Cell death and differentiationJul 16, 2026

Age-related drop in Lamtor5 leads to weaker immune defense and body aging through inflammation signaling

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 17, 2026

Abstract

Lamtor5 is identified as an age-dependent factor that controls macrophage senescence and peripheral aging.

Ablation of Lamtor5 in macrophages leads to features associated with cellular aging, including metabolic defects and altered gene expression.
The transfer of senescent macrophages lacking Lamtor5 accelerates aging in younger mice.
Transplanting young macrophages or eliminating senescent cells can reverse aging symptoms in mice lacking Lamtor5.
Lamtor5 interacts with and promotes the degradation of cGMP-AMP synthase (cGAS), which is linked to inflammation and tissue dysfunction.
Targeting the Lamtor5/cGAS interaction using specific small interfering RNA or peptides reduces aging-related inflammation in older mice.

Simplified

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.

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PubMed

Age-related drop in Lamtor5 leads to weaker immune defense and body aging through inflammation signaling

Abstract

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Funding

Competing interests

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