A metabolic atlas of mouse aging. bioRxiv; doi: https://doi.org/10.1101/2024.05.04.592445</ref>

== [http://mengwanglab.org/atlas Cell Atlas of Worm Aging (CAWA)] ==

<ref>Gao, S.M., Qi, Y., Zhang, Q. et al. Aging atlas reveals cell-type-specific effects of pro-longevity strategies. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00631-1</ref>

== [https://db.cngb.org/cdcp/hlma/ Human Muscle Ageing Cell Atlas (HMA)] ==
The Human Muscle Ageing Cell Atlas provides a series of integrated cellular and molecular explanations for sarcopenia and frailty development in advanced ages.<ref>Lai, Y., Ramírez-Pardo, I., Isern, J. et al. (2024). Multimodal cell atlas of the ageing human skeletal muscle. Nature https://doi.org/10.1038/s41586-024-07348-6 </ref><ref>[https://db.cngb.org/cdcp/hlma/ Human Muscle Ageing Cell Atlas (HMA)]</ref>

== [http://www.thua45.cn/geredb-wp/ Gene Expression Regulation Database (GREDB)] ==
GereDB is an comprehensive cohort of gene expression regulation relationships curiated from published literatures. Geredb has been continually devepleted for more than 4 years, making it the one of the most trusted and complete collection of gene expression regulation database in the community.<ref>Huang, T., Huang, X., Shi, B. & Yao, M. (2019). GEREDB: Gene expression regulation database curated by mining abstracts from literature. Journal of Bioinformatics and Computational Biology 17, 1950024 https://www.ncbi.nlm.nih.gov/pubmed/31617460</ref>

== voyAGEr: free web interface for the analysis of age-related gene expression alterations in human tissues ==
'''voyAGEr''' is an online graphical interface to explore age-related gene expression alterations in 49 human tissues.<ref>Schneider A.L., Martins-Silva R., Kaizeler A., Saraiva-Agostinho N., Barbosa-Morais N. (2023). voyAGEr: free web interface for the analysis of age-related gene expression alterations in human tissues. bioRxiv, 521681. [https://doi.org/10.1101/2022.12.22.521681 doi: 10.1101/2022.12.22.521681]; eLife 12:RP88623. https://doi.org/10.7554/eLife.88623.3</ref>
voyAGEr was created to assist researchers with no expertise in bioinformatics, providing a supportive framework for elaborating, testing and refining their hypotheses on the molecular nature of human ageing and its association with pathologies, thereby also aiding in the discovery of novel therapeutic targets. voyAGEr is freely available at https://compbio.imm.medicina.ulisboa.pt/app/voyAGEr.
voyAGEr reveals transcriptomic signatures of the known asynchronous ageing between tissues, allowing the observation of tissue-specific age-periods of major transcriptional changes, associated with alterations in different biological pathways, cellular composition, and disease conditions.

== GenAge ==
A major resource in HAGR is GenAge,<ref>[https://genomics.senescence.info/genes/index.html GenAge Database of Ageing-Related Genes]</ref> which includes a curated database of over 300 genes related to human ageing and a database of over 2,000 ageing- and longevity-associated genes in model organisms.

=== Aging-related gene sets ===
Functions for aging-related gene sets. All included genes are collected from aging-related literature and manually annotated. All gene sets are divided into ten sub-categories. The species currently listed include humans and mice.<ref>[https://ngdc.cncb.ac.cn/aging/age_related_genes Aging-related gene sets]</ref>

== CodeKeeper™ ==
[https://bioviva-codekeeper.com '''CodeKeeper'''™] is BioViva's open access database for gene therapy. It is designed for anyone interested in what is happening in the gene therapy space. Advanced tools are available for universities, companies, independent researchers, and anyone else who is interested in understanding or contributing to the state-of-the-art.

=== Senescence promoting genes ===
=== Epigenomics ===
==== [http://www.bioapp.org/ewasdb/ EWASdb : epigenome-wide association study database] ====

=== Single-cell transcriptomics ===
<ref>Ma, S., Chi, X., Cai, Y., Ji, Z., Wang, S., Ren, J., & Liu, G. H. (2023). Decoding aging hallmarks at the single-cell level. Annual Review of Biomedical Data Science, 6. [https://doi.org/10.1146/annurev-biodatasci-020722-120642 DOI: 10.1146/annurev-biodatasci-020722-120642]</ref>
<ref>Cai, Y., Xiong, M., Xin, Z., Liu, C., Ren, J., Yang, X., ... & Liu, G. H. (2023). Decoding aging-dependent regenerative decline across tissues at single-cell resolution. Cell Stem Cell. PMID: 37898124 [https://doi.org/10.1016/j.stem.2023.09.014 DOI: 10.1016/j.stem.2023.09.014] </ref>

=== Proteomics ===

=== GenAge Human Genes ===
This section of GenAge features genes possibly related to human ageing. Briefly, genes were selected for inclusion based on findings in model organisms put in context of human biology plus the few genes directly related to ageing in humans. As such, genes should be seen as candidate human ageing-associated genes.<ref>[https://genomics.senescence.info/genes/human.html GenAge Human Genes]</ref>

==== [http://www.genemed.tech/gene4denovo/home Gene4Denovo: an integrated database and analytic platform for de novo mutations in humans] ====

=== GenAge Model Organisms ===
Ageing and/or longevity in model organisms<ref>[https://genomics.senescence.info/genes/models.html GenAge Model Organisms]</ref>

== AnAge ==
Another major database in HAGR is AnAge.<ref>[https://genomics.senescence.info/species/index.html AnAge Database of Animal Ageing and Longevity]</ref> Featuring over 4,000 species, AnAge provides a compilation of data on ageing, longevity, and life history that is ideal for the comparative biology of ageing.

== DrugAge ==
DrugAge provides data on over 500 ageing-related drugs across model organisms.<ref>[https://genomics.senescence.info/drugs/ DrugAge Database of Anti-Ageing Drugs]</ref>

=== [https://drugcentral.org DrugCentral] ===
DrugCentral, accessible at https://drugcentral.org , is an open-access online drug information repository. It covers over 4950 drugs, incorporating structural, physicochemical, and pharmacological details to support drug discovery, development, and repositioning.<ref>Halip, L., Avram, S., Curpan, R., Borota, A., Bora, A., Bologa, C., & Oprea, T. I. (2023). Exploring DrugCentral: from molecular structures to clinical effects. Journal of Computer-Aided Molecular Design, 1-14. PMID: 37707619 DOI: 10.1007/s10822-023-00529-x</ref>

=== Pharmacogenomics ===

== [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ THE REJUVENATION ROADMAP] ==

== References ==
<references />
[[Category:Longevity genes]]
[[Category:Drugs]]
[[Category:Tools to study aging]]
[[Category:Main list]]
[[Category:Drafts]]
[[Category:Database]]

Lipofuscin

2024-07-30T16:02:29Z

Dmitry Dzhagarov: /* See also */

'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref>
[[File:Lipofuscin.jpg|thumb|Lipofuscin spots on the upper surface of the hands.]]
Lipofuscin is proposed as a [[Cellular senescence|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>

Accumulation of lipofuscin or "aging pigment" is part of normal aging, and should be distinguished from accumulation of '''ceroid''' - autofluorescent storage material associated with disease and usually produced under various pathological conditions not necessarily related to aging.<ref>Seehafer, S. S., & Pearce, D. A. (2006). You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiology of aging, 27(4), 576-588. PMID: 16455164 DOI: 10.1016/j.neurobiolaging.2005.12.006</ref> Ceroid has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis.<ref>
Albaghdadi, M. S., Ikegami, R., Kassab, M. B., Gardecki, J. A., Kunio, M., Chowdhury, M. M., ... & Jaffer, F. A. (2021). Near-infrared autofluorescence in atherosclerosis associates with ceroid and is generated by oxidized lipid-induced oxidative stress. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(7), e385-e398. PMID: 34011166 PMC8222195 DOI: 10.1161/ATVBAHA.120.315612</ref>

== Detection of lipofuscin ==
During the process of aging, lipofuscin accumulates in a nearly linear way in postmitotic senescencent cells (cardiomyocytes, retinal epithelial pigment cells, hepatocytes, neurons and keratinocytes),<ref name="biomarker">Georgakopoulou, E. A., Tsimaratou, K., Evangelou, K., Fernandez, M. P., Zoumpourlis, V., Trougakos, I. P., ... & Gorgoulis, V. G. (2013). Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY), 5(1), 37. PMID: 23449538 PMCID: PMC3616230 DOI: 10.18632/aging.100527</ref> and has been proposed as a detectable "marker" to estimate aging. This approach is particularly used to determine the age of crabs and other crustaceans either by labor histological fluorescent-microscopy examinations<ref>Jung, T., Höhn, A., & Grune, T. (2010). Lipofuscin: detection and quantification by microscopic techniques. Advanced Protocols in Oxidative Stress II, 173-193. PMID: 20072918 DOI: 10.1007/978-1-60761-411-1_13</ref> or simply by extractable lipofuscin solvent fluorescence measurements.<ref>Pinchuk, A. I., Harvey, H. R., & Eckert, G. L. (2016). Development of biochemical measures of age in the Alaskan red king crab Paralithodes camtschaticus (Anomura): Validation, refinement and initial assessment. Fisheries Research, 183, 92-98.https://doi.org/10.1016/j.fishres.2016.05.019</ref>

Detection of lipofuscin content can be used as a biomarker of old lysosome accumulation, either by its typical autofluorescence properties and fluorescence-based methods, or by selective staining with Sudan black B, which stained lipofuscin granules, allowing for detection in cells, tissues and body fluids.<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMCID: PMC5242262 DOI: 10.1111/acel.12545</ref><ref>Salmonowicz, H., & Passos, J. F. (2017). Detecting senescence: a new method for an old pigment. Aging Cell, 16(3), 432-434. </ref><ref>Lozano‐Torres, B., Blandez, J. F., García‐Fernández, A., Sancenón, F., & Martínez‐Máñez, R. (2022). Lipofuscin labelling through biorthogonal strain‐promoted azide‐alkyne cycloaddition for the detection of senescent cells. The FEBS Journal. PMID: 35527516 DOI: 10.1111/febs.16477</ref><ref>Evangelou, K., & Gorgoulis, V. G. (2017). Sudan Black B, the specific histochemical stain for lipofuscin: a novel method to detect senescent cells. In Oncogene-Induced Senescence (pp. 111-119). Humana Press, New York, NY. PMID: 27812872 DOI: 10.1007/978-1-4939-6670-7_10</ref>

== Relation to aging diseases ==
Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[Advanced glycation end products (AGEs)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>

Isolated lipofuscin aggregates, as shown in vitro, were readily incorporated by fibroblasts and caused cell death at low concentrations (LC50 = 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity.<ref>Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. (2024). Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. bioRxiv .03.25.586520; doi: https://doi.org/10.1101/2024.03.25.586520</ref>

Lipofuscin granules accumulation can lead to pathology and accelerate the aging process.<ref>Feldman, T. B., Dontsov, A. E., Yakovleva, M. A., & Ostrovsky, M. A. (2022). Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age. Biophysical Reviews, 1-15. PMID: 36124271 PMCID: PMC9481861 (available on 2023-08-08) DOI: 10.1007/s12551-022-00989-9</ref> The rate of lipofuscin formation has been shown to be negatively correlated with the life expectancy of postmitotic cells, i.e., the higher the rate, the shorter the lifespan of the cell due to decrease of cellular adaptability.<ref>Jung, T., Bader, N., & Grune, T. (2007). Lipofuscin: formation, distribution, and metabolic consequences. Annals of the New York Academy of Sciences, 1119(1), 97-111. PMID: 18056959 DOI: 10.1196/annals.1404.008</ref> Therefore, progressive deposition of lipofuscin might promote the development of age-related pathologies, including macular degeneration, heart failure, and neuro-degenerative diseases.

=== Dry AMD ===
One of the diseases associated with the accumulation of lipofuscin is dry [[Aging and eye disease|age-related macular degeneration]] (dry AMD) – a disease often diagnosed in people over 70 years of age and a leading cause of rapid vision loss. Dry AMD is a slow-progressing disease in which yellow drusen containing lipofuscin are deposited between the retinal pigment epithelial (RPE) cell layer and Bruch’s membrane.<ref>Jhingan, M., Singh, S. R., Samanta, A., Arora, S., Tucci, D., Amarasekera, S., ... & Chhablani, J. (2021). Drusen ooze: predictor for progression of dry age-related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology, 259(9), [tel:2687-2694 2687-2694]. DOI:[https://doi.org/10.1007/s00417-021-05147-7 10.1007/s00417-021-05147-7]</ref> A phototoxic components of lipofuscin such as A2E (Bis-retinoid N-retinyl-N-retinylidene ethanolamine) that induces inflammation and apoptosis in RPE cells,<ref>Sparrow, J. R., & Boulton, M. (2005). RPE lipofuscin and its role in retinal pathobiology. Experimental eye research, 80(5), 595-606.</ref> are accumulated with age and mediate damage under blue light exposure.<ref>Brandstetter, C., Mohr, L. K., Latz, E., Holz, F. G., & Krohne, T. U. (2015). Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. Journal of Molecular Medicine, 93(8), 905-916. PMID: 25783493 PMC4510924 DOI: 10.1007/s00109-015-1275-1</ref><ref name="Light">Jin, H. L., & Jeong, K. W. (2022). Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells. Biomolecules & therapeutics, 30(3), 291. PMID: 35074938 PMCID: PMC9047491 DOI: 10.4062/biomolther.2021.155</ref> It has been reported that iron levels increase in RPE during ageing and this intracellular iron can interact with bisretinoid lipofuscin in RPE to promote cell damage.<ref>Zhao, T., Guo, X., & Sun, Y. (2021). Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging and disease, 12(2), 529. PMID: 33815881 PMCID: PMC7990372 DOI: 10.14336/AD.2020.0912</ref> Therefore, to alleviate the deteriorating effects of lipofuscin on age-related macular degeneration, iron chelation, either independently or in combination with bisretinoid inhibitors could potentially serve as AMD treatments.<ref>Ueda, K., Kim, H. J., Zhao, J., Song, Y., Dunaief, J. L., & Sparrow, J. R. (2018). Iron promotes oxidative cell death caused by bisretinoids of retina. Proceedings of the National Academy of Sciences, 115(19), [tel:4963-4968 4963-4968]. PMID: 29686088 PMCID: PMC5948992 DOI: 10.1073/pnas.1722601115</ref> To protect human RPE cells from oxidative damage, caused by reactive oxygen species generated by the photo-excited lipofuscin, also is able L‐Citrulline, a naturally occurring amino acid with known antioxidant properties<ref>Hassel, C., Couchet, M., Jacquemot, N., Blavignac, C., Loï, C., Moinard, C., & Cia, D. (2022). Citrulline protects human retinal pigment epithelium from hydrogen peroxide and iron/ascorbate induced damages. Journal of Cellular and Molecular Medicine, 26(10), [tel:2808-2818 2808-2818]. PMID: 35460170 PMCID: PMC9097847 DOI: 10.1111/jcmm.17294</ref> and the main active component of ''Spirulina maxima'' P-phycocyanin - pigment with anti-inflammatory and antioxidant activities.<ref>Cho, H. M., Jo, Y. D., & Choung, S. Y. (2022). Protective Effects of Spirulina maxima against Blue Light-Induced Retinal Damages in A2E-Laden ARPE-19 Cells and Balb/c Mice. Nutrients, 14(3), 401. PMID: 35276761 PMCID: PMC8840079 DOI: 10.3390/nu14030401</ref>

The drug Lysoclear is an enzyme developed to enter RPE cells and break down lipofuscin deposits in the lysosomes, a therapeutic approach that proposes to reverse dry age-related macular degeneration and Stargardt's macular degeneration.<ref>www.ichortherapeutics.com</ref> Phase 1 clinical trials started in 2018.

