A previous study in our lab reported that loss of the lactate receptor, GPR81, is associated with impaired fatty acid metabolism and skeletal muscle aging using a mouse model of premature aging (progeria). Building on this, we investigated the role of GPR81 activation in alleviating vascular senescence. Specifically, we treated senescent vascular cells, human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs), with GPR81 agonist, 3-chloro-5-hydroxy BA (CHBA), for 7 days and examine lipid content and hallmarks of cellular senescence. Interestingly, CHBA treatment resulted in significant reduction in lipid accumulation, as well as increased cell proliferation and marked decrease in key senescence markers including inflammatory cytokines, DNA damage, reactive oxygen species (ROS) and expression of p21 as compared to untreated cells. Seahorse analysis further revealed that GPR81 activation restored lipid oxidation, fueling mitochondrial oxidative phosphorylation that was impaired by aging. Notably, CHBA decreased lipid peroxidation and the intracellular ferrous iron pool, reducing the levels of ferroptosis, a widely recognized programmed cell death pathway that is active in aged tissues and cells.
In addition, we employed a mouse model of premature aging to evaluate the role of GPR81 agonist in aged arteries. We discovered that treatment of progeria mice with CHBA for one month reduced lipid accumulation and reversed many of the aging hallmarks in aged arteries, including the levels of SA-b-gal, p21 and the high mobility group box 1 (HMGB1). Notably, activating GPR81 preserved elastin fibers and collagen content that were both compromised by aging.
Overall, our studies demonstrate the potential of lactate receptor GPR81 activation to restore lipid metabolism and reverse vascular senescence, suggesting that GPR81 agonist, CHBA, may be a promising therapeutic candidate in reversing or slowing cardiovascular aging and improving healthspan.