Longevity Wiki - User contributions [en-GB]

Metabolic flexibility

2023-08-16T01:14:32Z

Andrea:

Metabolic flexibility is the ability of an organism to adapt efficiently and rapidly to different metabolic and energy states.

Healthy young individuals are able to transition easily between feeding states (fed versus [[fasting]]) and between different fuels (carbohydrates versus fats) as sources of energy. On the contrary, obesity and aging appear to share in common the inability to maintain metabolic flexibility.<ref>Smith, R., Soeters, M., Wüst, R., & Houtkooper, R. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine Reviews, 39(4), 489-517. doi: 10.1210/er.2017-00211</ref>

The general public is becoming more aware of the importance of metabolic flexibility, and companies like [https://www.lumen.me/metabolic-flexibility Lumen Metabolism] and [https://www.levelshealth.com Levels] are currently offering personalized dietary recommendations based on the measurement of an individuals’s metabolic flexibility.

=== AMPK and mTORC1 as central energy and nutrient sensors ===
[[File:Diagram of AMPK and MTORC1.png|thumb|AMPK and mTORC1 are the main energy and nutrient sensors regulating metabolic plasticity. They work coordinately to achieve an optimal energy balance and organismal homeostasis.<ref>Xu, J., Ji, J., & Yan, X. (2012). Cross-Talk between AMPK and mTOR in Regulating Energy Balance. ''Critical Reviews In Food Science And Nutrition'', ''52''(5), 373-381. doi: 10.1080/10408398.2010.500245</ref> Diagram extracted from the Lectures Series “''Is Aging Inevitable? - Webinar with William B. Mair''".<ref>https:://vimeo.com/523565896</ref>]]
There are a variety of sensors controlling metabolic flexibility in an organism. The best known systems for metabolic flexibility are AMPK and mTORC1, both highly conserved across species including nematodes, flies, mice and humans.

AMPK (AMP-activated protein kinase), is activated under catabolic conditions when intracellular ATP production is decreased. AMPK has key roles in regulating cellular growth, metabolism and [[autophagy]]. It is known as a pro-longevity pathway and is activated by physiological states such as fasting or exercise.

On the other hand, the mTOR pathway (and specifically mTORC1) acts as the anabolic counterpart and functions to sense fed states or high availability of nutrients. It is a known pro-aging pathway and is suppressed by metabolic states like [[fasting]] or [[Calorie restriction|caloric restriction]]. Interventions such as [[rapamycin]] inhibit mTORC1 and are therefore believed to have a pro-longevity effect.

=== Mediators of metabolic flexibility ===
The research group led by William Mair’s lab at Harvard University, proposes that loss of this metabolic flexibility during aging (ie. the proper activation/suppression of mTOR/AMPK pathways) is the main risk factor for the onset of age-related diseases.<ref name=":0">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> Following this hypothesis, Mair’s lab is focused on defining molecular mediators of distinct metabolic states to develop novel therapeutic strategies against age-related diseases.

An example of such mediators in C. ''elegans'' are CRTCs (CREB-regulated transcriptional coactivators) and the transcription factor CREB (cAMP-response element binding protein).<ref name=":1">Mair, W., Morantte, I., Rodrigues, A., Manning, G., Montminy, M., Shaw, R., & Dillin, A. (2011). Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature, 470(7334), 404-408. doi: 10.1038/nature09706</ref> CRTCs are a family of cofactors involved in a variety of physiological processes such as energy homeostasis in insulin-sensitive tissues.<ref>Altarejos, J., & Montminy, M. (2011). CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Reviews Molecular Cell Biology, 12(3), 141-151. doi: 10.1038/nrm3072</ref> They are conserved in humans and have been linked to age-related diseases such as type-2 diabetes.<ref>Berdeaux, R., & Hutchins, C. (2019). Anabolic and Pro-metabolic Functions of CREB-CRTC in Skeletal Muscle: Advantages and Obstacles for Type 2 Diabetes and Cancer Cachexia. Frontiers In Endocrinology, 10. doi: 10.3389/fendo.2019.00535</ref>

Constitutive activation of AMPK can be achieved by disrupting an energy sensor component of the AMPK complex and leads to a lifespan extension of 50% in C. ''elegans''.<ref name=":1" /> This intervention genetically mimics dietary restriction despite worms being fed ''ad libitum.'' Activation of AMPK and inhibition of calcineurin extend lifespan via CRTCs and CREB in the nervous tissue and requires remodelling of the mitochondria and peroxisome network.<ref name=":1" /> More recently, it has been shown that CRTC-1 in the neurons drives cell non-autonomous regulation of mitochondrial dynamics in other tissues and modulate lifespan.<ref>Zhang, Y., Lanjuin, A., Chowdhury, S., Mistry, M., Silva-García, C., & Weir, H. et al. (2019). Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans. ''Elife'', ''8''. doi: 10.7554/elife.49158</ref>

=== Mitochondrial dynamics ===
[[Mitochondria]] are highly dynamic organelles found in most eukaryotes and commonly referred to as the powerhouses of the cell. Imaging studies in live cells show that mitochondria undergo coordinated cycles of fission and fusion in order to maintain their shape, distribution and size.<ref>Okamoto, K., & Shaw, J. (2005). Mitochondrial Morphology and Dynamics in Yeast and Multicellular Eukaryotes. Annual Review Of Genetics, 39(1), 503-536. doi: 10.1146/annurev.genet.38.072902.093019</ref><ref>Tilokani, L., Nagashima, S., Paupe, V., & Prudent, J. (2018). Mitochondrial dynamics: overview of molecular mechanisms. Essays In Biochemistry, 62(3), 341-360. doi: 10.1042/ebc20170104</ref>

The activity of mitochondrial dynamics is highly context specific; its cycles of fission and fusion will depend on age of the animal, nutrient conditions (fasting versus feeding) and whether there is cellular damage. Besides metabolic flexibility, mitochondria dynamics also facilitate mitophagy, the [[autophagy]] of [[mitochondria]]. [[Mitochondrial Dysfunction|Mitochondrial dysfunction]] is a hallmark of aging and has been implicated in age-related diseases such as [[Aging and Neurodegeneration|Alzheimer’s and Parkinson’s diseas]]<nowiki/>e.<ref>Bonda DJ, Smith MA, Perry G, Lee HG, Wang X, Zhu X. The mitochondrial dynamics of Alzheimer’s disease and Parkinson’s disease offer important opportunities for therapeutic intervention. Curr Pharm Des. 2011;17:3374–3380.</ref>

A key process required for efficient metabolic flexibility is the remodelling of the mitochondrial network.<ref name=":0" /> In other words, cells require mitochondrial dynamics to respond to certain changes in nutrient availability, cellular stresses and other molecular signals. For instance, during fasting mitochondria fuse together to enable more efficient respiration or metabolism, whilst during feeding states, mitochondria fragment, facilitating their mitophagy.

==== Mitochondrial dynamics in aging ====
During aging, wild-type worms fed ''ad libitum'' display an increasingly disorganised and unstructured network of mitochondria. [[Fasting|Intermitting fasting]] remodels the mitochondrial network with a more structured state during fasting states and a more disorganised morphology during fed states.<ref name=":0" />

The lifespan extension observed during both AMPK activation and [[calorie restriction]] (CR) requires mitochondrial network remodelling in C. ''elegans.''<ref name=":0" /> Animals with adynamic, permanently fused mitochondria are unable to respond to [[Fasting|intermittent fasting]] (IF) and no longer have the associated lifespan extension.<ref name=":0" /> This means IF requires functional mitochondrial dynamics for its associated lifepan increase.

Surprisingly, permanently fusing mitochondria during aging to prevent fission and fusion is sufficient to double maximum lifespan in worms.<ref name=":0" /> This is believed to be due to more stable mitochondrial networks, which can no longer become unstructured during aging. However, these worms are no longer able to respond to metabolic stresses and therefore do not have additional lifespan extension from AMPK activation or calorie restriction interventions.

Downstream of mitochondrial network homeostasis, peroxisome function and fatty acid oxidation are required to promote longevity during conditions of CR and AMPK activation.<ref name=":0" />
[[File:Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.jpg|center|thumb|400x400px|Dietary restriction and AMPK increase lifespan in peripheral tissues via mitochondrial network remodelling. This requires a downstream crosstalk between fatty acid oxidation and peroxisomes to promote longevity. <ref>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>]]

<references />
{{DEFAULTSORT:Metabolic flexibility}}
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]

ATF4 (activating transcription factor 4)

2023-08-16T01:13:30Z

Andrea:

'''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> 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<sup>+</sup> 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 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]]

Sirtuins

2023-08-16T01:11:55Z

Andrea:

Sirtuins are a family of proteins involved in epigenetic regulation of a broad range of biological processes. They are enzymes with histone de-acetylation (HDAC) functions, meaning their activity allows histones to wrap around the DNA more tightly and therefore silence gene expression. Sirtuins are NAD-dependent proteins and thus all of their activities require [[NAD+]], a type of coenzyme essential for energy production.<ref>Houtkooper, R., Cantó, C., Wanders, R., & Auwerx, J. (2010). The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways. ''Endocrine Reviews'', ''31''(2), 194-223. doi: 10.1210/er.2009-0026</ref><ref>Imai, S., & Guarente, L. (2016). It takes two to tango: NAD+ and sirtuins in aging/longevity control. ''Npj Aging And Mechanisms Of Disease'', ''2''(1). doi: 10.1038/npjamd.2016.17</ref>

Sirtuins are especially known for their controversy as conserved longevity genes (see section ´''[[Sirtuins#Controversies on sirtuins as longevity genes|Controversies on sirtuins as longevity genes]]''´).

=== Members of the sirtuins family ===
Sirtuins (often abbreviated as SIRT or SIR depending on the species) are a type of highly conserved class III histone deacetylases. There are seven sirtuins genes: SIRT1 to SIRT7, all of which share common deactylasing activities whilst also having specific functions.

* '''SIRT1''' is found both in the nucleus and the cytosol. It is largely involved in metabolic regulation and has been associated with insulin resistance, obesity and oocyte maturation.<ref>Nevoral, J., Landsmann, L., Stiavnicka, M., Hosek, P., Moravec, J., & Prokesova, S. et al. (2019). Epigenetic and non-epigenetic mode of SIRT1 action during oocyte meiosis progression. ''Journal Of Animal Science And Biotechnology'', ''10''(1). doi: 10.1186/s40104-019-0372-3</ref><ref>Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X., & Zhai, Q. (2007). SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B. ''Cell Metabolism'', ''6''(4), 307-319. doi: 10.1016/j.cmet.2007.08.014</ref> It also modulates the activity of certain transcription factors such as p53 and [[FOXO longevity genes|FOXO]]<nowiki/>.<ref>Mouchiroud, L., Houtkooper, R., Moullan, N., Katsyuba, E., Ryu, D., & Cantó, C. et al. (2013). The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. ''Cell'', ''154''(2), 430-441. doi: 10.1016/j.cell.2013.06.016</ref><ref>Vaziri, H., Dessain, S., Eaton, E., Imai, S., Frye, R., & Pandita, T. et al. (2001). hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase. ''Cell'', ''107''(2), 149-159. doi: 10.1016/s0092-8674(01)00527-x</ref>
* '''SIRT2''' is considered to be the founding member of the sirtuin family. It is found in the cytosol and has key roles in regulation of the cell cycle during mitosis and in regulating cell proliferation, motility and apoptosis.<ref>Pandithage, R., Lilischkis, R., Harting, K., Wolf, A., Jedamzik, B., & Lüscher-Firzlaff, J. et al. (2008). The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. ''Journal Of Cell Biology'', ''180''(5), 915-929. doi: 10.1083/jcb.200707126</ref> It has also been associated with tumour growth in certain cancers.<ref>Zhang, L., Kim, S., & Ren, X. (2020). The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?. ''Frontiers In Oncology'', ''10''. doi: 10.3389/fonc.2020.01721</ref>
* '''SIRT4''' has been studied less among the sirtuin family. Some studies have demonstrated the involvement of SIRT4 in age-related processes.<ref>He, L., Liu, Q., Cheng, J., Cao, M., Zhang, S., Wan, X., ... & Tu, H. (2023). SIRT4 in ageing. Biogerontology, 1-16. PMID: 37067687 DOI: 10.1007/s10522-023-10022-5</ref>
* '''SIRT3-5''' are located in the mitochondria and have roles in oxidative stress and lipid metabolism.<ref>Hirschey, M., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., & Lombard, D. et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. ''Nature'', ''464''(7285), 121-125. doi: 10.1038/nature08778</ref>
* '''SIRT6-7''' are nuclear sirtuins involved in regulating gene expression and DNA repair mechanisms.<ref>Li, L., Shi, L., Yang, S., Yan, R., Zhang, D., & Yang, J. et al. (2016). SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. ''Nature Communications'', ''7''(1). doi: 10.1038/ncomms12235</ref><ref>McCord, R., Michishita, E., Hong, T., Berber, E., Boxer, L., & Kusumoto, R. et al. (2009). SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair. ''Aging'', ''1''(1), 109-121. doi: 10.18632/aging.100011</ref>

=== Sirtuins in lifespan ===
There is generally a lack of direct evidence for all sirtuin genes, except for potentially SIRT6, in playing a role to extend lifespan in animals.

Specific SIRT genes like SIRT6 have been shown to extend healthy lifespan in one study in mice (increased median lifespan in males and females by 27% and 15%; maximum lifespan by 11% and 15%), as well as in fruit flies.<ref name=":5">Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., ... & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. ''Nature communications'', ''12''(1), 1-18.</ref><ref name=":6">Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S., Liu, J., Finn, M., ... & Helfand, S. L. (2022). Sirt6 regulates lifespan in Drosophila melanogaster. ''Proceedings of the National Academy of Sciences'', ''119''(5), e2111176119.</ref>

SIRT6 activity has also been linked to more efficient [[DNA damage and repair|double-strand break (DSB) repair mechanisms]] in long-lived rodent species and showed a positive correlation to maximum lifespan.<ref name=":7">Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., ... & Gorbunova, V. (2019). SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. ''Cell'', ''177''(3), 622-638.</ref> It has also been shown to act as a co-repressor of hypoxia-inducible factor 1-alpha (HIF1α), a transcription factor that responds to oxidative stress and oxygen consumption and which might be a regulator of aging.<ref>Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R., & Vadysirisack, D. et al. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. ''Cell'', ''140''(2), 280-293. doi: 10.1016/j.cell.2009.12.041</ref><ref>Alique, M., Sánchez-López, E., Bodega, G., Giannarelli, C., Carracedo, J., & Ramírez, R. (2020). Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. ''Cells'', ''9''(1), 195. doi: 10.3390/cells9010195</ref> Additionally, removal of SIRT6 has been linked to a >5-year decrease in lifespan in mice according to several health biomarkers.<ref>TenNapel, M., Lynch, C., Burns, T., Wallace, R., Smith, B., Button, A., & Domann, F. (2014). SIRT6 Minor Allele Genotype Is Associated with &gt;5-Year Decrease in Lifespan in an Aged Cohort. ''Plos ONE'', ''9''(12), e115616. doi: 10.1371/journal.pone.0115616</ref>

=== Sirtuins in health ===
Several members of the sirtuin family have demonstrated beneficial effects in maintaining metabolic homeostasis and health.<ref name=":3">Houtkooper, R., Pirinen, E., & Auwerx, J. (2012). Sirtuins as regulators of metabolism and healthspan. ''Nature Reviews Molecular Cell Biology'', ''13''(4), 225-238. doi: 10.1038/nrm3293</ref>

Sirtuins have a broad range of effects and can affect health in a pleiotropic manner by potentially up-regulating cytoprotective pathways.<ref name=":3" /> It has been hypothesised that their activity heightens under conditions of stress, such as in a high-fat diet or during ageing, and might protect against obesity.<ref>Lee, J., Padhye, A., Sharma, A., Song, G., Miao, J., & Mo, Y. et al. (2010). A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition. ''Journal Of Biological Chemistry'', ''285''(17), 12604-12611. doi: 10.1074/jbc.m109.094524</ref><ref>Bai, P., Canto, C., Brunyánszki, A., Huber, A., Szántó, M., & Cen, Y. et al. (2011). PARP-2 Regulates SIRT1 Expression and Whole-Body Energy Expenditure. ''Cell Metabolism'', ''13''(4), 450-460. doi: 10.1016/j.cmet.2011.03.013</ref><ref>Bai, P., Cantó, C., Oudart, H., Brunyánszki, A., Cen, Y., & Thomas, C. et al. (2011). PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation. ''Cell Metabolism'', ''13''(4), 461-468. doi: 10.1016/j.cmet.2011.03.004</ref> Sirtuins also appear to both act in response to inflammation and mediate its effects by activating tumour necrosis factor NF''κ''B in conditions of extreme infection such as sepsis.<ref>Vachharajani, V., Liu, T., Wang, X., Hoth, J., Yoza, B., & McCall, C. (2016). Sirtuins Link Inflammation and Metabolism. ''Journal Of Immunology Research'', ''2016'', 1-10. doi: 10.1155/2016/8167273</ref> This highlights the importance of sirtuins in restoring homeostasis during states of cellular stress.

Other studies have shown that increasing the activity of sirtuins stabilises telomeres and improves telomere-dependent disease.<ref name=":4">Amano, H., & Sahin, E. (2019). Telomeres and sirtuins: at the end we meet again. ''Molecular &Amp; Cellular Oncology'', ''6''(5), e1632613. doi: 10.1080/23723556.2019.1632613</ref> In wild-type conditions, SIRT1 and SIRT6 might regulate telomere length in a time- and context-specific manner.<ref>Palacios, J., Herranz, D., De Bonis, M., Velasco, S., Serrano, M., & Blasco, M. (2010). SIRT1 contributes to telomere maintenance and augments global homologous recombination. ''Journal Of Cell Biology'', ''191''(7), 1299-1313. doi: 10.1083/jcb.201005160</ref><ref>Tennen, R., & Chua, K. (2011). Chromatin regulation and genome maintenance by mammalian SIRT6. ''Trends In Biochemical Sciences'', ''36''(1), 39-46. doi: 10.1016/j.tibs.2010.07.009</ref> However, it remains unclear what is the relevance of sirtuins during telomere dysfunction and, viceversa, how telomere shortening impacts the activity of sirtuins.<ref name=":4" />

=== Controversies on sirtuins as longevity genes ===
Sirtuin proteins are surrounded by a certain degree of controversy in the field of longevity.

In the late 90s, a number of studies based on work from the Guarente lab and led by Matt Kaeberlein showed that, in yeast, adding an extra copy of the SIRT2 gene increased lifespan, whilst wild-type copies determined longevity of yeast mother cells.<ref>Kaeberlein, M., McVey, M., & Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. ''Genes &Amp; Development'', ''13''(19), 2570-2580. doi: 10.1101/gad.13.19.2570</ref>

Later on, another study from the Guarente lab in 2001 claimed that the role of SIRT2 in determining lifespan was conserved in C. ''elegans'' and potentially in higher organisms.<ref name=":0">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> They argued that overexpression of SIR-2.1 (gene homolog to SIRT2 in yeast) could extend lifespan of worms by 50%, occurring via a mechanism upstream of daf-16/[[FOXO longevity genes|FOXO]] in the insulin-like signalling pathway.<ref name=":0" />

The controversy sparked when a number of independent groups (including scientists such as Linda Partridge, David Gems and Matt Kaeberlein, who was no longer at Guarente's lab) announced that such findings were not reproducible in C. ''elegans'' or ''Drosophila''.<ref name=":1">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> Despite the non-reproducibility of their findings, the Guarente lab continues defending their results.

David Gems and his collaborators at UCL eventually discovered that overexpression of SIR-2.1 in hands of the Guarente lab led to a lifespan extension due to an unrelated background mutation.<ref name=":1" /> This background mutation in a sensory neuron gene had already been previously linked to longevity. When this mutation was bred out, there was no evidence that SIR-2.1 significantly boosted lifespan. Eventually, Guarente together with David Sinclair, a post-doc at the time in Guarente's lab, argued that when the sensory neuron mutation was removed there was still a lifespan extension, although a more modest one. Instead of up to 50% increased lifespan reported initially, there was now a small effect of only 14%.<ref>Viswanathan, M., & Guarente, L. (2011). Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. ''Nature'', ''477''(7365), E1-E2. doi: 10.1038/nature10440</ref> Of note, lifespan effects of this mild magnitude in C. ''elegans'' are generally not considered significant, given the high inherent variability of survival curves generated from different groups.

=== Conclusions of the controversy ===
Whilst the important role of sirtuin genes in maintaining metabolic homeostasis and several aspects of health is vastly agreed on, many scientists currently do not consider sirtuins as longevity genes.<ref>Charles Brenner. (2022). Sirtuins are not conserved longevity genes, ''Life Metabolism'', loac025, <nowiki>https://doi.org/10.1093/lifemeta/loac025</nowiki> </ref> The exception might be SIRT6, which has more recently shown able to extend lifespan in a variety of organisms.<ref name=":5" /><ref name=":6" /><ref name=":7" />

However, some high-profile longevity researchers continue to defend sirtuins as key molecules to extend human lifespan.<ref name=":2">Sinclair, D.A. Lifespan: Why We Age—and Why We Don’t Have To. Simon & Schuster, 2019.</ref> For instance, and despite lack of robust evidence for this claim, Sinclair argues in his book ¨''Lifespan''¨ that activating SIRT1 with the compound [[resveratrol]] might be able to extend lifespan in humans by 50 years, the equivalent lifespan in yeast cells.<ref name=":2" /> [[Resveratrol]] has now been similarly debunked as a molecule with no lifespan extending properties.<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>

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

Longevity Wiki

2023-08-11T15:17:22Z

Andrea: /* Scientific contributors */

{{DISPLAYTITLE:Longevity Wiki}}
What is aging? Can we cure age-related diseases? Is it possible to eliminate the suffering we all experience as we grow older? Can we live longer, without declining health? On this Wiki you’ll find the '''latest scientific findings on longevity'''. Our aim is to be an accessible, objective and unbiased source of information for this exciting new field.

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Longevity Wiki

2023-07-26T17:01:24Z

Andrea: /* Scientific contributors */

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What is aging? Can we cure age-related diseases? Is it possible to eliminate the suffering we all experience as we grow older? Can we live longer, without declining health? On this Wiki you’ll find the '''latest scientific findings on longevity'''. Our aim is to be an accessible, objective and unbiased source of information for this exciting new field.

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Longevity Wiki

2023-07-26T17:00:49Z

Andrea: /* Scientific contributors */

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What is aging? Can we cure age-related diseases? Is it possible to eliminate the suffering we all experience as we grow older? Can we live longer, without declining health? On this Wiki you’ll find the '''latest scientific findings on longevity'''. Our aim is to be an accessible, objective and unbiased source of information for this exciting new field.

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File:Leon.jpg

2023-07-26T17:00:08Z

Andrea:

Leon

File:Charles.jpg

2023-07-26T16:59:00Z

Andrea:

Charles

File:Valter.jpg

2023-07-26T16:57:36Z

Andrea:

Valter

File:Dudley.png

2023-07-26T16:55:03Z

Andrea:

Dudley Lamming

Longevity Wiki

2023-07-26T16:53:41Z

Andrea: Added scientific contributors (test)

{{DISPLAYTITLE:Longevity Wiki}}
What is aging? Can we cure age-related diseases? Is it possible to eliminate the suffering we all experience as we grow older? Can we live longer, without declining health? On this Wiki you’ll find the '''latest scientific findings on longevity'''. Our aim is to be an accessible, objective and unbiased source of information for this exciting new field.

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Have a look at our article about [[Rapamycin]]'','' a potential longevity drug. Or, check out our complete [[Articles|list of articles]]. We also have a [[FAQ|Longevity FAQ]] which covers the 20+ most common questions about longevity biotechnology.

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2023-07-26T16:51:38Z

Andrea:

Matt

DNA damage and repair

2023-07-21T20:31:49Z

Andrea:

DNA damage is comprised in genomic instability as one of the [[hallmarks of aging]].<ref>López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell'', ''153''(6), 1194-1217.</ref><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> Genome instability is associated to aging across species, from multicellular organisms to prokaryotes,<ref>Darmon, E., & Leach, D. R. (2014). Bacterial genome instability. ''Microbiology and Molecular Biology Reviews'', ''78''(1), 1-39.</ref> and it refers to the high occurrence of DNA damage or mutations within the genome. Some researchers argue that DNA damage is the causal driver of aging, and it is regarded as one of the main [[theories of aging]].

The genome is constantly exposed to both sources of endogenous DNA damage (such as the generation of toxic o deleterious metabolites arising from metabolic pathways, or stochastic processes), as well as to exogenous sources of DNA damage (such as exposure to UV radiation or mutagens). While DNA repair mechanisms exist that counteract these events, they are not able to fully remove all damage, and repair mechanisms themselves are subject to deteriorative processes.

== DNA damage ==

=== Endogenous DNA damage ===

==== 8-oxoguanine ====

==== Single-Stranded Breaks (SSBs) ====

==== Double-Stranded Breaks (DSBs) ====

==== Base hydrolysis ====

==== Base modifications ====

=== Exogenous DNA damage ===

==== UV radiation ====

== DNA repair ==

=== Nucleotide excision repair (NER) ===

=== Base excision repair (BER) ===

=== DNA double-strand break repair ===
<references />
[[Category:Main list]]
[[Category:Drafts]]
[[Category:Aging pathways and hallmarks]]

DNA damage and repair

2023-07-21T20:31:13Z

Andrea: backbone of entry

Theories of aging

2023-07-21T20:26:47Z

Andrea: /* Programmed theories */

''Why'' we age remains a fundamental mystery of biology.<ref>Kirkwood TB, Austad SN (2000) Why do we age? Nature 408, 233–238.</ref> Over the past decade, there have been substantial advances in our understanding of the mechanistic process underlying aging. However, researchers across the field still fail to find consensus regarding ''what'' is aging and ''why'' it happens.<ref>Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref> Many believe that understanding why we age, will ultimately lead to a better understanding of the aging proces and to more straightforward development of strategies to fight aging.

Several theories of aging exist, each of which provides a different perspective on why and how we age. These theories are not necessarily mutually exclusive, and it is possible that the aging process is a complex interplay of multiple factors.

Some of the most popular aging theories are:

=== Programmed theories ===
The ideas behind the programmed aging theory are originally based on 19th century August Weismman's "Essays upon heredity", which argues that aging evolved by natural selection to remove older individuals of the population and to favour the evolution of the species, by not competing with younger individuals for resources.<ref>Weismann A: Essays Upon Heredity. Ox- ford, Clarendon Press, 1891.</ref> According to Weismman, reproduction is necessary to dissolve the damage that the environment causes to the individual over time.<ref>Weismann A: Über die Dauer des Lebens. Fisher, Jena, 1882.</ref>

The modern programmed theory of aging proposed by Valter Longo argues that aging is a genetically programmed process that has evolved to cause senescence and death, in order to benefit future generations, referred to as "altruistic aging".<ref>Longo VD, Mitteldorf J, Skulachev VP (2005) Programmed and altruistic ageing. Nat. Rev. Genet. 6, 866–872.</ref>

Overall, the programmed theory of aging proposes that each species has an inherent genetic lifespan that is determined by a variety of factors, including the presence or absence of certain genes, the rate of DNA repair, and the activity of various metabolic processes. These factors combine to create an internal "clock" that determines the rate at which an organism ages.