==== Zinc deficiency ====
Zinc-deficient animals showed a greater number of lipofuscin granules.<ref>Julien, S., Biesemeier, A., Kokkinou, D., Eibl, O., & Schraermeyer, U. (2011). Zinc deficiency leads to lipofuscin accumulation in the retinal pigment epithelium of pigmented rats. PLoS One, 6(12), e29245. PMID: 22216222 PMCID: PMC3245262 DOI: 10.1371/journal.pone.0029245</ref> The relationship between zinc deficiency and enhanced lipofuscin accumulation suggest that zinc deficiency may result in the accumulation of substrates for autophagy whereas low zinc does not stimulate autophagy.<ref>Blasiak, J., Pawlowska, E., Chojnacki, J., Szczepanska, J., Chojnacki, C., & Kaarniranta, K. (2020). Zinc and autophagy in age-related macular degeneration. International Journal of Molecular Sciences, 21(14), 4994. PMID: 32679798 PMCID: PMC7404247 DOI: 10.3390/ijms21144994</ref> Autophagy is also inhibited when A2E-treated RPE cells are exposed to blue light.<ref name="Light"/> Currently, the only intervention available for the treatment of dry AMD is Age-Related Eye Disease Supplement (AREDS), an oral supplement containing vitamin C, vitamin E, lutein/zeaxanthin, and '''zinc'''. It was shown that AREDS can reduce the risk of advanced AMD by about 25% over a 5-year period in patients with intermediate AMD.<ref>Age-Related Eye Disease Study Research Group. (2001). A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Archives of ophthalmology, 119(10), 1417-1436. PMID: 11594942 PMCID: PMC1462955 DOI: 10.1001/archopht.119.10.1417</ref>

=== Lipofuscin accumulation in aging heart ===
Lipofuscin granules are found abundantly in myocardial cells.<ref>Kakimoto, Y., Okada, C., Kawabe, N., Sasaki, A., Tsukamoto, H., Nagao, R., & Osawa, M. (2019). Myocardial lipofuscin accumulation in ageing and sudden cardiac death. Scientific reports, 9(1), 1-8. PMID: 30824797 PMCID: PMC6397159 DOI: 10.1038/s41598-019-40250-0</ref><ref>Li, W. W., Wang, H. J., Tan, Y. Z., Wang, Y. L., Yu, S. N., & Li, Z. H. (2021). Reducing lipofuscin accumulation and cardiomyocytic senescence of aging heart by enhancing autophagy. Experimental Cell Research, 403(1), 112585. PMID: 33811905 DOI: 10.1016/j.yexcr.2021.112585</ref><ref>Wang, L., Xiao, C. Y., Li, J. H., Tang, G. C., & Xiao, S. S. (2022). Transport and Possible Outcome of Lipofuscin in Mouse Myocardium. Advances in Gerontology, 12(3), 247-263. </ref> The myocardial tissues of mice have the ability to eliminate the lipofuscin produced in the cardiomyocytes into the myocardial blood circulation. It is mainly carried out of cardiomyocytes into the myocardial interstitium in the form of small lipofuscin granules, using capsule-like protrusions that are formed on the sarcolemma.<ref>Wang, L., Xiao, C. Y., Li, J. H., Tang, G. C., & Xiao, S. S. (2020). Observation of the Transport and Removal of Lipofuscin from the Mouse Myocardium using Transmission Electron Microscope. BioRxiv. https://doi.org/10.1101/2020.03.10.985507</ref>

=== Role of lipofuscin in age-related neurodegeneration ===
Lipofuscin aggregation represents a risk factor for [[Aging and neurodegeneration|neurodegeneration]].<ref>Moreno-García, A., Kun, A., Calero, O., Medina, M., & Calero, M. (2018). An overview of the role of lipofuscin in age-related neurodegeneration. Frontiers in Neuroscience, 12, 464. PMID: 30026686 PMCID: PMC6041410 DOI: 10.3389/fnins.2018.00464</ref>

Progranulin neurons that normally have high levels of progranulin expression are more susceptible to age-related pathology, such as neuronal lipofuscinosis, in GRN−/− mice.<ref>Ahmed, Z., Sheng, H., Xu, Y. F., Lin, W. L., Innes, A. E., Gass, J., ... & Lewis, J. (2010). Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. The American journal of pathology, 177(1), 311-324. PMID: 20522652 PMCID: PMC2893674 DOI: 10.2353/ajpath.2010.090915</ref>

[[File:Lipofuscin in aged (60y) human epidermis.jpg|thumb|Lipofuscin granules (brown) accumulation in aged (60y) human epidermis according to Rübe et al., & Scherthan (2021).<ref>Rübe, C. E., Bäumert, C., Schuler, N., Isermann, A., Schmal, Z., Glanemann, M., ... & Scherthan, H. (2021). Human skin aging is associated with increased expression of the histone variant H2A. J in the epidermis. npj Aging and Mechanisms of Disease, 7(1), 1-11 PMID:33795696 PMC8016850 DOI:10.1038/s41514-021-00060-z</ref>]]
=== Lipofuscin-accumulating in skin cells ===
Lipofuscin is an endogenous photosensitizer that efficiently absorbs ultraviolet radiation and visible light, forming electronic excited states that transfer energy to surrounding molecules. It is assumed, that photosensitized lipofuscin is cytotoxic because of its ability to incorporate redox-active transition metals (Fe+2), resulting in a redox-active surface, able to catalyze the Fenton reaction. Reactive oxygen and nitrogen species (ROS/RNS) generated by photosensitization of lipofuscin leads to DNA damage and strand breaks.<ref>Tonolli, P. N., Baptista, M. S., & Chiarelli-Neto, O. (2021). Melanin, lipofuscin and the effects of visible light in the skin. Journal of Photochemistry and Photobiology, 7, 100044. https://doi.org/10.1016/j.jpap.2021.100044</ref><ref>Skoczyńska, A., Budzisz, E., Trznadel-Grodzka, E., & Rotsztejn, H. (2017). Melanin and lipofuscin as hallmarks of skin aging. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 34(2), 97-103. PMID: 28507486 PMCID: PMC5420599 DOI: 10.5114/ada.2017.67070</ref> It was observed that application of vitamin E may reduce the level of lipofuscin in skin biopsies as well as lighten the skin (but not in very old ones).<ref>Monji, A., Morimoto, N., Okuyama, I., Yamashita, N., & Tashiro, N. (1994). Effect of dietary vitamin E on lipofuscin accumulation with age in the rat brain. Brain research, 634(1), 62-68. PMID: 8156392 DOI: 10.1016/0006-8993(94)90258-5</ref><ref name="biomarker"/> Light-induced skin damage can be protected by regulating the ROS-ER stress-[[autophagy]]-apoptosis axis with '''hydrogen sulfide''' ('''H2S''').<ref>Zhu, S., Li, X., Wu, F., Cao, X., Gou, K., Wang, C., & Lin, C. (2022). Blue light induces skin apoptosis and degeneration through activation of the endoplasmic reticulum stress-autophagy apoptosis axis: Protective role of hydrogen sulfide. Journal of Photochemistry and Photobiology B: Biology, 229, 112426. https://doi.org/10.1016/j.jphotobiol.2022.112426</ref>

== Inhibitors of lipofuscin accumulation ==
It was suggested that formation of A2E and other toxic lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridinephosphatidyl-ethanolamine) and atRALdi-PE (all-trans-retinal dimer phosphatidylethanolamine), occurs in the retina in a non-enzymatic manner and can be considered a by-product of a properly functioning visual cycle.<ref>Sparrow, J. R., Gregory-Roberts, E., Yamamoto, K., Blonska, A., Ghosh, S. K., Ueda, K., & Zhou, J. (2012). The bisretinoids of retinal pigment epithelium. Progress in retinal and eye research, 31(2), 121-135. PMID: 22209824 PMCID: PMC3288746 DOI: 10.1016/j.preteyeres.2011.12.001</ref> The formation of A2E was completely inhibited in total darkness, so, humans with retinal or macular degeneration may slow progression of their disease by limiting exposure to light.<ref>Mata, N. L., Weng, J., & Travis, G. H. (2000). Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proceedings of the National Academy of Sciences, 97(13), [tel:7154-7159 7154-7159]. PMID: 10852960 PMCID: PMC16515 DOI: 10.1073/pnas.130110497</ref>

==== Meclofenoxate ====
'''Meclofenoxate''' is a cholinergic nootropic also known as '''centrophenoxine'''. It is an ester of dimethylethanolamine ('''DMAE''') and 4-chlorophenoxyacetic acid (pCPA).
Meclofenoxate, as well as DMAE, have been found to increase the dissolution and removal of lipofuscin<ref>Hasan, M., Glees, P., & Spoerri, P. E. (1974). Dissolution and removal of neuronal lipofuscin following dimethylaminoethyl p-chlorophenoxyacetate administration to guinea pigs. Cell and Tissue Research, 150(3), 369-375. PMID: 4367734 DOI: 10.1007/BF00220143</ref><ref>Riga, S., & Riga, D. (1974). Effects of centrophenoxine on the lipofuscin pigments in the nervous system of old rats. Brain Research, 72(2), 265-275. PMID: 4151704 DOI: 10.1016/0006-8993(74)90864-6</ref><ref>Spoerri, P. E., Glees, P., & El Ghazzawi, E. (1974). Accumulation of lipofuscin in the myocardium of senile guinea pigs: dissolution and removal of lipofuscin following dimethylaminoethyl p-chlorophenoxyacetate administration. An electron microscopic study. Mechanisms of Ageing and Development, 3, 311-321. PMID: 4618294 DOI: 10.1016/0047-6374(74)90027-x</ref> '''leading to lifespan extension of mice'''.<ref>Hochschild, R. (1973). Effect of dimethylaminoethanol on the life span of senile male A/J mice. Experimental Gerontology, 8(4), 185-191. https://doi.org/10.1016/0531-5565(73)90025-9</ref><ref>Hochschild, R. (1973). Effect of dimethylaminoethyl p-chlorophenoxyacetate on the life span of male Swiss Webster albino mice. Experimental gerontology, 8(4), 177-183. DOI: 10.1016/0531-5565(73)90024-7</ref> As a result of meclophenoxate treatment, a gradual decrease in the myocardial volume occupied by the pigment was noted. After 4-6 weeks of treatment, the pigment bodies were found lodged into the capillary endothelium and the lumen, facilitating the removal of the pigment via blood stream.<ref>Patro, N. I. S. H. A., Sharma, S. P., & Patro, I. K. (1992). Lipofuscin accumulation in ageing myocardium & its removal by meclophenoxate. The Indian Journal of Medical Research, 96, 192-198. PMID:[https://pubmed.ncbi.nlm.nih.gov/1512044/ 1512044]</ref><ref>Hochschild, R. (1973). Effect of dimethylaminoethanol on the life span of senile male A/J mice. Experimental Gerontology, 8(4), 185-191.</ref>

