Supraphysiological protection from replication stress does not extend mammalian lifespan

Abstract

Replication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the Chk1 and/or Rrm2 genes, which we previously showed extend the lifespan of a progeroid ATRhypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of Chk1, Rrm2 and Chk1/Rrm2 transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors-mainly lymphomas-irrespective of their genetic background. Interestingly, a higher but not statistically significant percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of normal aging.

Replication stress as a driver of cellular senescence and aging

“…Elevated Rrm2 gene dosage indeed prolonged survival of ATR mutant mice and depressed chromosomal breakage at fragile sites 169 . However, lifespan of wild-type laboratory mice was not https://doi.org/10.1038/s42003-024-06263-w extended by increased gene dosage of Rrm2 and/or Chk1, leading the authors to suggest that protection from replication stress using the transgenic mouse model system employed did not extend normal aging 172 .…”