LRRC8A Protein Shields Blood Vessels From Aging Via AMPK-SIRT1 Pathway
A newly identified protein in blood vessel walls slows vascular aging in mice — and gene therapy targeting it shows promising results.
Summary
Researchers at Xiamen University discovered that a protein called LRRC8A, found in the cells lining blood vessels, plays a critical role in slowing vascular aging. Its levels decline in aged mouse aortas, and when it is deleted, aging accelerates. LRRC8A works by activating AMPK, which then moves SIRT1 into the cell nucleus — suppressing a key senescence pathway driven by p53 and boosting antioxidant defenses via FOXO3. Importantly, existing AMPK and SIRT1 activator drugs could rescue cells even when LRRC8A was absent. A targeted gene therapy delivering LRRC8A via AAV also successfully delayed vascular aging in naturally aging mice, pointing toward a viable therapeutic strategy.
Detailed Summary
Vascular aging — the gradual deterioration of blood vessel function — is a root driver of heart disease, stroke, and other age-related conditions. Central to this process is the dysfunction of endothelial cells, which line the interior of every blood vessel. Identifying molecular targets that can slow or reverse this dysfunction is a major goal of cardiovascular longevity research.
This study focused on LRRC8A, a leucine-rich repeat-containing protein previously known to support vascular endothelial function, but never before studied in the context of aging. The researchers found that LRRC8A expression drops significantly in the aortas of aged mice, suggesting it may normally act as a brake on vascular aging.
Using a combination of single-cell RNA sequencing, bulk RNA sequencing, and lab experiments, the team showed that endothelial LRRC8A controls three key hallmarks of cellular aging: cell cycle arrest, cellular senescence, and oxidative stress. Mechanistically, LRRC8A phosphorylates AMPK at a specific site (T172), triggering SIRT1 to move into the cell nucleus. Once there, SIRT1 suppresses the p53-dependent senescence pathway and activates FOXO3-driven antioxidant defenses — a two-pronged protection against aging.
Critically, pharmacological drugs that activate AMPK or SIRT1 were able to rescue cellular senescence even when LRRC8A was absent, confirming the pathway's therapeutic relevance. Moreover, endothelial-targeted AAV gene therapy delivering LRRC8A successfully delayed vascular aging in naturally aging mice — a compelling proof-of-concept for gene-based intervention.
While the study is currently limited to mouse models, the findings identify LRRC8A as a novel and druggable node in the AMPK-SIRT1 longevity axis, opening new avenues for treating age-related vascular disease in humans.
Key Findings
- LRRC8A expression declines in aged mouse aortas, linking its loss to vascular aging onset.
- LRRC8A activates AMPK (T172), promoting SIRT1 nuclear entry to suppress p53-driven senescence.
- FOXO3-dependent antioxidant defenses are activated downstream of the LRRC8A-AMPK-SIRT1 axis.
- AMPK and SIRT1 pharmacological agonists rescue vascular aging even when LRRC8A is deleted.
- AAV-delivered LRRC8A gene therapy effectively delays vascular aging in naturally aging mice.
Methodology
The study used naturally aging mice and a D-galactose-induced accelerated aging mouse model, alongside endothelial-specific LRRC8A knockout mice. Integrated single-cell and bulk RNA sequencing was combined with functional experiments and AAV-mediated endothelial-targeted gene delivery to validate findings.
Study Limitations
All experiments were conducted in mouse models, and translation to human vascular biology remains unproven. The study does not address whether LRRC8A levels decline similarly in aged human vessels or how long AAV gene therapy effects persist.
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