Proponents of the programmed theory of aging point to the fact that different species have wildly different lifespans, which suggests that aging is not simply a matter of "wear and tear" on the body over time. They also note that certain species, such as lobsters or types of tortoises, appear to be able to live for centuries with [[negligible senescence]], suggesting that their internal genetic clock has been set to allow for this. However, recent studies show that animals with negligible senescence such as the naked mole rat do indeed age, and show signs of skin or epigenetic aging, despite the fact of not showing demographic aging (no increase in the risk of death over time).<ref>Kerepesi, C., Meer, M.V., Ablaeva, J. ''et al.'' Epigenetic aging of the demographically non-aging naked mole-rat. ''Nat Commun'' 13, 355 (2022). <nowiki>https://doi.org/10.1038/s41467-022-27959-9</nowiki></ref>

===== Arguments against programmed aging theories =====
It is argued that if aging was genetically programmed, animals kept in captivity would have the same lifespan as animals of the same species living in the wild. However, there is extensive evidence that animals kept in captivity, such as mice, cats, dogs or chimpanzees have significantly longer lifespans than those living in the wild. It is also now largely discredited that animals in the wild do not survive to old age. Steven Austad and colleagues showed there is widespread evidence for natural populations of animals living to the age of senescence, and for old animals having an increased risk of dying than their younger counterparts.<ref>Nussey DH, Froy H, Lemaitre JF, Gaillard JM, Austad SN. Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology. Ageing Res Rev. 2013 Jan;12(1):214-25. doi: 10.1016/j.arr.2012.07.004. Epub 2012 Aug 4. PMID: 22884974; PMCID: PMC4246505.</ref>

Other arguments against this theory point to the fact that no genes have been identified yet that have evolved to cause aging or death in old individuals.<ref>Gladyshev, V. N. (2016). Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. ''Aging cell'', ''15''(4), 594-602.</ref> Additionally, despite existing genome-wide knockdown screens in animals such as ''C. elegans'', no single gene mutations have been identified that lead to the disruption of the aging process or to biological immortality.

==== Evolutionary theories ====
Aging remains an evolutionary paradox. Genes are selected for to ensure their propagation across organisms.<ref>Dawkins, R. (2016). The Selfish Gene: (Oxford Landmark Science).</ref> Therefore, dying appears a counterproductive phenomenon for this mission. Evolutionary theories propose that aging is a result of evolutionary trade-offs between longevity and reproductive success. According to this theory, organisms have evolved to allocate resources to reproduction rather than maintaining their bodies indefinitely.

Evolutionary theories are based on the concept of mutation accumulation proposed by Medawar in the 50s<ref>Medawar PB (1952) An Unsolved Problem of Biology. London: HK Lewis.</ref>

=== Damage-based theories ===
Damage accumulation is arguably one of the most intuitive theories. Damage-based theories propose that aging occurs as a result of the accumulation of damage to cells and tissues over time. This damage can be caused by a variety of factors, including free radicals, radiation, toxins, [[Advanced glycation end products (AGEs)|AGEs]] and other environmental stressors, which eventually result in organismal dysfunction and death.

Many have argued that an increase of entropy, following the second law of thermodynamics, is responsible for damage accumulation in any type of matter over time. However, scientist argue that living organisms are open systems with the capability of receiving external energy supply and therefore are not necessarily subject to a fixed increase in entropy, and repair systems could exist to counteract entropy forces, in theory indefinitely.

An argument against damage-based theories is that they largely fail to explain the evolutionary origin of aging.

==== Free radical theory ====
The free radical theory is a type of DNA damage theory that proposes aging is caused by the accumulation of free-radicals over time generated by reactive oxygen species (ROS). Free radicals are produced during normal metabolism and are highly reactive, unstable molecules containing oxygen, which have the capability of oxidising other molecules. The free radical theory of aging was first presented in the 50s by Harman<ref>Harman D.Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300, 1956</ref> and it remains, as of 2022, the third most cited publication in the history of aging research.<ref>Haroon, Li Y-X, Ye C-X, Ahmad T, Khan M, Shah I, Su X-H, Xing L-X. The 100 Most Cited Publications in Aging Research: A Bibliometric Analysis. Electron J Gen Med. 2022;19(1):em342. <nowiki>https://doi.org/10.29333/ejgm/11413</nowiki></ref>

However, this theory has been now largely discredited: an increasing number of publications seem to contradict that aging can be solely explained by the accumulation of free radicals.<ref>Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal. 2014 Feb 1;20(4):727-31. doi: 10.1089/ars.2013.5228.</ref> Instead, free radicals appear to be one of the many hallmarks associated to the aging process. For instance, if free radicals were sufficient to cause aging, experiments in which antioxidants (which can neutralise free radicals) are overexpressed, such be able to extend lifespan. However, this is not seen in some animal models such as flies<ref>Mockett RJ, Sohal BH, and Sohal RS.Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of ''Drosophila melanogaster''. Free Radic Biol Med 49: 2028–2031, 2010</ref> or mice<ref>Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, and Richardson A.The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8: 73–75, 2009</ref>, and might some times even lead to lifespan shortening.<ref>Van Rammsdonk JM. and Hekimi S.Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in ''Caenorhabditis elegans''. PLoS Genet 5: e1000361, 2009 </ref> Another argument against the free radical theory of aging points towards the fact that aging still occurs under anaerobic conditions, such as in yeast cells, where ROS are generated to a very small degree.<ref>Koc A, Gasch AP, Rutherford JC, Kim HY, and Gladyshev VN.Methionine sulfoxide reductase regulation of yeast lifespan reveals reactive oxygen species-dependent and -independent components of aging. Proc Natl Acad Sci USA 101: 7999–8004, 2004 </ref>

Of note, recently mitochondria
=== Telomere shortening ===
[[Telomeres]] are the protective caps at the end of our chromosomes. Over time, telomeres gradually shorten, and this shortening is associated with the aging process.

=== Hormonal theories ===
These theories propose that changes in the levels of certain hormones, such as estrogen and testosterone, play a role in the aging process.

=== Immunological theories ===
These theories propose that the decline in immune system function with age leads to an increased susceptibility to disease and a decreased ability to fight off infections.

Theories of aging

2023-07-21T20:26:21Z

Andrea: /* Free radical theories */

''Why'' we age remains a fundamental mystery of biology.<ref>Kirkwood TB, Austad SN (2000) Why do we age? Nature 408, 233–238.</ref> Over the past decade, there have been substantial advances in our understanding of the mechanistic process underlying aging. However, researchers across the field still fail to find consensus regarding ''what'' is aging and ''why'' it happens.<ref>Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref> Many believe that understanding why we age, will ultimately lead to a better understanding of the aging proces and to more straightforward development of strategies to fight aging.

Several theories of aging exist, each of which provides a different perspective on why and how we age. These theories are not necessarily mutually exclusive, and it is possible that the aging process is a complex interplay of multiple factors.

Some of the most popular aging theories are:

=== Programmed theories ===
The ideas behind the programmed aging theory are originally based on 19th century August Weismman's "Essays upon heredity", which argues that aging evolved by natural selection to remove older individuals of the population and to favour the evolution of the species, by not competing with younger individuals for resources.<ref>Weismann A: Essays Upon Heredity. Ox- ford, Clarendon Press, 1891.</ref> According to Weismman, reproduction is necessary to dissolve the damage that the environment causes to the individual over time.<ref>Weismann A: Über die Dauer des Lebens. Fisher, Jena, 1882.</ref>

The modern programmed theory of aging proposed by Valter Longo argues that aging is a genetically programmed process that has evolved to cause senescence and death, in order to benefit future generations, referred to as "altruistic aging".<ref>Longo VD, Mitteldorf J, Skulachev VP (2005) Programmed and altruistic ageing. Nat. Rev. Genet. 6, 866–872.</ref>

Overall, the programmed theory of aging proposes that each species has an inherent genetic lifespan that is determined by a variety of factors, including the presence or absence of certain genes, the rate of DNA repair, and the activity of various metabolic processes. These factors combine to create an internal "clock" that determines the rate at which an organism ages.

Proponents of the programmed theory of aging point to the fact that different species have wildly different lifespans, which suggests that aging is not simply a matter of "wear and tear" on the body over time. They also note that certain species, such as lobsters or types of tortoises, appear to be able to live for centuries with [[negligible senescence]], suggesting that their internal genetic clock has been set to allow for this. However, recent studies show that animals with negligible senescence such as the naked mole rat do indeed age, and show signs of skin or epigenetic aging, despite the fact of not showing demographic aging (no increase in the risk of death over time).<ref>Kerepesi, C., Meer, M.V., Ablaeva, J. ''et al.'' Epigenetic aging of the demographically non-aging naked mole-rat. ''Nat Commun'' 13, 355 (2022). <nowiki>https://doi.org/10.1038/s41467-022-27959-9</nowiki></ref>

===== Arguments against programmed aging theories =====
It is argued that if aging was genetically programmed, animals kept in captivity would have the same lifespan as animals of the same species living in the wild. However, there is extensive evidence that animals kept in captivity, such as mice, cats, dogs or chimpanzees have significantly longer lifespans than those living in the wild. It is also now largely discredited that animals in the wild do not survive to old age. Steven Austad and colleagues showed there is widespread evidence for natural populations of animals living to the age of senescence, and for old animals having an increased risk of dying than their younger counterparts.<ref>Nussey DH, Froy H, Lemaitre JF, Gaillard JM, Austad SN. Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology. Ageing Res Rev. 2013 Jan;12(1):214-25. doi: 10.1016/j.arr.2012.07.004. Epub 2012 Aug 4. PMID: 22884974; PMCID: PMC4246505.</ref>

Other arguments against this theory point to the fact that no genes have been identified yet that have evolved to cause aging or death in old individuals.<ref>Gladyshev, V. N. (2016). Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. ''Aging cell'', ''15''(4), 594-602.</ref> Additionally, despite existing genome-wide knockdown screens in animals such as ''C. elegans'', no single gene mutations have been identified that lead to the disruption of the aging process or to biological immortality.

==== Evolutionary theories ====
Aging remains an evolutionary paradox. Genes are selected for to ensure their propagation across organisms.<ref>Dawkins, R. (2016). The Selfish Gene: (Oxford Landmark Science).</ref> Therefore, dying appears a counterproductive phenomenon for this mission. Evolutionary theories propose that aging is a result of evolutionary trade-offs between longevity and reproductive success. According to this theory, organisms have evolved to allocate resources to reproduction rather than maintaining their bodies indefinitely.

Evolutionary theories are based on the concept of mutation accumulation proposed by Medawar in the 50s<ref>Medawar PB (1952) An Unsolved Problem of Biology. London: HK Lewis.</ref>

=== Damage-based theories ===
Damage accumulation is arguably one of the most intuitive theories. Damage-based theories propose that aging occurs as a result of the accumulation of damage to cells and tissues over time. This damage can be caused by a variety of factors, including free radicals, radiation, toxins, [[Advanced glycation end products (AGEs)|AGEs]] and other environmental stressors, which eventually result in organismal dysfunction and death.

Many have argued that an increase of entropy, following the second law of thermodynamics, is responsible for damage accumulation in any type of matter over time. However, scientist argue that living organisms are open systems with the capability of receiving external energy supply and therefore are not necessarily subject to a fixed increase in entropy, and repair systems could exist to counteract entropy forces, in theory indefinitely.

An argument against damage-based theories is that they largely fail to explain the evolutionary origin of aging.

==== Free radical theories ====
The free radical theory is a type of DNA damage theory that proposes aging is caused by the accumulation of free-radicals over time generated by reactive oxygen species (ROS). Free radicals are produced during normal metabolism and are highly reactive, unstable molecules containing oxygen, which have the capability of oxidising other molecules. The free radical theory of aging was first presented in the 50s by Harman<ref>Harman D.Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300, 1956</ref> and it remains, as of 2022, the third most cited publication in the history of aging research.<ref>Haroon, Li Y-X, Ye C-X, Ahmad T, Khan M, Shah I, Su X-H, Xing L-X. The 100 Most Cited Publications in Aging Research: A Bibliometric Analysis. Electron J Gen Med. 2022;19(1):em342. <nowiki>https://doi.org/10.29333/ejgm/11413</nowiki></ref>

However, this theory has been now largely discredited: an increasing number of publications seem to contradict that aging can be solely explained by the accumulation of free radicals.<ref>Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal. 2014 Feb 1;20(4):727-31. doi: 10.1089/ars.2013.5228.</ref> Instead, free radicals appear to be one of the many hallmarks associated to the aging process. For instance, if free radicals were sufficient to cause aging, experiments in which antioxidants (which can neutralise free radicals) are overexpressed, such be able to extend lifespan. However, this is not seen in some animal models such as flies<ref>Mockett RJ, Sohal BH, and Sohal RS.Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of ''Drosophila melanogaster''. Free Radic Biol Med 49: 2028–2031, 2010</ref> or mice<ref>Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, and Richardson A.The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8: 73–75, 2009</ref>, and might some times even lead to lifespan shortening.<ref>Van Rammsdonk JM. and Hekimi S.Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in ''Caenorhabditis elegans''. PLoS Genet 5: e1000361, 2009 </ref> Another argument against the free radical theory of aging points towards the fact that aging still occurs under anaerobic conditions, such as in yeast cells, where ROS are generated to a very small degree.<ref>Koc A, Gasch AP, Rutherford JC, Kim HY, and Gladyshev VN.Methionine sulfoxide reductase regulation of yeast lifespan reveals reactive oxygen species-dependent and -independent components of aging. Proc Natl Acad Sci USA 101: 7999–8004, 2004 </ref>

Of note, recently mitochondria
=== Telomere shortening ===
[[Telomeres]] are the protective caps at the end of our chromosomes. Over time, telomeres gradually shorten, and this shortening is associated with the aging process.

=== Hormonal theories ===
These theories propose that changes in the levels of certain hormones, such as estrogen and testosterone, play a role in the aging process.

=== Immunological theories ===
These theories propose that the decline in immune system function with age leads to an increased susceptibility to disease and a decreased ability to fight off infections.

Is there a limit to human lifespan?

2023-07-21T20:10:32Z

Andrea: Created new entry

Currently, a big controversial topic in the field is whether there is a limit to human lifespan. The longest lived human known to date is the French woman Jeanne Louise Calment, who lived to 122 years old and 5 months. Demographers and researchers argue whether there is a hard limit to human longevity. Amongst those who believe it is fixed, some argue the hard limit is around 120 years, while others argue it is around 150 years or more.

Below are outlined some of the most popular arguments in favour and against to this idea:

=== In favour: ''Human maximum lifespan is limited'' ===

* One of the main arguments in favour of a limit to human maximum lifespan is based on demographic studies. It is argued that, while the overall aging population has increased exponentially over the past decades, there has been no change to the total number of supercentenarians (over 110 years old) in the population, suggesting there is a limit to human lifespan.

=== Against: ''Human maximum lifespan is not limited'' ===

* One of the main arguments against the existence of a hard limit to human lifespan is based on evidence from animal models. A wide range of interventions have been shown to increase maximum lifespan in animal models (such as worms, flies, or mice), which are then used as examples of the plasticity of maximum lifespan across species.

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

Lipofuscin

2023-07-21T00:07:57Z

Andrea:

'''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>

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 product (AGE)]] 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>

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<sup>+2</sup>), 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''' ('''H<sub>2</sub>S''').<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) 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 PMCID: PMC9415004 DOI: 10.3390/medicina58081129</ref>

== See also ==
* 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 <small>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.</small>
* 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]]

Hallmarks of aging

2023-07-20T19:09:29Z

Andrea: /* added hyperlink */

[[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.

== 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>

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). 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]]

DNA damage and repair

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Andrea: Create new entry

DNA damage is comprised in genomic instability as one of the [[hallmarks of aging]].

Mitochondria

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Andrea: /* Related entries */

Mitochondria are sub-cellular structures (organelles) that are responsible for the generation of ATP, a high-energy molecule that is used by cells as a store of energy. With the exception of mature red blood cells, mitochondria can be found in every cell in the human body. Mitochondria contain a genome separate from the genome found in the cell nucleus.

== Related entries to mitochondria & aging ==

* [[Mitochondrial dysfunction]]

[[Category:Glossary]]
[[Category:Main list]]

Killifish as an aging animal model

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Andrea: Added ref to /* Limitations of killifish */

[[File:Nothobranchius furzeri GRZ thumb.jpg|thumb|Male ''Nothobranchius furzeri'', also known as the turquoise killifish.<ref>https://en.wikipedia.org/wiki/Nothobranchius_furzeri</ref>|231x231px]]The African turquoise killifish (''Nothobranchius furzeri'') is the shortest lived vertebrate known to date, with a median lifespan of only 4 to 8 months. This short lifespan is closer to that of unicellular and invertebrate research organisms (such as the fruit fly) than to vertebrate research organisms such as mice or zebrafish.<ref name=":0">Hu, C., & Brunet, A. (2018). The African turquoise killifish: A research organism to study vertebrate aging and diapause. ''Aging Cell'', ''17''(3), e12757. [https://doi.org/10.1111/acel.12757 doi: 10.1111/acel.12757]</ref> This places the Turquoise Killifish in the unique position of allowing high repeatability and feasibility for experiments, whilst better recapitulating human aging traits.

==Habitat and life cycle of the turquoise killifish==
[[File:Killifish life cycle schematic.png|thumb|319x319px|The life cycle of killifish consists of two main stages: natural lifespan and diapause state. During the rainy season, the killifishes hatch and rapidly develop to reach sexual maturity. Subsequently, the killifish mate and constantly produce eggs. The eggs remain in a diapause state to survive the following dry phase, where the whole pond is desiccated, and all killifish die. <ref name=":1">Valenzano, D. R., Benayoun, B. A., Singh, P. P., Zhang, E., Etter, P. D., Hu, C.-K., Clément-Ziza, M., Willemsen, D., Cui, R., Harel, I., Machado, B. E., Yee, M.-C., Sharp, S. C., Bustamante, C. D., Beyer, A., Johnson, E. A., & Brunet, A. (2015). The African Turquoise Killifish Genome Provides Insights into Evolution and Genetic Architecture of Lifespan. ''Cell'', ''163''(6), 1539–1554. <nowiki>https://doi.org/10.1016/j.cell.2015.11.008</nowiki></ref>]]
The turquoise killifish's natural habitat is in freshwater ponds throughout central and eastern Africa, specifically the regions of Zimbabwe and Mozambique.<ref>''Nothobranchius furzeri summary page''. FishBase. Retrieved July 22, 2022, from https://www.fishbase.de/summary/Nothobranchius-furzeri.html</ref>

Due to alternating dry and rainy seasons, these regions have pronounced seasonal differences in water availability, causing the turquoise killifish to inhabit reservoirs of water that fill up during short rainy seasons and dry out entirely during the longer dry seasons.

To survive as a species, the turquoise killifish has developed a unique annual life cycle in which it can persist periods of drought through an extended period of embryonic stasis called diapause.<ref>Poeschla, M., & Valenzano, D. R. (2020). The turquoise killifish: A genetically tractable model for the study of aging. ''Journal of Experimental Biology'', ''223''(Suppl_1), jeb209296. https://doi.org/10.1242/jeb.209296</ref> With the onset of the wet season, the turquoise killifish then switches to a mode of explosive growth and sexual maturation, resulting in females laying up to 120 eggs per day.<ref>Vrtílek, M., & Reichard, M. (2016). Female fecundity traits in wild populations of African annual fish: the role of the aridity gradient. ''Ecology and Evolution'', ''6''(16), [tel:5921–5931 5921–5931]. https://doi.org/10.1002/ece3.2337</ref>

The process from hatching to sexually mature fish takes no more than 14 days, making it the fastest known rate of sexual maturation for vertebrates.<ref name=":2">Vrtílek, M., Žák, J., Pšenička, M., & Reichard, M. (2018). Extremely rapid maturation of a wild African annual fish. ''Current Biology'', ''28''(15), R822–R824. https://doi.org/10.1016/j.cub.2018.06.031</ref> Subsequently, the fertilized eggs enter the diapause state to endure the following dry season, and the circle starts again. As a result of this annual life cycle, the turquoise killifish has a short adult lifespan of four to eight months and displays aging-related transformations like lose of body colour and specific patterning (''see section'' [https://en.longevitywiki.org/index.php?title=Killifish_as_an_Aging_Animal_Model#Aging_features Aging features]).
==Lifespan==
While other standard model organisms such as mice and zebrafish have an average life expectancy of over 2.5 years in captivity, turquoise killifish live only four to eight months on average.<ref>Anon. 2017. ‘Non-Canonical Aging Model Systems and Why We Need Them’. ''The EMBO Journal'' 36(8):959–63. https://doi.org/10.15252/embj.201796837.</ref> Thereby, the lifespan of turquoise killifish is strongly strain-dependent. The original laboratory strain GRZ has the shortest lifespan of 11 to 18 weeks <ref name=":1" /><ref name=":3">Dodzian, Joanna, Sam Kean, Jens Seidel, and Dario Riccardo Valenzano. 2018. ‘A Protocol for Laboratory Housing of Turquoise Killifish (Nothobranchius furzeri)’. ''JoVE (Journal of Visualized Experiments)'' (134):e57073. https://doi.org/10.3791/57073</ref><ref name=":4">Kirschner, Jeanette, David Weber, Christina Neuschl, Andre Franke, Marco Böttger, Lea Zielke, Eileen Powalsky, Marco Groth, Dmitry Shagin, Andreas Petzold, Nils Hartmann, Christoph Englert, Gudrun A. Brockmann, Matthias Platzer, Alessandro Cellerino, and Kathrin Reichwald. 2012. ‘Mapping of Quantitative Trait Loci Controlling Lifespan in the Short-Lived Fish Nothobranchius Furzeri– a New Vertebrate Model for Age Research’. ''Aging Cell'' 11(2):252–61. https://doi.org/10.1111/j.1474-9726.2011.00780.x</ref>, while longer-lived strains like MZM0403 have a lifespan of 30 weeks<ref name=":4" />. Besides the strain, the lifespan also depends on diet, feeding frequency, and housing conditions.<ref name=":3" />

Although no sex-dependent difference in life expectancy is found in captivity<ref name=":1" /><ref name=":4" /><ref name=":6">Valenzano, Dario R., Eva Terzibasi, Tyrone Genade, Antonino Cattaneo, Luciano Domenici, and Alessandro Cellerino. 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>, significant differences in sex ratios are observed in the wild<ref>Reichard, M., M. Polačik, and O. Sedláček. 2009. ‘Distribution, Colour Polymorphism and Habitat Use of the African Killifish Nothobranchius Furzeri, the Vertebrate with the Shortest Life Span’. ''Journal of Fish Biology'' 74(1):198–212. https://doi.org/10.1111/j.1095-8649.2008.02129.x</ref>. During the rainy season, the proportion of the male population decreases, so that after three months at least two thirds of the population are female.<ref>Vrtílek, Milan, Jakub Žák, Matej Polačik, Radim Blažek, and Martin Reichard. 2018. ‘Longitudinal Demographic Study of Wild Populations of African Annual Killifish’. ''Scientific Reports'' 8(1):4774. https://doi.org/10.1038/s41598-018-22878-6</ref>

[[Calorie restriction|Dietary restriction]] can increase maximum lifespan of both the short-lived GRZ laboratory strain and the longer-lived wild-derived strain MZM-04/10P.<ref name=":10" /> However, in the wild strain MZM-04/10P, lifespan extension is associated with increased baseline mortality.<ref name=":10" /> In addition to dietary restriction, lowering the water temperature can also increase median lifespan significantly.<ref name=":9" /> This demonstrates that lifespan is malleable in killifish when subjecting them to specific interventions, as similarly observed in other animal models.
==Aging features==

===Macroscopic changes===
[[File:Young and old killifish.png|thumb|With age, the fish lose their body color, the fin structure deteriorates, and the spine becomes curved. <ref name=":5">Kim, Yumi, Hong Gil Nam, and Dario Riccardo Valenzano. 2016. ‘The Short-Lived African Turquoise Killifish: An Emerging Experimental Model for Ageing’. ''Disease Models & Mechanisms'' 9(2):115–29. https://doi.org/10.1242/dmm.023226</ref>]]Like most animals, killifishes show macroscopic signs of aging like a loss of color and pigmentation, emaciation, and a curved spine.<ref name=":5" /><ref name=":7">Terzibasi, Eva, Dario Riccardo Valenzano, Mauro Benedetti, Paola Roncaglia, Antonino Cattaneo, Luciano Domenici, and Alessandro Cellerino. 2008. ‘Large Differences in Aging Phenotype between Strains of the Short-Lived Annual Fish Nothobranchius Furzeri’. ''PLOS ONE'' 3(12):e3866. https://doi.org/10.1371/journal.pone.0003866</ref> The loss of color is more pronounced in males as they are more colorful than females, whereas females tend to lose their rotund appearance due to a prominent curved spine.<ref name=":5" /><ref name=":8">Genade, Tyrone, Mauro Benedetti, Eva Terzibasi, Paola Roncaglia, Dario Riccardo Valenzano, Antonino Cattaneo, and Alessandro Cellerino. 2005. ‘Annual Fishes of the Genus Nothobranchius as a Model System for Aging Research’. ''Aging Cell'' 4(5):223–33. https://doi.org/10.1111/j.1474-9726.2005.00165.x</ref>

Killifishes show substantial strain-dependent variation in the duration of this decrepit state. Fish from wild strains can remain in this state for several weeks before they finally die, while fish of the short-lived GRZ strain usually die before developing a macroscopic phenotype.<ref name=":7" />

===Regenerative capacity===
Besides an overall decrepit appearance, killifishes also show an impaired ability to regenerate the caudal fins with age, whereas young fish can regenerate them almost completely.<ref>Wendler, Sebastian, Nils Hartmann, Beate Hoppe, and Christoph Englert. 2015. ‘Age-Dependent Decline in Fin Regenerative Capacity in the Short-Lived Fish Nothobranchius Furzeri’. ''Aging Cell'' 14(5):857–66. https://doi.org/10.1111/acel.12367</ref>
===Mobility===
Open-field exploration is a standard behavioural test used in rodents that quantifies the amount of time an individual explores a new environment. Old killifish spend significantly less time exploring new environments compared to young fish and show a decreased moving velocity.<ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9">Valenzano, Dario R., Eva Terzibasi, Antonino Cattaneo, Luciano Domenici, and Alessandro Cellerino. 2006. ‘Temperature Affects Longevity and Age-Related Locomotor and Cognitive Decay in the Short-Lived Fish Nothobranchius Furzeri’. ''Aging Cell'' 5(3):275–78. https://doi.org/10.1111/j.1474-9726.2006.00212.x</ref> Killifishes generally show less spontaneous movement and swimming as they age.<ref name=":6" /><ref name=":8" /> However, interventions with [[resveratrol]] or reducing the water temperature to 22 °C (instead of 25 °C) significantly reduces age-related mobility deficits.<ref name=":6" /><ref name=":9" />

===Cognitive decline===
[[File:Age-dependent neurodegeneration in Killifish.png|thumb|Neurodegeneration in Stratum Griseum Superficiale of the Optic Tectum of Killifish and the effect of resveratrol detected by Fluoro-Jade B staining.<ref name=":6" />]]
To evaluate cognitive decline in aged killifish the active avoidance test is used. In this test, fish make an association between a red light and punishment. Both young and old fish succeed in learning the task, but young fish show significantly higher success rates than old fish.<ref name=":6" /><ref name=":7" /><ref name=":9" />

