Replicative Senescence: An Old Lives' Tale?

Abstract

One might imagine that cellular senescence could inhibit tissue repair. However, substantial numbers of proliferative cells can often be recovered from very old tissues, and wounds do heal even in very old mammals (although sometimes more slowly). Of course, senescent cells may comprise only a small fraction of aged tissue. Indeed, in situ staining for the senescence-linked β-galactosidase suggests that senescent cells are sparsely distributed in aged skin (Dimri et al. 1995xDimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E., Linskens, M., Rubelj, I., Pereira-Smith, O., Peacocke, M., and Campisi, J. Proc. Natl. Acad. Sci. USA. 1995; 92: 9363–9367Crossref | PubMed | Scopus (3798)See all ReferencesDimri et al. 1995). Thus, the growth arrest of senescent cells may not be a major problem in aged tissues, although it could certainly compromise the organism by delaying repair.By contrast, the altered function of senescent cells may have a substantial impact in aged tissue. For example (seeCampisi et al. 1996xSee all ReferencesCampisi et al. 1996), senescent human skin fibroblasts overexpress collagenase and underexpress collagenase inhibitors. This may well cause or contribute to the collagen breakdown and thin dermis typical of aged skin. Senescent fibroblasts also underexpress interleukin-6 and overexpress interleukin-1, cytokines with pleiotropic inflammatory and immune effects. Thus, senescence-linked changes in differentiation could, at least in principle, have rather profound and far-ranging consequences for tissue function. Moreover, relatively few senescent cells would be needed for some of these effects.Finally, resistance to apoptotic death may explain why senescent cells are not cleared and thus accumulate with age. Indeed, it was recently proposed that caloric restriction, which delays many age-related changes, may do so by increasing the incidence of apoptosis (Warner et al. 1995xWarner, H.R., Fernandes, G., and Wang, E. J. Gerontol. 1995; 50A: B107–B109CrossrefSee all ReferencesWarner et al. 1995).Thus, age-related decrements in tissue function may, at least in part, derive from an accumulation of senescent cells—which cannot proliferate, which resist apoptotic death, and which have an altered phenotype.Evolutionary theories of aging have suggested that traits selected to optimize health during the period of reproductive fitness can have unselected deleterious effects later in life. Replicative senescence may have been selected, at least in mammals, to help ensure the relative freedom from cancer that characterizes early adulthood. However, this trait may be deleterious late in life because dysfunctional senescent cells accumulate. Moreover, because cancer incidence rises with age, it also appears that cellular senescence is an imperfect tumor suppressive mechanism that fails increasingly with age. In fact, it would seem that late in life replicative senescence wreaks havoc—whether it succeeds or fails.