Lactate Receptor Activation Alleviates Senescence and Preserves Homeostasis of Aged Arteries
- 1University at Buffalo, State University of New York
Abstract
Arteries are among the first tissues to exhibit age-related dysfunction, yet the metabolic mechanisms driving vascular senescence remain poorly understood. Here, analysis of human aortic transcriptomic data identified HCAR1, encoding the lactate receptor GPR81, as one of the genes most significantly downregulated with age. We therefore investigated whether age-associated loss of GPR81 contributes to cellular senescence within the vessel wall. Senescent human endothelial cells and vascular smooth muscle cells accumulated neutral and oxidized lipids and exhibited increased labile iron and ferroptosis. Silencing GPR81 in early-passage cells recapitulated this metabolic phenotype together with multiple hallmarks of cellular senescence. Moreover, endothelial-specific deletion of GPR81 in young mice was sufficient to induce senescent cell accumulation, impaired lipid homeostasis, endothelial dysfunction, and elastin disorganization. Conversely, pharmacological activation of GPR81 with the agonist CHBA restored fatty acid metabolism, promoted glycolytic reprogramming, and attenuated ferroptotic stress and senescence-associated phenotypes. In lamin A knock-in (LAKI) progeroid mice, CHBA reduced arterial lipid accumulation and cellular senescence, shifted vascular cell composition toward a youthful state, improved endothelial integrity, and restored extracellular matrix homeostasis. Together, these findings identify age-associated loss of GPR81 as a driver of vascular metabolic dysfunction and cellular senescence and establish pharmacological GPR81 activation as a promising therapeutic strategy for preserving vascular homeostasis and mitigating age-associated cardiovascular disease.
Related
- Alpha-7 nicotinic acetylcholine receptor activation preserves podocyte integrity during sepsis-associated kidney injury
- ATF3 Preserves Macrophage Cholesterol Homeostasis during Metabolic Stress
- Simvastatin Preserves Human Microvascular Endothelial Barrier Function Through Mevalonate-Dependent Regulation of RhoB Localization and Activation
- A combined aqueous extract of Psidium guajava L. and Tithonia diversifolia (Hemsl.) A. gray improves metabolic homeostasis and preserves intestinal integrity in experimental rabbit colibacillosis
- Rewired mRNA homeostasis enforces cell-size associated senescence
BibTeX
@misc{wu2026lactate,
title = {{Lactate Receptor Activation Alleviates Senescence and Preserves Homeostasis of Aged Arteries}},
author = {Y. Wu and H. V. Senthil Kumar and S. H. Bhamidipati and H. Yu and P. Mehrotra and P. Lei and A. Das and P. Saari and M. Elsayed and L. Huang and S. T. Andreadis},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.753049},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.753049v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lactate Receptor Activation Alleviates Senescence and Preserves Homeostasis of Aged Arteries
AU - Y. Wu
AU - H. V. Senthil Kumar
AU - S. H. Bhamidipati
AU - H. Yu
AU - P. Mehrotra
AU - P. Lei
AU - A. Das
AU - P. Saari
AU - M. Elsayed
AU - L. Huang
AU - S. T. Andreadis
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.753049
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.753049v1
AB - Arteries are among the first tissues to exhibit age-related dysfunction, yet the metabolic mechanisms driving vascular senescence remain poorly understood. Here, analysis of human aortic transcriptomic data identified HCAR1, encoding the lactate receptor GPR81, as one of the genes most significantly downregulated with age. We therefore investigated whether age-associated loss of GPR81 contributes to cellular senescence within the vessel wall. Senescent human endothelial cells and vascular smooth muscle cells accumulated neutral and oxidized lipids and exhibited increased labile iron and ferroptosis. Silencing GPR81 in early-passage cells recapitulated this metabolic phenotype together with multiple hallmarks of cellular senescence. Moreover, endothelial-specific deletion of GPR81 in young mice was sufficient to induce senescent cell accumulation, impaired lipid homeostasis, endothelial dysfunction, and elastin disorganization. Conversely, pharmacological activation of GPR81 with the agonist CHBA restored fatty acid metabolism, promoted glycolytic reprogramming, and attenuated ferroptotic stress and senescence-associated phenotypes. In lamin A knock-in (LAKI) progeroid mice, CHBA reduced arterial lipid accumulation and cellular senescence, shifted vascular cell composition toward a youthful state, improved endothelial integrity, and restored extracellular matrix homeostasis. Together, these findings identify age-associated loss of GPR81 as a driver of vascular metabolic dysfunction and cellular senescence and establish pharmacological GPR81 activation as a promising therapeutic strategy for preserving vascular homeostasis and mitigating age-associated cardiovascular disease.
ER -