=== Remofuscin ===
'''Remofuscin''', a small molecule belonging to the tetrahydropyridoether class of compounds is able to remove lipofuscin from the RPE by accumulation specifically in RPE pigments and thus stimulation of the exocytosis.<ref>Julien, S., & Schraermeyer, U. (2012). Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys. Neurobiology of aging, 33(10), [tel:2390-2397 2390-2397]. PMID: 22244091 DOI: 10.1016/j.neurobiolaging.2011.12.009</ref> Remofuscin formerly known as '''Soraprazan''' a potent and reversible selective inhibitor of gastric H,K-ATPase may be a promising drug candidate to manage neurodegenerative diseases related to lipofuscin accumulation.<ref>Julien‐Schraermeyer, S., Illing, B., Tschulakow, A., Taubitz, T., Guezguez, J., Burnet, M., & Schraermeyer, U. (2020). Penetration, distribution, and elimination of remofuscin/soraprazan in Stargardt mouse eyes following a single intravitreal injection using pharmacokinetics and transmission electron microscopic autoradiography: Implication for the local treatment of Stargardt’s disease and dry age‐related macular degeneration. Pharmacology Research & Perspectives, 8(6), e00683. PMID: 33164337 PMCID: PMC7649431 DOI: 10.1002/prp2.683</ref> Remofuscin reverses lipofuscin accumulation in aged primary human RPE cells and is non-cytotoxic in aged SD mouse RPE cells in vitro.<ref name="reactive">Fang, Y., Taubitz, T., Tschulakow, A. V., Heiduschka, P., Szewczyk, G., Burnet, M., ... & Julien-Schraermeyer, S. (2022). Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species. Free Radical Biology and Medicine, 182, 132-149. PMID: 35219849 DOI: 10.1016/j.freeradbiomed.2022.02.025</ref> Mechanism causing lipofuscinolysis may involve the reactive oxygen species generated via the presence of remofuscin. Remofuscin binds to lipofuscin and is a superoxide generator when illuminated with light. Superoxide might help to degrade the polymeric lipofuscin into smaller units which then are transported out of the lysosomes by exocytosis.<ref name="reactive"/><ref name="elegans">Oh, M., Yeom, J., Schraermeyer, U., Julien-Schraermeyer, S., & Lim, Y. H. (2022). Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan. Scientific reports, 12(1), 1-13. PMID: 35504961 PMCID: PMC9064964 DOI: 10.1038/s41598-022-11325-2</ref> Remofuscin reduces existing levels of lipofuscin in the RPE instead of merely slowing down accumulation of further toxic Vitamin A aggregates.<ref>Sears, A. E., Bernstein, P. S., Cideciyan, A. V., Hoyng, C., Issa, P. C., Palczewski, K., ... & Scholl, H. P. (2017). Towards treatment of Stargardt disease: workshop organized and sponsored by the Foundation Fighting Blindness. Translational vision science & technology, 6(5), 6-6.PMID: 28920007 PMCID: PMC5599228 DOI: 10.1167/tvst.6.5.6</ref><ref name="elegans"/>

Aging biomarkers were improved in remofuscin-treated ''Caenorhabditis elegans'' worms, resulting in '''a significant (p <0.05) increase in their lifespan'''.<ref name="elegans"/> The expression levels of genes related to lysosomes, a nuclear hormone receptor, fatty acid beta-oxidation, and xenobiotic detoxification were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. ''elegans'' with loss-of-function mutations of genes related to lysosomes and xenobiotic detoxification, suggesting that these genes are associated with lifespan extension in remofuscin-treated C. ''elegans''.<ref name="elegans"/>

=== NMDA receptor antagonists ===
N-methyl-D-aspartate (NMDA) receptors signaling is a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. NMDA receptor antagonists, such as '''Ro 25-6981''', '''CP-101,606''' and '''AZD6765''', degrade lipofuscin via [[autophagy]] in human RPE cells.<ref>Lee, J. R., & Jeong, K. W. (2022). NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells. Medicina, 58(8), 1129. PMID: 36013596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415004 PMC9415004] DOI: 10.3390/medicina58081129</ref> Ro 25-6981 has not yet been approved for clinical use. Among the clinically approved NMDA antagonists, '''memantine''' and '''ifenprodil''' have been proposed as drug repositioning to remove N-retinylidene-N-retinylethanolamine (A2E), an intracellular lipofuscin component.<ref>Lee, J. R., & Jeong, K. W. (2023). N-retinylidene-N-retinylethanolamine degradation in human retinal pigment epithelial cells via memantine-and ifenprodil-mediated autophagy. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 27(5), 449. PMID: 37641807 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466070 PMC10466070] DOI: 10.4196/kjpp.2023.27.5.449</ref>

=== ATM inhibition ===
The increase in lipid peroxidation during oxidative stress increases the content of intra-lysosomal lipofuscins in fibroblasts during senescence.<ref>McHugh, D., & Gil, J. (2018). Senescence and aging: Causes, consequences, and therapeutic avenues. Journal of Cell Biology, 217(1), 65-77.</ref> Senescence amelioration in normal aging cells is mediated by the recovered mitochondrial function upon inhibition of a key mediator of DNA damage signaling and repair - Ataxia telangiectasia mutated (ATM).<ref>Khanna, K. K., Lavin, M. F., Jackson, S. P., & Mulhern, T. D. (2001). ATM, a central controller of cellular responses to DNA damage. Cell Death & Differentiation, 8(11), 1052-1065.</ref><ref>Kang, H. T., Park, J. T., Choi, K., Kim, Y., Choi, H. J. C., Jung, C. W., ... & Park, S. C. (2017). Chemical screening identifies ATM as a target for alleviating senescence. Nature chemical biology, 13(6), 616-623. PMID: 28346404 DOI: 10.1038/nchembio.2342</ref><ref>Song, S. B., & Hwang, E. S. (2020). High levels of ROS impair lysosomal acidity and autophagy flux in glucose-deprived fibroblasts by activating ATM and Erk pathways. Biomolecules, 10(5), 761. PMID: 32414146 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277562/ PMC7277562] DOI: 10.3390/biom10050761</ref>

ATM inhibitors '''KU-60019''', '''CP-466722''' or antioxidant '''N-acetyl-cysteine (NAC)''' significantly reduced lipofuscin accumulation.<ref>Song, S. B., Shim, W., & Hwang, E. S. (2023). Lipofuscin granule accumulation requires autophagy activation. Molecules and Cells, 46(8), 486-495. PMID: 37438887 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440269 PMC10440269] DOI: 10.14348/molcells.2023.0019</ref>

== See also ==
* Renteln, M. (2024). Toward systemic lipofuscin removal. Rejuvenation Research, (ja). https://doi.org/10.1089/rej.2024.0034
* Ilie, O. D., Ciobica, A., Riga, S., Dhunna, N., McKenna, J., Mavroudis, I., ... & Riga, D. (2020). Mini-review on lipofuscin and aging: focusing on the molecular interface, the biological recycling mechanism, oxidative stress, and the gut-brain axis functionality. Medicina, 56(11), 626. PMID: 33228124 PMCID: PMC7699382 DOI: 10.3390/medicina56110626
* Nasiri, L., Vaez-Mahdavi, M. R., Hassanpour, H., Ghazanfari, T., Ardestani, S. K., Askari, N., ... & Rahimlou, B. (2023). Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence. International Immunopharmacology, 114, 109549. https://doi.org/10.1016/j.intimp.2022.109549 Chronic oxidative stress and continuous inflammatory stimulation in veterans, due to mustard gas poisoning once in 1987, led to cells senescence with increased lipofuscin, and telomere shortening.
* Nociari, M. M., Lehmann, G. L., Perez Bay, A. E., Radu, R. A., Jiang, Z., Goicochea, S., ... & Rodriguez-Boulan, E. (2014). Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium. Proceedings of the National Academy of Sciences, 111(14), E1402-E1408. PMID: 24706818 PMCID: PMC3986126 DOI: 10.1073/pnas.1400530111

== References ==
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Age-related diseases]]

Calcium channel blockers (CCBs)

2024-07-29T09:47:20Z

Dmitry Dzhagarov:

Small nucleoli as a visible cellular hallmark of longevity and metabolic health

2024-07-29T03:03:57Z

Dmitry Dzhagarov: /* Small nucleolar RNAs */

The nucleolus is a nuclear subcompartment where ribosomal RNA is synthesized and assembled into ribosomal subunits. It is a dynamic organelle subject to inputs from growth signalling pathways, nutrients, and stress, whose size correlates with rRNA synthesis.<ref>Guarente, L. (1997). Link between aging and the nucleolus. Genes & development, 11(19), 2449-2455. PMID: 9334311 [https://genesdev.cshlp.org/content/11/19/2449.long DOI: 10.1101/gad.11.19.2449]</ref><ref>Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M., & Lamond, A. I. (2010). The nucleolus under stress. Molecular cell, 40(2), 216-227. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987465/ PMC2987465/] doi: 10.1016/j.molcel.2010.09.024</ref> The nucleolus is also a production site for other ribonucleoprotein particles, including various splicing factors, the signal recognition particle, stress granules and the siRNA machinery. The expression of nucleolar genes is an excellent predictor of a proliferation index (PRI).<ref>Wang, M., & Lemos, B. (2017). Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation. PLoS genetics, 13(9), e1006994. PMID: 28880866 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605086/ PMC5605086] DOI: 10.1371/journal.pgen.1006994</ref>

'''Despite not being included as one of the “[[hallmarks of aging]]”, numerous evidences indicate a role for nucleoli in ageing'''.<ref>Kasselimi, E., Pefani, D. E., Taraviras, S., & Lygerou, Z. (2022). Ribosomal DNA and the nucleolus at the heart of aging. Trends in Biochemical Sciences, 47(4), 328-341. PMID: 35063340 [https://doi.org/10.1016/j.tibs.2021.12.007 DOI: 10.1016/j.tibs.2021.12.007]</ref> Studies reveal that multiple longevity pathways strikingly reduce nucleolar size, and diminish expression of the nucleolar protein FIB-1, ribosomal RNA, and ribosomal proteins across different species.<ref>Yi, Y. H., Ma, T. H., Lee, L. W., Chiou, P. T., Chen, P. H., Lee, C. M., ... & Lo, S. J. (2015). A Genetic Cascade of let-7-ncl-1-fib-1 Modulates Nucleolar Size and rRNA Pool in Caenorhabditis elegans. PLoS genetics, 11(10), e1005580. PMID: 26492166 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619655/ PMC4619655] DOI: 10.1371/journal.pgen.1005580</ref><ref name="premature" >Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 328. PMID: 28855503 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577202/ PMC5577202] DOI: 10.1038/s41467-017-00322-z</ref><ref name="hallmark" >Tiku, V., Jain, C., Raz, Y., Nakamura, S., Heestand, B., Liu, W., ... & Antebi, A. (2017). Small nucleoli are a cellular hallmark of longevity. Nature communications, 8(1), 16083. PMID: 28853436 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582349/ PMC5582349] DOI: 10.1038/ncomms16083</ref> A significant correlation between aging and nucleolar size in healthy individuals was also found; specifically, cells derived from individuals with a premature ageing disorder Hutchinson–Gilford progeria syndrome (HGPS) exhibited large nucleoli, which were comparable in size to those of old healthy individuals.<ref name="premature" /><ref>Zlotorynski, E. (2017). Live longer with small nucleoli. Nat Rev Mol Cell Biol 18, 651 https://doi.org/10.1038/nrm.2017.100</ref>

It was assumed that expansion and fragmentation of the nucleolus are the result of the massive accumulation of extrachromosomal ribosomal DNA circles (ERCs) occupying more space and recruiting more ribosome biogenesis factors.<ref>Li, Y., Jiang, Y., Paxman, J., O’Laughlin, R., Klepin, S., Zhu, Y., ... & Hao, N. (2020). A programmable fate decision landscape underlies single-cell aging in yeast. Science, 369(6501), 325-329. PMID: 32675375 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437498/ PMC7437498] DOI: 10.1126/science.aax9552</ref> However, it was discovered that nucleolar expansion occurs independently of ERCs so cannot be taken as evidence of a contribution of ERCs alone to senescence - nucleolar enlargement also occurs in cells lacking ERCs.<ref name="rather" >Zylstra, A., Hadj-Moussa, H., Horkai, D., Whale, A. J., Piguet, B., & Houseley, J. (2023). Senescence in yeast is associated with amplified linear fragments of chromosome XII rather than ribosomal DNA circle accumulation. PLoS Biology, 21(8), e3002250. PMID: 37643194 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464983/ PMC10464983] DOI: 10.1371/journal.pbio.3002250</ref>

The senescence entry point (SEP) represents an abrupt transition in ageing at which yeast cells cease to divide rapidly and the cell cycle becomes slow and heterogeneous.<ref>Fehrmann, S., Paoletti, C., Goulev, Y., Ungureanu, A., Aguilaniu, H., & Charvin, G. (2013). Aging yeast cells undergo a sharp entry into senescence unrelated to the loss of mitochondrial membrane potential. Cell reports, 5(6), 1589-1599.</ref> Cells passed the SEP irrespective of ERCs, while at least in yeast, the SEP across a wide range of conditions and mutants is obviously tightly associated with copy number amplification of a region of chromosome XII between the rDNA and the telomere (ChrXIIr) forming linear fragments up to approximately 1.8 Mb size, which arises in aged cells through a different mechanism to ERCs.<ref name="rather" />

<ref>Sharifi, S., Chaudhari, P., Martirosyan, A., Eberhardt, A. O., Witt, F., Gollowitzer, A., ... & Ermolaeva, M. (2024). Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans. Nature Communications, 15(1), 1702. PMID: 38402241 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10894287/ PMC10894287] DOI: 10.1038/s41467-024-46037-w</ref>

Nucleolar stress induced by arginine-rich peptides leads to a generalized accumulation of orphan ribosomal proteins, which is toxic in cells and drives accelerated aging in mice. The toxicity of arginine-rich peptides is alleviated by targeting ribosome biogenesis pathways such as mTOR or MYC.<ref>Sirozh, O., Jung, B., Sanchez-Burgos, L., Ventoso, I., Lafarga, V., & Fernandez-Capetillo, O. (2024). Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice. bioRxiv, 2023-08. Molecular Cell https://doi.org/10.1016/j.molcel.2024.02.031
</ref>
<ref>Cockrell, A. J., & Gerton, J. L. (2022). Nucleolar organizer regions as transcription-based scaffolds of nucleolar structure and function. In Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine (pp. 551-580). Cham: Springer International Publishing. PMID: 36348121 DOI: 10.1007/978-3-031-06573-6_19</ref>

