Stem Cells and Aging

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Project Summary/Abstract: The Project Leader of Project 2 entitled: "Hematopoietic Bone Marrow Microenvironment in Aging and Age- related Leukemia" within the Stem Cells and Aging COBRE (1P20GM119943) is requesting an Administrative Supplement entitled: “The Pivotal Role of Middle-aged Female Bone Marrow Microenvironment in Aging Hematopoiesis”. The proposed research addresses the Strategic Goal 1 “Advancing rigorous research that is relevant to the health of women”, Objective 1.1 “Discover basic biological differences between females and males” of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research "Advancing Science for the Health of Women". Specifically, the proposed research is responsive to the Research Areas of Interest to NHLBI for this NOSI (NOT-GM-21-018) “Identification of mechanisms underlying women's resilience for certain heart, lung, blood, and sleep diseases”. Female sex is associated with less risk and better survival than male sex for many age-related blood diseases. Overall, male/female incidence ratio in myelodysplastic syndromes is 1.9 based on a survey of the 2012-2016 Surveillance, Epidemiology, and End Results Program (SEER) data. However, the cellular and molecular mechanisms underlying sex differences in the incidence, prognosis, and treatment responses of the blood disorders remain unclear. The paucity of studies in this area is also notable. Hence, the objective of this proposal to identify potential mechanisms underlying women's resilience for age-related blood diseases. Our long-term goal is to elucidate sex-effects on the pathogenesis and treatment of age-related blood diseases for an improved therapeutic outcome for women. We have recently discovered that a decline of hematopoietic gene expression in hematopoietic stem and progenitor cells (HSPCs) of female mice occurs much later in the aging process than that of male mice. Our preliminary study suggests that the observed sexual dimorphism in aging hematopoiesis may be mediated through the sex hormone follicle-stimulating hormone (FSH) and androgen signaling pathways. Our first objective here is to test the potential mechanisms with FSH and androgen receptors in mice. Next, we hypothesize that a sexual dimorphism in aging hematopoiesis also exists in humans with regard to hematopoietic gene expression and clonal expansion of the HSPCs. Combined, we propose the following specific aims: Aim 1. To determine the role of follicle-stimulating hormone and androgen signaling pathways in sustaining hematopoiesis in aging females. Aim 2. To demonstrate a sexual dimorphism of aging hematopoiesis in humans by surveying BM- derived CD34+ HSPCs. Aim 3. To determine the differences in clonal hematopoiesis on the HSPC level between women and men in different age groups.