Short-term intensive fasting improves red blood cell function and rejuvenates erythropoiesis via regulating MS4A3-CDK2 module

SUMMARY Fasting is known to improve health, but the precisely beneficial effects of specific types of fasting and their underlying mechanisms are not fully understood. We herein report that in humans, occasional short-term intensive fasting (STIF), a traditional fasting format favored by Asians, promotes erythropoiesis and boosts the function of red blood cells (RBCs) in oxygen transportation, ATP generation, antioxidant capacity, and innate immune response. The rejuvenation of erythropoiesis is more pronounced in humans with low RBC counts. Using mouse models and a human erythroid progenitor cell model, we found that occasional STIF rejuvenates erythropoiesis by enhancing megakaryocyte-erythroid progenitor selfrenewal and erythroid-biased differentiation without compromising normal hematopoiesis. Molecularly, STIF relies on an autophagy-dependent but erythropoietin (EPO) upregulation-independent MS4A3-CDK2 module to augment the production of RBCs. Our findings thus suggest that STIF can occasionally be practiced as an efficient noninvasive intervention for better erythropoiesis, particularly for adults with low RBC counts. Graphical abstract In brief Xu et al showed that short-term intensive fasting (STIF), when occasionally practiced, boosts red blood cell function and promotes erythropoiesis by regulating MS4A3-CDK2 module to enhance megakaryocyte-erythroid progenitor selfrenewal and erythroid-biased differentiation. Highlights Occasional STIF boosts the function of red blood cells Occasional STIF promotes erythropoiesis, which is more significant in adults with low red blood cell counts Occasional STIF selectively enhances MEP selfrenewal and erythroid-biased differentiation via MS4A3-CDK2 module The erythropoietic MS4A3-CDK2 response to STIF is autophagy-dependent but EPO upregulation-independent.