Project Summary The maintenance of the hematopoietic system throughout adult life relies on the persistence of hematopoietic stem cells (HSCs). With age, the ability of HSCs to self- renew declines and the differentiation potential of HSCs is dysregulated. HSC aging is thought to be a major cause of compromised maintenance of the hematopoietic system in the aged animals. Understanding the molecular mechanisms underlying HSC aging holds the promise to identify novel molecular targets to ameliorate age-related deterioration in HSCs and to prevent bone marrow failure. Calorie restriction (CR), a dietary regimen known to extend lifespan across species, greatly prevents hematopoietic senescence, improves HSC function, and suppresses myeloid leukemia development. We propose to use CR as a platform to search for genetic regulators that modulate HSC aging and diseases of HSC origin. We have established a CR mouse model to study the effects of nutrient on HSC aging. Using the established system, we will elucidate the nutrient sensors and their downstream signaling events that relay the nutrient signals to maintain mitochondrial metabolic homeostasis and regulate HSC fate choices. We will also determine how this process is dysregulated during the aging process. This application is significant because it addresses outstanding questions of the SHINE program: 1) What are the regulatory factors governing aged HSC fate choices? 2) Are HSC-intrinsic changes coordinated with extrinsic signals during aging? 3) How do HSC metabolic processes change with age? 4) Can these HSC metabolic processes be modified to rejuvenate the blood system?