Epigenetic profiling of hematopoietic stem cells from male mice identifies KDR and PU.1 as regulators of aging transcriptome and caloric restriction response

Caloric restriction (CR) provides anti-aging benefits but has also been reported to be associated with reduced immune function, and how hematopoietic stem cells (HSCs) potentially contribute to this decline remains unclear. Using lifelong and short-term CR in male mice, we found reducing the energy supply decreases total white blood cell production and shifts hematopoiesis towards myeloid and thrombo-erythroid lineages, prioritizing cells essential for survival (red blood cells, platelets, innate immune cells) over adaptive immunity. HSCs under CR enter cell cycle to support myeloid differentiation rather than self-renewal. Lifelong CR inhibits age-associated transcriptome changes in HSCs, though age-associated profiles appear shortly after ad libitum feeding. Epigenetic profiling identified KDR as a key CR response regulator, and Kdr knockdown in aged HSCs recapitulated the youthful transcriptome of lifelong CR HSCs. Finally, we show PU.1 acts as an intracellular regulator of CR response, controlling HSC self-renewal and differentiation through increased target gene binding under CR conditions.