Understanding the aging process in hematopoietic stem cells by alcohol-induced DNA damage

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Project Summary Alcohol is a common potential source of DNA damage in humans. Indeed, its metabolic byproducts, acetaldehyde and reactive oxygen species (ROS), mutate hematopoietic stem cells (HSCs). Importantly, DNA damage is central to the aging process by contributing to stem cell exhaustion, cellular senescence, inflammation, and deregulated nutrient sensing. Together, these findings have led us to hypothesize that alcohol-induced DNA damage accelerates aging in HSCs. Moreover, aged HSCs have myeloid-biased differentiation, reduced long- term repopulating potential and decreased DNA repair function, which may lend themselves to being more vulnerable to alcohol-induced DNA damage. Prior research has used very high doses of alcohol to study their DNA-damaging effects on HSCs, which is difficult to generalize to the broader aging population who may enjoy only moderate alcohol drinking. Also, the effects of moderate alcohol consumption on overall health in the general population remain controversial. The overarching goal of this proposal is to shed light on the key aspects of HSC aging using cell-based and animal models. We aim to identify DNA repair genes essential for repairing alcohol- induced DNA damage in HSCs by a pooled CRISPR screen. We also aim to determine whether aged HSCs are more vulnerable to moderate alcohol drinking using a mouse bone marrow transplant model and a single-cell RNA-sequencing approach. Our proposed studies will reveal genes that repair DNA lesions caused by alcohol and its toxic metabolic by-products. It will also inform us how aged HSCs respond differently to alcohol-induced DNA damage than younger HSCs. Identification of key differences in DNA damage response and DNA repair in aged HSCs will enable us to uncover ways to prevent aging due to alcohol and potentially due to other endogenous and exogenous DNA damaging agents as well.