Читать книгу Pathy's Principles and Practice of Geriatric Medicine - Группа авторов - Страница 46

Cellular senescence is a state of stable arrest of the cell cycle coupled to phenotypic changes, including the production of several molecules (especially matrix metalloproteases and pro‐inflammatory cytokines) collectively known as the senescence‐associated secretory phenotype (SASP),⁴⁷ that contributes to senescence spreading among others cells, inflammation, and tissue dysfunction. Of note, a better understanding of molecular mechanisms of cell senescence led to a more complex picture of a multi‐step progressive and dynamic phenomenon rather than a static endpoint.⁴⁸

As cited earlier, cellular senescence was originally described by Hayflick in human fibroblasts in vitro ²¹; this phenomenon, called replicative senescence, is now known to be caused by telomere shortening. Nevertheless, cell senescence can be triggered by other stimuli during ageing, notably non‐telomeric DNA damage and excessive mitogenic signalling, particularly by the p16Ink4a tumour‐suppressor protein upon epigenetic de‐repression of the ink4/ark locus.⁴⁹ p16Ink4a positively correlates with age in various tissues in mice and human skin.^50,51 In a meta‐analysis of 372 genome‐wide association studies (GWASs) aiming at identifying susceptibility polymorphisms for age‐associated diseases, the ink4/ark locus was linked to the greatest number of diseases, including Alzheimer’s, cardiovascular diseases, cancer, and type 2 diabetes.⁵² Furthermore, the number of cells expressing p16Ink4a in muscular fat correlates with muscle strength and walking performance.⁵³

Since the number of senescent cells is positively associated with age, it has been postulated that cell senescence contributes to ageing. However, this phenomenon may also be seen as a mechanism to prevent the propagation of damaged and potentially oncogenic cells and to trigger their elimination by the immune system. Tissue dysfunction and ageing could then only be explained by an impaired turnover of cells due to reduced clearance of senescent cells and/or reduced regeneration by progenitor cells. As described previously for free radicals, this dual role of cell senescence in ageing can reconcile apparently contradictory effects of experimental modulation of p16Ink4a activity on health and lifespan in mice.^15,54‐56

Interestingly, the selective elimination of senescent cells attenuates age‐related deterioration of several organs and extends lifespan in mice,⁵⁷ and the potential anti‐ageing effects of senolytic drugs is an intense area of research.⁵⁸