Remarkably, the age-related decline in cognitive performance is completely prevented in old killifish treated with [[resveratrol]].<ref name=":6" /> In addition, [[Calorie restriction|dietary restriction]] and reducing temperature from 25 °C to 22 °C also attenuates age-related cognitive decline.<ref name=":10">Terzibasi, Eva, Christel Lefrançois, Paolo Domenici, Nils Hartmann, Michael Graf, and Alessandro Cellerino. 2009. ‘Effects of Dietary Restriction on Mortality and Age-Related Phenotypes in the Short-Lived Fish Nothobranchius Furzeri’. ''Aging Cell'' 8(2):88–99. https://doi.org/10.1111/j.1474-9726.2009.00455.x</ref><ref name=":9" />

Additionally, old Killifish show molecular since of neurodegeneration, as detected by Fluoro-Jade B staining.<ref name=":6" /><ref name=":7" /> and neurodegeneration is accelerated in short-lived strains compared with longer-lived ones.<ref name=":7" /> [[Calorie restriction|Dietary restriction]] and [[resveratrol]] can reduce age-dependent neurodegeneration.<ref name=":6" /><ref name=":10" /> Furthermore, old Killifish can show pathological phenotypes similar to Parkinson’s disease.<ref>Matsui, Hideaki, Naoya Kenmochi, and Kazuhiko Namikawa. 2019. ‘Age- and α-Synuclein-Dependent Degeneration of Dopamine and Noradrenaline Neurons in the Annual Killifish Nothobranchius Furzeri’. ''Cell Reports'' 26(7):1727-1733.e6. https://doi.org/10.1016/j.celrep.2019.01.015</ref>

==Molecular markers of ageing==

===Telomere length===
[[Telomeres]] are protective caps at the ends of chromosomes that become shorter with age in various organisms. The telomere length of the short-lived killifish strain GRZ does not shorten with age, suggesting that the shorter lifespan of the strain is not a result of short [[telomeres]].<ref name=":11">Hartmann, N., Reichwald, K., Lechel, A., Graf, M., Kirschner, J., Dorn, A., Terzibasi, E., Wellner, J., Platzer, M., Rudolph, K. L., Cellerino, A., & Englert, C. (2009). Telomeres shorten while Tert expression increases during ageing of the short-lived fish Nothobranchius furzeri. ''Mechanisms of Ageing and Development'', ''130''(5), 290–296. https://doi.org/10.1016/j.mad.2009.01.003</ref> On the other hand, the [[telomeres]] of the longer-lived strain MZM0403 show significant telomere shortening within 16 weeks of life.<ref name=":11" /> Surprisingly, no upregulation of the telomere-preserving enzyme telomerase can be observed in old individuals of the short-lived strain GRZ, but upregulation can be observed in the longer-lived strain MZM0403.<ref name=":11" />

===Lipofuscin===
Lipofuscin, or age pigment, is an autofluorescent pigment that accumulates progressively with age within the cells of many species.<ref>Brunk, U. T., Jones, C. B., & Sohal, R. S. (1992). A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. ''Mutation Research'', ''275''(3–6), 395–403. https://doi.org/10.1016/0921-8734(92)90042-n</ref> In old killifish, elevated lipofuscin levels are detected in various cell types such as heart and liver cells.<ref name=":7" /><ref name=":8" /><ref name=":12">Ahuja et al. (2019). Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. ''EMBO Reports'', ''20''(4), e47407. https://doi.org/10.15252/embr.201847407</ref> Thereby, lipofuscin accumulation is faster in the short-lived strain GRZ than in the longer-lived strain MZM0403, suggesting that the short lifespan of the GRZ strain is associated with faster histological aging.<ref name=":7" />

Lowering water temperature (for instance from 25°C to 22°C) as well as [[Calorie restriction|dietary restriction]] can reduce age-related lipofuscin accumulation in old killifish.<ref name=":9" /><ref name=":10" />

===Mitochondria===
[[Mitochondria]] are the primary energy providers of most eukaryotic cells, and unlike other organelles, they are unique in that they contain their own DNA (mtDNA). Although large-scale, age-dependent mtDNA deletions are not observed in old killifish (unlike in mammals), the DNA copy number in old killifish decreases with age.<ref name=":13">Hartmann, N., Reichwald, K., Wittig, I., Dröse, S., Schmeisser, S., Lück, C., Hahn, C., Graf, M., Gausmann, U., Terzibasi, E., Cellerino, A., Ristow, M., Brandt, U., Platzer, M., & Englert, C. (2011). Mitochondrial DNA copy number and function decrease with age in the short-lived fish Nothobranchius furzeri. ''Aging Cell'', ''10''(5), 824–831. https://doi.org/10.1111/j.1474-9726.2011.00723.x</ref> Overall, old killifish show lower expression of mitochindria-associated proteins such as Pgc-1a, Tfam, and mtSsbp, and old muscle tissue has decreased levels of respiratory chain complexes.<ref name=":13" /> This indicates that oxidative phosphorylation (the process of energy production in mitochondria) might be impaired in old killifish (see also [[Mitochondrial dysfunction]]).<ref name=":13" />

===Replicative senescence===
After a certain number of replications, cells enter a state of growth arrest and altered function called [[Cellular senescence|replicative senescence]]. Replicative senescence is considered a [[Hallmarks of aging|hallmark of aging]], and senescent cells can be detected by markers such as the appearance of senescence-associated β-galactosidase (β-GAL).<ref>Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & 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 of the United States of America'', ''92''(20), [tel:9363–9367 9363–9367]. https://doi.org/10.1073%2Fpnas.92.20.9363</ref> Old killifish show increased β-GAL activity,<ref name=":8" /><ref name=":12" /> which is attenuated with lifespan-extending interventions like lowering water temperature.<ref name=":9" />

==Animal model for aging research==
[[File:The African turquoise killifish as a novel animal model to study aging.jpg|thumb|The African turquoise killifish as a novel animal model to study aging. Being a vertebrate with a short lifespan of 4-6 months places the killifish in an unique position to study aging.<ref name=":0" />]]Dr Dario Valenzano, trained at Brunet lab in Stanford and currently at the Leibniz Institute on Aging, is especially known for his contribution in characterising the turquoise killifish. He is considered to have established this species as a novel research model and as an aging animal model.

One of the main advantages of using killifish as an aging animal model is its close resemblance to human aging, usually seen in much longer lived animal models such as mice and zebrafish, and its short lifespan of 4 to 8 months, which allows for greater experimental scalability.<ref name=":02">Hu, C., & Brunet, A. (2018). The African turquoise killifish: A research organism to study vertebrate aging and diapause. ''Aging Cell'', ''17''(3), e12757. [https://doi.org/10.1111/acel.12757 doi: 10.1111/acel.12757]</ref>

The turquoise killifish has been recently established as a model for [[Aging and eye disease|age-related eye disease]].<ref name=":14">Vanhunsel, S., Bergmans, S., Beckers, A., Etienne, I., Van houcke, J., & Seuntjens, E. et al. (2021). The killifish visual system as an in vivo model to study brain aging and rejuvenation. ''Npj Aging And Mechanisms Of Disease'', ''7''(1). doi: 10.1038/s41514-021-00077-4</ref> Considering vision decline as a conserved aging hallmark, the aging-associated decline of the killifish visual system has been proposed as a useful ''in vivo'' model to study brain aging and rejuvenation.<ref name=":14" />

====Genetic tools available====
The group led by Anne Brunet in Stanford University has developed a genotype-to-phenotype platform using de-novo-assembled genome and CRISPR/Cas9 technology, which allows for high-throughput and high efficiency knock-out and knock-in studies in killifish.<ref name=":15">Harel, I., Benayoun, B., Machado, B., Singh, P., Hu, C., & Pech, M. et al. (2015). A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate. ''Cell'', ''160''(5), 1013-1026. doi: 10.1016/j.cell.2015.01.038</ref>

A key tool for generating transgenic species in fish is the transposase system. [[Transposons in aging|Transposon elements]] (TE) are genes capable of changing position within the genome, which can sometimes result in ''de novo'' mutations or changes in genome size.<ref>Bourque, G., Burns, K., Gehring, M., Gorbunova, V., Seluanov, A., & Hammell, M. et al. (2018). Ten things you should know about transposable elements. ''Genome Biology'', ''19''(1). doi: 10.1186/s13059-018-1577-z</ref> Transposase enzymes bind to the end of TE and catalyze their movement to other parts of the genome. In killifish, the Tol2 transposase system has been adapted from other model animals by Valenzano to integrate genes of interest into the host's genome in a stable and efficient manner.<ref>Valenzano, D., Sharp, S., & Brunet, A. (2011). Transposon-Mediated Transgenesis in the Short-Lived African KillifishNothobranchius furzeri, a Vertebrate Model for Aging. ''G3 Genes|Genomes|Genetics'', ''1''(7), 531-538. doi: 10.1534/g3.111.001271</ref>

Additional progress has been made in developing other genetic tools for killifish. <ref>Harel, I., Valenzano, D., & Brunet, A. (2016). Efficient genome engineering approaches for the short-lived African turquoise killifish. ''Nature Protocols'', ''11''(10), 2010-2028. doi: 10.1038/nprot.2016.103</ref><ref>Platzer, M., & Englert, C. (2016). Nothobranchius furzeri: A Model for Aging Research and More. ''Trends In Genetics'', ''32''(9), 543-552. doi: 10.1016/j.tig.2016.06.006</ref> Due to the fast life cycle of killifish, new stable transgenic lines can be generated as rapidly as in 2 to 3 months.<ref name=":15" />

==Limitations of killifish==
Whilst killifish can be a great alternative compared to more conventional animal models, they also suppose some limitations:

*Teleost fish such as killifish, which includes a large and very diverse group of ray-finned fishes, all possess a duplicated genome. This whole-genome duplication (WGD) occurred in an ancient common ancestor of all teleost fishes. Duplicated genes may sometimes serve different functions or lead to the non-functionalization of one of the genes.<ref>Glasauer, S., & Neuhauss, S. (2014). Whole-genome duplication in teleost fishes and its evolutionary consequences. ''Molecular Genetics And Genomics'', ''289''(6), 1045-1060. doi: 10.1007/s00438-014-0889-2</ref> This WGD might have occurred at least twice during evolution and may have led to highly fish-specific adaptations.<ref>Dehal, P., & Boore, J. (2005). Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate. ''Plos Biology'', ''3''(10), e314. doi: 10.1371/journal.pbio.0030314</ref> This poses significant limitations on findings derived from killifishes. Recent studies suggest that recent evolutionarily changes in chromatin accessibility at ancient gene duplications events have allowed killifish to develop mechanisms of suspended animation at embryonic stages in order to survive to extreme environments.<ref>Singh, P. P., Reeves, G. A., Contrepois, K., Ellenberger, M., Hu, C. K., Snyder, M. P., & Brunet, A. (2021). Evolution of diapause in the African turquoise killifish by remodeling ancient gene regulatory landscape. ''bioRxiv'', 2021-10.</ref>
*Each killifish requires approximately 1 liter of water.<ref>Dodzian, J., Kean, S., Seidel, J., & Valenzano, D. (2018). A Protocol for Laboratory Housing of Turquoise Killifish (&lt;em&gt;Nothobranchius furzeri&lt;/em&gt;). ''Journal Of Visualized Experiments'', (134). doi: 10.3791/57073</ref> This aspect becomes very troublesome for high throughput assays when taking into account space logistics. However, these restrictions apply mostly when keeping individuals in social isolation, and more killifish per liter could potentially be housed in groups. On the other hand, this might prohibit pharmacological approaches, given that incredibly large amounts of drugs would need to be diluted into 1L of water to potentially have an effect.

==References==
<references />
[[Category:Main list]]
[[Category:Tools to study aging]]

Killifish as an aging animal model

2023-07-03T11:20:05Z

Andrea: /* Literature update Limitations of killifish */

[[File:Nothobranchius furzeri GRZ thumb.jpg|thumb|Male ''Nothobranchius furzeri'', also known as the turquoise killifish.<ref>https://en.wikipedia.org/wiki/Nothobranchius_furzeri</ref>|231x231px]]The African turquoise killifish (''Nothobranchius furzeri'') is the shortest lived vertebrate known to date, with a median lifespan of only 4 to 8 months. This short lifespan is closer to that of unicellular and invertebrate research organisms (such as the fruit fly) than to vertebrate research organisms such as mice or zebrafish.<ref name=":0">Hu, C., & Brunet, A. (2018). The African turquoise killifish: A research organism to study vertebrate aging and diapause. ''Aging Cell'', ''17''(3), e12757. [https://doi.org/10.1111/acel.12757 doi: 10.1111/acel.12757]</ref> This places the Turquoise Killifish in the unique position of allowing high repeatability and feasibility for experiments, whilst better recapitulating human aging traits.

==Habitat and life cycle of the turquoise killifish==
[[File:Killifish life cycle schematic.png|thumb|319x319px|The life cycle of killifish consists of two main stages: natural lifespan and diapause state. During the rainy season, the killifishes hatch and rapidly develop to reach sexual maturity. Subsequently, the killifish mate and constantly produce eggs. The eggs remain in a diapause state to survive the following dry phase, where the whole pond is desiccated, and all killifish die. <ref name=":1">Valenzano, D. R., Benayoun, B. A., Singh, P. P., Zhang, E., Etter, P. D., Hu, C.-K., Clément-Ziza, M., Willemsen, D., Cui, R., Harel, I., Machado, B. E., Yee, M.-C., Sharp, S. C., Bustamante, C. D., Beyer, A., Johnson, E. A., & Brunet, A. (2015). The African Turquoise Killifish Genome Provides Insights into Evolution and Genetic Architecture of Lifespan. ''Cell'', ''163''(6), 1539–1554. <nowiki>https://doi.org/10.1016/j.cell.2015.11.008</nowiki></ref>]]
The turquoise killifish's natural habitat is in freshwater ponds throughout central and eastern Africa, specifically the regions of Zimbabwe and Mozambique.<ref>''Nothobranchius furzeri summary page''. FishBase. Retrieved July 22, 2022, from https://www.fishbase.de/summary/Nothobranchius-furzeri.html</ref>

Due to alternating dry and rainy seasons, these regions have pronounced seasonal differences in water availability, causing the turquoise killifish to inhabit reservoirs of water that fill up during short rainy seasons and dry out entirely during the longer dry seasons.

To survive as a species, the turquoise killifish has developed a unique annual life cycle in which it can persist periods of drought through an extended period of embryonic stasis called diapause.<ref>Poeschla, M., & Valenzano, D. R. (2020). The turquoise killifish: A genetically tractable model for the study of aging. ''Journal of Experimental Biology'', ''223''(Suppl_1), jeb209296. https://doi.org/10.1242/jeb.209296</ref> With the onset of the wet season, the turquoise killifish then switches to a mode of explosive growth and sexual maturation, resulting in females laying up to 120 eggs per day.<ref>Vrtílek, M., & Reichard, M. (2016). Female fecundity traits in wild populations of African annual fish: the role of the aridity gradient. ''Ecology and Evolution'', ''6''(16), [tel:5921–5931 5921–5931]. https://doi.org/10.1002/ece3.2337</ref>

The process from hatching to sexually mature fish takes no more than 14 days, making it the fastest known rate of sexual maturation for vertebrates.<ref name=":2">Vrtílek, M., Žák, J., Pšenička, M., & Reichard, M. (2018). Extremely rapid maturation of a wild African annual fish. ''Current Biology'', ''28''(15), R822–R824. https://doi.org/10.1016/j.cub.2018.06.031</ref> Subsequently, the fertilized eggs enter the diapause state to endure the following dry season, and the circle starts again. As a result of this annual life cycle, the turquoise killifish has a short adult lifespan of four to eight months and displays aging-related transformations like lose of body colour and specific patterning (''see section'' [https://en.longevitywiki.org/index.php?title=Killifish_as_an_Aging_Animal_Model#Aging_features Aging features]).
==Lifespan==
While other standard model organisms such as mice and zebrafish have an average life expectancy of over 2.5 years in captivity, turquoise killifish live only four to eight months on average.<ref>Anon. 2017. ‘Non-Canonical Aging Model Systems and Why We Need Them’. ''The EMBO Journal'' 36(8):959–63. https://doi.org/10.15252/embj.201796837.</ref> Thereby, the lifespan of turquoise killifish is strongly strain-dependent. The original laboratory strain GRZ has the shortest lifespan of 11 to 18 weeks <ref name=":1" /><ref name=":3">Dodzian, Joanna, Sam Kean, Jens Seidel, and Dario Riccardo Valenzano. 2018. ‘A Protocol for Laboratory Housing of Turquoise Killifish (Nothobranchius furzeri)’. ''JoVE (Journal of Visualized Experiments)'' (134):e57073. https://doi.org/10.3791/57073</ref><ref name=":4">Kirschner, Jeanette, David Weber, Christina Neuschl, Andre Franke, Marco Böttger, Lea Zielke, Eileen Powalsky, Marco Groth, Dmitry Shagin, Andreas Petzold, Nils Hartmann, Christoph Englert, Gudrun A. Brockmann, Matthias Platzer, Alessandro Cellerino, and Kathrin Reichwald. 2012. ‘Mapping of Quantitative Trait Loci Controlling Lifespan in the Short-Lived Fish Nothobranchius Furzeri– a New Vertebrate Model for Age Research’. ''Aging Cell'' 11(2):252–61. https://doi.org/10.1111/j.1474-9726.2011.00780.x</ref>, while longer-lived strains like MZM0403 have a lifespan of 30 weeks<ref name=":4" />. Besides the strain, the lifespan also depends on diet, feeding frequency, and housing conditions.<ref name=":3" />

Although no sex-dependent difference in life expectancy is found in captivity<ref name=":1" /><ref name=":4" /><ref name=":6">Valenzano, Dario R., Eva Terzibasi, Tyrone Genade, Antonino Cattaneo, Luciano Domenici, and Alessandro Cellerino. 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>, significant differences in sex ratios are observed in the wild<ref>Reichard, M., M. Polačik, and O. Sedláček. 2009. ‘Distribution, Colour Polymorphism and Habitat Use of the African Killifish Nothobranchius Furzeri, the Vertebrate with the Shortest Life Span’. ''Journal of Fish Biology'' 74(1):198–212. https://doi.org/10.1111/j.1095-8649.2008.02129.x</ref>. During the rainy season, the proportion of the male population decreases, so that after three months at least two thirds of the population are female.<ref>Vrtílek, Milan, Jakub Žák, Matej Polačik, Radim Blažek, and Martin Reichard. 2018. ‘Longitudinal Demographic Study of Wild Populations of African Annual Killifish’. ''Scientific Reports'' 8(1):4774. https://doi.org/10.1038/s41598-018-22878-6</ref>

[[Calorie restriction|Dietary restriction]] can increase maximum lifespan of both the short-lived GRZ laboratory strain and the longer-lived wild-derived strain MZM-04/10P.<ref name=":10" /> However, in the wild strain MZM-04/10P, lifespan extension is associated with increased baseline mortality.<ref name=":10" /> In addition to dietary restriction, lowering the water temperature can also increase median lifespan significantly.<ref name=":9" /> This demonstrates that lifespan is malleable in killifish when subjecting them to specific interventions, as similarly observed in other animal models.
==Aging features==

===Macroscopic changes===
[[File:Young and old killifish.png|thumb|With age, the fish lose their body color, the fin structure deteriorates, and the spine becomes curved. <ref name=":5">Kim, Yumi, Hong Gil Nam, and Dario Riccardo Valenzano. 2016. ‘The Short-Lived African Turquoise Killifish: An Emerging Experimental Model for Ageing’. ''Disease Models & Mechanisms'' 9(2):115–29. https://doi.org/10.1242/dmm.023226</ref>]]Like most animals, killifishes show macroscopic signs of aging like a loss of color and pigmentation, emaciation, and a curved spine.<ref name=":5" /><ref name=":7">Terzibasi, Eva, Dario Riccardo Valenzano, Mauro Benedetti, Paola Roncaglia, Antonino Cattaneo, Luciano Domenici, and Alessandro Cellerino. 2008. ‘Large Differences in Aging Phenotype between Strains of the Short-Lived Annual Fish Nothobranchius Furzeri’. ''PLOS ONE'' 3(12):e3866. https://doi.org/10.1371/journal.pone.0003866</ref> The loss of color is more pronounced in males as they are more colorful than females, whereas females tend to lose their rotund appearance due to a prominent curved spine.<ref name=":5" /><ref name=":8">Genade, Tyrone, Mauro Benedetti, Eva Terzibasi, Paola Roncaglia, Dario Riccardo Valenzano, Antonino Cattaneo, and Alessandro Cellerino. 2005. ‘Annual Fishes of the Genus Nothobranchius as a Model System for Aging Research’. ''Aging Cell'' 4(5):223–33. https://doi.org/10.1111/j.1474-9726.2005.00165.x</ref>

Killifishes show substantial strain-dependent variation in the duration of this decrepit state. Fish from wild strains can remain in this state for several weeks before they finally die, while fish of the short-lived GRZ strain usually die before developing a macroscopic phenotype.<ref name=":7" />

===Regenerative capacity===
Besides an overall decrepit appearance, killifishes also show an impaired ability to regenerate the caudal fins with age, whereas young fish can regenerate them almost completely.<ref>Wendler, Sebastian, Nils Hartmann, Beate Hoppe, and Christoph Englert. 2015. ‘Age-Dependent Decline in Fin Regenerative Capacity in the Short-Lived Fish Nothobranchius Furzeri’. ''Aging Cell'' 14(5):857–66. https://doi.org/10.1111/acel.12367</ref>
===Mobility===
Open-field exploration is a standard behavioural test used in rodents that quantifies the amount of time an individual explores a new environment. Old killifish spend significantly less time exploring new environments compared to young fish and show a decreased moving velocity.<ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9">Valenzano, Dario R., Eva Terzibasi, Antonino Cattaneo, Luciano Domenici, and Alessandro Cellerino. 2006. ‘Temperature Affects Longevity and Age-Related Locomotor and Cognitive Decay in the Short-Lived Fish Nothobranchius Furzeri’. ''Aging Cell'' 5(3):275–78. https://doi.org/10.1111/j.1474-9726.2006.00212.x</ref> Killifishes generally show less spontaneous movement and swimming as they age.<ref name=":6" /><ref name=":8" /> However, interventions with [[resveratrol]] or reducing the water temperature to 22 °C (instead of 25 °C) significantly reduces age-related mobility deficits.<ref name=":6" /><ref name=":9" />

===Cognitive decline===
[[File:Age-dependent neurodegeneration in Killifish.png|thumb|Neurodegeneration in Stratum Griseum Superficiale of the Optic Tectum of Killifish and the effect of resveratrol detected by Fluoro-Jade B staining.<ref name=":6" />]]
To evaluate cognitive decline in aged killifish the active avoidance test is used. In this test, fish make an association between a red light and punishment. Both young and old fish succeed in learning the task, but young fish show significantly higher success rates than old fish.<ref name=":6" /><ref name=":7" /><ref name=":9" />

Remarkably, the age-related decline in cognitive performance is completely prevented in old killifish treated with [[resveratrol]].<ref name=":6" /> In addition, [[Calorie restriction|dietary restriction]] and reducing temperature from 25 °C to 22 °C also attenuates age-related cognitive decline.<ref name=":10">Terzibasi, Eva, Christel Lefrançois, Paolo Domenici, Nils Hartmann, Michael Graf, and Alessandro Cellerino. 2009. ‘Effects of Dietary Restriction on Mortality and Age-Related Phenotypes in the Short-Lived Fish Nothobranchius Furzeri’. ''Aging Cell'' 8(2):88–99. https://doi.org/10.1111/j.1474-9726.2009.00455.x</ref><ref name=":9" />

Additionally, old Killifish show molecular since of neurodegeneration, as detected by Fluoro-Jade B staining.<ref name=":6" /><ref name=":7" /> and neurodegeneration is accelerated in short-lived strains compared with longer-lived ones.<ref name=":7" /> [[Calorie restriction|Dietary restriction]] and [[resveratrol]] can reduce age-dependent neurodegeneration.<ref name=":6" /><ref name=":10" /> Furthermore, old Killifish can show pathological phenotypes similar to Parkinson’s disease.<ref>Matsui, Hideaki, Naoya Kenmochi, and Kazuhiko Namikawa. 2019. ‘Age- and α-Synuclein-Dependent Degeneration of Dopamine and Noradrenaline Neurons in the Annual Killifish Nothobranchius Furzeri’. ''Cell Reports'' 26(7):1727-1733.e6. https://doi.org/10.1016/j.celrep.2019.01.015</ref>

==Molecular markers of ageing==

===Telomere length===
[[Telomeres]] are protective caps at the ends of chromosomes that become shorter with age in various organisms. The telomere length of the short-lived killifish strain GRZ does not shorten with age, suggesting that the shorter lifespan of the strain is not a result of short [[telomeres]].<ref name=":11">Hartmann, N., Reichwald, K., Lechel, A., Graf, M., Kirschner, J., Dorn, A., Terzibasi, E., Wellner, J., Platzer, M., Rudolph, K. L., Cellerino, A., & Englert, C. (2009). Telomeres shorten while Tert expression increases during ageing of the short-lived fish Nothobranchius furzeri. ''Mechanisms of Ageing and Development'', ''130''(5), 290–296. https://doi.org/10.1016/j.mad.2009.01.003</ref> On the other hand, the [[telomeres]] of the longer-lived strain MZM0403 show significant telomere shortening within 16 weeks of life.<ref name=":11" /> Surprisingly, no upregulation of the telomere-preserving enzyme telomerase can be observed in old individuals of the short-lived strain GRZ, but upregulation can be observed in the longer-lived strain MZM0403.<ref name=":11" />

===Lipofuscin===
Lipofuscin, or age pigment, is an autofluorescent pigment that accumulates progressively with age within the cells of many species.<ref>Brunk, U. T., Jones, C. B., & Sohal, R. S. (1992). A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis. ''Mutation Research'', ''275''(3–6), 395–403. https://doi.org/10.1016/0921-8734(92)90042-n</ref> In old killifish, elevated lipofuscin levels are detected in various cell types such as heart and liver cells.<ref name=":7" /><ref name=":8" /><ref name=":12">Ahuja et al. (2019). Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. ''EMBO Reports'', ''20''(4), e47407. https://doi.org/10.15252/embr.201847407</ref> Thereby, lipofuscin accumulation is faster in the short-lived strain GRZ than in the longer-lived strain MZM0403, suggesting that the short lifespan of the GRZ strain is associated with faster histological aging.<ref name=":7" />

Lowering water temperature (for instance from 25°C to 22°C) as well as [[Calorie restriction|dietary restriction]] can reduce age-related lipofuscin accumulation in old killifish.<ref name=":9" /><ref name=":10" />

===Mitochondria===
[[Mitochondria]] are the primary energy providers of most eukaryotic cells, and unlike other organelles, they are unique in that they contain their own DNA (mtDNA). Although large-scale, age-dependent mtDNA deletions are not observed in old killifish (unlike in mammals), the DNA copy number in old killifish decreases with age.<ref name=":13">Hartmann, N., Reichwald, K., Wittig, I., Dröse, S., Schmeisser, S., Lück, C., Hahn, C., Graf, M., Gausmann, U., Terzibasi, E., Cellerino, A., Ristow, M., Brandt, U., Platzer, M., & Englert, C. (2011). Mitochondrial DNA copy number and function decrease with age in the short-lived fish Nothobranchius furzeri. ''Aging Cell'', ''10''(5), 824–831. https://doi.org/10.1111/j.1474-9726.2011.00723.x</ref> Overall, old killifish show lower expression of mitochindria-associated proteins such as Pgc-1a, Tfam, and mtSsbp, and old muscle tissue has decreased levels of respiratory chain complexes.<ref name=":13" /> This indicates that oxidative phosphorylation (the process of energy production in mitochondria) might be impaired in old killifish (see also [[Mitochondrial dysfunction]]).<ref name=":13" />

===Replicative senescence===
After a certain number of replications, cells enter a state of growth arrest and altered function called [[Cellular senescence|replicative senescence]]. Replicative senescence is considered a [[Hallmarks of aging|hallmark of aging]], and senescent cells can be detected by markers such as the appearance of senescence-associated β-galactosidase (β-GAL).<ref>Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & 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 of the United States of America'', ''92''(20), [tel:9363–9367 9363–9367]. https://doi.org/10.1073%2Fpnas.92.20.9363</ref> Old killifish show increased β-GAL activity,<ref name=":8" /><ref name=":12" /> which is attenuated with lifespan-extending interventions like lowering water temperature.<ref name=":9" />

==Animal model for aging research==
[[File:The African turquoise killifish as a novel animal model to study aging.jpg|thumb|The African turquoise killifish as a novel animal model to study aging. Being a vertebrate with a short lifespan of 4-6 months places the killifish in an unique position to study aging.<ref name=":0" />]]Dr Dario Valenzano, trained at Brunet lab in Stanford and currently at the Leibniz Institute on Aging, is especially known for his contribution in characterising the turquoise killifish. He is considered to have established this species as a novel research model and as an aging animal model.

