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. Recent advances in HSC biology highlight mitochondrial stress as a driver of HSC aging. Outstanding questions remain unanswered. How does mitochondrial stress lead to functional deterioration of HSCs? Is mitochondrial stress-induced physiological HSC aging reversible? Our biochemical studies unravel a signaling pathway that regulates the mitochondrial stress response. Using a collection of mouse models, we will elucidate the signaling events that relay the mitochondrial stress to regulate HSC fate choices. We will also determine how this process is dysregulated during the aging process. This application is significant because it addresses an outstanding question of the SHINE program: what are the regulatory factors governing aged HSC fate choices?