Cell Death Differ. 2026 Jul 16.
Despite emerging evidences showing the close link between immunosenescence and organismal aging, whether and how aged innate immune system drives systemic aging remains an enigma, and importantly, how primary senescence is initiated and regulated needs to be addressed. Herein we identified late endosomal/lysosomal adapter, MAPK and mTOR activator 5 (Lamtor5) as an age-dependent factor that controlled macrophage senescence and peripheral aging. Specifically, we demonstrated that Lamtor5 ablating macrophages displayed senescent signatures, metabolic defects, aging-related transcriptomic and epigenetic features, nicely concurring with macrophages from naturally aging mice. Importantly, delivery of senescent Lamtor5 ablating macrophages accelerated aging in young mice, while transplantation of young macrophages or senolytic elimination of senescent cells corrected the aging manifestation in myeloid Lamtor5 conditional knockout (CKO) mice. Mechanistically, Lamtor5 physically interacted with cGMP-AMP synthase (cGAS) and promoted its degradation in an ESCRT manner. Accordingly, application of macrophage-targeting cGAS small interfering RNA (siRNA) or a small peptide targeting the Lamtor5/cGAS interface profoundly alleviated aging-associated inflammation and tissue dysfunction in aged mice. Collectively, the findings shed the light on immunosenescence and its central role during organismal aging, thereby opening a new avenue for developing macrophage-based therapeutics to improve healthy aging.