Endogenous DNA damage as a driver of senescence and aging

Abstract

Aging is defined as a loss of tissue homeostasis and resilience in the face of stress and is attributed to stochastic damage that occurs over time. However, in measuring the various types of cellular damage it is impossible to determine what damage caused aging and what is a consequence of it. Genetic depletion of the DNA repair enzyme in mice or cells leads to the accelerated accumulation of spontaneous endogenous DNA damage, which cannot be repaired. With this as an initiating event, we found that deletion of ERCC1‐XPF in primary fibroblasts causes a rapid acceleration of senescence. In vivo, depletion of ERCC1‐XPF also causes accelerated accumulation of senescent cells in numerous tissues including lung, heart, pancreas, liver, spleen, skin and brain. There is accelerated onset of age‐related pathology and spontaneous onset of multiple age‐related diseases including cerebral atrophy, chronic kidney disease, loss of vision and hearing, osteoporosis and disc degeneration. We also discovered increased production of reactive oxygen species and evidence of oxidative damage to multiple types of macromolecules in cells. Furthermore, in ERCC1‐XPF deficient mice we see loss of stem cell function, mitochondrial dysfunction, epigenetic changes, alterations in autophagy and stress responses. In all cases, changes seen in ERCC1‐XPF‐deficient mice were recapitulated in aged wild‐type mice. Finally, tissue‐specific deletion of ERCC1‐XPF is enough to cause rapid onset of age‐related disease such as cardiomyopathy, diabetes and dementia. These data establish endogenous DNA damage as a driver of aging. Furthermore, the response to DNA damage impacts all pillars of aging.Support or Funding InformationNIA P01 AG043376, NIA U19 AG056278, The Glenn FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.