The Hallmarks of Aging: Assessing accumulation of DNA lesions with age using single cell DNA sequencing in GESTALT

点击翻译按钮获取中文摘要

Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens. Evolution has selected a complex network of genome maintenance systems to repair the tens of thousands of different types of lesions that occurs into the genome each day and maintain its integrity over time. Investigators have suggested that unrepaired lesions accumulate with aging because repair is erroneous; the rate of lesions is above the capacity of the repair system or occasional failure to correctly replicate the genome during cell division. The accumulation of such lesions may lead to the development of the phenotypes of aging through different still hypothetical mechanisms including inflammation, cell senescence, apoptosis, mitochondrial dysfunction among others. Indeed, while there is evidence that DNA mutations accumulate in various organs and tissues in flies and mammals, it has never been established whether detectable accumulation of DNA damage occurs in humans and whether the frequency of these random lesions correlate with phenotypic manifestation of aging. To address this issue, we plan to study genome damage accumulation in single monocytes collected in 25 healthy individuals distributed over a wide age range and correlate them with the major phenotypes of aging and with a global measure of DNA repair (COMET assay) performed in the same individuals. This study will be implemented in the ongoing GESTALT study, a longitudinal study performed at the NIA clinical research unit that is aimed at understanding the biological mechanisms of aging.