The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and remains unexplored in the setting of metabolic disease. Recent large exome sequencing studies in humans have shown that aging is inevitably associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive growth advantage to the mutant cell and thus allow its clonal expansion (clonal hematopoiesis). Unexpectedly, these somatic mutations were associated with a higher rates of cardio-metabolic disease, suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells and these disease processes. However, whether there is a causal connection between these somatic mutations and metabolic dysfunction remains unclear and the potential underlying mechanisms are unknown, and this is the scientific premise of the proposed research.
The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and remains unexplored in the setting of metabolic disease. The proposed research seeks to determine if there is a causal connection between a relatively common somatic mutation in the hematopoietic system and metabolic dysfunction, and to ascertain the potential underlying mechanisms.
