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

The ability to cope with fluctuations in energy supply is essential for an organism's survival and health. While caloric restriction (CR) provides benefits towards many aspects of aging, it is associated with loss of immune function. The mechanisms by which the hematopoietic stem cells (HSCs) respond to this stress and potentially contribute to this loss of immunity remain unclear. In this study, using both lifelong and short-term CR mice models, we found that reduced energy supply leads to a decrease in total peripheral blood white blood cell production that is myeloid- and thrombo-erythroid-biased. This strategy prioritizes the production of cell types essential for survival, such as red blood cells, platelets, and innate immune cells, at the expense of adaptive immune cell differentiation. Consistent with change in blood composition, HSCs under CR are driven into cell cycle to support the myeloid differentiation rather than self-renewal. Interestingly, despite the altered hematopoietic output, lifelong CR mitigates age-associated transcriptome changes of the HSCs, but these modifications are swiftly lost after ad libitum feeding. Epigenetic profiling identified KDR as a key regulator of the CR response and experimental knockdown of Kdr in aged HSCs reproduced the more youthful aging transcriptome observed in lifelong CR HSCs. Additionally, we show that PU.1 acts as an intracellular regulator of the CR response, regulating HSC self-renewal and differentiation under CR conditions by increased binding to its target genes.