Mouse and cell study: lactate receptor GPR81 loss, senescence and aged arteries
In human aortic data, the gene for the lactate receptor GPR81 fell with age. In cells and mice, losing GPR81 promoted senescence-like changes, while the agonist CHBA reduced them in progeroid mice. These are preclinical findings, not proven human benefits. [1]
Automatic summary · not editorially reviewed
The key findings
In human aortic transcriptomic data, HCAR1, the gene for the lactate receptor GPR81, was among the genes most significantly downregulated with age. [1]
Silencing GPR81 in early-passage cells reproduced the metabolic phenotype and multiple hallmarks of cellular senescence. [1]
In lamin A knock-in progeroid mice, CHBA reduced arterial lipid accumulation and cellular senescence and improved endothelial integrity. [1]
The source at a glance
- Study type / format
- Preclinical laboratory study (abstract)
- Population / context
- Human aortic transcriptomic data, cultured human endothelial and vascular smooth muscle cells, young mice and lamin A knock-in progeroid mice.
- Summary based on
- Study abstract
- Publication status
- Preprint · peer-review status not confirmed
- Original publication
- September 25, 2026
GPR81 gene downregulated in human aortic data
The authors analysed human aortic transcriptomic data. There, HCAR1, the gene encoding the lactate receptor GPR81, was among the genes most significantly downregulated with age. The abstract frames arteries as among the first tissues to show age-related dysfunction and says the metabolic mechanisms behind vascular senescence remain poorly understood. This human data analysis is descriptive: it links lower GPR81 gene expression to older age but does not by itself show that the loss causes senescence in people.
Supporting source [1]
Cell and young-mouse experiments on GPR81 loss
Senescent human endothelial cells and vascular smooth muscle cells accumulated neutral and oxidized lipids and showed increased labile iron and ferroptosis. Silencing GPR81 in early-passage cells reproduced this metabolic phenotype plus several hallmarks of cellular senescence. In young mice, deleting GPR81 specifically in endothelial cells was sufficient to cause senescent cell accumulation, impaired lipid homeostasis, endothelial dysfunction and disorganized elastin. These are experimental manipulations in cells and mice, so they indicate mechanisms, not effects on human ageing.
Supporting source [1]
CHBA activation in cells and progeroid mice
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 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. The abstract calls GPR81 activation a promising strategy for preserving vascular homeostasis and mitigating age-associated cardiovascular disease. That is a proposed direction from preclinical work, not a demonstrated treatment or a validated product.
Supporting source [1]
How to interpret this
Abstract only; the full text was not reviewed. Findings come from human transcriptomic data analysis, cultured cells and mouse experiments, including a progeroid mouse model. The abstract reports no human trial, no human lifespan or cardiovascular outcome and no dosing. Proposed therapeutic use of GPR81 activation is not established.
Based on the study abstract; the full paper, tables and supplementary data were not reviewed.
Source & supporting passages
Wu Y, Senthil Kumar HV, Bhamidipati SH, Yu H, Mehrotra P, Lei P, Das A, Saari P, Elsayed M, Huang L, Andreadis ST. · europepmc.org · September 25, 2026