<ref name="hallmark" />

== Ribosome biogenesis ==
Eukaryotes partition many of the complex, essential process of ribosome biogenesis (RB) steps into the nucleolus, a phase-separated membraneless organelle within the enveloped nucleus. In human cells, three of the four mature ribosomal RNAs (rRNAs), the 18S, 5.8S and 28S rRNAs, are synthesized in the nucleolus as components of the polycistronic 47S primary pre-rRNA precursor transcript from tandem ribosomal DNA (rDNA) repeats by RNA Polymerase 1 (RNAP1). The 5S rRNA is separately transcribed in the nucleus by RNA Polymerase 3 (RNAP3). A myriad of ribosome assembly factors (AFs) execute endo- and exonucleolytic pre-rRNA processing and modification events to liberate the mature rRNAs from the 47S transcript, forming the small 40S and large 60S ribosomal subunits. AFs also facilitate the binding of structurally-constitutive ribosomal proteins (RPs) and the folding of the maturing subunits at the macromolecular scale. Defects in RB can trigger the nucleolar stress response during which labile members of the 5S RNP including RPL5 (uL18) or RPL11 (uL5) bind and sequester the TP53-specific E3 ligase MDM2, effectively stabilizing TP53 levels and leading to CDKN1A (p21) induction, cell cycle arrest, and apoptosis. In aging, there is a decrease in the cellular rate of ribosome synthesis, which includes reduced expression of both rRNA and r-proteins, and an associated decrease in nucleolar size.<ref>Correll, C. C., Bartek, J., & Dundr, M. (2019). The nucleolus: a multiphase condensate balancing ribosome synthesis and translational capacity in health, aging and ribosomopathies. Cells, 8(8), 869. PMID: 31405125 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721831/ PMC6721831] DOI: 10.3390/cells8080869</ref> <ref name="repressors" >Bryant, C. J., McCool, M. A., Rosado González, G. T., Abriola, L., Surovtseva, Y. V., & Baserga, S. J. (2024). Discovery of novel microRNA mimic repressors of ribosome biogenesis. Nucleic Acids Research, 52(4), 1988-2011. PMID: 38197221 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10899765/ PMC10899765] DOI: 10.1093/nar/gkad1235</ref><ref>Ganley, A. R., & Kobayashi, T. (2014). Ribosomal DNA and cellular senescence: new evidence supporting the connection between rDNA and aging. FEMS yeast research, 14(1), 49-59. PMID: 24373458 DOI: 10.1111/1567-1364.12133</ref><ref>Wang, M., & Lemos, B. (2019). Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome research, 29(3), 325-333. PMID: 30765617 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396418/ PMC6396418] DOI: 10.1101/gr.241745.118</ref>

== Small nucleolar RNAs ==
Small nucleolar RNAs (snoRNAs) are a large class of small noncoding RNAs present in all eukaryotes. They have been characterized as playing a central role in ribosome biogenesis, guiding either the sequence-specific chemical modification of pre-rRNA (ribosomal RNA) or its processing.<ref>Dupuis-Sandoval, F., Poirier, M., & Scott, M. S. (2015). The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdisciplinary Reviews: RNA, 6(4), 381-397. https://doi.org/10.1002/wrna.1284</ref><ref>Piñeiro Ugalde, A., Roiz del Valle, D., Moledo Nodar, L., Menéndez Caravia, X., Pérez Freije, J. M., & López Otín, C. (2024). Non-coding RNA contribution to aging and lifespan. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 79(4), glae058, https://doi.org/10.1093/gerona/glae058</ref>
Small nucleolar RNAs (snoRNAs) regulate cardiac-relevant signaling pathways, oxidative and metabolic cellular stress, gene expression, and intercellular communication.<ref name="snoRNAs" >Chabronova, A., Holmes, T. L., Hoang, D. M., Denning, C., James, V., Smith, J. G., & Peffers, M. J. (2024). SnoRNAs in cardiovascular development, function, and disease. Trends in Molecular Medicine. https://doi.org/10.1016/j.molmed.2024.03.004</ref> An association between levels of circulating snoRNAs and myocardial infarction and heart failure has been found, indicating the potential of these snoRNAs as biomarkers.<ref name="snoRNAs" />

The MIR-28 family members, '''hsa-miR-28-5p''' and '''hsa-miR-708-5p''', are strong inhibitors of pre-18S pre-rRNA processing (a key step in ribosome biogenesis) by way of potent downregulation of the levels of the mRNA of the ribosomal protein S28 (RPS28, a ribosomal protein component of the 40S ribosomal subunit.<ref name="repressors" /> <ref>Gawade, K., & Raczynska, K. D. (2024). Imprinted small nucleolar RNAs: Missing link in development and disease?. Wiley Interdisciplinary Reviews: RNA, 15(1), e1818. PMID: 37722601 DOI: 10.1002/wrna.1818</ref>

=== SNORA13 ===
SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13, a highly conserved H/ACA box snoRNA, is essential for multiple forms of senescence in human cells and in mice.<ref>Cheng, Y., Wang, S., Zhang, H., Lee, J. S., Ni, C., Guo, J., ... & Mendell, J. T. (2024). A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence. Cell. PMID: 38981482 [https://doi.org/10.1016/j.cell.2024.06.019 DOI: 10.1016/j.cell.2024.06.019]</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Stub]]
[[Category:Drafts]]
[[Category:Aging pathways and hallmarks]]
[[Category:Fundamentals]]

Calorie restriction

2024-07-28T18:46:29Z

Dmitry Dzhagarov: /* Humans */

The physiological decline of an organism, known as aging, is a process highly conserved across the evolutionary tree<ref>Jones, O., Scheuerlein, A., Salguero-Gómez, R., Camarda, C., Schaible, R., & Casper, B. et al. (2013). Diversity of ageing across the tree of life. ''Nature'', ''505''(7482), 169-173. doi: 10.1038/nature12789</ref>. External stressors such as excessive food intake, poor fitness or certain diseases can accelerate biological aging. Reducing calorie intake significantly below the levels of ''ad libitum'' (feeding without restriction) without malnutrition is commonly referred to as calorie restriction (CR) or dietary restriction (DR).<ref name=":19">Bales, C. W., & Kraus, W. E. (2013). Caloric restriction: implications for human cardiometabolic health. ''Journal of cardiopulmonary rehabilitation and prevention'', ''33''(4), 201.</ref>

A number of studies have indicated that CR can increase the lifespan (50-300%) and reduce the onset of age-related diseases in a variety of organisms (e.g. rats, mice, flies, worms, and yeast).<ref name=":0">Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie Restriction and Aging in Humans. ''Annual Review of Nutrition'', ''40'', 105-133.</ref> There is some evidence from human epidemiological and clinical trial data suggesting that CR could increase healthy lifespan by 1 to 5 years.<ref name=":0" />

Care should be taken when using CR as a means to increase lifespan and prevent age-related diseases. It is important to recognize that scientists point to the benefits of CR only when avoiding malnutrition and when performed under adequate nutrition.<ref name=":20">[https://doi.org/10.1016/j.arr.2010.05.002 Cerqueira, F., & Kowaltowski, A. (2010). Commonly adopted caloric restriction protocols often involve malnutrition. ''Ageing Research Reviews'', ''9''(4), 424-430. doi: 10.1016/j.arr.2010.05.002]</ref> Nutrient deficiencies are associated with various health deficits, and consuming less calories than recommended can also be detrimental. There is also concern that reductions in body fat mass could affect muscle bone and tissue functionality.<ref name=":0" /> Thus, it is important to have sufficient quality macronutrient intake along with CR.

Additionally, there are risks associated to impaired immune function during CR interventions, an example of a potential trade-off.<ref name=":0" /> There may be utility in combining CR with other interventions to maximize healthy longevity, but more data is needed from both animal and human studies.

Several mice studies have shown that different genetic backgrounds may substantially influence the response to CR.<ref name=":5" /> This means that while some mice strains obtain lifespan benefits, others may attain no benefit or even experience harmful consequences.

== Evidence ==
CR is the most widely researched intervention for slowing aging and preventing age-related diseases. Clive McCay first published his groundbreaking research in 1935 with the observation that rats with restricted diets experienced a 33% increase in lifespan.<ref>McCay, C. M., Crowell, M. F., & Maynard, L. A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. ''The journal of Nutrition'', ''10''(1), 63-79.</ref>

Similar survival experiments have shown that DR can increase the median and maximum lifespan of a variety of other organisms. Below we discuss in more details findings in each species:

=== Worms ===
''Caenorhabditis elegans'' is a roundworm nematode widely used as an aging animal model.<ref>Lakowski, B., & Hekimi, S. (1998). The genetics of caloric restriction in Caenorhabditis elegans. ''Proceedings of the National Academy of Sciences'', ''95''(22), [tel:13091-13096 13091-13096].</ref> Mutations in "''eat''" genes disrupt the function of the pharynx and the feeding behaviour of the worm, leading to partial starvation. ''Eat'' mutations are therefore considered CR-mimetics and can lengthen the lifespan of worms by up to 50%.<ref>Lakowski, B., & Hekimi, S. (1998). The genetics of caloric restriction in <nowiki>Caenorhabditis elegans</nowiki>. ''Proceedings Of The National Academy Of Sciences'', ''95''(22), [tel:13091-13096 13091-13096]. doi: 10.1073/pnas.95.22.13091</ref> The most studied "''eat''" gene in C. elegans, ''eat-2,'' extends lifespan through a mechanism independent of the insulin-signalling pathway, as it does not require the transcription factor [[FOXO longevity genes|''daf-16/FOXO'']] (a central component of the insulin signalling pathway) to extend lifespan. ''Eat-2'' mutants, as well as wild-type worms under CR, require the transcription factor ''pha-4/FOXA'' for the associated lifespan extension phenotype. More specifically, ''pha-4/FOXA'' is required in the intestinal tissue, but not in other tissues such as the nervous tissue, muscle or hypodermis.<ref>Panowski, S., Wolff, S., Aguilaniu, H. ''et al.'' (2007). PHA-4/Foxa mediates diet-restriction-induced longevity of ''C. elegans''. ''Nature'' 447, 550–555. <nowiki>https://doi.org/10.1038/nature05837</nowiki></ref>

In another study, it was found that when C. ''elegans'' experiences dietary restriction early during development, proteostasis is enhanced and adult lifespan is increased.<ref>Matai, L., Sarkar, G., Chamoli, M., Malik, Y., Kumar, S., & Rautela, U. et al. (2019). Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. ''Proceedings Of The National Academy Of Sciences'', ''116''(35), [tel:17383-17392 17383-17392]. doi: 10.1073/pnas.1900055116</ref> Similarly, both dietary restriction and dietary deprivation complete removal of food) in adulthood is reported to increase lifespan and to enhance thermotolerance and resistance to oxidative stress.<ref>Lee, G., Wilson, M., Zhu, M., Wolkow, C., de Cabo, R., Ingram, D., & Zou, S. (2006). Dietary deprivation extends lifespan in Caenorhabditis elegans. ''Aging Cell'', ''5''(6), 515-524. doi: 10.1111/j.1474-9726.2006.00241.x</ref>

=== Mice ===
A caloric-restriction experiment was conducted on wild mice to see if they would experience similar results as genetically bred lab mice.<ref>Harper, J., Leathers, C., & Austad, S. (2006). Does caloric restriction extend life in wild mice?. ''Aging Cell'', ''5''(6), 441-449. doi: 10.1111/j.1474-9726.2006.00236.x</ref> Whilst the 8.1% of longest-lived wild mice belonged to the CR test group, there was no robust longevity difference in mean lifespan between the groups. However, there was an anticancer effect in the CR group, as seen in other experiments with laboratory bred mice. Authors argued that strong differences in longevity were not noted possibly because wild animals have a higher genetic variation than inbred mice, which could affect CR strength.

In another study, it was noted that caloric restriction increased working memory in mice.<ref>Kuhla, A., Lange, S., Holzmann, C., Maass, F., Petersen, J., Vollmar, B., & Wree, A. (2013). Lifelong Caloric Restriction Increases Working Memory in Mice. ''Plos ONE'', ''8''(7), e68778. doi: 10.1371/journal.pone.0068778</ref> Male mice that experienced long periods of fasting between meals were found to live longer and healthier lifespans, regardless of the types of food they ate.

Inbred mice have shown to benefit significantly less from CR interventions than non-inbred mice, with some inbred mice strains not benefiting at all from CR.<ref name=":16">Swindell, W. (2012). Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. ''Ageing Research Reviews'', ''11''(2), 254-270. doi: 10.1016/j.arr.2011.12.006</ref> Therefore, this suggests rodent studies might be potentially biased when conducting experiments in laboratory inbred mice and encourages the diversification of CR studies in a wider genetic background.

=== Dogs ===

==== Purina Lifespan Study ====
The Purina Lifespan Study was performed on Labrador retrievers randomly assigned to either 25% caloric restriction or to control feeding, offering the same diet and only differing by quantity.<ref name=":6">Lawler, D., Larson, B., Ballam, J., Smith, G., Biery, D., & Evans, R. et al. (2007). Diet restriction and ageing in the dog: major observations over two decades. ''British Journal Of Nutrition'', ''99''(4), 793-805. doi: 10.1017/s0007114507871686</ref><ref name=":8">Kealy, R. D., Lawler, D. F., Ballam, J. M., Mantz, S. L., Biery, D. N., Greeley, E. H., ... & Stowe, H. D. (2002). Effects of diet restriction on life span and age-related changes in dogs. ''Journal of the American Veterinary Medical Association'', ''220''(9), 1315-1320.</ref> Over 14 years of follow up, there was a 1.8 year extension in median lifespan along with several improved health markers, such as delayed osteoarthritis.<ref name=":6" /><ref name=":8" /> Whilst various measures of immune function are expected to decline with age,<ref>Greeley, E., Ballam, J., Harrison, J., Kealy, R., Lawler, D., & Segre, M. (2001). The influence of age and gender on the immune system: a longitudinal study in Labrador Retriever dogs. ''Veterinary Immunology And Immunopathology'', ''82''(1-2), 57-71. doi: 10.1016/s0165-2427(01)00336-1</ref> the study showed that total lymphocytes, T-cells and CD8 cells did not decline in the CR group, in contrast to observed declines in the immune system function of the control diet group.<ref name=":6" />

==== Dog Aging Project ====
The [[Rapamycin|Dog Aging Project]] is an initiative that is studying thousands of dogs over their lifetimes to understand which environmental and genetic factors influence healthy aging.<ref name=":7" /> In an early study of 10.474 companion dogs, one-time daily feeding versus more frequent feeding was associated with better measures across multiple domains of health.<ref name=":7" /> This included lower scores on the Canine Cognitive Dysfunction Rating Scale, and lower odds of having gastrointestinal, dental, orthopedic, kidney, urinary, liver and pancreas disorders. The authors suggest that while this preliminary data is not sufficient to support recommendations for meal timing in pet dogs, this data might help guide future research into dietary variables that affect health.<ref name=":7">Bray, E. E., Zheng, Z., Tolbert, M. K., McCoy, B. M., Kaeberlein, M., & Kerr, K. F. (2022). Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project. ''GeroScience'', 1-12.</ref>

=== Primates ===

==== Restrikal study (2006) ====
The Restrikal study, initiated in 2006, studied the effect of chronic 30% CR in the grey mouse lemur primate, ''Microcebus murinus''.<ref name=":4">Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), 1-8.</ref> Results of the study indicated that CR prolonged lifespan by 50%, from 6.4 to 9.6 years, but affected brain structural integrity.<ref name=":4" /> It was observed that gray matter integrity in the cerebrum was compromised by CR, yet importantly, this did not result in any apparent changes to cognitive function.

