Fight Aging!

The size of the contribution of stochastic nuclear DNA damage to aging is debated. It causes cancer, when rare combinations of cancerous mutations occur and suppression of those early cancerous cells fails, but can it give rise to a meaningful degree of tissue dysfunction otherwise? The present consensus is that most such damage is irrelevant, occurring in cells that will not replicate further all that many times, and in genes that are not active. However, mutations in stem cells and progenitor cells can spread widely throughout tissue. Indeed, evidence shows that mice and humans exhibit a patterning of such distributed mutations. No robust evidence yet exists to pin down a size of effect of this spread of mutations on the progression of aging, however.

There are many ways in which DNA can become damaged, and cells possess highly efficient DNA repair mechanisms that quickly fix almost all issues. In today's open access paper, researchers show that the damage that occurs during replication of DNA does not have a significant influence on aging in mammals, despite the fact that it does appear to affect aging in short-lived lower species. The researchers engineered mice to improve repair of replicative DNA damage, but these mice did not live longer as a result. This is an interesting addition to the debate over the relevance of stochastic DNA damage to aging.

Supraphysiological protection from replication stress does not extend mammalian lifespan

In recent years, replication stress (RS) has been acknowledged as an important source of endogenous DNA damage. RS is a type of DNA damage that occurs when obstacles to replication lead to an accumulation of single stranded DNA (ssDNA) at stalled replication forks, which is recognized by ssDNA binding protein RPA. This initiates a signaling cascade involving Ataxia Telangiectasia and Rad3-related (ATR) kinase and CHK1 which promotes DNA repair, cell cycle arrest, and apoptosis.

Similar to other types of DNA damage, RS has been linked to aging. For instance, aged hematopoietic stem cells (HSCs) exhibit increased levels of RS compared to young HSCs. In addition, mutations in the ATR gene cause Seckel syndrome in humans, which is characterized by progeria, growth retardation, microcephaly, mental retardation, and dwarfism. The involvement of RS in premature aging has also been shown experimentally with a mouse model for Seckel syndrome. ATR-Seckel mice exhibit a phenotype similar to that of human patients, which is further aggravated in combination with several cancer-driving mutations such as the Myc oncogene or the absence of the tumor suppressor p53. ATR-Seckel mice show high levels of RS during embryonic development, accelerated aging in adult life and early lethality.

Interestingly, mice harbouring extra alleles of Chk1 (Chk1Tg) or of the ribonucleotide reductase (RNR) regulatory subunit Rrm2 (Rrm2Tg), which is a limiting factor for dNTP production, improved the lifespan and alleviated the progeroid phenotype of ATR mutant mice. These Chk1 and Rrm2 transgenic mice carry bacterial artificial chromosome (BAC) alleles of the respective genes, including exons and introns, under their own endogenous promoters. This strategy provides supraphysiological levels of CHK1 and RRM2 while preventing overexpression in tissues where these genes are normally not expressed, and was proven successful with the Trp53 BAC-transgenic mouse mode.

Collectively, these studies suggested that RS might have important implications in mammalian aging. However, the effect of Chk1 and Rrm2 expression levels on normal aging, in mice with physiological levels of ATR, remains to be elucidated. In the current study, we investigated the effect of supraphysiological levels of CHK1 and RRM2, which confer extra protection against RS, on normal aging. We utilized cohorts of wild type, Chk1Tg, Rrm2Tg and Chk1Tg;Rrm2Tg mice to assess tumor-free survival of these mice. We found no differences in survival between the genotypes and all mice exhibited similar signs of aging. Thus, supraphysiological levels of CHK1 and RRM2 do not affect normal aging in mice.