Accumulation of senescent cells in mitotic tissue of aging primates

Abstract

Cellular senescence, a stress induced growth arrest of somatic cells, was first documented in cell cultures over forty years ago, however its physiological significance has only recently been demonstrated. Using novel biomarkers of cellular senescence we examined whether senescent cells accumulate in tissues from baboons of ages encompassing the entire lifespan of this species. We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age. The number of dermal fibroblasts containing damaged telomeres reaches a value of over 15% of total fibroblasts, whereas 80% of cells contain high levels of the heterochromatin protein HIRA. In skeletal muscle, a postmitotic tissue, only a small percentage of myonuclei containing damaged telomeres were detected regardless of animal age. The presence of senescent cells in mitotic tissues might therefore be a contributing factor to aging and age related pathology and provides further evidence that cellular senescence is a physiological event.

Aging by epigenetics—A consequence of chromatin damage?

“…Second, the histone chaperone HIRA plays a key role in formation of SAHF [89][90][91][92]. As noted previously, based on immunostaining assays, this chaperone is upregulated in the dermal fibroblasts of aging baboons [40].…”

“…Consequently, they are key determinants of chromatin structure and function. Significantly, at least one of these, the histone chaperone HIRA, has been shown to increase in expression or undergo some level of regulation in aging baboon skin [40,41]. Although the HIRA histone chaperone may have some functions linked to transcription activation [42][43][44][45][46][47][48], this chaperone is known to have an evolutionarily conserved role in heterochromatin formation [49][50][51][52][53][54][55][56].…”

“…Because of senescence, most primary human cells have a finite proliferative lifespan, and evidence has been presented that senescence contributes to tissue aging in vivo, in part by limiting the self-renewal of tissues [61][62][63]. Specifically, senescent cells and/or molecular markers of the senescent phenotype have been reported to increase in some aging tissues [40,41,[64][65][66][67][68][69], and are linked to some age-associated tissue pathologies, such as osteoarthritis, atherosclerosis and liver cirrhosis [70][71][72]. Moreover, manipulation of the cell signals that initiate senescence, such as telomere length and expression of the proliferation inhibitor p16INK4a [66][67][68]70,[73][74][75][76][77][78][79][80], can modulate some aspects of organismal aging [70][71][72].…”

Âge et stress oxydant

“…Très étudiée en culture cellulaire [16][17][18][19], la sénescence joue un rôle physiopathologique in vivo [20,21]. Les cellules sénes-centes s'accumulent dans des endroits stratégiques de dommages cellulaires [21,22], par exemple dans la plaque athérosclérotique [23].…”

“…En effet, les ROS jouent un rôle crucial dans la physiologie de la cellule et dans des processus aussi variés que le développement, la croissance cellulaire ou le système immunitaire [36]. Nos données suggèrent que la longévité fonctionnelle de l'endothélium vasculaire est déterminée en grande partie durant la phase de maturation et qu'elle dépend de l'exposition physiologique [19,21]. De même, un stress oxydant modéré induit la surexpression d'enzymes et de molécules anti-oxydantes qui maintiennent l'homéostasie cellulaire [37,38].…”