Lamtor5 decline drives immunosenescence and systemic aging via cGAS-mediated paracrine inflammation
Background
The intricate link between immunosenescence and organismal aging is increasingly recognized, yet the precise mechanisms by which an aged innate immune system drives systemic aging remain largely unknown. A critical gap exists in understanding how primary cellular senescence is initiated and regulated within immune cells. Current approaches to mitigating age-related decline often overlook the central role of immune cell dysfunction, particularly in macrophages, which are key players in chronic low-grade inflammation, or inflammaging, a hallmark of aging.
Study Design
Researchers identified Lamtor5 as an age-dependent factor controlling macrophage senescence and peripheral aging. They generated Lamtor5 ablating macrophages and myeloid Lamtor5 conditional knockout (CKO) mice. To assess systemic impact, senescent Lamtor5 ablating macrophages were delivered to young mice, while young macrophages were transplanted into CKO mice. Senolytic agents were also used in CKO mice. Mechanistically, they investigated the interaction between Lamtor5 and cGMP-AMP synthase (cGAS). Finally, macrophage-targeting cGAS small interfering RNA (siRNA) or a small peptide designed to disrupt the Lamtor5/cGAS interface were applied to aged mice to evaluate therapeutic potential.
Results
Macrophages with Lamtor5 ablation displayed clear senescent signatures, metabolic defects, and aging-related transcriptomic and epigenetic features, mirroring those observed in macrophages from naturally aging mice. Importantly, the delivery of senescent Lamtor5 ablating macrophages significantly accelerated aging manifestations in young mice. Conversely, transplantation of young macrophages or senolytic elimination of senescent cells effectively corrected the aging phenotype in myeloid Lamtor5 CKO mice. Mechanistically, Lamtor5 was found to physically interact with cGAS and promote its degradation via an ESCRT-dependent pathway. This interaction is crucial because:
Application of macrophage-targeting
cGASsiRNA or a small peptide targeting the Lamtor5/cGASinterface profoundly alleviated aging-associated inflammation and tissue dysfunction in aged mice.
Key Findings
- Age-dependent decline of Lamtor5 drives macrophage senescence and peripheral aging.
- Lamtor5-ablating macrophages exhibit senescent signatures, metabolic defects, and aging-related transcriptomic/epigenetic changes.
- Delivery of senescent Lamtor5-ablating macrophages accelerates aging in young mice.
- Transplanting young macrophages or senolytics corrects aging in myeloid Lamtor5 CKO mice.
- Lamtor5 interacts with cGAS, promoting its ESCRT-mediated degradation, and targeting this interaction alleviates aging-associated inflammation.
Why It Matters
This research highlights the macrophage as a central driver of systemic aging through immunosenescence, offering a novel perspective on age-related decline. Targeting the Lamtor5/cGAS signaling pathway in macrophages presents a promising avenue for developing macrophage-based therapeutics to promote healthy aging. For biohackers and clinicians, this suggests that interventions aimed at modulating macrophage function, either through senolytic strategies or by directly influencing Lamtor5/cGAS activity, could potentially slow or reverse aspects of systemic aging. While a usable human protocol is still distant, the identification of a specific molecular interface provides a clear target for future drug development, potentially leading to new compounds that mimic the effects of the small peptide used here.
immunosenescence
systemic-aging
macrophages
cgasm-pathway
lamtor5
inflammation