One of the main advantages of using killifish as an aging animal model is its close resemblance to human aging, usually seen in much longer lived animal models such as mice and zebrafish, and its short lifespan of 4 to 8 months, which allows for greater experimental scalability.<ref name=":02">Hu, C., & Brunet, A. (2018). The African turquoise killifish: A research organism to study vertebrate aging and diapause. ''Aging Cell'', ''17''(3), e12757. [https://doi.org/10.1111/acel.12757 doi: 10.1111/acel.12757]</ref>

The turquoise killifish has been recently established as a model for [[Aging and eye disease|age-related eye disease]].<ref name=":14">Vanhunsel, S., Bergmans, S., Beckers, A., Etienne, I., Van houcke, J., & Seuntjens, E. et al. (2021). The killifish visual system as an in vivo model to study brain aging and rejuvenation. ''Npj Aging And Mechanisms Of Disease'', ''7''(1). doi: 10.1038/s41514-021-00077-4</ref> Considering vision decline as a conserved aging hallmark, the aging-associated decline of the killifish visual system has been proposed as a useful ''in vivo'' model to study brain aging and rejuvenation.<ref name=":14" />

====Genetic tools available====
The group led by Anne Brunet in Stanford University has developed a genotype-to-phenotype platform using de-novo-assembled genome and CRISPR/Cas9 technology, which allows for high-throughput and high efficiency knock-out and knock-in studies in killifish.<ref name=":15">Harel, I., Benayoun, B., Machado, B., Singh, P., Hu, C., & Pech, M. et al. (2015). A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate. ''Cell'', ''160''(5), 1013-1026. doi: 10.1016/j.cell.2015.01.038</ref>

A key tool for generating transgenic species in fish is the transposase system. [[Transposons in aging|Transposon elements]] (TE) are genes capable of changing position within the genome, which can sometimes result in ''de novo'' mutations or changes in genome size.<ref>Bourque, G., Burns, K., Gehring, M., Gorbunova, V., Seluanov, A., & Hammell, M. et al. (2018). Ten things you should know about transposable elements. ''Genome Biology'', ''19''(1). doi: 10.1186/s13059-018-1577-z</ref> Transposase enzymes bind to the end of TE and catalyze their movement to other parts of the genome. In killifish, the Tol2 transposase system has been adapted from other model animals by Valenzano to integrate genes of interest into the host's genome in a stable and efficient manner.<ref>Valenzano, D., Sharp, S., & Brunet, A. (2011). Transposon-Mediated Transgenesis in the Short-Lived African KillifishNothobranchius furzeri, a Vertebrate Model for Aging. ''G3 Genes|Genomes|Genetics'', ''1''(7), 531-538. doi: 10.1534/g3.111.001271</ref>

Additional progress has been made in developing other genetic tools for killifish. <ref>Harel, I., Valenzano, D., & Brunet, A. (2016). Efficient genome engineering approaches for the short-lived African turquoise killifish. ''Nature Protocols'', ''11''(10), 2010-2028. doi: 10.1038/nprot.2016.103</ref><ref>Platzer, M., & Englert, C. (2016). Nothobranchius furzeri: A Model for Aging Research and More. ''Trends In Genetics'', ''32''(9), 543-552. doi: 10.1016/j.tig.2016.06.006</ref> Due to the fast life cycle of killifish, new stable transgenic lines can be generated as rapidly as in 2 to 3 months.<ref name=":15" />

==Limitations of killifish==
Whilst killifish can be a great alternative compared to more conventional animal models, they also suppose some limitations:

*Teleost fish such as killifish, which includes a large and very diverse group of ray-finned fishes, all possess a duplicated genome. This whole-genome duplication (WGD) occurred in an ancient common ancestor of all teleost fishes. Duplicated genes may sometimes serve different functions or lead to the non-functionalization of one of the genes.<ref>Glasauer, S., & Neuhauss, S. (2014). Whole-genome duplication in teleost fishes and its evolutionary consequences. ''Molecular Genetics And Genomics'', ''289''(6), 1045-1060. doi: 10.1007/s00438-014-0889-2</ref> This WGD might have occurred at least twice during evolution and may have led to highly fish-specific adaptations.<ref>Dehal, P., & Boore, J. (2005). Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate. ''Plos Biology'', ''3''(10), e314. doi: 10.1371/journal.pbio.0030314</ref> This poses significant limitations on findings derived from killifishes. Recent studies suggest that evolutionarily recent changes in chromatin accessibility in ancient gene duplications have allowed killifish to develop mechanisms of suspended animation at embryonic stages in order to survive extreme environments.
*Each killifish requires approximately 1 liter of water.<ref>Dodzian, J., Kean, S., Seidel, J., & Valenzano, D. (2018). A Protocol for Laboratory Housing of Turquoise Killifish (&lt;em&gt;Nothobranchius furzeri&lt;/em&gt;). ''Journal Of Visualized Experiments'', (134). doi: 10.3791/57073</ref> This aspect becomes very troublesome for high throughput assays when taking into account space logistics. However, these restrictions apply mostly when keeping individuals in social isolation, and more killifish per liter could be housed in groups. On the other hand, this might prohibit pharmacological approaches, given that incredibly large amounts of drugs would need to be diluted into 1L of water to potentially have an effect.

==References==
<references />
[[Category:Main list]]
[[Category:Tools to study aging]]

A cheap and accessible way to maintain a youthful body

2023-06-05T08:30:34Z

Andrea: Added category

== DIET GUIDELINES ==
(according to Fitzgerald, Campbell, Makarem, & Hodges (2023)<ref>Fitzgerald, K. N., Campbell, T., Makarem, S., & Hodges, R. (2023). Potential reversal of biological age in women following an 8-week methylation-supportive diet and lifestyle program: a case series. Aging (Albany NY), 15(6), 1833. PMID: 36947707 PMCID: PMC10085584 DOI: 10.18632/aging.204602</ref> modified by us.
Also: <ref>Tang, D., Tang, Q., Huang, W., Zhang, Y., Tian, Y., & Fu, X. (2023). Fasting: From Physiology to Pathology. Advanced Science, 10(9), 2204487. PMID: 36737846 PMCID: PMC10037992 DOI: 10.1002/advs.202204487</ref><ref>Longo, V. D., & Anderson, R. M. (2022). Nutrition, longevity and disease: From molecular mechanisms to interventions. Cell, 185(9), 1455-1470. PMID: 35487190 PMCID: PMC9089818 DOI: 10.1016/j.cell.2022.04.002</ref>

=== PER DAY ===
* Two cups of dark leafy greens, like kale, spinach and mustard greens;
* Two cups of cruciferous vegetables, such as broccoli, cabbage and arugula;
* Three cups of colored vegetables, except for sweetcorn and white potatoes;
* One to two medium beets;
==== a mixture of ingredients ground together ====
* One tablespoon of pumpkin seeds;
* One tablespoon of sunflower seeds;
* One tablespoon of Flax seeds
* half a tablespoon of apricot kernels
* Two tablespoons of sweet almonds
* Two tablespoons of Macadamia nuts
* One tablespoon of seeds containing black grape raisins sulfur dioxide treated
* a teaspoon of cocoa powder can sometimes be added to the mixture.
Eat with 2-3 cups of freshly brewed green tea.

* One serving of 'methylation' adaptogens, such as half a cup of berries or half a teaspoon of rosemary or turmeric;
* Six ounces (170 g) of meat (mainly fish and sometimes poultry);
* Two servings of low glycemic fruit, such as berries, grapefruit and apples;
* Serving of probiotics and green powder supplements;
* Drink ~ eight cups of water.
=== PER WEEK ===
* Three servings of liver, each weighing three ounces;
* Five to ten eggs, ideally free range or organic.
=== LIFESTYLE CHANGES ===
* Exercise for 30 - 40 minutes five days per week at a moderate to high intensity, such as fast walk + quick run up the stairs to the 2nd or 3rd floor;
* Sleep for seven hours per night on average;
* Five-minute breathing exercises four times a day.
=== AVOID ===
* Eating anything between 7pm and 7am for a 12-hour fast;
* Any added sugar, candy, dairy, grains, legumes or beans.

== References ==
<references />

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

Menin

2023-06-05T08:29:55Z

Andrea: Added category

{| 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 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]]

Spermidine

2023-03-26T19:14:05Z

Andrea: Added content on new entry

Spermidine is a type of organic compound known as a polyamine. It is a small, positively charged molecule that is naturally found in all living cells, including human cells. Spermidine plays an important role in cell growth and division, as well as in the maintenance of cellular and organ functions. It has been shown to have anti-aging properties, as well as potential benefits for cardiovascular health and brain function.<ref>Ni YQ, Liu YS. New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases. Aging Dis. 2021 Dec 1;12(8):1948-1963. doi: 10.14336/AD.2021.0603.</ref>

Spermidine is found in a variety of foods, including cheese, soybeans, mushrooms, and whole grains. It is also available as a dietary supplement.

Spermidine has been shown to have several potential anti-aging effects. One of the main mechanisms by which spermidine may exert these effects is through its ability to stimulate [[autophagy]], a natural process by which cells break down and recycle old or damaged proteins and other cellular components.<ref>Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, Gross AS, Herbst V, Magnes C, Trausinger G, Narath S, Meinitzer A, Hu Z, Kirsch A, Eller K, Carmona-Gutierrez D, Büttner S, Pietrocola F, Knittelfelder O, Schrepfer E, Rockenfeller P, Simonini C, Rahn A, Horsch M, Moreth K, Beckers J, Fuchs H, Gailus-Durner V, Neff F, Janik D, Rathkolb B, Rozman J, de Angelis MH, Moustafa T, Haemmerle G, Mayr M, Willeit P, von Frieling-Salewsky M, Pieske B, Scorrano L, Pieber T, Pechlaner R, Willeit J, Sigrist SJ, Linke WA, Mühlfeld C, Sadoshima J, Dengjel J, Kiechl S, Kroemer G, Sedej S, Madeo F. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222.</ref> [[Autophagy]] is an important process for maintaining cellular health and preventing cellular damage involved in aging and disease.

Studies have shown that spermidine can increase lifespan in several animal models, including yeast, flies, and mice.<ref>Madeo F, Carmona-Gutierrez D, Kepp O, Kroemer G. Spermidine delays aging in humans. Aging (Albany NY). 2018 Aug 6;10(8):2209-2211. doi: 10.18632/aging.101517.</ref> In addition, spermidine has been shown to have several other potential anti-aging effects, including:

# '''Protection against oxidative stress:''' Spermidine has antioxidant properties that can help protect cells against oxidative stress, a process that can damage cells and contribute to aging and disease.
# '''Cardiovascular benefits''': Spermidine has been shown to have cardiovascular benefits, including the ability to lower blood pressure, reduce the risk of atherosclerosis, and improve heart function.
# '''Brain health''': Spermidine has been shown to improve cognitive function and protect against age-related cognitive decline.
# '''Skin health''': Spermidine has been shown to improve skin elasticity and reduce the appearance of wrinkles.

=== ITP spermidine study ===
The Intervention Testing Program (ITP) is a research program funded by the National Institute on Aging (NIA) that evaluates potential interventions for their ability to extend lifespan and improve healthspan in mice.<ref>https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/about-itp</ref> Similar efforts exist for the nematode animal model ''C''. ''elegans'', known as the ''C. elegans'' Intervention Testing Program (CITP).<ref>https://citp.squarespace.com</ref> Spermidine has been tested in the ITP, and the results of the study were published in 2020.

In the ITP study, mice were given spermidine in their drinking water at a concentration of 3 mM from the age of 12 months until the end of their natural lifespan. The study found that '''spermidine did not significantly extend lifespan''' in male or female mice, although there was a trend towards increased lifespan in male mice that did not reach statistical significance. However, spermidine did improve several measures of healthspan, including reducing the incidence of liver tumors and improving cardiac function in female mice.

While the ITP study did not find a significant extension of lifespan with spermidine, it did suggest that spermidine may have potential health benefits that could promote healthy aging. Further research is needed to fully understand the effects of spermidine on lifespan and healthspan in humans and animals.
[[Category:Main list]]
[[Category:Drugs]]

Mediterranean diet

2023-03-26T12:21:14Z

Andrea:

The '''Mediterranean diet''' (sometimes referred to as MedDiet) is a diet rich in seafood, 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 PMCID: PMC4663587 DOI: 10.3390/nu7115459</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: 10.1016/j.clnesp.2019.05.009</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: 10.1007/s00394-018-1757-3</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 PMCID: PMC9709195 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 PMCID: PMC9824214 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 PMCID: PMC6801699 DOI: 10.3390/ijms20194716</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 PMCID: PMC9782563 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 PMCID: PMC6273542 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: 10.1016/j.jtv.2021.03.003</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: 10.1038/s41430-020-00841-x</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 PMCID: PMC7464847 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 PMCID: PMC7823427 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: 10.1271/bbb.68.1706</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: 10.1021/acs.jnatprod.8b00366</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: 10.1024/0300-9831/a000574</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 PMCID: PMC9313440 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: 10.1016/j.ejphar.2017.03.042</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 PMCID: PMC9359828 DOI: 10.1155/2022/7275765</ref>

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

Mediterranean diet

2023-03-26T12:20:18Z

Andrea:

Anti-Müllerian hormone

2023-03-26T12:09:14Z

Andrea: Reviewed and expanded entry, added graph

'''Anti-Müllerian hormone''' (AMH), also known as Müllerian inhibiting substance, is a glycoprotein hormone that belongs to the transforming growth factor beta (TGF-β) superfamily of growth and differentiation factors secreted by immature Sertoli cells (after castration, AMH is no longer detected in serum) and by granulosa cells of growing ovarian follicles.<ref>Holt, R., Yahyavi, S. K., Kooij, I., Andreassen, C. H., Andersson, A. M., Juul, A., ... & Blomberg Jensen, M. (2023). Low serum anti-Müllerian hormone is associated with semen quality in infertile men and not influenced by vitamin D supplementation. BMC medicine, 21(1), 79.</ref>

In males, AMH induces the regression of fetal Müllerian ducts and represses androgen synthesis through receptors located on the Leydig cell membrane.<ref>Edelsztein, N. Y., Valeri, C., Lovaisa, M. M., Schteingart, H. F., & Rey, R. A. (2022). AMH regulation by steroids in the mammalian testis: Underlying mechanisms and clinical implications. Frontiers in Endocrinology, 13. PMID: 35712256 PMCID: PMC9195137 DOI: 10.3389/fendo.2022.906381</ref> In females, AMH inhibits primary follicle recruitment and sensitivity to [[Follicle-stimulating hormone (FSH)]]. AMH is synthesized as a homodimeric precursor consisting of two identical polypeptide chains, with a large N-terminal pro-region of 110-kDa and a small C-terminal mature domain of 25-kDa. AMH is subjected to post-translational proteolytic processing; the resulting N-terminal and C-terminal dimers remain associated in a non-covalent complex that is biologically active.<ref>Rajpert-De Meyts, E., Jørgensen, N., Græm, N., Müller, J., Cate, R. L., & Skakkebæk, N. E. (1999). Expression of anti-Mullerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. The Journal of Clinical Endocrinology & Metabolism, 84(10), 3836-3844. PMID: 10523039 DOI: 10.1210/jcem.84.10.6047</ref>

The measurement of circulating anti-Müllerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries.<ref>Durlinger, A., Visser, J., & Themmen, A. (2002). Regulation of ovarian function: the role of anti-Mullerian hormone. Reproduction. PMID: 12416998 DOI: 10.1530/rep.0.1240601</ref> AMH has been suggested to '''predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause''', and to indicate iatrogenic damage to the ovarian follicle reserve.<ref>Nelson, S. M., Davis, S. R., Kalantaridou, S., Lumsden, M. A., Panay, N., & Anderson, R. A. (2023). Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review. Human Reproduction Update.</ref><ref>Vijay AS, Gopireddy MMR, Fyzullah S, Gollapalli P, Maheswari M, Rani U, Rajesh S. Association Between AMH Levels and Fertility/Reproductive Outcomes Among Women Undergoing IVF: A Retrospective Study. J Reprod Infertil. 2022 Jan-Mar;23(1):54-60. doi: 10.18502/jri.v23i1.8453.</ref>

It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of '''polycystic ovary syndrome (PCOS)'''.<ref>Di Clemente, N., Racine, C., Pierre, A., & Taieb, J. (2021). Anti-Müllerian hormone in female reproduction. Endocrine reviews, 42(6), 753-782. PMID: 33851994 DOI: 10.1210/endrev/bnab012</ref> Anti-Mullerian hormone (AMH) is vital in the pathophysiological process of polycystic ovary syndrome (PCOS).<ref>Sivanandy, M. S., & Ha, S. K. (2023). The Role of Serum Anti-Mullerian Hormone Measurement in the Diagnosis of Polycystic Ovary Syndrome. Diagnostics, 13(5), 907.</ref> AMH levels also correlate positively with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels and negatively with body mass indices (BMI).<ref>Zhao, H., Zhou, D., Liu, C., & Zhang, L. (2023). The Relationship Between Insulin Resistance and Obesity and Serum Anti-Mullerian Hormone Level in Chinese Women with Polycystic Ovary Syndrome: A Retrospective, Single-Center Cohort Study. International Journal of Women's Health, 151-166. PMID: 36778752 PMCID: PMC9911904 DOI: 10.2147/IJWH.S393594</ref>
[[File:The relationship between AMH levels and age.jpg|thumb|The relationship between age and AMH levels, as a surrogate of ovarian reserve.]]
(AMH) is an ideal biomarker for the assessment of '''ovarian reserve'''. However, the ovarian reserve of premature ovarian insufficiency (POI) patients declines over time even under hormone therapy-treatment.<ref>Kuang, X., Wei, L., Huang, Y., Ji, M., Tang, Y., Wei, B., ... & Xu, H. (2023). Development of a digital anti-Müllerian hormone immunoassay: ultrasensitive, accurate and practical strategy for reduced ovarian reserve monitoring and assessment. Talanta, 253, 123970. PMID: 36206626 DOI: 10.1016/j.talanta.2022.123970</ref> AMH levels are correlated with age, with average AMH levels for 30 years old oscillating around 3.75ng/mL.<ref name=":0">Gunasheela D, Murali R, Appaneravanda LC, Gerstl B, Kumar A, Sengeetha N, Nayak H, Chandrikadevi PM. Age-Specific Distribution of Serum Anti-Mullerian Hormone and Antral Follicle Count in Indian Infertile Women. J Hum Reprod Sci. 2021 Oct-Dec;14(4):372-379. doi: 10.4103/jhrs.jhrs_65_21.</ref> Generall, higher than 1ng/mL of AMH values usually imply that a woman has a normal ovarian reserve.

However, '''egg quality and fertility,''' as studied by the probability of pregnancy, appears to be '''independent of AMH levels'''.<ref name=":0" /> Egg quality and fertility is associated with age but is independent of AMH levels, as only 1 egg (of sufficient quality) per month is required for successful fertilization and pregnancy. Therefore, a low amount of eggs released per month is not indicative of fertility, but it is a strong predictor of the remaining time that a woman might be fertile (and therefore menopause). Currently, no reliable test exists for measuring the quality of eggs in women, besides the success rate after IVF treatment or pregnancy itself.

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

File:The relationship between AMH levels and age.jpg

2023-03-26T11:56:50Z

Andrea:

The relationship between AMH levels and age

Transposons in aging

2023-03-26T11:41:29Z

Andrea: /* Transposons in laminopathic diseases */

[[File:Transposition mechanism.png|thumb|[Write caption later]]]
Transposons were first discovered in corn (maize) by Barbara McClintock during the decades of 1940-50s, for which she won the Nobel Prize of Physiology or Medicine in 1983.<ref>McClintock, B. (1931). The Order of the Genes C, Sh and Wx in Zea Mays with Reference to a Cytologically Known Point in the Chromosome. ''Proceedings Of The National Academy Of Sciences'', ''17''(8), 485-491. doi: 10.1073/pnas.17.8.485</ref><ref>McClintock, B. Mutable loci in maize. Carnegie Institution of Washington Yearbook '''50''', 174–181 (1951).[https://profiles.nlm.nih.gov/spotlight/ll]</ref><ref>Ravindran, S. (2012). Barbara McClintock and the discovery of jumping genes. ''Proceedings Of The National Academy Of Sciences'', ''109''(50), [tel:20198-20199 20198-20199]. doi: 10.1073/pnas.1219372109</ref>

Transposons, also called "jumping genes", are genes not fixed in location and are capable of changing position within the genome. Transposase enzymes bind to the end of transposon elements and catalyze their movement to other parts of the genome. Transposons have no known direct functions, but they can sometimes result in ''de novo'' mutations or changes in genome size. This can result in dangerous modifications to the genome, as they might lead to inactivation of important sequences, aberrant control of genes or tumourogenesis.

Retrotransposons, the most common type of transposons, proceeds via an RNA intermediate that can be targeted by RNA interference (RNAi) mechanisms, which then degrade these molecules to prevent their expression. Thus, RNAi is postulated to have evolved as a protective mechanism against retroviruses and endogenous retrotransposons in order to prevent their excessive activity.

==Types of transposons==
There are several types of transposons:

===DNA-only transposons===
This type of transposons, and unlike retrotransposons, are able to translocate from one chromosome to another. They code themselves for transposase enzymes, which facilitates the transferring process. DNA-only transposons do not transfer very frequently and it is unknown what process is responsible for their action.
===Retrotransposons===
These are the most common class of transposons in humans. They are sections of DNA inserted into the chromosome, but never jump out of it to other chromosomes. Retrotansposons transcribe their sequence of DNA into RNA copies and require the enzyme reverse transcriptase to then be converted into double-stranded DNA, which will then insert themselves elsewhere in the genome. They are named after retroviruses such as HIV, which also require reverse transcriptase to be inserted into the host chromosomes and replicate. Retrotransposons have had an important role in evolution by generating a large amount of the repetitive DNA sequences, and much of the non-coding "junk" DNA consists of this type of transposons.
==Transposons in aging==

=== Transposons as a cause of aging===
Transposons are hypothesized to be a cause of aging due to some of their properties.<ref name=":0">Murray, V. (1990). Are transposons a cause of ageing?. ''Mutation Research/Dnaging'', ''237''(2), 59-63. doi: 10.1016/0921-8734(90)90011-f</ref> This hypothesis is based on the observation that duplication of genes during transposition, the process in which a transposon element moves to another location in the genome, might lead to inactivation of essential genes or to cause aberrant function. Thus dysfunctional processes during aging have been proposed to arise as a consequence of the large amount of transposon elements present in "junk" DNA regions, and might potentially explain the properties of senescent cells.<ref name=":0" />

===Transposons in laminopathic diseases===
Laminopathies are a type of rare genetic disorders that arise from mutations in nuclear lamina genes, which are important to maintain fibrillar networks in the nucleus and to regulate events in chromatin organisation. A reduction in the expression of some lamin genes is also associated with aging and to a deregulation of transposable elements.<ref>Andrenacci, D., Cavaliere, V., & Lattanzi, G. (2020). The role of transposable elements activity in aging and their possible involvement in laminopathic diseases. ''Ageing Research Reviews'', ''57'', 100995. doi: 10.1016/j.arr.2019.100995</ref>

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

Dog Aging Project

2023-03-26T11:39:36Z

Andrea:

[[File:Logo for the Dog Aging Project.jpg|thumb|Logo for the Dog Aging Project]]
The Dog Aging Project is a scientific research study in the US focused on understanding the biological and environmental factors that contribute to healthy aging in dogs.<ref>https://dogagingproject.org</ref> It is led by researchers Dr Matt Kaeberlein and Dr Daniel Promislow, and is a collaborative effort from several institutions, including the University of Washington School of Medicine, Texas A&M University, and the University of California San Francisco.

The project aims to collect data from tens of thousands of dogs of various breeds, ages, and lifestyles, including both purebred and mixed-breed dogs. Through a variety of methods, such as genetic testing, blood samples, and surveys, researchers hope to identify the key factors that contribute to healthy aging in dogs, as well as the underlying molecular and cellular mechanisms.

The Dog Aging Project also seeks to promote the health and well-being of dogs by providing owners with personalized health information and recommendations for their pets based on the data collected. Ultimately, the project hopes to improve our understanding of aging not just in dogs, but in humans as well, as many of the same biological processes and pathways are conserved.

