This open access review of cellular senescence in aging is perhaps noteworthy for being authored in part by Vadim Gladyshev, one of the more pessimistic researchers in our community. Simplified a little, his opinion is that aging and metabolism are too complex and poorly understood to hope for rapid progress towards rejuvenation and life extension in our lifetimes. He is not in agreement with the proposition that one can bypass the requirement for greater understanding of aging by targeting the root causes of aging - one of which is the accumulation of senescent cells - as I don't think he considers the SENS portfolio of causes of aging sufficiently proven. It is thus interesting to see him engage in detail with the topic of cellular senescence, particularly given the past few years of promising results in mice due to senolytic therapies capable of selectively destroying these cells.
Some animals are characterized by the so-called negligible senescence, such as a species within the genus of Cnidaria - Hydra, although it is known that their individual cells do age. This apparent nonaging phenotype can be achieved by replacing cells that accumulated damage over time with new cells generated from abundant stem cells that can give rise to any cell type in the body. However, this nonaging strategy is not applicable to the great majority of organisms with specialized, nonreplaceable cells and structures. When organisms are unable to replace cells at will or dilute damage, intracellular damage accumulates, exerting its deleterious effect on the host cell as well as other cells, impairing their function and ultimately contributing to age-related diseases and to aging itself.
The macroscopic age-associated changes in organisms are so obvious and severe that identifying their molecular bases would seem to be an easy task. Yet, all the research conducted so far has not led to the unambiguous identification of the causal factors orchestrating aging.
With recently published evidence, the role of cellular senescence in organismal aging has become increasingly clear. The phenomenon of cellular senescence has a special meaning in the context of damage accumulation in aging. Cells triggered to senesce by damaging insults exhibit higher basal levels of damaged macromolecules than healthy cells and also generate damage at a higher rate. This notion posits senescent cells as organismal carriers of damage. It is especially relevant for the irreparable forms of damage such as telomere-associated breaks and lipid-protein aggregates of lipofuscin.
Kinetics of senescent cell accumulation in response to lifespan-modulating interventions differs from the kinetics of irreparable and reparable types of damage. This is due to yet another layer of complexity in the regulation of senescent cell population in vivo that is mediated by the immune system. Subjected to a life-extending intervention, an organism can remove senescence-related damage, in contrast to other types of irreparable damage. A change from life-extending to life-shortening conditions does not, however, abolish the beneficial effects of the former. As shown for calorie restriction, animals on short-term calorie restriction maintain the status of low senescent cell abundance after the end of the treatment.
Accumulation of senescent cells is an integral part of the damage accumulation process. Senescent cells then emerge as causal to age-related diseases. This model explains the recently published evidence that elimination of senescent cells can alleviate multiple age-related diseases and increase health span but does not greatly affect the rate of aging/maximum lifespan. As senescent cells contain high levels of irreparable damage, we do not imply that a certain effect on the rate of aging is impossible. However, we argue that elimination of senescent cells is unlikely to be the intervention that would very significantly prolong human maximum lifespan.