Age- and Sex-Specific Roles of Sirtuin 1 on Hematopoietic Stem Cell Function and Lineage Determination

Michelle Winkler (Advisor: Pamela Wenzel, PhD)

Aging impairs lymphopoiesis, rewires immune signaling, and reduces hematopoietic stem cell (HSC) function. Sirtuin 1 (SIRT1) has often been viewed as a pro-longevity or rejuvenating factor, yet emerging evidence indicates that it can also exert maladaptive effects in old HSCs. We therefore tested the impact of lifelong SIRT1 overexpression on hematopoietic aging in male and female mice. In wild-type mice, aging reshaped transcriptional programs in HSCs and common lymphoid progenitors (CLPs) of both sexes, including pathways linked to lymphocyte differentiation and leukocyte migration. Sex-specific immune remodeling also emerged, with rewiring of interferon-associated programs in females and a decline in B cells in aging males. SIRT1 overexpression selectively intensified this male phenotype by reducing B lymphopoiesis in old males beginning near the pro-B cell stage in the marrow and extending into splenic CD19-positive B-cell subsets. Old male SIRT1-overexpressing HSCs also showed a profound defect in blood-repopulating activity, with severe impairments in reconstitution after serial transplantation. By contrast, female SIRT1-overexpressing stem cells developed dysfunction only after serial regenerative stress, and young SIRT1-overexpressing donor marrow of both sexes retained largely normal repopulating activity. Mechanistically, male stem and progenitor cells showed stage-specific pathway changes, including chromatin-associated signatures in CLPs by middle age, followed by altered apoptotic stress signaling in CLPs and negative regulation of cytokine-mediated signaling in HSCs in old age. These findings identify sustained SIRT1 activity as a driver of age- and sex-dependent hematopoietic dysfunction and challenge the view that increasing SIRT1 activity is uniformly beneficial in the aging blood system.

Advisory Committee:

• Pamela Wenzel, PhD, Chair
• Hyun-Eui Kim, PhD
• Dung-Fang Lee, PhD
• Kevin McBride, PhD
• Travis Moore, PhD