Genome maintenance and human longevity

Abstract

Accumulation of DNA damage and mutations is considered an important causal factor in age-related diseases. Genetic defects in DNA repair cause premature onset and accelerated progression of aging-related diseases and a shorter life span in humans and mice, providing strong evidence that genome maintenance is a bona fide longevity assurance pathway. However, the contribution of genome maintenance to human longevity itself remains to be established. Here, we review the results of human genetics studies, including genome wide association studies, and attempted to catalogue all genes involved in major DNA repair pathways that harbor variants associated with longevity. We hope to provide a comprehensive review to facilitate future endeavors aimed at uncovering the functional role of genome maintenance genes in human longevity.

Cell-centric hypotheses of aging

“…The DNA damage theory arose from the idea that aging might result from DNA damages that remain un-repaired and that such damages contribute to the age related pathologies. Consistent with such a theory, defects in the DNA nucleotide excision repair are associated with accelerated aging in mice while certain single nucleotide polymorphism in DNA repair genes are associated with extended life-span in humans (28)(29)(30)(31)(32). DNA endures damage such as single-and doublestrand breaks, adducts, and crosslinks and mutations throughout life by a host of internal and environmental factors (33).…”

Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

“…The DNA repair machinery involves divergent pathways, each aimed to correct certain forms of DNA damage ( Figure 2 ). These protective mechanisms have been in the focus of cancer and aging research for a long time (Zimmermann, 1971; Lombard et al, 2005; Cho and Suh, 2014). Defects in DNA repair genes, like the Bloom syndrome RecQ like helicase ( BLM ) and the Werner syndrome RecQ like helicase ( WRN ), can lead to severe illnesses, called progeria syndromes in humans, which are characterized by premature aging and other symptoms, including cognitive disabilities and a higher rate of tumorigenesis (Ellis et al, 1995; Yu et al, 1996; Martin, 2005; Arora et al, 2014).…”

“…Mutations in other DNA repair genes were also reported to increase cancer risk (Jeggo et al, 2016) and thus lead to a reduction in expected lifespan. More importantly, polymorphisms in several genes of the DNA damage response machinery have been actually linked to longevity in humans (Cho and Suh, 2014). Intriguingly, no canine progeria syndrome has been documented in scientific literature.…”

Maillard reaction and aging: can bacteria shed light on the link?

“…Furthermore, because of the complex regulatory networks, mutations in regulatory DNA sequences may be quite more harmful than mutations in a single protein-encoding gene while mutations affecting DNA repair mechanisms themselves are further contributing to excessive DNA damage. Experiments indeed have shown that defects in DNA repair cause premature aging [74][75][76][77][78] and vice versa, enhanced activity of DNA repair enzymes leads to longer life span [79][80][81][82]. Many studies reveal a link between the accumulation of mutations in DNA with age and cancer predisposition of elderly people [83][84][85].…”