==== NIA (2012) & Wisconsin NPRC (2014) studies controversy ====
The National Institute on Aging (NIA) study in Maryland, USA, performed CR in rhesus monkeys and saw no differences between survival of monkeys fed control versus calorie-restricted diets.<ref name=":17">Mattison, J. A., Roth, G. S., Beasley, T. M., Tilmont, E. M., Handy, A. M., Herbert, R. L., ... & De Cabo, R. (2012). Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. ''Nature'', ''489''(7415), 318-321.</ref> The diet of controls in this study was not reported as fully ''ad libitum'', but rather control monkeys were subject to a slight dietary restriction to prevent obesity.

On the other hand, in the Wisconsin National Primate Research Centre (WNPRC) study, rhesus monkeys subjected to long-term 30% dietary restriction showed a significantly reduced risk of all-cause mortality and age-related mortality compared to control group monkeys. This suggested the benefits of CR on aging might be conserved in primates.<ref name=":18">Colman, R. J., Beasley, T. M., Kemnitz, J. W., Johnson, S. C., Weindruch, R., & Anderson, R. M. (2014). Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. ''Nature communications'', ''5''(1), 1-5.</ref>

Given that the Wisconsin and NIA primate studies found contradictory results, researchers have attempted to determine why slowed aging was only demonstrated in the Wisconsin study. The observed differences between these two studies is particularly controversial because the control primates in the NIA study lived longer than the CR group in the Wisconsin study, suggesting differences in methodology played an important role.

Some have suggested that diet composition is important, due to clear differences in feeding quality and composition between the Wisconsin and NIA studies. A key difference is certainly the fact that the Wisconsin study subjected monkeys to strict ''ad libitum'' in the control group, whilst the NIA study did not in order to prevent obesity. The latter is generally considered a better controlled experiment.

=== Humans ===
There is currently no definite evidence that calorie restriction extends healthy human lifespan.<ref name=":5">Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref> However, there is early clinical evidence suggesting that CR without malnutrition may lead to various health benefits related to aging, based on several randomized controlled trials. In many human studies, CR is defined as a restriction of calories by ≥10% compared to feeding without restriction (''ad libitum'').<ref name=":19" />

'''The population of Okinawa'''

Studies into certain populations known for their exceptional longevity, such as in Okinawa - a small island of Japan - have provided some insights into potential lifestyle determinants of longevity. Okinawans have long been recognized as one of the longest-lived populations on the planet, and this is typically attributed to their diet (fish and vegetables). However, more recently, some attention in the scientific community has deviated from the contents of Okinawan’s diets and focused, instead, on their caloric deficits. Six generations of Okinawans aged 65+ were studied; their diet composition, energy intake and expenditure, and survival patterns were analyzed, among many other factors. The results lent support to the wide-ranging health benefits of caloric restriction in humans. Some researchers have speculated that the introduction of Westernized diets may in part explain recent decreases in Okinawan population lifespan.<ref name=":0" />

'''Biosphere-II'''

The Biosphere II experiment was an ecological investigation that provided an unexpected opportunity to measure the effects of CR.<ref>Walford, R., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period. ''The Journals Of Gerontology Series A: Biological Sciences And Medical Sciences'', ''57''(6), B211-B224. doi: 10.1093/gerona/57.6.b211</ref> Eight volunteers were kept in an ecological ecosystem for two years and allowed to harvest 85% of their food. The food consisted mainly of fruits, vegetables, grains and minimal protein. During the experiment, because of food scarcity, the energy intake of the volunteers decreased by 38% for 6 months. After leaving the experiment the volunteers had a 6% slowing of metabolism which lasted for another 6 months.

Years later, a Biosphere-II participant founded the ''CR Society International,'' which consists of a group of volunteers that have chosen to restrict their calorie intake around 30% for a period of 3 to 15 years.<ref>Fontana, L., Meyer, T., Klein, S., & Holloszy, J. (2004). Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. ''Proceedings Of The National Academy Of Sciences'', ''101''(17), [tel:6659-6663 6659-6663]. doi: 10.1073/pnas.0308291101</ref> Individuals of the CR society appear leaner, have lower body fat, better cardiometabolic health and lower inflammation. However, this data is sparse and largely limited to self-reports.

'''CALERIE trials'''

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) research network has produced one of the most rigorous clinical studies conducted in humans. It started with clinical study involving 2 years of sustained 25% calorie restriction in men aged 21–50 years and women aged 21–47 years that aims to explore whether sustained calorie restriction can extend lifespan, improve metabolic health, and potentially delay the onset of age-related conditions. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.<ref>Das, J. K., Banskota, N., Candia, J., Griswold, M. E., Orenduff, M., de Cabo, R., ... & Ferrucci, L. (2023). Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study. Aging cell, 22(12), e13963. PMID: 37823711 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10726900/ PMC10726900] DOI: 10.1111/acel.13963</ref> CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various [[Epigenetic clock|DNAm clocks]] including PhenoAge and GrimAge.<ref>PMID: 37118425 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148951/ PMC10148951] DOI: 10.1038/s43587-022-00357-y</ref>

Over a period of nine years, three pilot trials were conducted followed by a randomized study (CALERIE 2).<ref name=":1">Kraus, W. E., Bhapkar, M., Huffman, K. M., Pieper, C. F., Das, S. K., Redman, L. M., ... & CALERIE Investigators. (2019). 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. ''The lancet Diabetes & endocrinology'', ''7''(9), 673-683.</ref><ref name=":2">Rickman, A. D., Williamson, D. A., Martin, C. K., Gilhooly, C. H., Stein, R. I., Bales, C. W., ... & Das, S. K. (2011). The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. ''Contemporary clinical trials'', ''32''(6), 874-881.</ref>
(CALERIE™) 2 trial tested randomized healthy, nonobese men and premenopausal women (age 21-50y; BMI 22.0-27.9 kg/m2), to 25% CR or ad-libitum (AL) control (2:1) for 2 years to test effects of CR on telomere length (TL) attrition. TL was quantified in blood samples collected at baseline, 12-, and 24-months by quantitative PCR (absolute TL; aTL). No differences were observed when considering TL change across the study duration from baseline to 24-months.<ref>Hastings, W. J., Ye, Q., Wolf, S. E., Ryan, C. P., Das, S. K., Huffman, K. M., ... & Shalev, I. (2024). Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis. Aging cell, e14149. PMID: 38504468 [https://doi.org/10.1111/acel.14149 DOI: 10.1111/acel.14149]</ref>

During phase 1 of the trial, three differing degrees of CR (20%, 25%, and 30%) were tested in a variety of age groups with an overweight BMI status. The trial lasted for 6 – 12 months, and the studies were used to develop and advance the following Phase 2 trial.

In Phase 2 of CALERIE, participants were able to restrict caloric intake by 11.9% and experienced ~10% weight loss over two years, despite the identified target of 25% CR. It must be noted that the level of CR achieved in this study required intensive intervention, involving personalized treatments, algorithmic/computer tracking, and various educational initiatives.<ref name=":2" /> Therefore, the feasibility of such a CR intervention in the real world is something that remains uncharacterized. However, despite participants in the CR group achieving a lower CR target than intended, various improvements to health were noted. The trial resulted in lower levels of T3 and TNF-ɑ, while also reducing certain cardiometabolic risk factors.<ref name=":1" />

Additional analyses suggested a slow down in the rate of biological aging and found that weight loss did not appear to account for these effects.<ref name=":3">Belsky, D. W., Huffman, K. M., Pieper, C. F., Shalev, I., & Kraus, W. E. (2018). Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis. ''The Journals of Gerontology: Series A'', ''73''(1), 4-10.</ref> The authors highlighted that, based on prior knowledge that a divergence in biological aging trajectories can be observed as early as early adulthood, CR may be more effective in humans when started young.<ref>Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., ... & Moffitt, T. E. (2015). Quantification of biological aging in young adults. ''Proceedings of the National Academy of Sciences'', ''112''(30), E4104-E4110.</ref> Moreover, potential CR-related toxicities were posited to be better tolerated in younger adults.<ref name=":3" />

'''CR and immune function - randomized controlled trial'''

One clinical study investigated moderate CR versus ''ad-libitum'' feeding over 2 years. It was found that CR without malnutrition may induce health benefits without impairing cell-mediated immunity or increasing infection risk in non-obese humans.<ref>Meydani, S. N., Das, S. K., Pieper, C. F., Lewis, M. R., Klein, S., Dixit, V. D., ... & Fontana, L. (2016). Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. ''Aging (Albany NY)'', ''8''(7), 1416.</ref>

== Underlying biological mechanisms ==
[[File:The two primary molecular regulators of lifespan.jpg|thumb|The two primary molecular regulators of lifespan in case of food shortage or its pharmacological imitation. According to an article by Packer M.<ref>Packer, M. (2020). Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure. European Heart Journal, 41(39), 3856-3861. PMID: 32460327 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599035/ PMC7599035] DOI: 10.1093/eurheartj/ehaa360</ref>]]
Consuming extra calories can lead to cellular glycotoxicity and lipotoxicity, which causes inflammation and oxidative stress and thus increases the risk of age-related diseases (e.g. cancer, diabetes, cardiovascular disorders).<ref name=":0" /> Some proposed health benefits of CR include preservation of cognition, protection of colon health and reduced risk of arthritis, amongst others.

Evidence suggests that CR may lead to a variety of health benefits via the following biological pathways:<ref name=":0" />

* Inhibition of mTOR pathway and consequent induction of a[[Autophagy|utophagy]], a specific process that recycles cellular waste.
*Activation of known pro-longevity pathways such as FOXO/AMPK/SIRT, which are evolutionarily conserved across various species.
*Increase in coenzyme Q10 (CoQ) dependent reductases within the plasma membrane, thus protecting phospholipids and preventing the lipid peroxidation reaction progression.
*Reduction in oxidative damage due to a decreased production of Reactive Oxygen Species (ROS).
*Decrease in the systemic risk factors for cardiovascular disease (glucose levels, blood pressure, plasma lipid levels).
* Alteration in the sympathetic nervous system, as well as the neuroendocrine system in lab animals and, sometimes, humans.

== Caveats of caloric restriction ==
An exhaustive review of calorie restriction experiments in rodents highlighted some of the most common questions and caveats of CR:<ref name=":11">Ingram, D., & de Cabo, R. (2017). Calorie restriction in rodents: Caveats to consider. ''Ageing Research Reviews'', ''39'', 15-28. doi: 10.1016/j.arr.2017.05.008</ref>

===== 1. Until what age is CR effective? =====
One important aspect to consider is whether CR interventions are effective regardless of age of the individual. Whilst the question remains open as of today, available evidence suggests that performing CR in advanced age leads to a wide range of health benefits (especially in motor function) and is able to extend lifespan. However, it seems that late-life CR can extend lifespan to a significantly lesser degree than early-adulthood CR, although definitive evidence is missing.<ref name=":11" /><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397416/ Dhahbi, J. M., Kim, H. J., Mote, P. L., Beaver, R. J., & Spindler, S. R. (2004). Temporal linkage between the phenotypic and genomic responses to caloric restriction. ''Proceedings of the National Academy of Sciences'', ''101''(15), 5524-5529.]</ref>

In humans, there is concern that late-life CR may exacerbate age-related muscle loss (sarcopenia) and potentiate the effects of falls.<ref name=":9">Flanagan, E. W., Most, J., Mey, J. T., & Redman, L. M. (2020). Calorie restriction and aging in humans. ''Annual review of nutrition'', ''40'', 105.</ref> While various pre-clinical studies have shown potential for treating or preventing sarcopenia, there is a lack of clinical evidence supporting its use in older, otherwise non-obese patients.<ref name=":9" /><ref>Liu, P., Li, Y., & Ma, L. (2021). Caloric Restriction May Help Delay the Onset of Frailty and Support Frailty Management. ''Frontiers in Nutrition'', ''8''.</ref><ref>Racette, S. B., Weiss, E. P., Villareal, D. T., Arif, H., Steger-May, K., Schechtman, K. B., ... & Holloszy, J. O. (2006). One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. ''The Journals of Gerontology Series A: Biological Sciences and Medical Sciences'', ''61''(9), 943-950.