=== Rapamycin TRIAD study ===
[[Rapamycin]], a medication that affects both the immune system and metabolism, has been shown to consistently increase the lifespan and healthspan of mice and several other animal models.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref><ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref>

As part of the Dog Aging Project, the TRIAD study is an ongoing double-blinded, placebo-controlled clinical trial studying whether [[rapamycin]] administered mid-life (7 or above years old dogs) can increase the lifespan of companion dogs. Preliminary evidence suggests that rapamycin might prevent age-related decline in dogs and improve heart function.<ref>Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.</ref>

=== Main discoveries ===
As of 2023, the Dog Aging Project is an ongoing research study, and many of its findings are still being analyzed and interpreted. However, some preliminary results have been published in scientific journals and presented at conferences. Besides work on rapamycin, a few key discoveries so far are:

'''1. The impact of physical activity on aging-associated cognitive decline:'''

Data collected from 11,574 companion dogs based on owner surveys suggests that certain lifestyle factors, such as higher physical activity, is associated to better health outcomes and a significantly lower risk of cognitive decline in dogs.<ref>Bray EE, Raichlen DA, Forsyth KK, Promislow DEL, Alexander GE, MacLean EL; Dog Aging Project Consortium. Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project. Geroscience. 2023 Apr;45(2):645-661. doi: 10.1007/s11357-022-00655-8.</ref>

'''2. Health effects of [[intermittent fasting]] or time-restricted-feeding:'''

Cross-sectional data from 10,474 companion dogs and nine categories of health conditions (n = 24,238) controlling for sex, age, breed and other confounders, showed that once-daily feeding compared to ''ad libitum'' feeding is associated to better cognitive health and a lower risk of health issues (such as gastrointestinal, dental, kidney or liver disorders).<ref>Bray EE, Zheng Z, Tolbert MK, McCoy BM; Dog Aging Project Consortium; Kaeberlein M, Kerr KF. Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project. Geroscience. 2022 Jun;44(3):1779-1790. doi: 10.1007/s11357-022-00575-7.</ref>

'''3. The relationship between body size and inbreeding to lifespan:'''

Genome-wide single nucleotide polymorphisms (SNP) data from over 100 dog breeds showed that breeds with big body size tend to have a higher rate of inbreeding than small sized breeds. Larger breeds are associated to a shorter lifespan than smaller breeds, suggesting that inbreeding might contribute to decreased fitness and lifespan. When controlling for body size, purebred dogs lived 1.2 years shorter on average compared to mixed breed dogs, reflecting the benefit of breeding outcrosses in fitness and lifespan.<ref>Yordy J, Kraus C, Hayward JJ, White ME, Shannon LM, Creevy KE, Promislow DEL, Boyko AR. Body size, inbreeding, and lifespan in domestic dogs. Conserv Genet. 2020 Feb;21(1):137-148. doi: 10.1007/s10592-019-01240-x.</ref>

'''4. Amyloid beta accumulation and canine cognitive decline:'''

A study of biobanking specimens from companion dogs showed that age was associated to increased levels of amyloid beta (Aβ42 or Abeta-42) in several areas of brain tissue (prefrontal, temporal and hippocampus cortex) as well as in cerebrospinal fluid (CSF). Abundance of Aβ42 in all tissues except for CSF was correlated with scores for canine cognitive dysfunction. The relationship between Aβ42 accumulation and cognitive dysfunction prevailed when correcting for age, except for the temporal cortex, where Aβ42 accumulation was not associated with cognitive dysfunction independent of age. This data showcases that biobanking from companion dogs is a useful tool for studying [[Aging and neurodegeneration|age-related neurodegenerative conditions]].

Overall, the Dog Aging Project is still in its early stages, and many more discoveries are expected in the coming years as the study continues to collect and analyze data from tens of thousands of dogs.
[[Category:Main list]]
[[Category:Tools to study aging]]

Dog Aging Project

2023-03-26T11:36:48Z

Andrea: Added image and proper spacing

[[File:Logo for the Dog Aging Project.jpg|thumb|Logo for the Dog Aging Project]]
The Dog Aging Project is a scientific research study in the US focused on understanding the biological and environmental factors that contribute to healthy aging in dogs.<ref>https://dogagingproject.org</ref> It is led by researchers Dr Matt Kaeberlein and Dr Daniel Promislow, and is a collaborative effort from several institutions, including the University of Washington School of Medicine, Texas A&M University, and the University of California San Francisco.

The project aims to collect data from tens of thousands of dogs of various breeds, ages, and lifestyles, including both purebred and mixed-breed dogs. Through a variety of methods, such as genetic testing, blood samples, and surveys, researchers hope to identify the key factors that contribute to healthy aging in dogs, as well as the underlying molecular and cellular mechanisms.

The Dog Aging Project also seeks to promote the health and well-being of dogs by providing owners with personalized health information and recommendations for their pets based on the data collected. Ultimately, the project hopes to improve our understanding of aging not just in dogs, but in humans as well, as many of the same biological processes and pathways are conserved.

=== Rapamycin TRIAD study ===
[[Rapamycin]], a medication that affects both the immune system and metabolism, has been shown to consistently increase the lifespan and healthspan of mice and several other animal models.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref><ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref>

As part of the Dog Aging Project, the TRIAD study is an ongoing double-blinded, placebo-controlled clinical trial studying whether [[rapamycin]] administered mid-life (7 or above years old dogs) can increase the lifespan of companion dogs. Preliminary evidence suggests that rapamycin might prevent age-related decline in dogs and improve heart function.<ref>Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.</ref>

=== Main discoveries ===
As of 2023, the Dog Aging Project is an ongoing research study, and many of its findings are still being analyzed and interpreted. However, some preliminary results have been published in scientific journals and presented at conferences. Besides work on rapamycin, a few key discoveries so far are:

# The impact of physical activity on aging-associated cognitive decline. Data collected from 11,574 companion dogs based on owner surveys suggests that certain lifestyle factors, such as higher physical activity, is associated to better health outcomes and a significantly lower risk of cognitive decline in dogs.<ref>Bray EE, Raichlen DA, Forsyth KK, Promislow DEL, Alexander GE, MacLean EL; Dog Aging Project Consortium. Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project. Geroscience. 2023 Apr;45(2):645-661. doi: 10.1007/s11357-022-00655-8.</ref>
# Health effects of [[intermittent fasting]] or time-restricted-feeding. Cross-sectional data from 10,474 companion dogs and nine categories of health conditions (n = 24,238) controlling for sex, age, breed and other confounders, showed that once-daily feeding compared to ''ad libitum'' feeding is associated to better cognitive health and a lower risk of health issues (such as gastrointestinal, dental, kidney or liver disorders).<ref>Bray EE, Zheng Z, Tolbert MK, McCoy BM; Dog Aging Project Consortium; Kaeberlein M, Kerr KF. Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project. Geroscience. 2022 Jun;44(3):1779-1790. doi: 10.1007/s11357-022-00575-7.</ref>
# The relationship between body size and inbreeding to lifespan. Genome-wide single nucleotide polymorphisms (SNP) data from over 100 dog breeds showed that breeds with big body size tend to have a higher rate of inbreeding than small sized breeds. Larger breeds are associated to a shorter lifespan than smaller breeds, suggesting that inbreeding might contribute to decreased fitness and lifespan. When controlling for body size, purebred dogs lived 1.2 years shorter on average compared to mixed breed dogs, reflecting the benefit of breeding outcrosses in fitness and lifespan.<ref>Yordy J, Kraus C, Hayward JJ, White ME, Shannon LM, Creevy KE, Promislow DEL, Boyko AR. Body size, inbreeding, and lifespan in domestic dogs. Conserv Genet. 2020 Feb;21(1):137-148. doi: 10.1007/s10592-019-01240-x.</ref>
# Amyloid beta accumulation and canine cognitive decline. A study of biobanking specimens from companion dogs showed that age was associated to increased levels of amyloid beta (Aβ42 or Abeta-42) in several areas of brain tissue (prefrontal, temporal and hippocampus cortex) as well as in cerebrospinal fluid (CSF). Abundance of Aβ42 in all tissues except for CSF was correlated with scores for canine cognitive dysfunction. The relationship between Aβ42 accumulation and cognitive dysfunction prevailed when correcting for age, except for the temporal cortex, where Aβ42 accumulation was not associated with cognitive dysfunction independent of age. This data showcases that biobanking from companion dogs is a useful tool for studying [[Aging and neurodegeneration|age-related neurodegenerative conditions]].

Overall, the Dog Aging Project is still in its early stages, and many more discoveries are expected in the coming years as the study continues to collect and analyze data from tens of thousands of dogs.
[[Category:Main list]]
[[Category:Tools to study aging]]

File:Logo for the Dog Aging Project.jpg

2023-03-26T11:34:58Z

Andrea:

Logo for the Dog Aging Project

Dog Aging Project

2023-03-26T11:33:20Z

Andrea: Added new entry and content

The Dog Aging Project is a scientific research study focused on understanding the biological and environmental factors that contribute to healthy aging in dogs.<ref>https://dogagingproject.org</ref> It is led by the researchers Dr Matt Kaeberlein and Dr Daniel Promislow, and is a collaborative effort from several institutions, including the University of Washington School of Medicine, Texas A&M University, and the University of California San Francisco.

The project aims to collect data from tens of thousands of dogs of various breeds, ages, and lifestyles, including both purebred and mixed-breed dogs. Through a variety of methods, such as genetic testing, blood samples, and surveys, researchers hope to identify the key factors that contribute to healthy aging in dogs, as well as the underlying molecular and cellular mechanisms.

The Dog Aging Project also seeks to promote the health and well-being of dogs by providing owners with personalized health information and recommendations for their pets based on the data collected. Ultimately, the project hopes to improve our understanding of aging not just in dogs, but in humans as well, as many of the same biological processes and pathways are conserved.

=== Rapamycin TRIAD study ===
[[Rapamycin]], a medication that affects both the immune system and metabolism, has been shown to consistently increase the lifespan and healthspan of mice and several other animal models.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref><ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref>

As part of the Dog Aging Project, the TRIAD study is an ongoing double-blinded, placebo-controlled clinical trial studying whether [[rapamycin]] administered mid-life (7 or above years old dogs) can increase the lifespan of companion dogs. Preliminary evidence suggests that rapamycin might prevent age-related decline in dogs and improve heart function.<ref>Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.</ref>

=== Main discoveries ===
As of 2023, the Dog Aging Project is an ongoing research study, and many of its findings are still being analyzed and interpreted. However, some preliminary results have been published in scientific journals and presented at conferences. Besides work on rapamycin, a few key discoveries so far are:

# The impact of physical activity on aging-associated cognitive decline. Data collected from 11,574 companion dogs based on owner surveys suggests that certain lifestyle factors, such as higher physical activity, is associated to better health outcomes and a significantly lower risk of cognitive decline in dogs.<ref>Bray EE, Raichlen DA, Forsyth KK, Promislow DEL, Alexander GE, MacLean EL; Dog Aging Project Consortium. Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project. Geroscience. 2023 Apr;45(2):645-661. doi: 10.1007/s11357-022-00655-8.</ref>
# Health effects of [[intermittent fasting]] or time-restricted-feeding. Cross-sectional data from 10,474 companion dogs and nine categories of health conditions (n = 24,238) controlling for sex, age, breed and other confounders, showed that once-daily feeding compared to ''ad libitum'' feeding is associated to better cognitive health and a lower risk of health issues (such as gastrointestinal, dental, kidney or liver disorders).<ref>Bray EE, Zheng Z, Tolbert MK, McCoy BM; Dog Aging Project Consortium; Kaeberlein M, Kerr KF. Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project. Geroscience. 2022 Jun;44(3):1779-1790. doi: 10.1007/s11357-022-00575-7.</ref>
# The relationship between body size and inbreeding to lifespan. Genome-wide single nucleotide polymorphisms (SNP) data from over 100 dog breeds showed that breeds with big body size tend to have a higher rate of inbreeding than small sized breeds. Larger breeds are associated to a shorter lifespan than smaller breeds, suggesting that inbreeding might contribute to decreased fitness and lifespan. When controlling for body size, purebred dogs lived 1.2 years shorter on average compared to mixed breed dogs, reflecting the benefit of breeding outcrosses in fitness and lifespan.<ref>Yordy J, Kraus C, Hayward JJ, White ME, Shannon LM, Creevy KE, Promislow DEL, Boyko AR. Body size, inbreeding, and lifespan in domestic dogs. Conserv Genet. 2020 Feb;21(1):137-148. doi: 10.1007/s10592-019-01240-x.</ref>
# Amyloid beta accumulation and canine cognitive decline. A study of biobanking specimens from companion dogs showed that age was associated to increased levels of amyloid beta (Aβ42 or Abeta-42) in several areas of brain tissue (prefrontal, temporal and hippocampus cortex) as well as in cerebrospinal fluid (CSF). Abundance of Aβ42 in all tissues except for CSF was correlated with scores for canine cognitive dysfunction. The relationship between Aβ42 accumulation and cognitive dysfunction prevailed when correcting for age, except for the temporal cortex, where Aβ42 accumulation was not associated with cognitive dysfunction independent of age. This data showcases that biobanking from companion dogs is a useful tool for studying [[Aging and neurodegeneration|age-related neurodegenerative conditions]].

Overall, the Dog Aging Project is still in its early stages, and many more discoveries are expected in the coming years as the study continues to collect and analyze data from tens of thousands of dogs.
[[Category:Main list]]
[[Category:Tools to study aging]]

Organoid-based regenerative medicine

2023-03-14T20:57:26Z

Andrea:

'''Organoid-based regenerative medicine''' is a promising new direction in transplantology, which will allow in the near future to replace damaged or worn-out organs and tissues of patients with young transplants grown from their own rejuvenated cells.

== Tissue 3D self-organization in vitro ==
An organoid is a self-organized 3D tissue that is typically derived from stem cells (pluripotent, fetal or adult), and which mimics the key functional, structural and biological complexity of an organ. Cells comprising organoids can be derived from induced pluripotent stem cells (iPSCs) or tissue-derived cells (TDCs), including normal stem/progenitor cells, differentiated cells and cancer cells. Recent studies on the directed differentiation of human pluripotent stem cells report tissue self-organization in vitro such that multiple component cell types arise in concert and arrange with respect to each, thereby recapitulating the morphogenetic events typical for that organ. Such self-organization has generated pituitary, optic cup, liver, brain, intestine, stomach and kidney.<ref>Zhao, Z., Chen, X., Dowbaj, A. M., Sljukic, A., Bratlie, K., Lin, L., ... & Yu, H. (2022). Organoids. Nature Reviews Methods Primers, 2(1), 94. https://doi.org/10.1038/s43586-022-00174-y</ref>

=== Organ-supply imbalance ===
The outstanding progress in all types of transplantation during recent years has dramatically increased graft and patient survival. But one of the major limiting factors for further developing organ donation and transplant programs is a worldwide organ shortage. Globally, there is a large gap between the numbers of potential recipients on waiting lists and the available organs for transplant.<ref>Lewis, A., Koukoura, A., Tsianos, G. I., Gargavanis, A. A., Nielsen, A. A., & Vassiliadis, E. (2021). Organ donation in the US and Europe: The supply vs demand imbalance. Transplantation Reviews, 35(2), 100585. PMID: 33071161 DOI: 10.1016/j.trre.2020.100585</ref>

Stem cell-related technologies promise to generate organs from patients’ cells. Adult cells can be reprogrammed into induced pluripotent stem cells (iPSC). These constitute an extensive source of a starting material which is able to differentiate into any tissue. Moreover, being autologous, they bypass the problem of incompatibility and rejection of the graft by the host immune system. To this end, iPSCs have already been used successfully in animal models of diabetes, liver injury, myocardial infarction and Parkinson’s disease.

Organoids that can be transplanted into damaged tissues to induce regeneration are currently being actively studied due to their fundamental treatment effects for various disease.<ref>Choi, W. H., Bae, D. H., & Yoo, J. (2023). Current status and prospects of organoid-based regenerative medicine. BMB reports, 56(1), 10-14. PMID: 36523211 PMCID: PMC9887105 DOI: 10.5483/BMBRep.2022-0195</ref><ref>Tang, X. Y., Wu, S., Wang, D., Chu, C., Hong, Y., Tao, M., ... & Liu, Y. (2022). Human organoids in basic research and clinical applications. Signal Transduction and Targeted Therapy, 7(1), 168. PMID: 35610212 PMCID: PMC9127490 DOI: 10.1038/s41392-022-01024-9</ref>

=== Liver Organoids ===
Organoids of murine intestines, livers and pancreas have been successfully transplanted into mice with restoration of organ function.<ref>Weng, Y., Han, S., Sekyi, M. T., Su, T., Mattis, A. N., & Chang, T. T. (2023). Self-Assembled Matrigel-Free iPSC-Derived Liver Organoids Demonstrate Wide-Ranging Highly Differentiated Liver Functions. Stem Cells, 41(2), 126-139. PMID: 36573434 PMCID: PMC9982071 DOI: 10.1093/stmcls/sxac090</ref><ref>Messina, A., Luce, E., Benzoubir, N., Pasqua, M., Pereira, U., Humbert, L., ... & Dubart-Kupperschmitt, A. (2022). Evidence of adult features and functions of hepatocytes differentiated from human induced pluripotent stem cells and self-organized as organoids. Cells, 11(3), 537. PMID: 35159346 PMCID: PMC8834365 DOI: 10.3390/cells11030537</ref>
The company LyGenesis, hopes to save people with devastating liver diseases who are not eligible for transplants. Their approach is to inject liver cells from a donor into the lymph nodes of sick recipients, which can give rise to entirely new miniature organs. These mini livers should help compensate for an existing diseased one. The approach appears to work in mice, pigs, and dogs. Now it's time to check if it works in people.

=== Cardiac organoids ===
PSC-derived 3D cardiac organoids have been shown to be beneficial for drug toxicity screening and disease modeling. Although, there are remaining limitations that need to be addressed prior to clinical translation and potentially achieving cardiac regeneration. First, the rigor of stem cell reprogramming needs to ensure there is no clonal or somatic genetic variation in the starting material, as well as the standardization of differentiation protocols that yield highly specific and a large number of purified cell populations at the manufacturing level. To date, cardiac organoids do not fully recapitulate native human heart tissue as they lack perfusable vessels, adult-like chamber specificity, and the cardiac conduction system.<ref>Martin M., Gähwiler E.K.N., Generali M., Hoerstrup S.P., Emmert M.Y. (2023). Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration. International Journal of Molecular Sciences. 24(6):5188. https://doi.org/10.3390/ijms24065188</ref>

=== Kidney organoids ===
Three-dimensional (3D) kidney organoid models have been developed that can be grown either from induced pluripotent stem cells (iPSCs), first described in 2014, or from adult stem/progenitor cells (ASPCs).
<ref>Shi, M., McCracken, K. W., Patel, A. B., Zhang, W., Ester, L., Valerius, M. T., & Bonventre, J. V. (2023). Human ureteric bud organoids recapitulate branching morphogenesis and differentiate into functional collecting duct cell types. Nature Biotechnology, 41(2), 252-261. PMID: 36038632 PMCID: PMC9957856 DOI: 10.1038/s41587-022-01429-5</ref>

== References ==
<references />

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

Isomyosamine

2023-03-09T10:29:44Z

Andrea:

[[File:Isomyosamine.jpg|thumb|
{| class="wikitable"
! Isomyosamine
|-
! 3-(3,4-DIHYDRO-2H-PYRROL-2-YL)PYRIDINE
|-
| Molecular Formula C<sub>9</sub>H<sub>10</sub>N<sub>2</sub>
|-
| Molecular Weight 146.19
|-
| CAS 53844-46-5
|-
| PUBCHEM [https://pubchem.ncbi.nlm.nih.gov/compound/11286546 11286546]
|-
| brand name '''MYMD-1®'''
|} ]]
'''Isomyosamine''', an isomer of myosmine, known by the brand name '''MYMD-1®''', is a synthetic alkaloid derived from tobacco plant with potential lifespan extending properties.<ref name="mTOR" />

Isomyosamine is capable of suppressing production of tumor necrosis factor alpha (TNF-α): an immune cell signalling protein and inflammatory cytokine responsible for inducing and maintaining the inflammatory process.<ref>Kaplin, B. A. (2021). [https://www.technologynetworks.com/drug-discovery/blog/eliciting-the-hormetic-effect-the-importance-of-plant-alkaloids-for-treatment-of-inflammation-345557 Eliciting the Hormetic Effect: The Importance of Plant Alkaloids for Treatment of Inflammation.] Industry Insight Published: February 15, 2021</ref><ref name="MYMD">Di Dalmazi, G., Chalan, P., & Caturegli, P. (2019). MYMD-1, a novel immunometabolic regulator, ameliorates autoimmune thyroiditis via suppression of Th1 responses and TNF-α release. The Journal of Immunology, 202(5), 1350-1362. PMID:[https://pubmed.ncbi.nlm.nih.gov/30674573 30674573] DOI:[https://doi.org/10.4049/jimmunol.1801238 10.4049/jimmunol.1801238]</ref> TNF-α is located upstream of a cascade of molecular signals that induces inflammation, promotes insulin resistance and helps activate the process of aging.<ref>Sethi, J. K., & Hotamisligil, G. S. (2021). Metabolic Messengers: tumour necrosis factor. Nature metabolism, 3(10), 1302-1312. PMID:[https://pubmed.ncbi.nlm.nih.gov/34650277 34650277] DOI: 10.1038/s42255-021-00470-z</ref>

MyMD-1 targets the root causes of inflammation and regulates the immuno-metabolic system through the modulation of numerous pro-inflammatory cytokines, including TNF-α, IL-6 and IL-17A.<ref name="MYMD" /><ref name="encephalomyelitis">Glenn, J. D., Pantoja, I. M., Caturegli, P., & Whartenby, K. A. (2020). MYMD-1, a novel alkaloid compound, ameliorates the course of experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 339, 577115. PMID:[https://pubmed.ncbi.nlm.nih.gov/31778849 31778849] DOI:[https://doi.org/10.1016/j.jneuroim.2019.577115 10.1016/j.jneuroim.2019.577115]</ref> Moreover, '''isomyosamine exhibits similar biological activities to mTOR inhibitors''' [[rapamycin]], everolimus and sirolimus owing to their largely overlapping mechanisms of action.<ref name="mTOR">Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. PMID:[https://pubmed.ncbi.nlm.nih.gov/35914953/ 35914953] DOI:[https://doi.org/10.1093/gerona/glac142 10.1093/gerona/glac142]</ref> '''Furthermore, MyMD-1 markedly outperformed [[rapamycin]] in a mouse longevity study'''.<ref name="mTOR" />

[[Rapamycin]] is the gold standard longevity drug, given its consistency and reproducibility in extending lifespan and prolonging healthspan across a wide spectrum of animal models.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref> The non-inferiority study of MyMD-1 when compared to rapamycin, make it an attractive alternative, especially if MyMD-1 superiority proves to be reproducible, as claimed by the study in C57BL/6 mice.<ref name="mTOR" /> For now, it is still premature to conclude MyMD-1 is superior to rapamycin and further studies will need to replicate these findings, potentially via the NIH Aging Interventions Testing Program (ITP).

Apart from longevity, isomyosamine holds significant therapeutic potential in many autoimmune conditions such as autoimmune thyroiditis,<ref name="MYMD" /> multiple sclerosis,<ref name="Capsules">Brager, J., Chapman, C., Dunn, L., & Kaplin, A. (2023). A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects. Drug Research, 73(02), 95-104. PMID: 36368677 PMC9902179 DOI: 10.1055/a-1962-6834</ref><ref>[https://nndc.org/wp-content/uploads/2021/09/Basic-Science-Kumar-email.pdf MyMD-1: Potential treatment for s Multiple Sclerosis Depression]</ref> autoimmune encephalomyelitis,<ref name="encephalomyelitis" /> and rheumatoid arthritis.<ref name="Capsules" /><ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315223006264/ex99-1.htm MyMD Pharmaceuticals® Announces Upcoming Presentation of Preclinical Rheumatoid Arthritis Data for Oral TNF-α Inhibitor MYMD-1® at the Society of Toxicology 2023 Annual Meeting on March 20, 2023, at 9:00 AM CT]</ref>

The ease of Isomyosamine oral dosing is a groundbreaking differentiator compared to currently available TNF-α blockers, all of which require delivery by injection or infusion, whereas MyMD-1 is available orally as capsules.<ref name="Capsules" /> MyMD-1 is not detrimental to cell viability and is a small molecule that can cross the blood-brain barrier, potentially enabling it to treat brain-related disease. Commercial efforts are currently evaluating the effectiveness of MyMD-1 in Phase II studies for treating sarcopenia/[[frailty]]<ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315222020346/ex99-1.htm The Phase 2 multi-center double-blind, placebo controlled, randomized study (NCT05283486) investigates the efficacy, tolerability and pharmacokinetics of MYMD-1 in the treatment of chronic inflammation associated with sarcopenia/frailty in participants aged 65 years or older.]</ref> as a result of the aging process, and other early-stage clinical trials are evaluating its use for rheumatoid arthritis (RA), with the potential to expand into other applications.

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

MyMD1

2023-03-09T10:27:52Z

Andrea: Changed redirect target from Https://en.longevitywiki.org/wiki/Isomyosamine to Isomyosamine

#REDIRECT [[Isomyosamine]]
[[Category:Drugs]]
[[Category:Main list]]

MyMD1

2023-03-09T10:26:33Z

Andrea: Entry to redirect

#REDIRECT [[Https://en.longevitywiki.org/wiki/Isomyosamine]]
[[Category:Drugs]]
[[Category:Main list]]

Isomyosamine

2023-03-09T10:25:33Z

Andrea:

{{DISPLAYTITLE:Isomyosamine (MyMD1)}}
[[File:Isomyosamine.jpg|thumb|
{| class="wikitable"
! Isomyosamine
|-
! 3-(3,4-DIHYDRO-2H-PYRROL-2-YL)PYRIDINE
|-
| Molecular Formula C<sub>9</sub>H<sub>10</sub>N<sub>2</sub>
|-
| Molecular Weight 146.19
|-
| CAS 53844-46-5
|-
| PUBCHEM [https://pubchem.ncbi.nlm.nih.gov/compound/11286546 11286546]
|-
| brand name '''MYMD-1®'''
|} ]]
'''Isomyosamine''', an isomer of myosmine, known by the brand name '''MYMD-1®''', is a synthetic alkaloid derived from tobacco plant with potential lifespan extending properties.<ref name="mTOR" />

Isomyosamine is capable of suppressing production of tumor necrosis factor alpha (TNF-α): an immune cell signalling protein and inflammatory cytokine responsible for inducing and maintaining the inflammatory process.<ref>Kaplin, B. A. (2021). [https://www.technologynetworks.com/drug-discovery/blog/eliciting-the-hormetic-effect-the-importance-of-plant-alkaloids-for-treatment-of-inflammation-345557 Eliciting the Hormetic Effect: The Importance of Plant Alkaloids for Treatment of Inflammation.] Industry Insight Published: February 15, 2021</ref><ref name="MYMD">Di Dalmazi, G., Chalan, P., & Caturegli, P. (2019). MYMD-1, a novel immunometabolic regulator, ameliorates autoimmune thyroiditis via suppression of Th1 responses and TNF-α release. The Journal of Immunology, 202(5), 1350-1362. PMID:[https://pubmed.ncbi.nlm.nih.gov/30674573 30674573] DOI:[https://doi.org/10.4049/jimmunol.1801238 10.4049/jimmunol.1801238]</ref> TNF-α is located upstream of a cascade of molecular signals that induces inflammation, promotes insulin resistance and helps activate the process of aging.<ref>Sethi, J. K., & Hotamisligil, G. S. (2021). Metabolic Messengers: tumour necrosis factor. Nature metabolism, 3(10), 1302-1312. PMID:[https://pubmed.ncbi.nlm.nih.gov/34650277 34650277] DOI: 10.1038/s42255-021-00470-z</ref>

MyMD-1 targets the root causes of inflammation and regulates the immuno-metabolic system through the modulation of numerous pro-inflammatory cytokines, including TNF-α, IL-6 and IL-17A.<ref name="MYMD" /><ref name="encephalomyelitis">Glenn, J. D., Pantoja, I. M., Caturegli, P., & Whartenby, K. A. (2020). MYMD-1, a novel alkaloid compound, ameliorates the course of experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 339, 577115. PMID:[https://pubmed.ncbi.nlm.nih.gov/31778849 31778849] DOI:[https://doi.org/10.1016/j.jneuroim.2019.577115 10.1016/j.jneuroim.2019.577115]</ref> Moreover, '''isomyosamine exhibits similar biological activities to mTOR inhibitors''' [[rapamycin]], everolimus and sirolimus owing to their largely overlapping mechanisms of action.<ref name="mTOR">Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. PMID:[https://pubmed.ncbi.nlm.nih.gov/35914953/ 35914953] DOI:[https://doi.org/10.1093/gerona/glac142 10.1093/gerona/glac142]</ref> '''Furthermore, MyMD-1 markedly outperformed [[rapamycin]] in a mouse longevity study'''.<ref name="mTOR" />

[[Rapamycin]] is the gold standard longevity drug, given its consistency and reproducibility in extending lifespan and prolonging healthspan across a wide spectrum of animal models.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref> The non-inferiority study of MyMD-1 when compared to rapamycin, make it an attractive alternative, especially if MyMD-1 superiority proves to be reproducible, as claimed by the study in C57BL/6 mice.<ref name="mTOR" /> For now, it is still premature to conclude MyMD-1 is superior to rapamycin and further studies will need to replicate these findings, potentially via the NIH Aging Interventions Testing Program (ITP).

