Targeting SIRT7 Regulation of Mitochondrial Quality Control to Short Circuit Agerelated Diseases of the Hematopoietic System (Project 1)

ABSTRACT SIRT7 is a longevity regulator and integrator of many cell stress response pathways. SIRT7 expression is decreased with chronological age, as such SIRT7 KO mice are short lived and mimic many facets of human aging such as hepatic steatosis, cardiac dysfunction, and a myeloid-skewed hematopoietic system. Here, I aim to demonstrate that mitochondrial quality control (mitoQC) responses are dysregulated with age due to loss of SIRT7 and that this contributes to defects in the aged hematopoietic system, such as clonal hematopoiesis. Clonal hematopoiesis is a pre-leukemic state driven by the outgrowth of hematopoietic stem and progenitor cell (HSPC) clones and is associated with an increased risk for acute myeloid leukemia as well as diseases of the periphery like cardiovascular disease due to the actions of HSPC progeny - tissue infiltrating innate immune cells. Targeting the SIRT7-mitoQC axis in the aged hematopoietic system will have far reaching effects as the hematopoietic system touches all tissues through immune surveillance and immune cell’s ability to take up residence in peripheral tissues.