Replication stress vs. lifespan, across evolution

Replication stress, defined as the harmful effects of partially replicated DNA persisting in the nucleus, has a negative impact on the chronological lifespan of yeast, according to a recently published study by Weinberger et al.. The authors propose that a variety of life-extension techniques (including calorie restriction) might benefit cells primarily by preventing them from attempting to synthesize DNA, causing cell-cycle arrest in G1 (when the nuclear DNA is well-ordered and intact) as opposed to S (at which point an arrest results in stalled replication forks and other lesions that will likely be deleterious if they persist).

Chronological lifespan is distinct from replicative lifespan — the former is the time a yeast cell can persist in a nutrient-limited environment, the latter is the number of times a given mother cell can bud. Still, I can’t help but be reminded of recent observations by d’Adda di Fagagna and co-workers that DNA hyper-replication in response to oncogenic stimulation (which also results in stalled replication forks and other structural abnormalities in the DNA) has a baleful influence on the replicative lifespan of mammalian cells in culture. Granted that yeast have no reason to senesce (do they?), the similarities in these two stories suggest a conserved mechanism by which DNA damage (even if self-induced) can limit longevity.

The Weinberger study is at PLoS ONE, by the way, if you’d like to add your own commentary/annotation at the online version of the article.