Investigation of sex differences in hematopoietic stem cell aging in mouse model

Biological sex has been considered one of the most significant variables affecting human health, disease status, quality of aging as well as life expectancy, and accumulating evidence has revealed a strong sexual dimorphism in age-related diseases and life span. Adult stem cells, found in many tissues and organs in the body, are responsible for the integrity and regeneration of the tissues they reside in; therefore, stem cell exhaustion has been suggested as a pivotal mechanism in aging. Although hematopoietic stem cells (HSCs), which are responsible for lifelong production of blood and immune system cells, are the most extensively studied adult stem cell type in aging research and significant sex-specific differences in age-related hematological/oncological diseases have been reported, the role of sex in HSC aging has not been investigated. We examined sex-associated differences in hematopoietic system aging in the peripheral blood, bone marrow and spleen compartments using a C57BL/6J mouse model. The effect of sex on age-related alterations in the number and frequency of mature blood and immune cells in peripheral blood, in the level of inflammatory cytokines, in addition, in the prevalence of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and spleen as well as in the functional capacity, self-renewal potential, mitochondria content and transcriptional profiles of HSCs have been analyzed. Our data showed that biological sex significantly influences the aging pattern in all hematopoietic compartments and at all stages of the hematopoietic system, from HSPCs to mature blood cells, as well as in the global gene expression profile of HSCs. Furthermore, our study revealed distinct differences between old female and male HSCs in terms of differentiation potential, self-renewal capacity, metabolic requirements, immune response, and bone marrow microenvironment (P< 0.05). Our results strikingly highlight the importance of incorporating both sexes in preclinical and clinical research related to the hematopoietic system, including targeted therapies and antiaging studies.