Chicago</ref>

===== 2. Does CR improve cognitive decline? =====
CR has been shown to attenuate cognitive decline in mice models of Alzheimer's disease and to dramatically improve the behavioral phenotype of progeroid DNA-repair deficient mice.<ref>Dhurandhar, E., Allison, D., van Groen, T., & Kadish, I. (2013). Hunger in the Absence of Caloric Restriction Improves Cognition and Attenuates Alzheimer's Disease Pathology in a Mouse Model. ''Plos ONE'', ''8''(4), e60437. doi: 10.1371/journal.pone.0060437</ref><ref>Vermeij, W., Dollé, M., Reiling, E., Jaarsma, D., Payan-Gomez, C., & Bombardieri, C. et al. (2016). Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. ''Nature'', ''537''(7620), 427-431. doi: 10.1038/nature19329</ref>

Despite this encouraging evidence, whether CR improves cognitive function in wild-type backgrounds appears largely inconsistent across experiments. A main issue might be the lack of systematic research and the range of differences in CR protocols, which has so far hindered extracting definitive conclusions. Similarly, several studies have shown inconclusive results in other species, such as in the fly ''Drosophila'' ''Melanogaster'' and the grey mouse lemur primate.<ref>Kerr, F., Augustin, H., Piper, M. D., Gandy, C., Allen, M. J., Lovestone, S., & Partridge, L. (2011). Dietary restriction delays aging, but not neuronal dysfunction, in Drosophila models of Alzheimer's disease. ''Neurobiology of aging'', ''32''(11), 1977-1989.</ref><ref>Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., ... & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), 1-8.</ref>

In humans, the CALERIE trial included multiple tests of cognitive function and found that in non-obese, healthy adults, working memory was slightly improved after 2 years of CR.<ref name=":15">Leclerc, E., Trevizol, A. P., Grigolon, R. B., Subramaniapillai, M., McIntyre, R. S., Brietzke, E., & Mansur, R. B. (2020). The effect of caloric restriction on working memory in healthy non-obese adults. ''CNS spectrums'', ''25''(1), 2-8.</ref> However, this was a post-hoc analysis, which is not sufficient evidence to support causation.<ref name=":15" />

===== 3. What are the deleterious effects of CR? =====

====== Bone health ======
In rodents, conventional 30% CR interventions have been associated to reduced body mass and reduced bone density, specially when CR is initiated in early life but also when initiated at mature or older ages.<ref>Baek, K., Barlow, A., Allen, M., & Bloomfield, S. (2008). Food restriction and simulated microgravity: effects on bone and serum leptin. ''Journal Of Applied Physiology'', ''104''(4), 1086-1093. doi: 10.1152/japplphysiol.01209.2007</ref><ref>Banu, J., Orhii, P., Okafor, M., Wang, L., & Kalu, D. (2001). Analysis of the effects of growth hormone, exercise and food restriction on cancellous bone in different bone sites in middle-aged female rats. ''Mechanisms Of Ageing And Development'', ''122''(8), 849-864. doi: 10.1016/s0047-6374(01)00243-3</ref> More sophisticated studies have indicated that CR does not negatively impact bone material properties, despite its association to reduced bone size and decreased whole-bone strength.<ref>Huang, T., & Ables, G. (2016). Dietary restrictions, bone density, and bone quality. ''Annals Of The New York Academy Of Sciences'', ''1363''(1), 26-39. doi: 10.1111/nyas.13004</ref>

====== Wound healing ======
Experiments in both mice and rats has so far shown that animals under CR have a diminished capacity for skin wound healing than normally fed controls.<ref name=":12">Hunt, N., Li, G., Zhu, M., Levette, A., Chachich, M., & Spangler, E. et al. (2011). Effect of calorie restriction and refeeding on skin wound healing in the rat. ''AGE'', ''34''(6), 1453-1458. doi: 10.1007/s11357-011-9321-6</ref><ref name=":13">Reed, M., Penn, P., Li, Y., Birnbaum, R., Vernon, R., & Johnson, T. et al. (1996). Enhanced cell proliferation and biosynthesis mediate improved wound repair in refed, caloric-restricted mice. ''Mechanisms Of Ageing And Development'', ''89''(1), 21-43. doi: 10.1016/0047-6374(96)01737-x</ref> This appears to be consistent ''in vitro'', where CR mice-derived cells were reported to have reduced proliferation compared to control cells.<ref>Hsieh, E., Chai, C., & Hellerstein, M. (2005). Effects of caloric restriction on cell proliferation in several tissues in mice: role of intermittent feeding. ''American Journal Of Physiology-Endocrinology And Metabolism'', ''288''(5), E965-E972. doi: 10.1152/ajpendo.00368.2004</ref> Importantly, ''in vivo'' experiments found that wound healing capacity was restored to that of control levels a short period after rodents were normally fed again.<ref name=":12" /><ref name=":13" />

====== Immune response ======
Several studies have shown that mice undergoing CR have an increased risk of infection than those on ''ad libitum'' diets. This is presumably due to a less efficient immune response, given that CR animals are not able to respond as well to the higher metabolic demands that an infection supposes.<ref>Kristan, D. (2007). Chronic calorie restriction increases susceptibility of laboratory mice (Mus musculus) to a primary intestinal parasite infection. ''Aging Cell'', ''6''(6), 817-825. doi: 10.1111/j.1474-9726.2007.00345.x</ref><ref>Kristan, D. (2008). Calorie restriction and susceptibility to intact pathogens. ''AGE'', ''30''(2-3), 147-156. doi: 10.1007/s11357-008-9056-1</ref> However, similar to wound healing experiments, animals showed a recovered capacity to fight infection shortly after being re-fed. On the contrary, other studies have reported no deleterious effects of CR in response to infection or even beneficial ones.<ref>Hasegawa, A., Iwasaka, H., Hagiwara, S., Asai, N., Nishida, T., & Noguchi, T. (2012). Alternate Day Calorie Restriction Improves Systemic Inflammation in a Mouse Model of Sepsis Induced by Cecal Ligation and Puncture. ''Journal Of Surgical Research'', ''174''(1), 136-141. doi: 10.1016/j.jss.2010.11.883</ref>

===== 4. Are feeding times in CR important? =====

====== Time of feeding ======
The benefits of caloric restriction in mice appear to be affected by the timing of feeding during the day. As nocturnal animals, mice that underwent CR during their normally active feeding period (night time) showed increased health benefits compared to mice undergoing CR during their rest time (daylight), as measured by structural changes in the gut microbiota.<ref>Zhang, L., Xue, X., Zhai, R., Yang, X., Li, H., Zhao, L., & Zhang, C. (2019). Timing of Calorie Restriction in Mice Impacts Host Metabolic Phenotype with Correlative Changes in Gut Microbiota. ''Msystems'', ''4''(6). doi: 10.1128/msystems.00348-19</ref> This showcases the important link between circadian clocks, CR interventions and potentially lifespan.

====== CR and Intermittent Fasting ======
''See the full article on [[fasting]].''

Intermittent fasting (IF) has attained popular interest in recent years for its various potential health benefits, including for treating disease and extending lifespan.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.

Chicago</ref><ref name=":10">Longo, V. D., Di Tano, M., Mattson, M. P., & Guidi, N. (2021). Intermittent and periodic fasting, longevity and disease. ''Nature aging'', ''1''(1), 47-59.</ref> Some preclinical evidence shows that certain IF regimens can prevent the onset of many age-related diseases. However, IF is not always associated with benefits in healthspan and may increase or decrease lifespan.<ref name=":10" /> It has been proposed that at least part of the lifespan extending effect of CR in humans is related to fasting, and in rodents fasting is required for a CR diet to protect from [[frailty]] and extend lifespan.<ref name=":10" /><ref>Pak, H. H., Haws, S. A., Green, C. L., Koller, M., Lavarias, M. T., Richardson, N. E., ... & Lamming, D. W. (2021). Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. ''Nature metabolism'', ''3''(10), 1327-1341.</ref> In rodent models, the evidence for IF preventing cancer development or growth is ambiguous, with studies showing no effect or potential harm with IF. More studies are required to better understand IF, both for preclinical and clinical research.<ref>Clifton, K. K., Ma, C. X., Fontana, L., & Peterson, L. L. (2021). Intermittent fasting in the prevention and treatment of cancer. ''CA: a cancer journal for clinicians'', ''71''(6), 527-546.</ref>

A recent study in China randomized 139 obese adults to either calorie restriction alone or to calorie restriction with time-restricted eating (a 16-hour intermittent fast and a 8-hour period for eating).<ref>Liu, D., Huang, Y., Huang, C., Yang, S., Wei, X., & Zhang, P. et al. (2022). Calorie Restriction with or without Time-Restricted Eating in Weight Loss. ''New England Journal Of Medicine'', ''386''(16), 1495-1504. doi: 10.1056/nejmoa2114833</ref> After one year, both groups had lost 7-10% of body weight and showed healthier markers for blood sugar, blood fat levels and insulin sensitivity. Importantly, there was no statistically significant difference between both groups, suggesting calorie restriction is responsible for the health-associated benefits and that intermittent fasting has no added benefits to CR diets.

===== 5. How long should CR interventions last? =====
Current evidence in rodents suggests that short-term CR (considered as interventions ranging from 1 day to a few months) can still have beneficial effects in health, similar to traditional long-term CR.<ref>Robertson, L., & Mitchell, J. (2013). Benefits of short-term dietary restriction in mammals. ''Experimental Gerontology'', ''48''(10), 1043-1048. doi: 10.1016/j.exger.2013.01.009</ref> Short-term CR has also been associated to increased health biomarkers, to improve diseased-states in models of hypertensive rats and to enhance the benefits of chemotherapy in cancer mouse models.<ref>Chiba, T., & Ezaki, O. (2010). Dietary restriction suppresses inflammation and delays the onset of stroke in stroke-prone spontaneously hypertensive rats. ''Biochemical And Biophysical Research Communications'', ''399''(1), 98-103. doi: 10.1016/j.bbrc.2010.07.048</ref><ref>Mitchell, J., Verweij, M., Brand, K., van de Ven, M., Goemaere, N., & van den Engel, S. et al. (2010). Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice. ''Aging Cell'', ''9''(1), 40-53. doi: 10.1111/j.1474-9726.2009.00532.x</ref>

===== 6. What are the genotype and gender effects on CR? =====
There is strong evidence that genotype and gender within the same species can have a dramatic effect on the efficiency of CR. A meta-analysis from mice studies performed between 1934 and 2012 revealed that lifespan extension could vary within gender of the same strain and also between different strains, with the degree of lifespan extension ranging between 4 to 27%.<ref>Swindell, W. (2012). Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan. ''Ageing Research Reviews'', ''11''(2), 254-270. doi: 10.1016/j.arr.2011.12.006</ref><ref>Mitchell, S., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., & González-Reyes, J. et al. (2016). Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. ''Cell Metabolism'', ''23''(6), 1093-1112. doi: 10.1016/j.cmet.2016.05.027</ref> Strains belonging to the lower end of percentage of lifespan extension are often recombinant inbred strains.<ref name=":16" /> Other studies have demonstrated that certain mice genotypes are highly unresponsive to CR interventions, although it is argued that different genotypes might be responsive to different strengths of CR.<ref>Liao, C., Rikke, B., Johnson, T., Diaz, V., & Nelson, J. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging Cell'', ''9''(1), 92-95. doi: 10.1111/j.1474-9726.2009.00533.x</ref><ref>Rikke, B., Liao, C., McQueen, M., Nelson, J., & Johnson, T. (2010). Genetic dissection of dietary restriction in mice supports the metabolic efficiency model of life extension. ''Experimental Gerontology'', ''45''(9), 691-701. doi: 10.1016/j.exger.2010.04.008</ref> As previously discussed in [[Calorie restriction#Primates|primates]], similar observations have been reported in rhesus monkeys undergoing 30% CR, where independent groups reported similar health benefits but largely dissimilar survival curves, highlighthing the complexity of genotypic and/or environmental factors in the efficiency of CR.<ref name=":17" /><ref name=":18" />

===== 7. Is diet composition important in CR? =====
''See the full article on [[protein restriction]].''

Diet composition in CR is likely to be important. As mentioned previously, there is a general agreement that CR should reduce the total amount of calories ingested whilst avoiding malnutrition (ie. without reducing protein or macronutrient intake), in order to maximise health benefits.<ref name=":19" /><ref name=":20" /> In fact, an exhaustive review of literature suggested that most commonly adopted CR protocols led to malnutrition in rodents, which they argue might have added to the observed discrepancies in survival curves across CR interventions.<ref>Cerqueira, F., & Kowaltowski, A. (2010). Commonly adopted caloric restriction protocols often involve malnutrition. ''Ageing Research Reviews'', ''9''(4), 424-430. doi: 10.1016/j.arr.2010.05.002</ref>

Some scientists have proposed that [[protein restriction]] (PR) in particular is responsible for the benefits observed in CR.<ref>Simpson, S., & Raubenheimer, D. (2007). Caloric Restriction and Aging Revisited: The Need for a Geometric Analysis of the Nutritional Bases of Aging. ''The Journals Of Gerontology Series A: Biological Sciences And Medical Sciences'', ''62''(7), 707-713. doi: 10.1093/gerona/62.7.707</ref><ref>Raubenheimer, D., Simpson, S., & Tait, A. (2012). Match and mismatch: conservation physiology, nutritional ecology and the timescales of biological adaptation. ''Philosophical Transactions Of The Royal Society B: Biological Sciences'', ''367''(1596), 1628-1646. doi: 10.1098/rstb.2012.0007</ref> However, more recent studies reviewing all published data since the early 1930s until 2016 concluded that lifespan extension in rodents is due to CR alone and not due to a reduction of protein or any other macronutrients.<ref>Speakman, J., Mitchell, S., & Mazidi, M. (2016). Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. ''Experimental Gerontology'', ''86'', 28-38. doi: 10.1016/j.exger.2016.03.011</ref><ref>Pamplona, R., & Barja, G. (2006). Mitochondrial oxidative stress, aging and caloric restriction: The protein and methionine connection. ''Biochimica Et Biophysica Acta (BBA) - Bioenergetics'', ''1757''(5-6), 496-508. doi: 10.1016/j.bbabio.2006.01.009</ref>

== Controversies of calorie restriction research ==
There are several criticisms against CR, some of which are highlighted by Sohal and Forster (2014) in “''Caloric Restriction and the Aging Process: A Critique''”.<ref>Sohal, R. S., & Forster, M. J. (2014). Caloric restriction and the aging process: a critique. ''Free radical biology & medicine'', ''73'', 366–382. <nowiki>https://doi.org/10.1016/j.freeradbiomed.2014.05.015</nowiki></ref> The authors highlight that there is a large disparity in CR-related longevity increases: namely, that longevity effects are not universal and sometimes are not shared across genetic strains of the same species. Moreover, control animals in widely-cited caloric restriction studies were mostly fed ''ad libitum'', causing them to become overweight and vulnerable to disease and early death. Therefore the relative benefit in the CR group was exaggerated compared to control subjects. In other words, animals with CR diets may live relatively longer because the control animals were dying from complications of excess feeding.