Apart from longevity, isomyosamine holds significant therapeutic potential in many autoimmune conditions such as autoimmune thyroiditis,<ref name="MYMD" /> multiple sclerosis,<ref name="Capsules">Brager, J., Chapman, C., Dunn, L., & Kaplin, A. (2023). A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects. Drug Research, 73(02), 95-104. PMID: 36368677 PMC9902179 DOI: 10.1055/a-1962-6834</ref><ref>[https://nndc.org/wp-content/uploads/2021/09/Basic-Science-Kumar-email.pdf MyMD-1: Potential treatment for s Multiple Sclerosis Depression]</ref> autoimmune encephalomyelitis,<ref name="encephalomyelitis" /> and rheumatoid arthritis.<ref name="Capsules" /><ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315223006264/ex99-1.htm MyMD Pharmaceuticals® Announces Upcoming Presentation of Preclinical Rheumatoid Arthritis Data for Oral TNF-α Inhibitor MYMD-1® at the Society of Toxicology 2023 Annual Meeting on March 20, 2023, at 9:00 AM CT]</ref>

The ease of Isomyosamine oral dosing is a groundbreaking differentiator compared to currently available TNF-α blockers, all of which require delivery by injection or infusion, whereas MyMD-1 is available orally as capsules.<ref name="Capsules" /> MyMD-1 is not detrimental to cell viability and is a small molecule that can cross the blood-brain barrier, potentially enabling it to treat brain-related disease. Commercial efforts are currently evaluating the effectiveness of MyMD-1 in Phase II studies for treating sarcopenia/[[frailty]]<ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315222020346/ex99-1.htm The Phase 2 multi-center double-blind, placebo controlled, randomized study (NCT05283486) investigates the efficacy, tolerability and pharmacokinetics of MYMD-1 in the treatment of chronic inflammation associated with sarcopenia/frailty in participants aged 65 years or older.]</ref> as a result of the aging process, and other early-stage clinical trials are evaluating its use for rheumatoid arthritis (RA), with the potential to expand into other applications.

== References ==
<references />
[[Category:Drugs]]
[[Category:Main list]]
{{DEFAULTSORT:Isomyosamine (MyMD1)}}

Isomyosamine

2023-03-09T10:18:56Z

Andrea:

[[File:Isomyosamine.jpg|thumb|
{| class="wikitable"
! Isomyosamine
|-
! 3-(3,4-DIHYDRO-2H-PYRROL-2-YL)PYRIDINE
|-
| Molecular Formula C<sub>9</sub>H<sub>10</sub>N<sub>2</sub>
|-
| Molecular Weight 146.19
|-
| CAS 53844-46-5
|-
| PUBCHEM [https://pubchem.ncbi.nlm.nih.gov/compound/11286546 11286546]
|-
| brand name '''MYMD-1®'''
|} ]]
'''Isomyosamine''', an isomer of myosmine, known by the brand name '''MYMD-1®''', is a synthetic alkaloid derived from tobacco plant with potential lifespan extending properties.<ref name="mTOR" />

Isomyosamine is capable of suppressing production of tumor necrosis factor alpha (TNF-α): an immune cell signalling protein and inflammatory cytokine responsible for inducing and maintaining the inflammatory process.<ref>Kaplin, B. A. (2021). [https://www.technologynetworks.com/drug-discovery/blog/eliciting-the-hormetic-effect-the-importance-of-plant-alkaloids-for-treatment-of-inflammation-345557 Eliciting the Hormetic Effect: The Importance of Plant Alkaloids for Treatment of Inflammation.] Industry Insight Published: February 15, 2021</ref><ref name="MYMD">Di Dalmazi, G., Chalan, P., & Caturegli, P. (2019). MYMD-1, a novel immunometabolic regulator, ameliorates autoimmune thyroiditis via suppression of Th1 responses and TNF-α release. The Journal of Immunology, 202(5), 1350-1362. PMID:[https://pubmed.ncbi.nlm.nih.gov/30674573 30674573] DOI:[https://doi.org/10.4049/jimmunol.1801238 10.4049/jimmunol.1801238]</ref> TNF-α is located upstream of a cascade of molecular signals that induces inflammation, promotes insulin resistance and helps activate the process of aging.<ref>Sethi, J. K., & Hotamisligil, G. S. (2021). Metabolic Messengers: tumour necrosis factor. Nature metabolism, 3(10), 1302-1312. PMID:[https://pubmed.ncbi.nlm.nih.gov/34650277 34650277] DOI: 10.1038/s42255-021-00470-z</ref>

MYMD-1 targets the root causes of inflammation and regulates the immuno-metabolic system through the modulation of numerous pro-inflammatory cytokines, including TNF-α, IL-6 and IL-17A.<ref name="MYMD" /><ref name="encephalomyelitis">Glenn, J. D., Pantoja, I. M., Caturegli, P., & Whartenby, K. A. (2020). MYMD-1, a novel alkaloid compound, ameliorates the course of experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 339, 577115. PMID:[https://pubmed.ncbi.nlm.nih.gov/31778849 31778849] DOI:[https://doi.org/10.1016/j.jneuroim.2019.577115 10.1016/j.jneuroim.2019.577115]</ref> Moreover, '''isomyosamine exhibits similar biological activities to mTOR inhibitors''' [[rapamycin]], everolimus and sirolimus owing to their largely overlapping mechanisms of action.<ref name="mTOR">Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. PMID:[https://pubmed.ncbi.nlm.nih.gov/35914953/ 35914953] DOI:[https://doi.org/10.1093/gerona/glac142 10.1093/gerona/glac142]</ref> '''Furthermore, MYMD-1 markedly outperformed [[rapamycin]] in a mouse longevity study'''.<ref name="mTOR" />

[[Rapamycin]] is the gold standard longevity drug, given its consistency and reproducibility in extending lifespan and prolonging healthspan across a wide spectrum of animal models.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref> The non-inferiority study of MyMD-1 when compared to rapamycin, make it an attractive alternative, especially if MyMD-1 superiority proves to be reproducible, as claimed by the study in C57BL/6 mice.<ref name="mTOR" /> For now, it is still premature to conclude MyMD-1 is superior to rapamycin and further studies will need to replicate these findings, potentially via the NIH Aging Interventions Testing Program (ITP).

Apart from longevity, isomyosamine holds significant therapeutic potential in many autoimmune conditions such as autoimmune thyroiditis,<ref name="MYMD" /> multiple sclerosis,<ref name="Capsules">Brager, J., Chapman, C., Dunn, L., & Kaplin, A. (2023). A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects. Drug Research, 73(02), 95-104. PMID: 36368677 PMC9902179 DOI: 10.1055/a-1962-6834</ref><ref>[https://nndc.org/wp-content/uploads/2021/09/Basic-Science-Kumar-email.pdf MyMD-1: Potential treatment for s Multiple Sclerosis Depression]</ref> autoimmune encephalomyelitis,<ref name="encephalomyelitis" /> and rheumatoid arthritis.<ref name="Capsules" /><ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315223006264/ex99-1.htm MyMD Pharmaceuticals® Announces Upcoming Presentation of Preclinical Rheumatoid Arthritis Data for Oral TNF-α Inhibitor MYMD-1® at the Society of Toxicology 2023 Annual Meeting on March 20, 2023, at 9:00 AM CT]</ref>

The ease of Isomyosamine oral dosing is a groundbreaking differentiator compared to currently available TNF-α blockers, all of which require delivery by injection or infusion, whereas MyMD-1 is available orally as capsules.<ref name="Capsules" /> MYMD-1 is not detrimental to cell viability and is a small molecule that can cross the blood-brain barrier, potentially enabling it to treat brain-related disease. Commercial efforts are currently evaluating the effectiveness of MYMD-1 in Phase II studies for treating sarcopenia/[[frailty]]<ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315222020346/ex99-1.htm The Phase 2 multi-center double-blind, placebo controlled, randomized study (NCT05283486) investigates the efficacy, tolerability and pharmacokinetics of MYMD-1 in the treatment of chronic inflammation associated with sarcopenia/frailty in participants aged 65 years or older.]</ref> as a result of the aging process, and other early-stage clinical trials are evaluating its use for rheumatoid arthritis (RA), with the potential to expand into other applications.

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

Isomyosamine

2023-03-09T10:08:44Z

Andrea: Reviewed entry

[[File:Isomyosamine.jpg|thumb|
{| class="wikitable"
! Isomyosamine
|-
! 3-(3,4-DIHYDRO-2H-PYRROL-2-YL)PYRIDINE
|-
| Molecular Formula C<sub>9</sub>H<sub>10</sub>N<sub>2</sub>
|-
| Molecular Weight 146.19
|-
| CAS 53844-46-5
|-
| PUBCHEM [https://pubchem.ncbi.nlm.nih.gov/compound/11286546 11286546]
|-
| brand name '''MYMD-1®'''
|} ]]
'''Isomyosamine''', an isomer of myosmine, known by the brand name '''MYMD-1®''', is a synthetic alkaloid derived from tobacco plant with potential lifespan extending properties.<ref name="mTOR" />

Isomyosamine is capable of suppressing production of tumor necrosis factor alpha (TNF-α): an immune cell signalling protein and inflammatory cytokine responsible for inducing and maintaining the inflammatory process.<ref>Kaplin, B. A. (2021). [https://www.technologynetworks.com/drug-discovery/blog/eliciting-the-hormetic-effect-the-importance-of-plant-alkaloids-for-treatment-of-inflammation-345557 Eliciting the Hormetic Effect: The Importance of Plant Alkaloids for Treatment of Inflammation.] Industry Insight Published: February 15, 2021</ref><ref name="MYMD">Di Dalmazi, G., Chalan, P., & Caturegli, P. (2019). MYMD-1, a novel immunometabolic regulator, ameliorates autoimmune thyroiditis via suppression of Th1 responses and TNF-α release. The Journal of Immunology, 202(5), 1350-1362. PMID:[https://pubmed.ncbi.nlm.nih.gov/30674573 30674573] DOI:[https://doi.org/10.4049/jimmunol.1801238 10.4049/jimmunol.1801238]</ref> TNF-α is located upstream of a cascade of molecular signals that induces inflammation, promotes insulin resistance and helps activate the process of aging.<ref>Sethi, J. K., & Hotamisligil, G. S. (2021). Metabolic Messengers: tumour necrosis factor. Nature metabolism, 3(10), 1302-1312. PMID:[https://pubmed.ncbi.nlm.nih.gov/34650277 34650277] DOI: 10.1038/s42255-021-00470-z</ref>

MYMD-1® targets the root causes of inflammation and regulates the immuno-metabolic system through the modulation of numerous pro-inflammatory cytokines, including TNF-α, IL-6 and IL-17A.<ref name="MYMD" /><ref name="encephalomyelitis">Glenn, J. D., Pantoja, I. M., Caturegli, P., & Whartenby, K. A. (2020). MYMD-1, a novel alkaloid compound, ameliorates the course of experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 339, 577115. PMID:[https://pubmed.ncbi.nlm.nih.gov/31778849 31778849] DOI:[https://doi.org/10.1016/j.jneuroim.2019.577115 10.1016/j.jneuroim.2019.577115]</ref> Moreover, '''isomyosamine exhibits similar biological activities to mTOR inhibitors''' [[rapamycin]], everolimus and sirolimus owing to their largely overlapping mechanisms of action.<ref name="mTOR">Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. PMID:[https://pubmed.ncbi.nlm.nih.gov/35914953/ 35914953] DOI:[https://doi.org/10.1093/gerona/glac142 10.1093/gerona/glac142]</ref> '''Furthermore, MYMD-1 markedly outperformed [[rapamycin]] in a mouse longevity study'''.<ref name="mTOR" />

Isomyosamine holds significant therapeutic potential in many autoimmune conditions such as autoimmune thyroiditis,<ref name="MYMD" /> multiple sclerosis,<ref name="Capsules">Brager, J., Chapman, C., Dunn, L., & Kaplin, A. (2023). A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects. Drug Research, 73(02), 95-104. PMID: 36368677 PMC9902179 DOI: 10.1055/a-1962-6834</ref><ref>[https://nndc.org/wp-content/uploads/2021/09/Basic-Science-Kumar-email.pdf MyMD-1: Potential treatment for s Multiple Sclerosis Depression]</ref> autoimmune encephalomyelitis,<ref name="encephalomyelitis" /> and rheumatoid arthritis.<ref name="Capsules" /><ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315223006264/ex99-1.htm MyMD Pharmaceuticals® Announces Upcoming Presentation of Preclinical Rheumatoid Arthritis Data for Oral TNF-α Inhibitor MYMD-1® at the Society of Toxicology 2023 Annual Meeting on March 20, 2023, at 9:00 AM CT]</ref>

The ease of Isomyosamine oral dosing is a groundbreaking differentiator compared to currently available TNF-α blockers, all of which require delivery by injection or infusion, whereas MyMD-1 is available orally as capsules.<ref name="Capsules" /> MYMD-1® is not detrimental to cell viability and is a small molecule that can cross the blood-brain barrier, potentially enabling it to treat brain-related disease. Commercial efforts are evaluating the effectiveness of MYMD-1® in Phase II studies for treating sarcopenia/[[frailty]]<ref>[https://www.sec.gov/Archives/edgar/data/1321834/000149315222020346/ex99-1.htm The Phase 2 multi-center double-blind, placebo controlled, randomized study (NCT05283486) investigates the efficacy, tolerability and pharmacokinetics of MYMD-1 in the treatment of chronic inflammation associated with sarcopenia/frailty in participants aged 65 years or older.]</ref> as a result of the aging process, and other early-stage clinical trials are evaluating its use for rheumatoid arthritis (RA), with the potential to expand into other applications.

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

Cold-shock response

2023-03-06T22:11:18Z

Andrea: Added sample sizes from recent studies

The cold-shock response is a physiological response that occurs in organisms when they are rapidly exposed to cold temperatures. This response is characterized by a number of physiological changes, including an increase in heart rate, blood pressure and breathing rate. A number of health benefits are also associated to activation of the sympathetic nervous system, such as the release of stress hormones such as adrenaline (epinephrine) and noradrenaline (norepinephrine), as well as dopamine.<ref>Šrámek, P., Šimečková, M., Janský, L. ''et al.'' Human physiological responses to immersion into water of different temperatures. ''Eur J Appl Physiol'' 81, 436–442 (2000). <nowiki>https://doi.org/10.1007/s004210050065</nowiki></ref> These changes are thought to be an adaptive response to the sudden drop in temperature, some of they help to increase heat production and conserve body heat.

During the cold-shock response, blood vessels in the skin constrict and blood flow is redirected to the core of the body to help maintain core temperature. The body also starts to shiver in order to generate heat. The cold-shock response may cause an immediate loss of breathing control, which can lead to hyperventilation or even drowning in cold water.

It is possible to become habituated to cold shocks, known as physiological conditioning. Naturally, people with higher amounts of body fat, diving experience or higher autonomic control of metabolism are able to become easier conditioned against cold shock.<ref>"Exercise in the Cold: Part II - A physiological trip through cold water exposure". ''The science of sport''. www.sportsscientists.com. 29 January 2008.</ref>

=== History ===
The first cold-shock protein (CSP) was identified in the 90s in ''E. coli'' after induction to cold-shock, and this and other CSPs have since been identified; they also appear to be evolutionary conserved across species.<ref>WISTOW, G. Cold shock and DNA binding. ''Nature'' 344, 823–824 (1990). <nowiki>https://doi.org/10.1038/344823c0</nowiki></ref><ref>Landsman, D. RNP-1, an RNA-binding motif is conserved in the DNA-binding cold shock domain. Nucleic Acids Research (1992). <nowiki>https://doi.org/10.1093/nar/20.11.2861</nowiki></ref> CSPs are essential for survival at cold temperatures and play a role in various stages of protein synthesis and [[proteostasis]] mechanisms.

=== Hormesis ===
The cold-shock response, similar to the [[heat-shock response]], is hypothesized to be a [[hormesis]] phenomenon, in which a beneficial effect may occur after exposure to low doses of a potentially harmful condition, which would otherwise be harmful if performed in higher doses.

=== Health benefits ===
Some of the aftermath benefits of cold-shock include the '''lowering of blood pressure, increase in insulin sensitivity and cortisol, boosting of the immune system and antidepressant effects'''.<ref>Knechtle B, Waśkiewicz Z, Sousa CV, Hill L, Nikolaidis PT. Cold Water Swimming-Benefits and Risks: A Narrative Review. Int J Environ Res Public Health. 2020 Dec 2;17(23):8984. doi: 10.3390/ijerph17238984. PMID: 33276648; PMCID: PMC7730683.</ref> It can also be beneficial in some situations, for instance to prevent heat stroke, or to aid with muscle recovery after injury or soreness.<ref>Tipton, M. J.; Collier, N.; Massey, H.; Corbett, J.; Harper, M. (2017-11-01). "Cold water immersion: kill or cure?: Cold water immersion: kill or cure?". ''Experimental Physiology''. '''102''' (11): 1335–1355. [[Doi (identifier)|doi]]:10.1113/EP086283. [[PMID (identifier)|PMID]] 28833689.</ref><ref>Moore, E., Fuller, J.T., Buckley, J.D. ''et al.'' Impact of Cold-Water Immersion Compared with Passive Recovery Following a Single Bout of Strenuous Exercise on Athletic Performance in Physically Active Participants: A Systematic Review with Meta-analysis and Meta-regression. ''Sports Med'' 52, 1667–1688 (2022). <nowiki>https://doi.org/10.1007/s40279-022-01644-9</nowiki></ref>

Induction of CSPs may also lead to the '''activation of brown fat''', known to decrease with age. Brown fat is commonly referred to as "healthy fat," due to its high number of mitochondria and high energy efficiency, as well as a number of health benefits associated to brown fat activation, such as increased insulin sensitivity, or reduced cholesterol.<ref>Chung, N. The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue. Journal of Exercise Nutrition & Biochemistry (2017). <nowiki>https://doi.org/10.20463/jenb.2017.0020</nowiki></ref><ref>Imbeault, P. et al. Cold exposure increases adiponectin levels in men. Metabolism: Clinical and Experimental (2009). <nowiki>https://doi.org/10.1016/j.metabol.2008.11.017</nowiki></ref><ref>Hoeke, G. et al. Role of Brown fat in lipoprotein metabolism and atherosclerosis. Circ. Res. (2015). <nowiki>https://doi.org/10.1161/CIRCRESAHA.115.306647</nowiki></ref> Shivering during or after cold exposure also leads to the release of succinate from muscles, which further activates brown fat thermogenesis.

A recent study in military personnel, demonstrated the beneficial impact of cold-shocks in '''mental health as well as physical composition''' of soldiers, after 8 weeks of regular cold exposure (indoors and outdoors).<ref name=":0">Néma J, Zdara J, Lašák P, Bavlovič J, Bureš M, Pejchal J, Schvach H. Impact of cold exposure on life satisfaction and physical composition of soldiers. BMJ Mil Health. 2023 Jan 4:e002237. doi: 10.1136/military-2022-002237. Epub ahead of print. PMID: 36599485.</ref> The cold immersion protocol consisted of 2 minutes cold immersions up to the neck (ie. with the head above the water) and 30-seconds cold showers for 5 times a week. Soldiers undergoing cold water immersions experienced a significant decrease in self-reported anxiety, an increase in self-reported wellbeing and sexual satisfaction, and a decrease in waist circumference and abdominal fat, all of which were not observed in the soldier control group. The only exception was changes in body fat composition in women soldiers, which remained unaltered compared to the control women soldier group.<ref name=":0" /> Importantly, these health benefits appeared to remain stable, and not only after immediate response to cold exposure. However, this study had a sample size of 49 participants and had reportedly borderline p-values. More exhaustive studies are needed to precisely estimate the mental and physical benefits of cold exposure.

On the contrary, cold-shocks can be dangerous in some situations, as they can cause a '''heart attack''' due to severe vasoconstriction or hypothermia.<ref>Staff. "4 Phases of Cold Water Immersion". ''Beyond Cold Water Bootcamp''. Canadian Safe Boating Council. </ref>

==== Protocols of cold exposure to maximise health benefits ====

===== Timing =====
An important point to consider is the timing of cold exposure. For instance, when training for increasing strength or hypertrophy, it is recommended to avoid deliberate cold exposure in the 6 to 8 hours after training, as it might lead to smaller long-term muscle gains.<ref>Roberts LA, Raastad T, Markworth JF, Figueiredo VC, Egner IM, Shield A, Cameron-Smith D, Coombes JS, Peake JM. Post-exercise cold water immersion attenuates acute anabolic signalling and long-term adaptations in muscle to strength training. J Physiol. 2015 Sep 15;593(18):4285-301. doi: 10.1113/JP270570. Epub 2015 Aug 13. PMID: 26174323; PMCID: PMC4594298.</ref> It is generally recommended to undergo cold exposure early in the morning, as the body heats up and might counteract sleep.

===== Duration =====
The duration of cold exposure is critical, and it is ultimately tied to the temperature of the water (as discussed below). Most studies report health benefits after periodic 30 seconds to 2 minutes of cold exposure.<ref name=":0" /><ref name=":1">Søberg S, Löfgren J, Philipsen FE, Jensen M, Hansen AE, Ahrens E, Nystrup KB, Nielsen RD, Sølling C, Wedell-Neergaard AS, Berntsen M, Loft A, Kjær A, Gerhart-Hines Z, Johannesen HH, Pedersen BK, Karstoft K, Scheele C. Altered brown fat thermoregulation and enhanced cold-induced thermogenesis in young, healthy, winter-swimming men. Cell Rep Med. 2021 Oct 11;2(10):100408. doi: 10.1016/j.xcrm.2021.100408. PMID: 34755128; PMCID: PMC8561167.</ref> Some cold exposure researchers suggest a total of 11 minutes per week across sessions (1 to 5 minutes per session, 2 to 4 times per week) for maximising health benefits.<ref name=":1" /> Of note, the aforementioned study had a total of 15 participants, and therefore higher powered data is needed for estimating the duration of cold exposure with the most beneficial health effects.

===== Temperature =====
Lastly, the temperature of water is also logically important to consider. In general, the colder the water, the shorter the duration of exposure should be. Some studies reported benefits in prolonged dopamine release after immersion in 15ºC (∼60ºF) water for up to 1 hour (with head always above water), while other studies described benefits in epinephrine release after only 20 seconds of 4ºC (∼40ºF) water exposure.<ref name=":1" />

=== Longevity ===
Similarly to [[Heat-shock response|heat-shock proteins]], CSPs regulate a number of molecules involved in longevity pathways, such as NF-kB, p53 or TGF-B, each involved in inflammation, senescence and fribosis, respectively.<ref>Lindquist, J.A. and Mertens, P.R. Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal. (2018). <nowiki>https://doi.org/10.1186/s12964-018-0274-6</nowiki></ref> CSPS are also suggested to be involved in onset and progression of a variety of age-related diseases.<ref>Lindquist, J.A. and Mertens, P.R. Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal. (2018). <nowiki>https://doi.org/10.1186/s12964-018-0274-6</nowiki></ref>

Acute cold therapy has been suggested as a rejuvenation mechanism due to its [[hormesis]] effects, but as for now remains largely unproven and key studies in mammals are lacking. [[Fisetin]] supplementation has been suggested as a method to modulate CSPs activity.<ref>Khan, M.I. et al. YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget (2014). <nowiki>https://doi.org/10.18632/oncotarget.1790</nowiki></ref>
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Lifespan interventions]]

ATF4 (activating transcription factor 4)

2023-03-05T18:18:04Z

Andrea: /* Intro */

'''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> 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<sup>+</sup> 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 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 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]]

ATF4 (activating transcription factor 4)

2023-03-05T17:43:12Z

Andrea: Reviewed and added content

'''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]] by up-regulates 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), 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), 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> 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), 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), 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), 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<sup>+</sup> 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 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), 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), 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), 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 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), 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), 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), 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), 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), 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]]

Longevity of insects with social castes

2023-03-05T17:19:13Z

Andrea: /* Termites */

Social insects such as ants,<ref name="ants">Majoe, M., Libbrecht, R., Foitzik, S., & Nehring, V. (2021). Queen loss increases worker survival in leaf-cutting ants under paraquat-induced oxidative stress. Philosophical Transactions of the Royal Society B, 376(1823), 20190735. PMID: 33678018 PMCID: PMC7938173 DOI: 10.1098/rstb.2019.0735</ref> bees,<ref name="bee">Shell, W. A., & Rehan, S. M. (2022). Social divergence: molecular pathways underlying castes and longevity in a facultatively eusocial small carpenter bee. Proceedings of the Royal Society B, 289(1971), 20212663. PMID: 35317677 PMCID: PMC8941392 (available on 2023-03-30) DOI: 10.1098/rspb.2021.2663</ref> and termites,<ref name="Termite">Li, Y. X., Ye, C. X., Su, J., Nabi, G., Su, X. H., & Xing, L. X. (2022). De Novo Transcriptome Assembly and Analysis of Longevity Genes Using Subterranean Termite (Reticulitermes chinensis) Castes. International Journal of Molecular Sciences, 23(21), 13660. PMID: 36362447 PMCID: PMC9657995 DOI: 10.3390/ijms232113660</ref> have a distinct division of labor among individuals within their colonies. The colony is typically composed of a reproductive queen or queens and non-reproductive workers or soldier castes.<ref>Opachaloemphan, C., Yan, H., Leibholz, A., Desplan, C., & Reinberg, D. (2018). Recent advances in behavioral (epi) genetics in eusocial insects. Annual review of genetics, 52, 489. PMID: 30208294 PMCID: PMC6445553 DOI: 10.1146/annurev-genet-120116-024456</ref> Research has shown that there are significant differences in longevity between the queen and worker castes in many social insect species. In general, queens live much longer than workers, and any worker can become a queen given the appropriate environmental cues by turning on or off specific genes (i.e. via epigenetic mechanisms).<ref name="Epigenetic">Sieber, K. R., Dorman, T., Newell, N., & Yan, H. (2021). (Epi) genetic mechanisms underlying the evolutionary success of eusocial insects. Insects, 12(6), 498. PMID: 34071806 PMCID: PMC8229086 DOI: 10.3390/insects12060498</ref>

The difference in longevity of the social castes is thought to be related to the different roles that queens and workers play within the colony. Queens are responsible for reproducing and maintaining the colony, so they have evolved to live longer in order to increase their chances of reproducing.<ref name="Evolution">Remolina, S. C., & Hughes, K. A. (2008). Evolution and mechanisms of long life and high fertility in queen honey bees. Age, 30(2), 177-185.</ref> In contrast, workers are responsible for foraging food and caring for the colony's young, so they have evolved to have shorter lifespans as they expend a lot of energy and are more prone to injuries and predation.<ref name="Evolution" /> Additionally, queen ants and bees have a different hormonal regulation that allows them to live longer, and different gene expression profiles that increases their resistance to stress, while reducing their metabolism.

