Lactate receptor activation reduces cellular senescence and protects vascular health in mice
Loss of the lactate receptor GPR81 drives arterial senescence and lipid accumulation, while pharmacological stimulation restores vascular homeostasis in progeroid mice.
bioRxiv · Wu Y et al. · Paper published 25 Sep 2026
In a preprint analyzing human aortic transcriptomic data, cultured human vascular cells, and mice, researchers investigated how the lactate receptor GPR81 regulates vascular aging. Human transcriptomic data revealed that HCAR1, which encodes GPR81, declines significantly with age. In cultured human endothelial and vascular smooth muscle cells, senescence was marked by lipid accumulation, elevated labile iron, and ferroptosis. Silencing GPR81 in early-passage cells induced these metabolic defects alongside senescence markers. Young mice lacking endothelial GPR81 developed senescent cell accumulation, disrupted lipid balance, endothelial dysfunction, and disorganized elastin. When the authors treated lamin A knock-in progeroid mice with the GPR81 agonist CHBA, the drug restored fatty acid metabolism, supported glycolytic reprogramming, and decreased ferroptotic stress. Treatment also lowered arterial senescence, reduced lipid buildup, improved endothelial integrity, and repaired extracellular matrix homeostasis.
Why it matters
Vascular dysfunction is a key early feature of aging. These findings identify GPR81 as a metabolic regulator linking lactate sensing to arterial senescence and extracellular matrix integrity.
Caveats
The findings come from a preprint that has not completed peer review. In vivo therapeutic interventions were evaluated in progeroid mice, meaning outcomes must still be confirmed in naturally aged models and humans.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
Lactate Receptor Activation Alleviates Senescence and Preserves Homeostasis of Aged Arteries
Wu Y, Senthil Kumar HV, Bhamidipati SH et al.
bioRxiv · 25 Sep 2026 · Preprint, not yet peer-reviewed
- Relevance
- Core geroscience
- News value
- Important
- Evidence
- Animals
- Status
- Preprint
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