A NAD + Metabolic Checkpoint Regulates Hematopoietic Stem Cell Activation and Aging

How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here we show that CD38, a NAD+ metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism at young age. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration due to compromised mitochondrial stress management. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system. Blocking mitochondrial Ca2+ influx inhibits HSC proliferation at young age yet prevents HSC aging. Our study highlights a NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging. To investigate the function of CD38 in regulating HSC fate decisions under homeostasis, ex vivo cytokine stimulation, and chronological aging, freshly isolated HSCs (Lin-ckit+scal1+) from 2-month-old or 24-month-old WT or CD38 KO mice were subjected to 3' Tag RNA sequencing directly or after ex vivo stimulation for 24 hours.