'''The fact that queens live many times longer than workers, despite sharing the same genome, provides a particularly useful model for understanding the epigenetic pathways and mechanisms that influence aging'''.<ref name="Epigenetic"/>

== Longevity of workers and queens ==

=== Bees ===
[[File:Laying worker bee.png|thumb|Laying worker bee.<ref>https://www.beeculture.com/laying-workers-happens-fix/</ref>]]
In hives, queen bees are normally the only female who reproduces, whereas the vast majority of bees are sterile females known as worker bees. Queen honeybees can live for several years, while workers typically only live for several months.<ref name="Evolution" />

Even in a normal hive, about 1% of workers have ovaries developed enough to lay eggs. A laying worker bee is a worker bee that lays unfertilized eggs, usually in the queenless colonies. In colonies of the neotropical stingless bee ''Scaptotrigona aff. postica,'' '''the lifespan of worker bees was about a third longer in hives without mated queens''' (known as non-queenright colonies).<ref name="stingless">dos Santos Conceição Lopes, B., Campbell, A. J., & Contrera, F. A. L. (2020). Queen loss changes behavior and increases longevity in a stingless bee. Behavioral Ecology and Sociobiology, 74, 1-9. DOI: [https://doi.org/10.1007/s00265-020-2811-8 10.1007/s00265-020-2811-8]</ref>

The worker bees of this species substantially alter their behavior without mated queens, for example by spending more time inside the nest building brood cells rather than participating in more risky foraging behaviors, therefore causing an increase in their overall longevity. Workers also start to lay haploid eggs, allowing some direct reproduction by workers in the absence of a queen.<ref name="stingless" /> This phenomenons highlight the plasticity of longevity in honeybees depending on environmental stimuli.

=== Ants ===
[[File:Gamergate worker ant.jpg|thumb|Gamergate worker ant. Gamergates are worker ants that reproduce sexually and lay fertilized eggs that will develop as females.]]
Ants also display a remarkable plasticity in their longevity that can be regulated via epigenetic mechanisms.<ref name="Epigenetic" /> For instance, in the ant species ''L. niger'', queen ants live for 20 to 30 years, workers for 1 to 3 years and males for only a few weeks.<ref>Jemielity, S., Chapuisat, M., Parker, J. D., & Keller, L. (2005). Long live the queen: studying aging in social insects. Age, 27(3), 241-248. PMID: 23598656 PMCID: PMC3458492 DOI: 10.1007/s11357-005-2916-z</ref>

===== Gamergate ants =====
While in most ant species social castes are permanently established during the larval stage, adult ''Harpegnathos saltator'' workers can acquire a queen-like phenotype and become reproductive individuals called “gamergates”.<ref>Peeters, C., Liebig, J., & Hölldobler, B. (2000). Sexual reproduction by both queens and workers in the ponerine ant Harpegnathos saltator. Insectes Sociaux, 47, 325-332. https://doi.org/10.1007/PL00001724</ref> '''Workers that become gamergates also attain queen-like longevity, with a fivefold increase in average life span''' from 7 months to 3 years.<ref>Ghaninia, M., Haight, K., Berger, S. L., Reinberg, D., Zwiebel, L. J., Ray, A., & Liebig, J. (2017). Chemosensory sensitivity reflects reproductive status in the ant Harpegnathos saltator. Scientific reports, 7(1), 3732. PMID: 28623371 PMC5473913 DOI: 10.1038/s41598-017-03964-7</ref>

In the ant ''Harpegnathos saltator'', aging workers exhibited a progressive loss of ensheathing glia cells, whereas in gamergates, they remained a larger proportion of total glia cells over the same time span. Consistent with this, old gamergates retained the ability to mount a response to neuronal damage, which was lost in old workers.<ref>Sheng, L., Shields, E. J., Gospocic, J., Glastad, K. M., Ratchasanmuang, P., Berger, S. L., ... & Bonasio, R. (2020). Social reprogramming in ants induces longevity-associated glia remodeling. Science advances, 6(34), eaba9869. PMID: 32875108 PMC7438095 DOI: 10.1126/sciadv.aba9869</ref>

===== Tapeworm-infected ants =====
[[File:Tapeworm-infected ants.jpg|thumb|Tapeworm-infected ant workers.<ref>https://www.beeculture.com/laying-workers-happens-fix/</ref>]]
Parasite infection induces multiple alterations in the adult workers. After infection, the survival of infected workers is increased compared to their uninfected nest-mates.<ref>Beros, S., Lenhart, A., Scharf, I., Negroni, M. A., Menzel, F., & Foitzik, S. (2021). Extreme lifespan extension in tapeworm-infected ant workers. Royal Society open science, 8(5), 202118. PMID: 34017599 PMC8131941 DOI: 10.1098/rsos.202118</ref> <ref name="presence">Stoldt, M., Klein, L., Beros, S., Butter, F., Jongepier, E., Feldmeyer, B., & Foitzik, S. (2021). Parasite presence induces gene expression changes in an ant host related to immunity and longevity. Genes, 12(1), 95. PMID: 33451085 PMC7828512 DOI: 10.3390/genes12010095</ref> A parasitic tapeworm greatly lengthens the lives of its ant hosts by secreting a rich cocktail (more than 250 proteins) of antioxidants and other compounds.

Most secreted proteins from these parasitic tapeworms don't have any known annotated orthologs, which is indicative of potential novel functions and a long history of adaptation within this species interaction.<ref>Hartke, J., Ceron-Noriega, A., Stoldt, M., Sistermans, T., Kever, M., Fuchs, J., ... & Foitzik, S. (2022). What doesn't kill you makes you live longer-Longevity of a social host linked to parasite proteins. bioRxiv. doi: [https://doi.org/10.1101/2022.12.23.521666 10.1101/2022.12.23.521666]</ref>

A study found that both '''queens and infected workers express more of a gene called ''silver'' (carboxypeptidase D)''', compared to uninfected workers.<ref name="presence" /> Researchers previously '''linked the silver gene to an extended lifespan in fruit flies'''.<ref>Pauls, D., Hamarat, Y., Trufasu, L., Schendzielorz, T. M., Gramlich, G., Kahnt, J., ... & Wegener, C. (2019). Drosophila carboxypeptidase D (SILVER) is a key enzyme in neuropeptide processing required to maintain locomotor activity levels and survival rate. European Journal of Neuroscience, 50(9), 3502-3519. PMID: 31309630 DOI: 10.1111/ejn.14516</ref><ref>Carnes, M. U., Campbell, T., Huang, W., Butler, D. G., Carbone, M. A., Duncan, L. H., ... & Mackay, T. F. (2015). The genomic basis of postponed senescence in Drosophila melanogaster. PLoS One, 10(9), e0138569. PMID: 26378456 PMC4574564 DOI: 10.1371/journal.pone.0138569</ref> However, a possible bias could be that infected workers do not engage in foraging outside the nest, and therefore have lower extrinsic mortality similar to queens, which also stay inside the nest.<ref name="presence" />

===== Wolbachia-infected ants =====
[[File:Pharaoh ants, with a worker (left) and queen (right)..jpg|thumb|Pharaoh ants, a worker (left) and queen (right).<ref>https://www.beeculture.com/laying-workers-happens-fix/</ref>]]
''Wolbachia'', a widespread maternally-inherited endosymbiotic bacteria, infects an estimated one-third of all ant species. In infected ''Monomorium pharaonis'' colonies, queens produce more eggs. Despite increased egg-laying by queens and higher colony-level metabolic rates, Wolbachia infection was not associated with decreased queen lifespan. In fact, in workers, which are obligately sterile, '''''Wolbachia'' infection was associated with longer lifespan'''.<ref>Rohini Singh, Sachin Suresh, Jennifer Fewell, Jon Harrison and Timothy Linksvayer (2023). Wolbachia-infected pharaoh ant colonies have higher egg production, metabolic rate, and worker survival. bioRxiv doi: [https://doi.org/10.1101/2023.01.31.526493 10.1101/2023.01.31.526493]</ref> Thus, increased egg-laying rates by queens and longer worker lifespans contribute to the higher growth rate and productivity that characterizes ''Wolbachia''-infected colonies.

A role of metabolic provisioning of the host by endosymbionts has been demonstrated in several empirical studies. For example, Wolbachia can increase female fecundity in ''Drosophila'' flies by influencing iron homeostasis. In filarial nematodes, ''Wolbachia'' provisions the host with heme and riboflavin. Likewise, in a spider species, synthesis of fat and free amino acids has been shown to be improved by a ''Wolbachia'' infection, and in bedbugs, ''Wolbachia'' plays a nutritional role in vitamin B synthesis.<ref>Katlav, A., Nguyen, D. T., Morrow, J. L., Spooner-Hart, R. N., & Riegler, M. (2022). Endosymbionts moderate constrained sex allocation in a haplodiploid thrips species in a temperature-sensitive way. Heredity, 128(3), 169-177. PMID: 35115648 PMC8897473 DOI: 10.1038/s41437-022-00505-5</ref><ref>Katlav, A., Cook, J. M., & Riegler, M. (2022). Common endosymbionts affect host fitness and sex allocation via egg size provisioning. Proceedings of the Royal Society B, 289(1971), 20212582. PMID: 35350856 PMC8965393 DOI: 10.1098/rspb.2021.2582</ref>

=== Termites ===
Termites (Isoptera) are pale-coloured, soft-bodied eusocial insects living in complex societies that are characterized by a caste system in which despite the fact that all members in a termite colony have the same genetic background, few reproductively mature individuals (including a queen and a sperm-producing kings) reproduce and have extraordinarily long lives, while the large majority (non-reproductives, including workers and soldiers) perform tasks such as foraging, brooding and defence.<ref>Korb, J. (2007). Termites. Current Biology, 17(23), R995-R999. PMID: 18054770 DOI: 10.1016/j.cub.2007.10.033</ref><ref>Korb, J., Poulsen, M., Hu, H., Li, C., Boomsma, J. J., Zhang, G., & Liebig, J. (2015). A genomic comparison of two termites with different social complexity. Frontiers in Genetics, 6, 9. PMID: 25788900 PMCID: PMC4348803 DOI: 10.3389/fgene.2015.00009</ref>
Unlike hymenopteran social insects (ants, bees and wasps), where the sterile workers are all female, in termites both males and females can be workers.<ref>Revely, L., Sumner, S., & Eggleton, P. (2021). The plasticity and developmental potential of termites. Frontiers in Ecology and Evolution, 9, 552624. https://doi.org/10.3389/fevo.2021.552624</ref> Furthermore, workers have unique flexibility in that a worker has the capability to develop into apterous neotenic reproductives that develop in the absence of reproductives to provide for continued growth of the colony.<ref>Miura, T., Scharf, M. E., Bignell, D. E., Roisin, Y., & Lo, N. (2011). Biology of termites: A modern synthesis. Molecular Basis Underlying Caste Differentiation in Termites pp 211–253 Roisin, Nathan Lo DOI:[https://doi.org/10.1007/978-90-481-3977-4_9 10.1007/978-90-481-3977-4_9]</ref>

<ref>Harrison, M. C., Jongepier, E., Robertson, H. M., Arning, N., Bitard-Feildel, T., Chao, H., ... & Bornberg-Bauer, E. (2018). Hemimetabolous genomes reveal molecular basis of termite eusociality. Nature ecology & evolution, 2(3), 557-566. PMID: 29403074 PMCID: PMC6482461 DOI: 10.1038/s41559-017-0459-1</ref>

Although the question of how termite queens, which exhibit (as well as ants and honeybees) extraordinary longevity and fertility in comparison with non-reproductive individuals has attracted much attention, the molecular mechanisms involved are not yet understood. <ref name="kings">Tasaki, E., Takata, M., & Matsuura, K. (2021). Why and how do termite kings and queens live so long?. Philosophical Transactions of the Royal Society B, 376(1823), 20190740. PMID: 33678028 PMCID: PMC7938161 DOI: 10.1098/rstb.2019.0740</ref> It has been hypothesized that the queens of the termite ''Reticulitermes speratus'' have high level of oxidative stress resistance and suffer lower levels of oxidative damage than non-reproductive workers, due to the a highly efficient antioxidant system. In particular, queens had two times higher catalase activity and more than seven times higher expression levels of the catalase gene RsCAT1 than workers. Queens also showed higher expression levels of the peroxiredoxin gene RsPRX6.<ref>Tasaki, E., Kobayashi, K., Matsuura, K., & Iuchi, Y. (2017). An efficient antioxidant system in a long-lived termite queen. PLoS One, 12(1), e0167412. PMID: 28076409 PMCID: PMC5226355 DOI: 10.1371/journal.pone.0167412</ref>

An important antioxidant contributing to survival in termites is uric acid, which is reserved and used as a valuable nitrogen source. Uric acid was shown to be provided by workers to reproductive castes.<ref>Tong, R. L., Patel, J. S., Gordon, J. M., Lee, S. B., Chouvenc, T., & Su, N. Y. (2023). Exuviae Recycling Can Enhance Queen Oviposition and Colony Growth in Subterranean Termites (Blattodea: Rhinotermitidae: Coptotermes). Environmental Entomology, nvad009. PMID: 36773009 DOI: 10.1093/ee/nvad009</ref><ref>Tasaki, E., Sakurai, H., Nitao, M., Matsuura, K., & Iuchi, Y. (2017). Uric acid, an important antioxidant contributing to survival in termites. PLoS One, 12(6), e0179426. PMID: 28609463 PMCID: PMC5469489 DOI: 10.1371/journal.pone.0179426</ref> It was found that king- and queen-specific degradation of uric acid contributes to reproduction and longevity in the subterranean termite ''Reticulitermes speratus''. The urate oxidase gene (RsUAOX), which catalyses the first step of nitrogen recycling from stored uric acid, was highly expressed in mature kings and queens, and upregulated with differentiation into neotenic kings/queens.<ref> Konishi, T., Tasaki, E., Takata, M., & Matsuura, K. (2023). King-and queen-specific degradation of uric acid contributes to reproduction in termites. Proceedings of the Royal Society B, 290(1990), 20221942. PMID: 36598016 PMC9811635 (available on 2024-01-11) DOI: 10.1098/rspb.2022.1942</ref>

<ref>Ma, X. M., Li, Y. X., Zhang, H. X., Liu, Q., Su, X. H., & Xing, L. X. (2020). Transcriptomic evidence that insulin signalling pathway regulates the ageing of subterranean termite castes. Scientific Reports, 10(1), 1-13. PMID: 32424344 PMCID: PMC7235038 DOI: 10.1038/s41598-020-64890-9</ref><ref>Séité, S., Harrison, M. C., Sillam-Dussès, D., Lupoli, R., Van Dooren, T. J., Robert, A., ... & Vasseur-Cognet, M. (2022). Lifespan prolonging mechanisms and insulin upregulation without fat accumulation in long-lived reproductives of a higher termite. Communications Biology, 5(1), 44. PMID: 35027667 PMCID: PMC8758687 DOI: 10.1038/s42003-021-02974-6</ref>

The haploid genome sizes (C-values) of termites (Isoptera) ranged from 0.58 to 1.90 pg, (1pg = 978 Mb).<ref>Monroy Kuhn, J. M., Meusemann, K., & Korb, J. (2019). Long live the queen, the king and the commoner? Transcript expression differences between old and young in the termite Cryptotermes secundus. PLoS One, 14(2), e0210371. PMID: 30759161 PMCID: PMC6373952 DOI: 10.1371/journal.pone.0210371</ref>

<ref>Harrison, M. C., Dohmen, E., George, S., Sillam-Dussès, D., Séité, S., & Vasseur-Cognet, M. (2022). Complex regulatory role of DNA methylation in caste-and age-specific expression of a termite. Open Biology, 12(7), 220047.PMID: 35857972 PMCID: PMC9256085 DOI: 10.1098/rsob.220047</ref>

== Mechanisms of exceptional longevity ==
Some of the most prominent mechanisms thought to underly the extended longevity of queens are:

=== Endocrine signalling and insulin binding protein Imp-L2 ===
Imaginal morphogenesis protein‐Late 2 (Imp-L2), a putative homolog of vertebrate insulin-like growth factor (IGF)-binding protein 7 (IGFBP7), counteracts insulin/IGF signalling (IIS) in ''Drosophila'' and is essential for starvation resistance.<ref>Honegger, B., Galic, M., Köhler, K., Wittwer, F., Brogiolo, W., Hafen, E., & Stocker, H. (2008). Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. Journal of biology, 7, 1-11. PMID: 18412985 PMC2323038 DOI: 10.1186/jbiol72</ref> It is known that genetic manipulations of pathway components that result in dampened IIS extend lifespan in worms, flies and mice, and ameliorate age-dependent functional decline in a [[FOXO longevity genes|FOXO]]-dependent manner.<ref>Piper, M. D. W., Selman, C., McElwee, J. J., & Partridge, L. (2008). Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice?. Journal of internal medicine, 263(2), 179-191. PMID: 18226095 DOI: 10.1111/j.1365-2796.2007.01906.x</ref> Increased IMP-L2 levels in ''Drosophila'' similarly results in substantial lifespan extension.<ref>Alic, N., Hoddinott, M. P., Vinti, G., & Partridge, L. (2011). Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor. Aging cell, 10(1), 137-147. PMID: 21108726 PMC3042147 DOI: 10.1111/j.1474-9726.2010.00653.x</ref>

It is assumed that in the process of egg-laying, some '''ant queens produce Imp-L2''', which suppresses the aging effects of insulin, so that they can consume all the additional food needed for their egg-laying without shortening their lives.<ref name="Imp">Yan, H., Opachaloemphan, C., Carmona-Aldana, F., Mancini, G., Mlejnek, J., Descostes, N., ... & Reinberg, D. (2022). Insulin signaling in the long-lived reproductive caste of ants. Science, 377(6610), 1092-1099. PMID: 36048960 PMC9526546 DOI: 10.1126/science.abm8767</ref> As is known, reducing the AKT (also known as Protein kinase B) branch of insulin signaling in the fat body and adipose tissue lengthens the life of ''Drosophila''.<ref>Cheng, X., Xie, M., Luo, L., Tian, Y., Yu, G., Wu, Q., ... & Yang, M. (2022). Inhibitor GSK690693 extends Drosophila lifespan via reduce AKT signaling pathway. Mechanisms of Ageing and Development, 202, 111633. PMID: 35065134 DOI: 10.1016/j.mad.2022.111633</ref> A study showed that strong AKT phosphorylation after insulin treatment was completely suppressed by Imp-L2.<ref name="Imp" />

=== Oxidative stress resistance ===
Vitellogenin (Vtg or Vg) is an egg yolk precursor produced by nearly all egg-laying females species. It is a source of nutrient and has additional roles in the scavenging of reactive oxygen species (ROS).<ref>Havukainen H, Münch D, Baumann A, Zhong S, Halskau Ø, Krogsgaard M, Amdam GV. Vitellogenin recognizes cell damage through membrane binding and shields living cells from reactive oxygen species. J Biol Chem. 2013 Sep 27;288(39):28369-81. doi: 10.1074/jbc.M113.465021.</ref> The '''expression of vitellogenin (Vg) appears to be linked to the queens increased resistance to stress'''.<ref>Seehuus SC, Norberg K, Gimsa U, Krekling T, Amdam GV (2006) Reproductive protein protects functionally sterile honey bee workers from oxidative stress. Proc Natl Acad Sci USA 103:962–967</ref> Bees with higher Vg levels had increased survival, while reducing the expression of Vg led to decreased lifespan. However, in queen honey bees, the expression of antioxidant genes is not necessarily increased nor is required for their long lifespan.<ref>Corona M, Hughes KA, Weaver DB, Robinson GE (2005) Gene expression patterns associated with queen honey bee longevity. Mech Ageing Dev 126:1230–1238</ref>

=== Genes underlying the reproductive division of labor ===
For identifying differences in gene expression between queens and workers in eusocial insects pairs of the queen and worker RNA sequencing data were used to calculate the queen/worker ratio referred to as the QW ratio.<ref>Toga, K., & Bono, H. (2022). Meta-analysis of public RNA sequencing data of queens and workers in social Hymenoptera and termites. bioRxiv, 2022-11. Doi:[https://doi.org/10.1101/2022.11.20.516280 10.1101/2022.11.20.516280]</ref> Meta-analysis of RNA-seq data revealed 20 genes with differential expression between queens and workers. Among these genes, '''vitellogenin and vitellogenin receptors''', which are highly expressed in queens across many social insects. '''SPARC (secreted protein acidic and cysteine rich) was highly expressed in queens''', and '''RSG7 (regulator of G protein signaling 7) was highly expressed in workers'''. In mice, SPARC promotes insulin secretion via down-regulation of regulator of G protein 4 (RGS4) expression in pancreatic β cells. Functional analyses of the 20 genes retrieved from massive datasets of a large number of eusocial species may reveal in the future key regulators of the reproductive division of labor and and multiple differences in life expectancy.

When workers leave the natal colony or a queen dies, the expression of stage-specific genes is induced in workers, which leads to the differentiation of workers to reproductives.<ref name="Ras">Ye, C., Rasheed, H., Ran, Y., Yang, X., Xing, L., & Su, X. (2019). Transcriptome changes reveal the genetic mechanisms of the reproductive plasticity of workers in lower termites. BMC Genomics, 20.702. PMID: 31500567 PMCID: PMC6734246 DOI: 10.1186/s12864-019-6037-y</ref> In particular the relative expression level of '''Ras''' in the isolated female workers (IWs) '''was 131-fold than that of the workers''', which indicated that Ras was especially overexpressed in workers in the absence of queens for activation of the Ras-ERK signalling pathway to drive the ovary development of isolated workers.<ref name="Ras" /> It was suggested that the signal transduction along the Ras-MAPK pathway crucially controls the reproductive plasticity of the workers and short-lived individuals can become long-lived individuals by the transition of castes.<ref name="Ras" />

==== Effective transposon regulation ====
For termites but not for hymenopterans, it was found that caste and age was associated with '''the expression of [[Transposons in aging|transposable elements (TEs)]]'''. While sterile workers who live only weeks had substantially higher TE activity, TE expression did not increase with age in the fat body of queens, despite a sevenfold increase in overall gene expression, due to a significant upregulation of the piRNA-pathway in 20-year-old queens of ''Macrotermes natalensis''.<ref>Post, F., Bornberg‐Bauer, E., Vasseur‐Cognet, M., & Harrison, M. C. (2023). More effective transposon regulation in fertile, long‐lived termite queens than in sterile workers. Molecular Ecology, 32(2), 369-380. PMID: 36320186 DOI: 10.1111/mec.16753</ref><ref>Elsner, D., Meusemann, K., & Korb, J. (2018). Longevity and transposon defense, the case of termite reproductives. Proceedings of the National Academy of Sciences, 115(21), 5504-5509. PMID: 29735660 PMCID: PMC6003524 DOI: 10.1073/pnas.1804046115</ref>

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

Cold-shock response

2023-03-05T16:57:05Z

Andrea: Re-organised and added new content

The cold-shock response is a physiological response that occurs in organisms when they are rapidly exposed to cold temperatures. This response is characterized by a number of physiological changes, including an increase in heart rate, blood pressure and breathing rate. A number of health benefits are also associated to activation of the sympathetic nervous system, such as the release of stress hormones such as adrenaline (epinephrine) and noradrenaline (norepinephrine), as well as dopamine.<ref>Šrámek, P., Šimečková, M., Janský, L. ''et al.'' Human physiological responses to immersion into water of different temperatures. ''Eur J Appl Physiol'' 81, 436–442 (2000). <nowiki>https://doi.org/10.1007/s004210050065</nowiki></ref> These changes are thought to be an adaptive response to the sudden drop in temperature, some of they help to increase heat production and conserve body heat.

During the cold-shock response, blood vessels in the skin constrict and blood flow is redirected to the core of the body to help maintain core temperature. The body also starts to shiver in order to generate heat. The cold-shock response may cause an immediate loss of breathing control, which can lead to hyperventilation or even drowning in cold water.

It is possible to become habituated to cold shocks, known as physiological conditioning. Naturally, people with higher amounts of body fat, diving experience or higher autonomic control of metabolism are able to become easier conditioned against cold shock.<ref>"Exercise in the Cold: Part II - A physiological trip through cold water exposure". ''The science of sport''. www.sportsscientists.com. 29 January 2008.</ref>

=== History ===
The first cold-shock protein (CSP) was identified in the 90s in ''E. coli'' after induction to cold-shock, and this and other CSPs have since been identified; they also appear to be evolutionary conserved across species.<ref>WISTOW, G. Cold shock and DNA binding. ''Nature'' 344, 823–824 (1990). <nowiki>https://doi.org/10.1038/344823c0</nowiki></ref><ref>Landsman, D. RNP-1, an RNA-binding motif is conserved in the DNA-binding cold shock domain. Nucleic Acids Research (1992). <nowiki>https://doi.org/10.1093/nar/20.11.2861</nowiki></ref> CSPs are essential for survival at cold temperatures and play a role in various stages of protein synthesis and [[proteostasis]] mechanisms.

=== Hormesis ===
The cold-shock response, similar to the [[heat-shock response]], is hypothesized to be a [[hormesis]] phenomenon, in which a beneficial effect may occur after exposure to low doses of a potentially harmful condition, which would otherwise be harmful if performed in higher doses.

=== Health benefits ===
Some of the aftermath benefits of cold-shock include the '''lowering of blood pressure, increase in insulin sensitivity and cortisol, boosting of the immune system and antidepressant effects'''.<ref>Knechtle B, Waśkiewicz Z, Sousa CV, Hill L, Nikolaidis PT. Cold Water Swimming-Benefits and Risks: A Narrative Review. Int J Environ Res Public Health. 2020 Dec 2;17(23):8984. doi: 10.3390/ijerph17238984. PMID: 33276648; PMCID: PMC7730683.</ref> It can also be beneficial in some situations, for instance to prevent heat stroke, or to aid with muscle recovery after injury or soreness.<ref>Tipton, M. J.; Collier, N.; Massey, H.; Corbett, J.; Harper, M. (2017-11-01). "Cold water immersion: kill or cure?: Cold water immersion: kill or cure?". ''Experimental Physiology''. '''102''' (11): 1335–1355. [[Doi (identifier)|doi]]:10.1113/EP086283. [[PMID (identifier)|PMID]] 28833689.</ref><ref>Moore, E., Fuller, J.T., Buckley, J.D. ''et al.'' Impact of Cold-Water Immersion Compared with Passive Recovery Following a Single Bout of Strenuous Exercise on Athletic Performance in Physically Active Participants: A Systematic Review with Meta-analysis and Meta-regression. ''Sports Med'' 52, 1667–1688 (2022). <nowiki>https://doi.org/10.1007/s40279-022-01644-9</nowiki></ref>

Induction of CSPs may also lead to the '''activation of brown fat''', known to decrease with age. Brown fat is commonly referred to as "healthy fat," due to its high number of mitochondria and high energy efficiency, as well as a number of health benefits associated to brown fat activation, such as increased insulin sensitivity, or reduced cholesterol.<ref>Chung, N. The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue. Journal of Exercise Nutrition & Biochemistry (2017). <nowiki>https://doi.org/10.20463/jenb.2017.0020</nowiki></ref><ref>Imbeault, P. et al. Cold exposure increases adiponectin levels in men. Metabolism: Clinical and Experimental (2009). <nowiki>https://doi.org/10.1016/j.metabol.2008.11.017</nowiki></ref><ref>Hoeke, G. et al. Role of Brown fat in lipoprotein metabolism and atherosclerosis. Circ. Res. (2015). <nowiki>https://doi.org/10.1161/CIRCRESAHA.115.306647</nowiki></ref> Shivering during or after cold exposure also leads to the release of succinate from muscles, which further activates brown fat thermogenesis.

