Cellular senescence

From Longevity Wiki

Senescent cells (SCs) are cells that have stopped dividing and are no longer able to grow or divide, a phenomenon known as the "Hayflick limit".[1] SCs have been hypothesized to be drivers of aging and are associated to aging and age-related diseaeses.[2] Cellular senescence is considered to be one of the hallmarks of aging.[3]

Mechanism

Senescent cells produce pro-inflammatory signalling molecules such as the senescence-associated secretory phenotype (SASP),[4] releasing various factors that can trigger inflammation and dysfunction, while promoting apoptosis (cell death) in nearby tissues.

SASP

Typical components and central biomarkers of the SASP according to Aging Biomarker Consortium., Bao, H., Cao, J. et al. 2023[5]

Subcategory Component
Chemokines IL-8, GROα, GROβ, GROγ, MCP1, MCP2, MCP4, CCL1, CCL3, CCL5, CCL11, CCL16, CCL20, CCL25, CCL26
Cytokines IL-6, IL-11*, IL-7, IL-1α, IL-1b, IL-13, IL-15, IL23a, TNFα
Other inflammatory factors TGF-β, GM-CSF, M-CSF, G-CSF, IFN-α1, IFN-γ, CCL13, MIF, LIF
Growth factors AREG, EREG, heregulin, EGF, bFGF, HGF, FGF7, VEGF, ANG, SCF, CXCL12, GDF15, GDNF, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP6, IGFBP7
Proteases and inhibitors MMP1, MMP2, MMP3, MMP8, MMP10, MMP12, MMP14, TIMP1, TIMP2, PAI-1, PAI-2, tPA, uPA, cathepsin B, SPINK1, SERPINs
Receptors and ligands ICAM1, ICAM3, OPG, sTNFRI, sTNFRII, TRAIL-R3, Fas, uPAR, SGP130, EGF-R, WNT16B
Insoluble molecules Collagens, fibronectin, laminin
*Added by us later based on literature data

Data are derived and processed from cellular senescence- and aging-related literatures (Acosta et al., 2008; Coppe et al., 2008a; Coppe et al., 2010; Coppe et al., 2008b; Gorgoulis et al., 2019; Kuilman et al., 2008; Rodier et al., 2011; Sun et al., 2012). See also: Wang et al., 2024[6]

Preliminary identification of specific SASP proteins associated with aging traits in humans was carried out in the work of Evans et al., 2024. [7] Among the 28 age-associated SASP proteins, 18 were associated with 1 or more clinical age-related traits. GDF-15 (Growth/differentiation factor 15), CST3 (Cystatin 3) also known as Cystatin-C (lysosomal and extracellular cysteine protease inhibitor С), and IGFBP-2 (Insulin-like growth factor-binding protein 2) were the most significantly associated with age, and each of these proteins was associated with 5 or more clinical traits. GDF-15 and IGFBP-2 were both significantly associated with age, inflammatory markers, fasting glucose, RDW, albumin, and grip strength. Higher levels of Cystatin-C were significantly associated with higher IL6, higher BUN, lower albumin, and poorer physical performance (lower grip strength and slower gait speed), and higher levels of Cystatin-C’s target, Cathepsin Z, were significantly associated with higher waist circumference, higher CRP, and slower gait speed.[7]

Circulating concentrations of senescence biomarkers of the SASP, could predict mortality in older adults. Elevated levels of a stress-induced cytokine growth factor GDF15 are most strongly associated with an increased risk of death in populations of all ages, even after adjustment for several risk factors.[8][9][10][11][7]

Cellular senescence and aging

Due to the negative impact that SCs may have in neighbouring cells and tissues, some scientists believe that the clearance of senescent cells via senolytics may have therapeutic benefits, especially for treating age-related diseases such as cancer, cardiovascular disease or neurodegeneration.[2] Cellular senescence has also been suggested as a driver of fibrotic pulmonary disease.[12]

Cellular senescence can be viewed as a necessary, adaptive response of the body in response to injury, infection or other stresses.[13] It also serves key purposes during tissue remodelling, wound repair or embryogenesis. However, chronic senescence can be maladaptive and lead to age-related diseases.[14]

It is not clear whether removing senescent cells might have deleterious effects in vivo, and several studies are suggesting that they play a fundamental role in physiology and thus might be detrimental to remove them, even when accumulated chronically. For instance, eliminating senescent cells in mice promoted the development and progression of pulmonary hypertension.[15]

Senolytics

See the full article on senolytics.

