In Replicative Senescence, Cells Become Senescent Slowly as Telomeres Shorten

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. Telomere length is reduced with each cell division, and when telomeres become too short cells become senescent and either undergo programmed cell death or are removed by the immune system. This ensures cell turnover in tissues, and acts to reduce the risk of cell lineages becoming damaged enough to become cancerous.

Researchers here present evidence for the onset of this replicative senescence to be a slow process, changes assembling and growing as telomeres become shorter. The implication is that while senescent cells are known to be harmful when they accumulate with age, perhaps the burden of pre-senescent cells in old tissues is also meaningfully harmful. Whether or not this is the case has yet to be determined; the challenge is never in identifying a mechanism, the challenge lies in determining how important it is.

In 1961, researchers discovered that human fibroblast cells cultured in the laboratory could only divide a limited number of times, after which they stopped multiplying but remained metabolically active. This state was termed replicative senescence and was found to occur in a range of cell types. Further research revealed that senescence is caused by the shortening of caps, or 'telomeres', on the end of chromosomes. Every time a cell divides, its telomeres shrink until they reach a critical length that stops the cell from multiplying. New evidence showed that senescence is induced by cell stress as well as successive divisions, and that the number of senescent cells increases as tissues age.

Despite almost 60 years of research, many questions still remain about senescence; for instance, what happens to cells as they transition in to the senescent state? How does their metabolism change during this shift, and do they take on a new cell identity? Now researchers report the results of experiments that exquisitely profile the roadmap cells take on their path to senescence.

The team used a new experimental design to survey the entire genome and repertoire of RNAs, proteins, and metabolites present in fibroblasts cultured in the laboratory. These patterns were traced over time as the cells grew until they stopped dividing. The data revealed that RNAs known to be expressed in fully senescent cells progressively accumulate throughout the cell cycle. This suggests that senescent cells in vivo may be slowly amassing these features, but not yet expressing the classic biomarkers associated with the end-point of senescence, such as the beta-galactosidase enzyme.

The findings suggest that cells gradually acquire a number of changes on the path to replicative senescence: they express different genes, rewire their metabolic reactions and take on a new identity similar to mesenchymal cells. Previous studies have shown that removing senescent cells can increase the health- and life-span of mice. Therefore, interventions that target these early changes could help improve the well-being of individuals by stopping the cascade of events that lead to replicative senescence.


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