Senescent Cells and Somatic Mutations as Distinct Drivers of Aging
Senescent cells accumulate with age, likely largely because the aging of the immune system slows down the clearance of senescent cells, but the relative importance of different contributions to the growing burden of senescence in aging tissues is an area of ongoing discussion. Senescent cells secrete inflammatory signals that are disruptive to tissue structure and function when sustained over the long term. Separately, cells throughout the body accumulate mutations over the course of aging. Much of this has little to no effect, occurring in cells with few replications remaining, or in genes not used by the cell. However, a growing burden of mutation in stem cell populations spreads slowly into the tissues they support via the daughter somatic cells generated to replace those cells lost to the Hayflick limit; this somatic mosaicism is thought to produce a meaningful disruption of function, as well as set the stage for rare cancer-inducing mutations to prosper. All distinct causes of aging are thought to interact with one another, to make one another worse, which is one of the reasons why degenerative aging is not a linear process, but cellular senescence and somatic mutation are somewhat challenging to reason about in this respect. Nonetheless, researchers here make the attempt.
Cellular senescence is widely recognized as a driver of age-related phenotypes, intrinsically linked to other aging hallmarks such as telomere dysfunction, chronic inflammation, and stem cell exhaustion. Differently, the potential interplay of somatic mutations (as distinct from the broader concept of genome instability) with the other hallmarks of aging is still unprobed, and the contribution of an altered DNA sequence to aging needs deeper understanding. More broadly, our discussion of cellular senescence and somatic mutations illustrates the wider challenge of biogerontology in distinguishing driver from passenger mechanisms of aging.
Cellular senescence and mutation accumulation are distinct events, and it is presently unclear how these pathways relate to each other. Notably, among the limited evidence connecting the two paradigms, an important discovery is that they can functionally converge when mutations cause oncogene activation and consequent cellular senescence. In addition, although senescent cells are mitotically arrested and thus immune to replication errors, they may still accumulate mutations due to increased production of genotoxic reactive oxygen species and the reactivation of retrotransposons, which can cause insertional mutagenesis. The observation that senescent cells repress several DNA repair genes and have decreased repair efficiency upon irradiation, combined with their resistance to apoptosis, provide the bases for mutation accumulation in these cells.
Defining the interplay between cellular senescence and mutations remains a significant challenge, with a limited number of dedicated studies in the literature, because both processes derive from DNA damage and are difficult to disentangle. Such analyses are further complicated by the low abundance of senescent cells in aged tissues and by the impossibility of expanding these arrested cells. Therefore, elucidating this relationship represents a largely unexplored area of research in the field, one that will refine our understanding of the aging network.