Transplanting ANXA1⁻ CD8⁺ Naïve T cells Delay Aging Through Senolysis

Abstract Immunosenescence is a hallmark of aging, yet strategies using defined immune subsets to counteract it are largely unexplored. We performed paired scRNA/TCR-seq on CD45⁺ cells from human bone marrow (15 donors, 3-91 years). T cells were the most altered lineage, with CD8⁺ naïve T cell contraction and functional impairment. We identified an expanding ANXA1⁺ CD8⁺ naïve subset with senescence signatures and impaired function. ANXA1-deficient CD8⁺ T cells exhibited increased resting stemness and enhanced activation/cytotoxicity upon stimulation. ANXA1⁻ cells showed senolytic activity in vitro and reduced senescence burden in vivo . Monthly transfer of syngeneic ANXA1⁻ CD8⁺ naïve T cells into aged mice extended median lifespan by >30 weeks, improving cardiac function, bone density, motor coordination, and marrow immune microenvironment. Our study identifies ANXA1 as critical in CD8⁺ naïve T cell aging and establishes ANXA1⁻ cell transfer as a strategy to counter immunosenescence and promote healthy aging.