Another challenge related to CR as an effective intervention for human aging is the difficulty in compliance over long periods of time.<ref name=":0" /> Concerns over mental and sexual health have also been raised with more severe CR. There are concerns over the loss of weight and fat mass in younger people practicing CR. Exercising along with CR and good nutrition (high protein diet) appears to be highly beneficial for loss of free fat.<ref name=":0" /> New nutritional approaches such as intermittent fasting have emerged. However, there is comparatively limited research on the topic, with CR being the most well-studied nutritional intervention for healthy aging. Furthermore, studies in worms showed that Allantoin, rapamycin, TSA and LY-294002 led to a slower decline in pharyngeal pumping, indicating a reduced aging rate.<ref name=":14">Calvert, S., Tacutu, R., Sharifi, S., Teixeira, R., Ghosh, P., & de Magalhães, J. P. (2016). A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. ''Aging cell'', ''15''(2), 256-266.</ref> Thus, the study uncovered that not only could drug treatments mimicking CR increase longevity, but they could also improve the organism’s healthfulness.<ref name=":14" />

It is important to note that researchers are increasingly aware that CR or strict intermittent fasting are not a “one size fits all”, but rather an efficient strategy for certain individuals in specific metabolic contexts. For instance, some studies have shown that two people's glucose responses are significantly different even after eating the same food.<ref>Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D., & Weinberger, A. et al. (2015). Personalized Nutrition by Prediction of Glycemic Responses. ''Cell'', ''163''(5), 1079-1094. doi: 10.1016/j.cell.2015.11.001</ref> Supporting these findings, companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are offering personalized dietary recommendations based on the measurement of an individuals’s [[metabolic flexibility]].

Similar to non-human primates, the effects of CR on lifespan remain controversial in humans. However, what seems clear from obesity studies is that eating too much results in poor health and decreased longevity.<ref>Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., Chahory, S., Cordonnier, N., Desquilbet, L., Hurion, M. and Zahariev, A., 2018. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. ''Communications biology'', ''1''(1), pp.1-8.</ref>

== References ==
<references />
[[Category:Main list]]
[[Category:Lifespan interventions]]
[[Category:Fundamentals]]

Calcium channel blockers (CCBs)

2024-07-28T17:38:36Z

Dmitry Dzhagarov:

Senolytics

2024-07-28T12:38:42Z

Dmitry Dzhagarov: /* Senolytic CAR T cells */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]] (due to [[Autophagy#Mitophagy|mitophagy]]), remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref>João Pedro de Magalhães (2024). [https://www.science.org/doi/10.1126/science.adj7050 Cellular senescence in normal physiology].Science, 384, 1300-1301. DOI:10.1126/science.adj7050</ref><ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.<ref>Lemaitre, J. M. (2024). Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin. Journal of the European Academy of Dermatology and Venereology, 38, 5-14.https://doi.org/10.1111/jdv.19820</ref>
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

==== Markers of cellular senescence ====
The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21CIP1/WAF1,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16INK4a, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the de-repression of the '''p16INK4a''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been shown that the removal of senescent p16INK4a-positive cells can slow the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> However, whether cells that express '''p16INK4a''' are actually 'senescent cells', and if removal of such cells could cause harm in specific contexts has been questioned by more recent work.<ref name=":1" /> Moreover, a limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations of the genome. It can instead be easier to use small molecule senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics are thought to start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells, such as by differentiation of resident stem cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Notably, this is dependent on the availability of stem cell pools which are known to decline with aging, and this has been identified as a theoretical limitation of senolytics, if the lack of such stem cells means new tissue is not formed. It has also been speculated that '''if''' '''the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
Therapeutics for killing senescent cells could take the form of senolytic small molecules or immune-based clearance (antibodies or cytotoxic T cells).<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref> Senescent cells rely on prosurvival stress response adaptations to avoid apoptosis. This suggests that an attractive senescent cell killing approach would be to use small-molecule inhibitors to block cell death-resistance pathways, thereby using the endogenous stress to drive these cells into apoptosis. Existing inhibitors of prosurvival pathways used in cancer therapy may have utility for senescent cell killing, and could be even more effective for this use given that senescent cells, unlike cancer, do not proliferate.
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

Long-term study of the intermittent dasatinib plus quercetin (5 mg/kg + 50 mg/kg) exposure (two consecutive days monthly for 6 months) on aging outcomes and inflammation in nonhuman primates resulted in significant positive body composition changes with improvement in immune cell profiles and reduced glycosylated hemoglobin A1c.<ref>Ruggiero AD, Vemuri R, Blawas M et al (2023) Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design. Geroscience. https://doi.org/10.1007/s11357-023-00830-5</ref>

A computer-assisted expression analysis study suggested that '''piperlongumine''' (a known natural senolytic found in long pepper ''Piper longum''<ref>Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., ... & Zheng, G. (2016). Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY), 8(11), 2915. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191878/ PMC5191878] DOI: 10.18632/aging.101100</ref>) combination with quercetin (“P+Q”) may be a natural-compound alternative to the combination of dasatinib and quercetin (“D+Q”).<ref>Meiners, F., Secci, R., Sueto, S., Fuellen, G., & Barrantes, I. (2022). Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. bioRxiv, 2022-05. https://doi.org/10.1101/2022.05.26.492763</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Flavonoid 4,4′-dimethoxychalcone ===
The flavonoid 4,4′-dimethoxychalcone (DMC) is particularly abundant in the plant ''Angelica keiskei koidzumi'', which has been used in Asian traditional medicine, and was documented for its ability to promote autophagy-dependent longevity and health.<ref>Carmona-Gutierrez, D., Zimmermann, A., Kainz, K., Pietrocola, F., Chen, G., Maglioni, S., ... & Madeo, F. (2019). The flavonoid 4, 4′-dimethoxychalcone promotes autophagy-dependent longevity across species. Nature communications, 10(1), 651. PMID: 30783116 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180/ PMC6381180] DOI: 10.1038/s41467-019-08555-w</ref> By inhibiting the enzymatic activity of a metalloenzyme ferrochelatase, DMC induces iron accumulation and further ferroptosis.<ref>Yang, C., Wang, T., Zhao, Y., Meng, X., Ding, W., Wang, Q., ... & Deng, H. (2022). Flavonoid 4, 4′-dimethoxychalcone induced ferroptosis in cancer cells by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH. Free Radical Biology and Medicine, 188, 14-23. PMID: 35697292 [https://doi.org/10.1016/j.freeradbiomed.2022.06.010 DOI: 10.1016/j.freeradbiomed.2022.06.010]</ref> Since ferrochelatase was highly expressed in senescent cells compared to non-senescent cells DMC inhibited ferrochelatase and induced ferritinophagy, which led to an increase of labile iron pool, triggering ferroptosis of senescent cells.<ref>Wang, T., Yang, C., Li, Z., Li, T., Zhang, R., Zhao, Y., ... & Deng, H. (2024). Flavonoid 4, 4′-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy. Redox Biology, 69, 103017. PMID: 38176315 [https://doi.org/10.1016/j.redox.2023.103017 DOI: 10.1016/j.redox.2023.103017] </ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Supramolecular senolytics ===
Supramolecular senolytics is organic molecules that selectively target receptors overexpressed in the membranes of aging cells. By leveraging the higher levels of reactive oxygen species (ROS) found in aging cells, these molecules promote the formation of disulfide bonds and create oligomers that bind together. Self-assembly of these oligomers '''occurred only inside the mitochondria of senescent cells''' due to selective localization of the peptides by cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells.<ref>Kim, S., Chae, J. B., Kim, D., Park, C. W., Sim, Y., Lee, H., ... & Ryu, J. H. (2023). Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells. Journal of the American Chemical Society. PMID: 37664981 [https://doi.org/10.1021/jacs.3c06898 DOI: 10.1021/jacs.3c06898]</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== Salvestrols ===
Salvestrol (lat. ''salvus'' - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens.
Under the influence of the '''cytochrome P450 enzyme CYP1B1''', which was reported to be involved in performance of two important factors of aging: mitochondrial function and reactive oxygen species (ROS) production,<ref>Lu, Y., Nanayakkara, G., Sun, Y., Liu, L., Xu, K., Drummer IV, C., ... & Yang, X. (2021). Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation. Redox Biology, 47, 102142. PMID: 34598017 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487079/ PMC8487079] DOI: 10.1016/j.redox.2021.102142 </ref> and which is expressed in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence,<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref><ref>Huynh, D. T. M., Hai, H. T., Hau, N. M., Lan, H. K., Vinh, T. P., De Tran, V., & Pham, D. T. (2023). Preparations and characterizations of effervescent granules containing azithromycin solid dispersion for children and elder: Solubility enhancement, taste-masking, and digestive acidic protection. Heliyon, 9(6). e16592 PMID: 37292293 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245243/ PMC10245243] DOI: 10.1016/j.heliyon.2023.e16592</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== BET degraders as senolytic drugs ====
[[File:Super-enhancer-associated oncogenes.jpg|thumb|Super-enhancers activate gene transcription and induce tumorigenesis using densely bound proteins BRD4 and master transcription factors (according to Qian, H et al., 2023).<ref name="Super" >Qian, H., Zhu, M., Tan, X., Zhang, Y., Liu, X., & Yang, L. (2023). Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets. Cell Death Discovery, 9(1), 470. PMID: 38135679 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10746725/ PMC10746725] DOI: 10.1038/s41420-023-01775-6</ref>]]
'''Super-enhancers''' are large clusters of enhancers that are in close genomic proximity, are densely bound by the '''BET bromodomain protein BRD4''' and master transcription factors, and are characterized by massive H3K27ac and H3K4me signals in '''ChIP sequencing (Chromatin immunoprecipitation followed by sequencing)'''.<ref>Blayney, J. W., Francis, H., Rampasekova, A., Camellato, B., Mitchell, L., Stolper, R., ... & Kassouf, M. (2023). Super-enhancers include classical enhancers and facilitators to fully activate gene expression. Cell, 186(26), 5826-5839. PMID: 38101409 [https://doi.org/10.1016/j.cell.2023.11.030 DOI: 10.1016/j.cell.2023.11.030]</ref>
Super-enhancers and their reader BRD4 are critical tumorigenic drivers.<ref name="Super" />

Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, '''ARV-825''', that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref> In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment.<ref>Sato, S., Koyama, K., Ogawa, H., Murakami, K., Imakura, T., Yamashita, Y., ... & Nishioka, Y. (2023). A novel BRD4 degrader, ARV-825, attenuates lung fibrosis through senolysis and antifibrotic effect. Respiratory Investigation, 61(6), 781-792. PMID: 37741093 DOI: 10.1016/j.resinv.2023.08.003</ref>

'''BETd-246''', a BRD degrader belonging to the second generation, exhibits favorable selectivity and anti-neoplastic properties. BETd-246 exhibits significant therapeutic efficacy against lung cancer and hematological cancer.<ref>Zhang, M., Li, Y., Zhang, Z., Zhang, X., Wang, W., Song, X., & Zhang, D. (2023). BRD4 Protein as a Target for Lung Cancer and Hematological Cancer Therapy: A Review. Current Drug Targets, 24(14), 1079-1092. https://doi.org/10.2174/0113894501269090231012090351</ref>
BRD4 is also a repressor in cardiac reprogramming, acting primarily through cytokine oncostatin-M, and transient, but not permanent, degradation of BRD4 by a BET degrader, senolytic BETd-246 treatment can enhance cardiac-reprogramming-based regeneration in vivo.<ref>Liu, L., Guo, Y., Tian, S., Lei, I., Gao, W., Li, Z., ... & Wang, Z. (2024). Transient BRD4 degradation improves cardiac reprogramming by inhibiting macrophage/Oncostatin M induced JAK/STAT pathway. bioRxiv, 2023-12. https://doi.org/10.1101/2023.12.31.573781</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

Garcia H. et al., describe a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with Proteo-Lipid Vehicles (PLVs). These PLVs employ fusion-associated small transmembrane (FAST) proteins that can efficiently transduce a wide range of cells in vivo. Selective ablation of target cells is then achieved through the expression of a potent pro-apoptotic transgene driven by a specific senescence-associated promoter such as p16Ink4A or p53. Aged mice treated with '''FAST-PLV senolytic''' showed significantly reduced senescent cell burden. Mice treated with senolytic PLVs had an increased median post-treatment survival of 160%, lower clinical frailty,
and improved physical and heart function. Spontaneous tumor burden in these mice was reduced.<ref>Garcia H. et al., & Lewis J.D. (2023). SYSTEMIC SENOLYSIS USING A GENETIC MEDICINE IMPROVES HEALTHSPAN IN NATURALLY AGED MICE. Abstracts of 13TH INTERNATIONAL CONFERENCE ON FRAILTY & SARCOPENIA RESEARCH (ICFSR)</ref>

==== Senolytic CAR T cells and natural killer (NK) cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>
Diminished Natural killer (NK) cells activity in elderly individuals is associated with disorders such as atherosclerosis, the development of hypertension<ref>Delaney, J. A., Olson, N. C., Sitlani, C. M., Fohner, A. E., Huber, S. A., Landay, A. L., ... & Doyle, M. F. (2021). Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA). BMC Cardiovascular Disorders, 21, 1-9. PMID: 33482725 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821496/ PMC7821496] DOI: 10.1186/s12872-021-01857-2</ref><ref>Lee, Y. K., Suh, E., Oh, H., Haam, J. H., & Kim, Y. S. (2024). Decreased natural killer cell activity as a potential predictor of hypertensive incidence. Frontiers in Immunology, 15, 1376421. PMID: 38715619 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074345/ PMC11074345] DOI: 10.3389/fimmu.2024.1376421</ref> and an elevated risk of mortality.<ref>Cho, A. R., Suh, E., Oh, H., Cho, B. H., Gil, M., & Lee, Y. K. (2023). Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. International Journal of Molecular Sciences, 24(15), 12505. PMID: 37569879 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419953/ PMC10419953] DOI: 10.3390/ijms241512505</ref><ref>Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., & Nomura, T. (1997). Natural killer cells in the late decades of human life. Clinical Immunology and Immunopathology, 84(3), 269-275. PMID: 9281385 DOI: 10.1006/clin.1997.4401</ref><ref>Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., ... & Dan, K. (2001). Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology, 124(3), 392-397. PMID: 11472399 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906081/ PMC1906081] DOI: 10.1046/j.1365-2249.2001.01571.x</ref>

Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or p16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

Senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the '''senescence-associated protein urokinase plasminogen activator receptor (uPAR)''' can safely eliminate uPAR-positive senescent cells that accumulate during aging.<ref name="uPAR" /> Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.<ref>Amor, C., Fernández-Maestre, I., Chowdhury, S. et al. (2024). Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging https://doi.org/10.1038/s43587-023-00560-5
PMID: 37841853 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571605/ PMC10571605] DOI: 10.21203/rs.3.rs-3385749/v1</ref>

Alternatively, NK-cell-based therapies show promise in rejuvenating immunosenescence, eliminating senescent cells and alleviating SASPs, that lead to aging-associated diseases.<ref>Qi, C., & Liu, Q. (2023). Natural killer cells in aging and age-related diseases. Neurobiology of Disease, 183, 106156. PMID: 37209924 DOI: 10.1016/j.nbd.2023.106156</ref> The rapid development of inexpensive and accessible non-viral methods for engineering immune cells makes this approach a promising way to combat diseases of aging.<ref>Bexte, T., & Ullrich, E. (2024). Empowering virus-free CAR immune cell therapies. Molecular Therapy. 32(6), P1609-1611 PMID 38795701 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184381 PMC 11184381] doi:10.1016/j.ymthe.2024.05.023</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Senolytics

2024-07-28T06:47:50Z

Dmitry Dzhagarov: /* Senolytic CAR T cells */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]] (due to [[Autophagy#Mitophagy|mitophagy]]), remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref>João Pedro de Magalhães (2024). [https://www.science.org/doi/10.1126/science.adj7050 Cellular senescence in normal physiology].Science, 384, 1300-1301. DOI:10.1126/science.adj7050</ref><ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.<ref>Lemaitre, J. M. (2024). Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin. Journal of the European Academy of Dermatology and Venereology, 38, 5-14.https://doi.org/10.1111/jdv.19820</ref>
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

==== Markers of cellular senescence ====
The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21CIP1/WAF1,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16INK4a, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the de-repression of the '''p16INK4a''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been shown that the removal of senescent p16INK4a-positive cells can slow the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> However, whether cells that express '''p16INK4a''' are actually 'senescent cells', and if removal of such cells could cause harm in specific contexts has been questioned by more recent work.<ref name=":1" /> Moreover, a limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations of the genome. It can instead be easier to use small molecule senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics are thought to start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells, such as by differentiation of resident stem cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Notably, this is dependent on the availability of stem cell pools which are known to decline with aging, and this has been identified as a theoretical limitation of senolytics, if the lack of such stem cells means new tissue is not formed. It has also been speculated that '''if''' '''the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
Therapeutics for killing senescent cells could take the form of senolytic small molecules or immune-based clearance (antibodies or cytotoxic T cells).<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref> Senescent cells rely on prosurvival stress response adaptations to avoid apoptosis. This suggests that an attractive senescent cell killing approach would be to use small-molecule inhibitors to block cell death-resistance pathways, thereby using the endogenous stress to drive these cells into apoptosis. Existing inhibitors of prosurvival pathways used in cancer therapy may have utility for senescent cell killing, and could be even more effective for this use given that senescent cells, unlike cancer, do not proliferate.
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

Long-term study of the intermittent dasatinib plus quercetin (5 mg/kg + 50 mg/kg) exposure (two consecutive days monthly for 6 months) on aging outcomes and inflammation in nonhuman primates resulted in significant positive body composition changes with improvement in immune cell profiles and reduced glycosylated hemoglobin A1c.<ref>Ruggiero AD, Vemuri R, Blawas M et al (2023) Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design. Geroscience. https://doi.org/10.1007/s11357-023-00830-5</ref>

A computer-assisted expression analysis study suggested that '''piperlongumine''' (a known natural senolytic found in long pepper ''Piper longum''<ref>Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., ... & Zheng, G. (2016). Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY), 8(11), 2915. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191878/ PMC5191878] DOI: 10.18632/aging.101100</ref>) combination with quercetin (“P+Q”) may be a natural-compound alternative to the combination of dasatinib and quercetin (“D+Q”).<ref>Meiners, F., Secci, R., Sueto, S., Fuellen, G., & Barrantes, I. (2022). Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. bioRxiv, 2022-05. https://doi.org/10.1101/2022.05.26.492763</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Flavonoid 4,4′-dimethoxychalcone ===
The flavonoid 4,4′-dimethoxychalcone (DMC) is particularly abundant in the plant ''Angelica keiskei koidzumi'', which has been used in Asian traditional medicine, and was documented for its ability to promote autophagy-dependent longevity and health.<ref>Carmona-Gutierrez, D., Zimmermann, A., Kainz, K., Pietrocola, F., Chen, G., Maglioni, S., ... & Madeo, F. (2019). The flavonoid 4, 4′-dimethoxychalcone promotes autophagy-dependent longevity across species. Nature communications, 10(1), 651. PMID: 30783116 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180/ PMC6381180] DOI: 10.1038/s41467-019-08555-w</ref> By inhibiting the enzymatic activity of a metalloenzyme ferrochelatase, DMC induces iron accumulation and further ferroptosis.<ref>Yang, C., Wang, T., Zhao, Y., Meng, X., Ding, W., Wang, Q., ... & Deng, H. (2022). Flavonoid 4, 4′-dimethoxychalcone induced ferroptosis in cancer cells by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH. Free Radical Biology and Medicine, 188, 14-23. PMID: 35697292 [https://doi.org/10.1016/j.freeradbiomed.2022.06.010 DOI: 10.1016/j.freeradbiomed.2022.06.010]</ref> Since ferrochelatase was highly expressed in senescent cells compared to non-senescent cells DMC inhibited ferrochelatase and induced ferritinophagy, which led to an increase of labile iron pool, triggering ferroptosis of senescent cells.<ref>Wang, T., Yang, C., Li, Z., Li, T., Zhang, R., Zhao, Y., ... & Deng, H. (2024). Flavonoid 4, 4′-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy. Redox Biology, 69, 103017. PMID: 38176315 [https://doi.org/10.1016/j.redox.2023.103017 DOI: 10.1016/j.redox.2023.103017] </ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Supramolecular senolytics ===
Supramolecular senolytics is organic molecules that selectively target receptors overexpressed in the membranes of aging cells. By leveraging the higher levels of reactive oxygen species (ROS) found in aging cells, these molecules promote the formation of disulfide bonds and create oligomers that bind together. Self-assembly of these oligomers '''occurred only inside the mitochondria of senescent cells''' due to selective localization of the peptides by cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells.<ref>Kim, S., Chae, J. B., Kim, D., Park, C. W., Sim, Y., Lee, H., ... & Ryu, J. H. (2023). Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells. Journal of the American Chemical Society. PMID: 37664981 [https://doi.org/10.1021/jacs.3c06898 DOI: 10.1021/jacs.3c06898]</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== Salvestrols ===
Salvestrol (lat. ''salvus'' - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens.
Under the influence of the '''cytochrome P450 enzyme CYP1B1''', which was reported to be involved in performance of two important factors of aging: mitochondrial function and reactive oxygen species (ROS) production,<ref>Lu, Y., Nanayakkara, G., Sun, Y., Liu, L., Xu, K., Drummer IV, C., ... & Yang, X. (2021). Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation. Redox Biology, 47, 102142. PMID: 34598017 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487079/ PMC8487079] DOI: 10.1016/j.redox.2021.102142 </ref> and which is expressed in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence,<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref><ref>Huynh, D. T. M., Hai, H. T., Hau, N. M., Lan, H. K., Vinh, T. P., De Tran, V., & Pham, D. T. (2023). Preparations and characterizations of effervescent granules containing azithromycin solid dispersion for children and elder: Solubility enhancement, taste-masking, and digestive acidic protection. Heliyon, 9(6). e16592 PMID: 37292293 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245243/ PMC10245243] DOI: 10.1016/j.heliyon.2023.e16592</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== BET degraders as senolytic drugs ====
[[File:Super-enhancer-associated oncogenes.jpg|thumb|Super-enhancers activate gene transcription and induce tumorigenesis using densely bound proteins BRD4 and master transcription factors (according to Qian, H et al., 2023).<ref name="Super" >Qian, H., Zhu, M., Tan, X., Zhang, Y., Liu, X., & Yang, L. (2023). Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets. Cell Death Discovery, 9(1), 470. PMID: 38135679 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10746725/ PMC10746725] DOI: 10.1038/s41420-023-01775-6</ref>]]
'''Super-enhancers''' are large clusters of enhancers that are in close genomic proximity, are densely bound by the '''BET bromodomain protein BRD4''' and master transcription factors, and are characterized by massive H3K27ac and H3K4me signals in '''ChIP sequencing (Chromatin immunoprecipitation followed by sequencing)'''.<ref>Blayney, J. W., Francis, H., Rampasekova, A., Camellato, B., Mitchell, L., Stolper, R., ... & Kassouf, M. (2023). Super-enhancers include classical enhancers and facilitators to fully activate gene expression. Cell, 186(26), 5826-5839. PMID: 38101409 [https://doi.org/10.1016/j.cell.2023.11.030 DOI: 10.1016/j.cell.2023.11.030]</ref>
Super-enhancers and their reader BRD4 are critical tumorigenic drivers.<ref name="Super" />

Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, '''ARV-825''', that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref> In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment.<ref>Sato, S., Koyama, K., Ogawa, H., Murakami, K., Imakura, T., Yamashita, Y., ... & Nishioka, Y. (2023). A novel BRD4 degrader, ARV-825, attenuates lung fibrosis through senolysis and antifibrotic effect. Respiratory Investigation, 61(6), 781-792. PMID: 37741093 DOI: 10.1016/j.resinv.2023.08.003</ref>

'''BETd-246''', a BRD degrader belonging to the second generation, exhibits favorable selectivity and anti-neoplastic properties. BETd-246 exhibits significant therapeutic efficacy against lung cancer and hematological cancer.<ref>Zhang, M., Li, Y., Zhang, Z., Zhang, X., Wang, W., Song, X., & Zhang, D. (2023). BRD4 Protein as a Target for Lung Cancer and Hematological Cancer Therapy: A Review. Current Drug Targets, 24(14), 1079-1092. https://doi.org/10.2174/0113894501269090231012090351</ref>
BRD4 is also a repressor in cardiac reprogramming, acting primarily through cytokine oncostatin-M, and transient, but not permanent, degradation of BRD4 by a BET degrader, senolytic BETd-246 treatment can enhance cardiac-reprogramming-based regeneration in vivo.<ref>Liu, L., Guo, Y., Tian, S., Lei, I., Gao, W., Li, Z., ... & Wang, Z. (2024). Transient BRD4 degradation improves cardiac reprogramming by inhibiting macrophage/Oncostatin M induced JAK/STAT pathway. bioRxiv, 2023-12. https://doi.org/10.1101/2023.12.31.573781</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

Garcia H. et al., describe a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with Proteo-Lipid Vehicles (PLVs). These PLVs employ fusion-associated small transmembrane (FAST) proteins that can efficiently transduce a wide range of cells in vivo. Selective ablation of target cells is then achieved through the expression of a potent pro-apoptotic transgene driven by a specific senescence-associated promoter such as p16Ink4A or p53. Aged mice treated with '''FAST-PLV senolytic''' showed significantly reduced senescent cell burden. Mice treated with senolytic PLVs had an increased median post-treatment survival of 160%, lower clinical frailty,
and improved physical and heart function. Spontaneous tumor burden in these mice was reduced.<ref>Garcia H. et al., & Lewis J.D. (2023). SYSTEMIC SENOLYSIS USING A GENETIC MEDICINE IMPROVES HEALTHSPAN IN NATURALLY AGED MICE. Abstracts of 13TH INTERNATIONAL CONFERENCE ON FRAILTY & SARCOPENIA RESEARCH (ICFSR)</ref>

==== Senolytic CAR T cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>
Diminished Natural killer (NK) cells activity in elderly individuals is associated with disorders such as atherosclerosis, the development of hypertension<ref>Lee, Y. K., Suh, E., Oh, H., Haam, J. H., & Kim, Y. S. (2024). Decreased natural killer cell activity as a potential predictor of hypertensive incidence. Frontiers in Immunology, 15, 1376421. PMID: 38715619 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074345/ PMC11074345] DOI: 10.3389/fimmu.2024.1376421</ref> and an elevated risk of mortality.<ref>Cho, A. R., Suh, E., Oh, H., Cho, B. H., Gil, M., & Lee, Y. K. (2023). Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. International Journal of Molecular Sciences, 24(15), 12505. PMID: 37569879 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419953/ PMC10419953] DOI: 10.3390/ijms241512505</ref><ref>Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., & Nomura, T. (1997). Natural killer cells in the late decades of human life. Clinical Immunology and Immunopathology, 84(3), 269-275. PMID: 9281385 DOI: 10.1006/clin.1997.4401</ref><ref>Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., ... & Dan, K. (2001). Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology, 124(3), 392-397. PMID: 11472399 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906081/ PMC1906081] DOI: 10.1046/j.1365-2249.2001.01571.x</ref>

Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or p16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

Senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the '''senescence-associated protein urokinase plasminogen activator receptor (uPAR)''' can safely eliminate uPAR-positive senescent cells that accumulate during aging.<ref name="uPAR" /> Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.<ref>Amor, C., Fernández-Maestre, I., Chowdhury, S. et al. (2024). Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging https://doi.org/10.1038/s43587-023-00560-5
PMID: 37841853 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571605/ PMC10571605] DOI: 10.21203/rs.3.rs-3385749/v1</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
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