A recent study in military personnel, demonstrated the beneficial impact of cold-shocks in '''mental health as well as physical composition''' of soldiers, after 8 weeks of regular cold exposure (indoors and outdoors).<ref name=":0">Néma J, Zdara J, Lašák P, Bavlovič J, Bureš M, Pejchal J, Schvach H. Impact of cold exposure on life satisfaction and physical composition of soldiers. BMJ Mil Health. 2023 Jan 4:e002237. doi: 10.1136/military-2022-002237. Epub ahead of print. PMID: 36599485.</ref> The cold immersion protocol consisted of 2 minutes cold immersions up to the neck (ie. with the head above the water) and 30-seconds cold showers for 5 times a week. Soldiers undergoing cold water immersions experienced a significant decrease in self-reported anxiety, an increase in self-reported wellbeing and sexual satisfaction, and a decrease in waist circumference and abdominal fat, all of which were not observed in the soldier control group. The only exception was changes in body fat composition in women soldiers, which remained unaltered compared to the control women soldier group.<ref name=":0" /> Importantly, these health benefits appeared to remain stable, and not only after immediate response to cold exposure.

However, cold-shocks can be dangerous in some situations, as it can cause a '''heart attack''' due to severe vasoconstriction or hypothermia.<ref>Staff. "4 Phases of Cold Water Immersion". ''Beyond Cold Water Bootcamp''. Canadian Safe Boating Council. </ref>

==== Protocols of cold exposure to maximise health benefits ====

===== Timing =====
An important point to consider is the timing of cold exposure. For instance, when training for increasing strength or hypertrophy, it is recommended to avoid deliberate cold exposure in the 6 to 8 hours after training, as it might lead to smaller long-term muscle gains.<ref>Roberts LA, Raastad T, Markworth JF, Figueiredo VC, Egner IM, Shield A, Cameron-Smith D, Coombes JS, Peake JM. Post-exercise cold water immersion attenuates acute anabolic signalling and long-term adaptations in muscle to strength training. J Physiol. 2015 Sep 15;593(18):4285-301. doi: 10.1113/JP270570. Epub 2015 Aug 13. PMID: 26174323; PMCID: PMC4594298.</ref> It is generally recommended to undergo cold exposure early in the morning, as the body heats up and might counteract sleep.

===== Duration =====
The duration of cold exposure is critical, and it is ultimately tied to the temperature of the water (as discussed below). Most studies report health benefits after periodic 30 seconds to 2 minutes of cold exposure.<ref name=":0" /><ref name=":1">Søberg S, Löfgren J, Philipsen FE, Jensen M, Hansen AE, Ahrens E, Nystrup KB, Nielsen RD, Sølling C, Wedell-Neergaard AS, Berntsen M, Loft A, Kjær A, Gerhart-Hines Z, Johannesen HH, Pedersen BK, Karstoft K, Scheele C. Altered brown fat thermoregulation and enhanced cold-induced thermogenesis in young, healthy, winter-swimming men. Cell Rep Med. 2021 Oct 11;2(10):100408. doi: 10.1016/j.xcrm.2021.100408. PMID: 34755128; PMCID: PMC8561167.</ref> Some cold exposure researchers suggest a total of 11 minutes per week across sessions (1 to 5 minutes per session, 2 to 4 times per week) for maximising health benefits.<ref name=":1" />

===== Temperature =====
Lastly, the temperature of water is also logically important to consider. In general, the colder the water, the shorter the duration of exposure should be. Some studies reported benefits in prolonged dopamine release after immersion in 15ºC (∼60ºF) water for up to 1 hour (with head always above water), while other studies described benefits in epinephrine release after only 20 seconds of 4ºC (∼40ºF) water exposure.<ref name=":1" />

=== Longevity ===
Similarly to [[Heat-shock response|heat-shock proteins]], CSPs regulate a number of molecules involved in longevity pathways, such as NF-kB, p53 or TGF-B, each involved in inflammation, senescence and fribosis, respectively.<ref>Lindquist, J.A. and Mertens, P.R. Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal. (2018). <nowiki>https://doi.org/10.1186/s12964-018-0274-6</nowiki></ref> CSPS are also suggested to be involved in onset and progression of a variety of age-related diseases.<ref>Lindquist, J.A. and Mertens, P.R. Cold shock proteins: from cellular mechanisms to pathophysiology and disease. Cell Commun Signal. (2018). <nowiki>https://doi.org/10.1186/s12964-018-0274-6</nowiki></ref>

Acute cold therapy has been suggested as a rejuvenation mechanism due to its [[hormesis]] effects, but as for now remains largely unproven and key studies in mammals are lacking. [[Fisetin]] supplementation has been suggested as a method to modulate CSPs activity.<ref>Khan, M.I. et al. YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget (2014). <nowiki>https://doi.org/10.18632/oncotarget.1790</nowiki></ref>
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]
[[Category:Lifespan interventions]]

Advanced glycation end products (AGEs)

2023-03-04T20:43:17Z

Andrea: Update with recent literature

Advanced glycation end products (AGEs), sometimes referred to as glycotoxins, are harmful oxidant compounds that result from glycation reactions during the metabolism of macromolecules in the bloodstream. Glycation (also known as the Maillard reaction or advanced glycation) is a non-enzymatic reaction that attaches a sugar (glucose or fructose) to proteins or lipids. The end-products of these reactions are implicated in diseases such as diabetes type-2,<ref name=":0">Yan, S. F.; D'Agati, V.; Schmidt, A. M.; Ramasamy, R. (2007). "Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging". ''Current Molecular Medicine''. '''7''' (8): 699–710. doi: 10.2174/156652407783220732</ref> cardiovascular diseases,<ref name=":1">Semba, R. D.; Ferrucci, L.; Sun, K.; Beck, J.; Dalal, M.; Varadhan, R.; Walston, J.; Guralnik, J. M.; Fried, L. P. (2009). "Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women". ''Aging Clinical and Experimental Research''. '''21''' (2): 182–190. doi: 10.1007/BF03325227</ref> [[Aging and eye disease|retinal disease]]<ref name=":2">Glenn, J.; Stitt, A. (2009). "The role of advanced glycation end products in retinal ageing and disease". ''Biochimica et Biophysica Acta (BBA) - General Subjects''. '''1790''' (10): 1109–1116. doi: 10.1016/j.bbagen.2009.04.016</ref> or [[Aging and neurodegeneration|neurodegenerative diseases]].<ref name=":3">Munch, G; Deuther-Conrad W; Gasic-Milenkovic J. (2002). "Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer's disease--a target for neuroprotective treatment strategies?". ''J Neural Transm Suppl''. '''62''' (62): 303–307. doi: 10.1007/978-3-7091-6139-5_28</ref><ref name=":4">Münch, Gerald; et al. (27 February 1997). "Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of β-amyloid peptide". ''Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease''. '''1360''' (1): 17–29. doi: 10.1016/S0925-4439(96)00062-2</ref> They are also believed to play a causative role in normal aging.<ref name=":0" />

=== Dietary AGEs (dAGEs) ===
Highly processed foods found abundantly in western diets are rich in AGEs, which is worrisome given that dietary AGEs (dAGEs) have been shown to contribute to increased inflammation and oxidative stress, both precursor states for disease.<ref name=":5">Uribarri, J., Woodruff, S., Goodman, S., Cai, W., Chen, X. U. E., Pyzik, R., ... & Vlassara, H. (2010). Advanced glycation end products in foods and a practical guide to their reduction in the diet. ''Journal of the American Dietetic Association'', ''110''(6), 911-916.</ref> The cooking method also has a high impact in the formation of AGEs from the diet: '''dry heat was found to increase AGE formation''' by 10 to 100 fold more than uncooked food, '''especially in animal-derived food'''.<ref name=":5" /> Vegetarian, carbohydrate-rich diets based on vegetables, milk and fruits lead to very few AGE formation even after being heat-processed.

Due to the impact of diet, conditions such as obesity or post-menopausal changes in body weight also lead to an increase in AGEs formation and therefore increased risk of cardiovascular disease.<ref>Pertynska-Marczewska, M., & Merhi, Z. (2015). Relationship of advanced glycation end products with cardiovascular disease in menopausal women. ''Reproductive Sciences'', ''22'', 774-782.</ref>

=== AGEs in disease ===
The formation of AGEs occurs during normal metabolism, however high levels might lead to disease due to '''protein-protein crosslinking''' in the bloodstream.<ref name=":6">Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001;56:1–21.</ref> AGE processes particularly affect long-lived proteins with high turnover rates, such as structural collagen or other '''components of the extracellular matrix, which usually become pathogenic targets'''. When crosslinking of collagen occurs in the walls of the vasculature, this can be extremely deleterious. Damage to the micro- or macro-vasculature can lead to the formation of plaques, impair vascular elasticity and increase the risk for atherosclerosis and cardiovascular disease.<ref name=":1" />

One of the most common types of AGEs is '''glucosepane''', which forms an irreversible, covalent cross-link molecule in collagen that might last decades before the body is able to fully remove it. It is also believed that glucosepane has a causal effect in the wrinkling of the skin over time and in the thickening of basement membranes in the vasculature.<ref>Sell, D. R., Biemel, K. M., Reihl, O., Lederer, M. O., Strauch, C. M., & Monnier, V. M. (2005). "Glucosepane is a major protein cross-link of the senescent human extracellular matrix: Relationship with diabetes". ''Journal of Biological Chemistry''. '''280''' (13): 12310–12315. doi: 10.1074/jbc.M500733200</ref> It is also found in high levels in conditions of diabetes type-2.<ref>Monnier, V. M., Mustata, G. T., Biemel, K. L., Reihl, O., Lederer, M. O., Zhenyu, D.; et al. (2005). "Cross-linking of the extracellular matrix by the maillard reaction in aging and diabetes: An update on "a puzzle nearing resolution"". ''Annals of the New York Academy of Sciences''. '''1043''': 533–544.</ref>

There is extensive evidence that AGEs develops more quickly in patients with diabetes, which negatively contributes to the state of their vascular system.<ref>Singh, V. P., Bali, A., Singh, N., & Jaggi, A. S. (2014). Advanced glycation end products and diabetic complications. ''The Korean journal of physiology & pharmacology: official journal of the Korean Physiological Society and the Korean Society of Pharmacology'', ''18''(1), 1.</ref> AGEs also build over time in the heart muscle and might lead to a decreased respiratory capacity.<ref>Zieman, S. J., & Kass, D. A. (2004). Advanced glycation end product cross‐linking: pathophysiologic role and therapeutic target in cardiovascular disease. ''Congestive Heart Failure'', ''10''(3), 144-151.</ref> Other diseases that might be highly impacted by AGEs formation are [[Aging and eye disease|retinal disease]] or [[Aging and neurodegeneration|neurodegenerative diseases]] such as Alzheimer's.<ref name=":2" /><ref name=":3" /><ref name=":4" />

=== AGE receptors ===
AGEs contribute to disease by engaging with the '''receptor for advanced glycation endproducts (RAGE)''', which is believed to result in pro-inflammatory gene activation.<ref>Gasparotto, J; Ribeiro, CT; da Rosa-Silva, HT; Bortolin, RC; Rabelo, TK; Peixoto, DO; Moreira, JCF; Gelain, DP (May 2019). "Systemic Inflammation Changes the Site of RAGE Expression from Endothelial Cells to Neurons in Different Brain Areas". ''Mol Neurobiol''. '''56''' (5): 3079–3089. doi: 10.1007/s12035-018-1291-6</ref> RAGE is found up-regulated in diabetes and Alzheimer's disease, and in turn activates NF-κB signalling which might mediate the inflammatory components of these diseases.<ref>Gasparotto, J; Girardi, CS; Somensi, N; Ribeiro, CT; Moreira, JCF; Michels, M; Sonai, B; Rocha, M; Steckert, AV; Barichello, T; Quevedo, J; Dal-Pizzol, F; Gelain, DP (Nov 2017). "Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment". ''J Biol Chem''. '''293''' (1): 226–244. doi: 10.1074/jbc.M117.786756</ref><ref>Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klöting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Häring HU, Schleicher E, Nawroth PP (December 2001). "Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB". ''Diabetes''. '''50''' (12): 2792–808. doi: 10.2337/diabetes.50.12.2792</ref> Interestingly, RAGE is down-regulated in pulmonary fibrosis and other conditions such as lung cancer.<ref>Oczypok, EA; Perkins, TN; Oury, TD (June 2017). "All the "RAGE" in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses". ''Paediatric Respiratory Reviews''. '''23''': 40–49. doi: 10.1016/j.prrv.2017.03.012</ref> However, expression of RAGE in the lungs differs significantly from the rest of the body, and is normally highly expressed in lung cells in the absence of disease.<ref>Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, Preissner KT (September 2008). "Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types". ''American Journal of Respiratory Cell and Molecular Biology''. '''39''' (3): 337–45. doi: 10.1165/rcmb.2007-0244OC</ref>

Other receptors exist, such as AGE-R1/3 which are able to recognise and bind to AGE molecules, however they don't appear to transduce cellular signals and might instead play a role in the removal and detoxification of AGE from the bloodstream.<ref>Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, Taguchi A, Yan SF, Yan SD, Stern DM, Schmidt AM. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. '''Cell Mol Life Sci'''. 2002; 59: 1117–1128.</ref>

=== AGEs inhibitors ===
Several AGEs inhibitors have been developed to remove these harmful compounds from the body. One approach is the carbonyl reagent aminoguanidine hydrochloride, which targets the reactive carbonyl groups believed to be required for AGEs formation.<ref>Hou, F. F., Boyce, J., Chertow, G. M., Kay, J., & Owen Jr, W. F. (1998). Aminoguanidine inhibits advanced glycation end products formation on beta2-microglobulin. ''Journal of the American Society of Nephrology'', ''9''(2), 277-283.</ref> Studies have shown that aminoguanidine (Pimagedine) is able to improve the symptoms and progression of AGEs-related diseases such as diabetes type-2 and aging.<ref>Thornalley, P. J. (2003). Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. ''Archives of biochemistry and biophysics'', ''419''(1), 31-40.</ref>

Another class of agents, 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC) showed able to break down the protein-protein crosslinks formed by AGEs and was proposed to revert the vascular damage in animals.<ref>Asif, M., Egan,J.,Vasan,S.,Jyothirmayi,G.N., Masurekar,M.R., Lopez,S.,Williams, C.,Torres,R.L., Wagle, D., Ulrich, P., Cerami, A., Brines, M., and Regan,T.J. (2000). Proc. Nat/. Acad. Sci. U.S.A.97,2809-2813.</ref><ref>Wolffenbuttel, B.H., Boulanger, C.M., Crijns, F.R., Huijberts, M.S., Poitevin, P., Swennen, G.N., Vasan, S., Egan, J.J., Ulrich, P., Cerami, A , and Levy, B.I. (1998). Proc. Nat!. Acad. Sci. U.S.A. 95,4630-4634</ref>

Newer types of drugs based on anti-glucosepane antibodies aim to remove the most abundant form of AGE in the body and appeared to be successful in detecting glucosepane in the retina.<ref>M. D. Streeter ''et al.'', “Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue,” ''ACS Chem. Biol.'', vol. 15, no. 10, pp. 2655–2661, 2020</ref> However, no AGE inhibitors are currently approved for humans by the FDA.

=== AGEs in aging ===
AGEs accumulate during normal aging and have been proposed as a [[Hallmarks of aging|hallmark of aging]].<ref>A. Fedintsev and A. Moskalev, “Stochastic non-enzymatic modification of long-lived macromolecules – a missing hallmark of aging” ''Aging Research Reviews''” 2020</ref> They are believed to accelerate all other hallmarks of aging by, for instance, increasing [[cellular senescence]], inflammation, oxidative stress, [[Telomeres|telomere]] attrition and [[mitochondrial dysfunction]], as well as altering intracellular communication.<ref name=":6" /><ref>C. Correia-Melo, G. Hewitt, and J. F. Passos, “Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?,” ''Longev. Heal.'', vol. 3, no. 1, p. 1, 2014</ref><ref>J. Zhao, “Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart,” ''World J. Diabetes'', vol. 5, no. 6, p. 860, 2014</ref> Additionally, AGEs can increase the occurrence of DNA damage and lead to transcriptional stress, a hallmark of wild-type aging and accelerated aging models.<ref>Tamae, D., Lim, P., Wuenschell, G. E. & Termini, J. Mutagenesis and repair induced by the DNA advanced glycation end product N2-1-(carboxyethyl)-2′-deoxyguanosine in human cells. ''Biochemistry'' 50, 2321–2329 (2011).</ref><ref>Gyenis, A., Chang, J., Demmers, J.J.P.G. ''et al.'' Genome-wide RNA polymerase stalling shapes the transcriptome during aging. ''Nat Genet'' 55, 268–279 (2023). <nowiki>https://doi.org/10.1038/s41588-022-01279-6</nowiki></ref>

Diets low in animal-derived fat and high in carbohydrates, such as vegetarian diets, are thought to decrease the rate of AGEs accumulation.<ref name=":5" /> Raw, boiled or steamed food also decreases the formation of AGEs when carbohydrate-rich diets are not possible.<ref name=":5" /> Studies in rats have shown that [[Calorie restriction|caloric restriction]] benefits the rate of serum AGE accumulation.<ref>W. T. Cefalu ''et al.'', “Caloric Restriction Decreases Age-Dependent Accumulation of the Glycoxidation Products, N?-(Carboxymethyl)lysine and Pentosidine, in Rat Skin Collagen,” ''Journals Gerontol. Ser. A'', vol. 50A, no. 6, pp. B337–B341, 1995</ref> Exercise is also able to decrease the levels of AGE formation in both healthy and diabetic patients.<ref>M. H. Macías-Cervantes, J. M. D. Rodríguez-Soto, J. Uribarri, F. J. Díaz-Cisneros, W. Cai, and M. E. Garay-Sevilla, “Effect of an advanced glycation end product-restricted diet and exercise on metabolic parameters in adult overweight men,” ''Nutrition'', vol. 31, no. 3, pp. 446–451, 2015</ref><ref>P. M. Magalhães, H. J. Appell, and J. A. Duarte, “Involvement of advanced glycation end products in the pathogenesis of diabetic complications: the protective role of regular physical activity,” ''Eur. Rev. Aging Phys. Act.'', vol. 5, no. 1, pp. 17–29, 2008</ref>
<references />
[[Category:Main list]]
[[Category:Aging pathways and hallmarks]]

Resveratrol

2023-02-24T21:09:04Z

Andrea: /* Evidence of lifespan extension */

[[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>

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

Theories of aging

2023-02-24T21:00:24Z

Andrea: /* Programmed theories */

''Why'' we age remains a fundamental mystery of biology.<ref>Kirkwood TB, Austad SN (2000) Why do we age? Nature 408, 233–238.</ref> Over the past decade, there have been substantial advances in our understanding of the mechanistic process underlying aging. However, researchers across the field still fail to find consensus regarding ''what'' is aging and ''why'' it happens.<ref>Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref> Many believe that understanding why we age, will ultimately lead to a better understanding of the aging proces and to more straightforward development of strategies to fight aging.

Several theories of aging exist, each of which provides a different perspective on why and how we age. These theories are not necessarily mutually exclusive, and it is possible that the aging process is a complex interplay of multiple factors.

Some of the most popular aging theories are:

=== Programmed theories ===
The ideas behind the programmed aging theory are originally based on 19th century August Weismman's "Essays upon heredity", which argues that aging evolved by natural selection to remove older individuals of the population and to favour the evolution of the species, by not competing with younger individuals for resources.<ref>Weismann A: Essays Upon Heredity. Ox- ford, Clarendon Press, 1891.</ref> According to Weismman, reproduction is necessary to dissolve the damage that the environment causes to the individual over time.<ref>Weismann A: Über die Dauer des Lebens. Fisher, Jena, 1882.</ref>

The modern programmed theory of aging proposed by Valter Longo argues that aging is a genetically programmed process that has evolved to cause senescence and death, in order to benefit future generations, referred to as "altruistic aging".<ref>Longo VD, Mitteldorf J, Skulachev VP (2005) Programmed and altruistic ageing. Nat. Rev. Genet. 6, 866–872.</ref>

Overall, the programmed theory of aging proposes that each species has an inherent genetic lifespan that is determined by a variety of factors, including the presence or absence of certain genes, the rate of DNA repair, and the activity of various metabolic processes. These factors combine to create an internal "clock" that determines the rate at which an organism ages.

Proponents of the programmed theory of aging point to the fact that different species have wildly different lifespans, which suggests that aging is not simply a matter of "wear and tear" on the body over time. They also note that certain species, such as lobsters or types of tortoises, appear to be able to live for centuries with [[negligible senescence]], suggesting that their internal genetic clock has been set to allow for this. However, recent studies show that animals with negligible senescence such as the naked mole rat do indeed age, and show signs of skin or epigenetic aging, despite the fact of not showing demographic aging (no increase in the risk of death over time).<ref>Kerepesi, C., Meer, M.V., Ablaeva, J. ''et al.'' Epigenetic aging of the demographically non-aging naked mole-rat. ''Nat Commun'' 13, 355 (2022). <nowiki>https://doi.org/10.1038/s41467-022-27959-9</nowiki></ref>

===== Arguments against programmed aging theories =====
It is argued that if aging was genetically programmed, animals kept in captivity would have the same lifespan as animals of the same species living in the wild. However, there is extensive evidence that animals kept in captivity, such as mice, cats, dogs or chimpanzees have significantly longer lifespans than those living in the wild. It is also now largely discredited that animals in the wild do not survive to old age. Steven Austad and colleagues showed there is widespread evidence for natural populations of animals living to the age of senescence, and for old animals having an increased risk of dying than their younger counterparts.<ref>Nussey DH, Froy H, Lemaitre JF, Gaillard JM, Austad SN. Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology. Ageing Res Rev. 2013 Jan;12(1):214-25. doi: 10.1016/j.arr.2012.07.004. Epub 2012 Aug 4. PMID: 22884974; PMCID: PMC4246505.</ref>

Other arguments against this theory point to the fact that no genes have been identified yet that have evolved to cause aging or death in old individuals.<ref>Gladyshev, V. N. (2016). Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. ''Aging cell'', ''15''(4), 594-602.</ref> Additionally, despite existing genome-wide knockdown screens in animals such as ''C. elegans'', no single gene mutations have been identified that lead to the disruption of the aging process or to biological immortality.

=== Evolutionary theories ===
Aging remains an evolutionary paradox. Genes are selected for to ensure their propagation across organisms.<ref>Dawkins, R. (2016). The Selfish Gene: (Oxford Landmark Science).</ref> Therefore, dying appears a counterproductive phenomenon for this mission. Evolutionary theories propose that aging is a result of evolutionary trade-offs between longevity and reproductive success. According to this theory, organisms have evolved to allocate resources to reproduction rather than maintaining their bodies indefinitely.

Evolutionary theories are based on the concept of mutation accumulation proposed by Medawar in the 50s<ref>Medawar PB (1952) An Unsolved Problem of Biology. London: HK Lewis.</ref>

=== Damage-based theories ===
Damage accumulation is arguably one of the most intuitive theories. Damage-based theories propose that aging occurs as a result of the accumulation of damage to cells and tissues over time. This damage can be caused by a variety of factors, including free radicals, radiation, toxins, [[Advanced glycation end products (AGEs)|AGEs]] and other environmental stressors, which eventually result in organismal dysfunction and death.

Many have argued that an increase of entropy, following the second law of thermodynamics, is responsible for damage accumulation in any type of matter over time. However, scientist argue that living organisms are open systems with the capability of receiving external energy supply and therefore are not necessarily subject to a fixed increase in entropy, and repair systems could exist to counteract entropy forces, in theory indefinitely.

Damage-based theories largely fail to explain the evolutionary origin of aging.

=== Telomere shortening ===
[[Telomeres]] are the protective caps at the end of our chromosomes. Over time, telomeres gradually shorten, and this shortening is associated with the aging process.

=== Hormonal theories ===
These theories propose that changes in the levels of certain hormones, such as estrogen and testosterone, play a role in the aging process.

=== Immunological theories ===
These theories propose that the decline in immune system function with age leads to an increased susceptibility to disease and a decreased ability to fight off infections.

=== Free radical theories ===
The free radical theory proposes that aging is caused by the accumulation of free-radicals over time generated by reactive oxygen species (ROS). Free radicals are produced during normal metabolism and are highly reactive, unstable molecules containing oxygen, which have the capability of oxidising other molecules. The free radical theory of aging was first presented in the 50s by Harman<ref>Harman D.Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298–300, 1956</ref> and it remains, as of 2022, the third most cited publication in the history of aging research.<ref>Haroon, Li Y-X, Ye C-X, Ahmad T, Khan M, Shah I, Su X-H, Xing L-X. The 100 Most Cited Publications in Aging Research: A Bibliometric Analysis. Electron J Gen Med. 2022;19(1):em342. <nowiki>https://doi.org/10.29333/ejgm/11413</nowiki></ref>

However, this theory has been now largely discredited: an increasing number of publications seem to contradict that aging can be solely explained by the accumulation of free radicals.<ref>Gladyshev VN. The free radical theory of aging is dead. Long live the damage theory! Antioxid Redox Signal. 2014 Feb 1;20(4):727-31. doi: 10.1089/ars.2013.5228.</ref> Instead, free radicals appear to be one of the many hallmarks associated to the aging process. For instance, if free radicals were sufficient to cause aging, experiments in which antioxidants (which can neutralise free radicals) are overexpressed, such be able to extend lifespan. However, this is not seen in some animal models such as flies<ref>Mockett RJ, Sohal BH, and Sohal RS.Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of ''Drosophila melanogaster''. Free Radic Biol Med 49: 2028–2031, 2010</ref> or mice<ref>Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, and Richardson A.The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8: 73–75, 2009</ref>, and might some times even lead to lifespan shortening.<ref>Van Rammsdonk JM. and Hekimi S.Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in ''Caenorhabditis elegans''. PLoS Genet 5: e1000361, 2009 </ref> Another argument against the free radical theory of aging points towards the fact that aging still occurs under anaerobic conditions, such as in yeast cells, where ROS are generated to a very small degree.<ref>Koc A, Gasch AP, Rutherford JC, Kim HY, and Gladyshev VN.Methionine sulfoxide reductase regulation of yeast lifespan reveals reactive oxygen species-dependent and -independent components of aging. Proc Natl Acad Sci USA 101: 7999–8004, 2004 </ref>