Anti-aging interventions reverse hematopoietic stem cell aging via regulation of micrornas

Alterations in aging hematopoietic stem cells (HSCs) include reduced self-renewal capacity, myeloid-biased differentiation, and reduced production of mature lymphocytes and red blood cells. Calorie restriction (CR) and rapamycin treatment (Rapa) have been shown to increase lifespan and to delay the onset of age-related diseases, and some studies have demonstrated that they may improve HSC function through poorly understood mechanisms. We and others have demonstrated that microRNAs (miRNAs) regulate HSC self-renewal and HSPC lineage specification programs. We hypothesized that miRNAs may mediate the functional changes in HSCs observed in anti-aging mouse models, and thus we characterized HSCs from old mice as well as mice treated with anti-aging interventions. We first evaluated the effects of CR and Rapa on HSC function. Anti-aging interventions reversed/inhibited numerous age-related changes, resulting in reduced HSC frequency, increased erythroid and lymphoid progenitors, increased peripheral red cells and B cells, and decreased platelets (in C57BL/6 mice). Using a TaqMan-based qPCR expression profiling method measuring 750 miRNAs, we found that old HSCs exhibited altered expression of 91 miRNAs compared to young mice (FDR <0.1, P <0.05). Moreover, 60 of these miRNAs showed reversal of age-associated changes in both CR and Rapa treated mice. miR-125b, a miRNA shown to positively regulate HSC self-renewal, was reduced 2.2-fold in old mice and its expression was restored in CR and Rapa treated HSCs, suggesting it is a potential mediator of HSC aging. Reintroduction of miR-125b into old HSCs restored their long-term reconstitution capacity and self-renewal as demonstrated by serial transplantation assays, and this change was accompanied by increased frequencies of lymphoid biased HSCs, erythroid and lymphoid progenitors, and peripheral blood B- and T-cells compared to controls. Overall, our findings demonstrate that anti-aging interventions can inhibit/reverse HSC aging phenotypes and that alterations in miR-125b expression contribute to the molecular basis of their functional rejuvenation.