Senescent cells survive their own SASP, since they are protected by networks of senescent cell anti-apoptotic pathways (SCAPs). One mechanism of senolytics, therefore, is to interfere with these networks, so that the SASP also induce apoptosis in the senescent cells themselves. Senescent cells take time to re-build once they are ablated. Hence, an advantage of senolytic treatment is that it can be done in a "hit-and-run" fashion, thus avoiding off-target effects in comparison to other types of treatments.

A way to track if senolytics have any effect is to check out for senescent biomarkers. Some known markers of SCs are p16, p21 and senescence-associated β-galactosidase activity (SA-β-gal).

https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy

Cellular senescence as an adaptive process

Negligible senescence

See the full article on negligible senescence.

The phenomenon of showing no signs of senescence, such as age-related dysfunctions.

References

  1. ↑ Shay, J., Wright, W. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol 1, 72–76 (2000). https://doi.org/10.1038/35036093
  2. ↑ 2.0 2.1 van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439-46. doi: 10.1038/nature13193. PMID: 24848057; PMCID: PMC4214092.
  3. ↑ López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
  4. ↑ Huna, A., Massemin, A., Makulyte, G., Flaman, J. M., Martin, N., & Bernard, D. (2024). Regulation of cell function and identity by cellular senescence. Journal of Cell Biology, 223(8). PMID: 38865089 PMC11169915 DOI: 10.1083/jcb.202401112
  5. ↑ 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
  6. ↑ Wang, B., Han, J., Elisseeff, J.H. et al. (2024). The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol https://doi.org/10.1038/s41580-024-00727-x
  7. ↑ 7.0 7.1 7.2 Evans, D. S., Young, D., Tanaka, T., Basisty, N., Bandinelli, S., Ferrucci, L., ... & Schilling, B. Proteomic Analysis of the Senescence Associated Secretory Phenotype (SASP): GDF-15, IGFBP-2, and Cystatin-C Are Associated with Multiple Aging Traits. The journals of gerontology. Series A, Biological sciences and medical sciences, 79(3), glad265. PMID: 37982669 PMC10876076 DOI: 10.1093/gerona/glad265
  8. ↑ Eggers, K. M., Kempf, T., Wallentin, L., Wollert, K. C., & Lind, L. (2013). Change in growth differentiation factor 15 concentrations over time independently predicts mortality in community-dwelling elderly individuals. Clinical Chemistry, 59(7), 1091–1098. https://doi.org/10.1373/clinchem.2012.201210
  9. ↑ St. Sauver, J. L., Weston, S. A., Atkinson, E. J., Mc Gree, M. E., Mielke, M. M., White, T. A., ... & LeBrasseur, N. K. (2023). Biomarkers of cellular senescence and risk of death in humans. Aging Cell, e14006. https://doi.org/10.1111/acel.14006
  10. ↑ Wischhusen, J., Melero, I., & Fridman, W. H. (2020). Growth/differentiation Factor-15 (GDF-15): From biomarker to novel targetable immune checkpoint. Frontiers in Immunology, 11, 951. https://doi.org/10.3389/fimmu.2020.00951
  11. ↑ Wan, Y., & Fu, J. (2023). GDF15 as a key disease target and biomarker: linking chronic lung diseases and ageing. Molecular and Cellular Biochemistry, 1-14. PMID: 37093513 PMC10123484 DOI: 10.1007/s11010-023-04743-x
  12. ↑ Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532. doi: 10.1038/ncomms14532. PMID: 28230051; PMCID: PMC5331226.
  13. ↑ Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell. 2010 Oct;9(5):667-84. doi: 10.1111/j.1474-9726.2010.00608.x. Epub 2010 Aug 15. PMID: 20701600; PMCID: PMC2941545.
  14. ↑ Huang, W., Hickson, L.J., Eirin, A. et al. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 18, 611–627 (2022). https://doi.org/10.1038/s41581-022-00601-z
  15. ↑ Born, E. et al. (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” Circulation[Preprint]. Available at: https://doi.org/10.1161/circulationaha.122.058794.
  16. ↑ João Pedro de Magalhães (2024). Cellular senescence in normal physiology.Science, 384, 1300-1301 DOI:10.1126/science.adj7050
Retrieved from ‘https://en.longevitywiki.org/index.php?title=Cellular_senescence&oldid=3332’
Creative Commons Attribution-ShareAlike
Powered by MediaWiki