Cells can enter a senescent state in response to damage, ceasing to divide. This reduces the risk of cancer under most circumstances, but is also a part of the wound healing process. This isn't all good, however. Senescent cells secrete factors that harm surrounding tissue function over the long term, and the growing numbers of these cells with age is one of the causes of age-related disease and dysfunction. Researchers here look more deeply into how various mechanisms in a cell conspire to cause senescence. They are aiming to produce a more unified view of the varied entry points to this cell state. You should scroll down in the open access paper to the diagram near the end - this is a collection of mechanisms that really benefits from a visual explanation:
Genome integrity is preserved by the DNA damage response (DDR) that, in the presence of DNA damage, arrests the cell cycle progression while coordinating DNA repair events. If damage is not resolved, cells can enter into an irreversible state of proliferative arrest called cellular senescence. In the past years, a strong link between telomere-initiated cellular senescence and organismal ageing has emerged, [where aging is] associated with accumulation of markers of cellular senescence and DDR persistence at telomeres.
Since the vast majority of the cells in mammals are non-proliferating, how do they age?Telomere-initiated cellular senescence seems to be a plausible mechanism to explain the ageing-associated functional decline of proliferating tissues in vivo. However, it is reasonable to assume that some other mechanisms may be in place in non-proliferating cells in which no telomeric attrition due to the end replication problem is expected to occur, either because these cells are quiescent or differentiated. Surprisingly however, we and others have shown that telomeres might have a central role in senescence establishment independently from their shortening.
In these reports, random DNA damage [leads] to DDR activation that preferentially persists at telomeres over time. Cells with persistent DDR activation show a senescent phenotype that cannot be prevented by exogenous expression of telomerase, further excluding a contribution of telomere shortening. The mechanism proposed to explain this phenomenon is the suppression of effective DNA repair at telomeres by TRF2, a telomeric DNA binding protein. Consistent with this model, DDR activation at telomeres is more frequent in mouse and baboon tissues from aged animals, when compared with their young counterparts. This observation also suggests that having long telomeres may have an important drawback, since more telomeric DNA can offer a wider target for random DNA damage that cannot be repaired. Indeed, in different mammalian species, telomere length and lifespan are inversely correlated.