Online Archive of University of Virginia Scholarship
Somatic Mesaicism in Aging and Disease4 views
Author
Cochran, Jesse, Biochemistry and Molecular Genetics - School of Medicine, University of Virginia
Advisors
Walsh, Kenneth, MD-INMD CV Medicine, University of Virginia
McNamara, Coleen, MD-INMD CV Medicine, University of Virginia
Abstract
While aging has long been recognized as the most significant risk factor for cardiovascular disease, the biological mechanisms underlying this association remained largely elusive for decades. However, the turn of the millennium ushered in major advances in molecular biology that have begun to illuminate these links. In particular, it is now understood that as we age, we accumulate somatic mutations in cells throughout the body. Hematopoietic cells are disproportionately affected due to their high turnover rate. Although most somatic mutations are benign, mutations in certain genes can augment cellular fitness to allow clonal expansion, but most importantly, these mutations can alter the biology of downstream leukocyte progeny, which in turn contribute to multiple hallmarks of aging, including disrupted cell–cell communication, cellular senescence, mitochondrial dysfunction, and chronic inflammation.
In canonical clonal hematopoiesis (CH), these mutations occur in driver genes associated with hematologic malignancies. However, unlike cancer, CH is not associated with any overt changes in hematologic parameters. In addition to canonical CH, hematopoietic loss of the Y chromosome in males and loss of a single X chromosome in females represent the most common acquired somatic mutations in blood cells in their respective sexes. Our laboratory was the first to uncover the molecular mechanisms linking clonal hematopoiesis to increased cardiovascular risk, and the first to both epidemiologically associate hematopoietic loss of the Y chromosome with cardiovascular disease and experimentally establish its causal role.
My thesis research focused on investigating how different somatic mutations in hematopoietic cells contribute to cardiovascular disease, as well as how intrinsic and extrinsic factors influence the development of these mutations and the expansion of mutant clones. Through further molecular characterization, we have delineated the pathogenic mechanisms by which these mutant immune cells promote cardiovascular disease and have proposed potential therapeutic strategies targeting these pathways.
Cochran, Jesse. Somatic Mesaicism in Aging and Disease. University of Virginia, Biochemistry and Molecular Genetics - School of Medicine, PHD (Doctor of Philosophy), 2026-05-20, https://doi.org/10.18130/6y14-9658.
