Functional and multi-omic aging rejuvenation with GLP-1R agonism [bulk RNA-seq]

Identifying readily implementable methods that can effectively counteract aging is urgently needed for tackling age-related degenerative disorders. Here, we conducted functional assessments and deep molecular phenotyping in the aging mouse to demonstrate that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment attenuates body-wide age-related changes. In male mice treated with a GLP-1RA from 11 months of age for 30 weeks, we observed improvements in physical and cognitive performance, alongside age-counteracting effects that are prominently evident at multiple omic levels. These span the transcriptomes and DNA methylomes of various tissues, organs and circulating white blood cells, as well as the plasma metabolome. Importantly, the beneficial effects are specific to the aging mice, not young adults, and are achieved with a relatively low dosage of GLP-1RA which has a negligible impact on food consumption and body weight. In older mice treated with a GLP-1RA from 18 months of age for 13 weeks, the molecular rejuvenation effects are even more prominent and generally dependent on hypothalamic GLP-1R, pointing to a brain-body axis of aging modulation. We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies. Our findings have broad implications for understanding the mechanistic basis of the clinically observed pleiotropic effects of GLP-1RAs, the design of intervention trials for age-related diseases, and the development of anti-aging-based therapeutics.