1. Supraphysiological protection from replication stress does not extend mammalian lifespan
- Author
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Eliene Albers, Alexandra Avram, Andrés J. López-Contreras, Mauro Sbroggiò, and Oscar Fernandez-Capetillo
- Subjects
Genome instability ,Genetically modified mouse ,DNA Replication ,Aging ,medicine.medical_specialty ,Ribonucleoside Diphosphate Reductase ,DNA damage ,replication stress ,Longevity ,Context (language use) ,Endogeny ,Mice, Transgenic ,Biology ,Mouse models ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,cancer ,Animals ,mouse models ,Gene ,Cancer ,030304 developmental biology ,0303 health sciences ,Progeria ,aging ,Replication stress ,Cell Biology ,medicine.disease ,Accelerated aging ,Endocrinology ,030220 oncology & carcinogenesis ,Checkpoint Kinase 1 ,Priority Research Paper - 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 ATR-hypomorphic 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 slightly higher 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.
- Published
- 2020
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