DNA damage has long been posited as a root cause of aging. In particular, DNA double-stranded breaks (DSBs) have been the subject of intense research, owing to their association with a number of accelerated aging phenomena. Many congenital progeroid syndromes have elevated levels of DSBs, and individuals exposed to high levels of DSB-inducing radiation and chemotherapy have been shown to age more quickly. In both our lab and others, the controlled administration of DSBs through radiation exposure, chemotherapy, or restriction enzyme expression has been demonstrated to accelerate features of aging in mice.
Despite such intense interest, the precise mechanism by which DSBs accelerate aging is not fully known. One theory is that DSBs cause extensive mutations and genomic rearrangements in cells over the course of an organism’s life, leading to gradual tissue dysfunction as cells lose their genomic fidelity. Alternatively, the DNA damage response itself may contribute to gradual organismal decline by insidiously disrupting epigenetic homeostasis, a classic example of antagonistic pleiotropy. To delineate these hypotheses, there is a need for precise—both spatial and temporal—administration of DSBs and/or the DNA damage response independent of DSBs.
I am interested in determining which of these hypotheses are correct and to what extent. I am particularly interested in how the epigenome may change in response to DNA damage. To study DNA damage in the context of aging, I am taking advantage of CRISPR/Cas9 technology to precisely administer DSBs and study their consequences for aging relevant phenotypes.