Long‐term mid‐onset dietary restriction rejuvenates hematopoietic stem cells and improves regeneration capacity of total bone marrow from aged mice

Currently, the world's aging population is expanding rapidly, leading to a rise in aged hematopoietic cell transplantation (HCT) recipients and aged donors. However, the age of donors is negatively related to the prognosis after transplantation due to functional decline in hematopoietic stem cells (HSCs) during aging. Previously, we showed that an early‐onset dietary restriction (DR) significantly retards early aging of HSCs. However, the effects of a mid‐onset DR on HSCs remain unknown. In the current study, we performed 30% DR in 15‐ to 18‐month‐old mice (equivalent to 50–60 human years) for short‐term (4 months) and long‐term (9 months). We show that DR reduces and rectifies the imbalance of the HSC pool in aged mice. Short‐term DR improves hematopoietic reconstitution in purified HSC transplantations, but not in bone marrow transplantations. Intriguingly, long‐term mid‐onset DR improves the hematopoietic regeneration of aging HSCs with a particular enhancement of lymphoid outputs even in total bone marrow transplantation settings. Mechanistically, long‐term DR rejuvenates the aberrantly regulated mitochondrial pathways in aging HSCs and is accompanied by increased quiescence and reduced DNA damage signaling in HSCs. Short‐term DR showed a similar trend of rescuing these aging hallmarks but to a much lesser extent. Together, the current study suggests that mid‐onset DR ameliorates the function of aging HSCs and long‐term DR even improved hematopoietic reconstitution in bone marrow transplantation, which could potentially have considerable implications in HCT of humans when only old donors are available.