Study finds GLP-1 drugs improve strength and reverse aging biology in mice

New multi-omic data reveal that GLP-1 signaling in the brain can drive body-wide rejuvenation, offering a potential weight-neutral path to preserving strength and organ resilience with age.

Study: Body-wide multi-omic counteraction of aging with GLP-1R agonism. Image Credit: CI Photos / Shutterstock

In a recent study published in the journal Cell Metabolism, a group of researchers evaluated whether glucagon-like peptide-1 receptor (GLP-1R) agonism counteracts aging across organs in a largely weight-neutral context, defined its hypothalamic dependence, and benchmarked effects against mammalian target of rapamycin (mTOR) inhibition.

Aging Burden Highlights Need for Safe, Systemic Interventions

By 2050, one in six people will be older than 65, and many will live longer with chronic conditions that strain families and health systems. Aging rewires metabolism, immunity, and gene regulation across organs, steadily sapping strength, cognition, and resilience.

Interventions that mimic calorie restriction, clear senescent cells, or inhibit the mTOR show promise but raise concerns about safety, dosing, or feasibility. Glucagon-like peptide-1 (GLP-1) biology links appetite, metabolism, and brain circuits and is already targeted in clinics. 

The authors note that GLP-1R agonism meets several criteria proposed for an effective anti-aging strategy, but whether this pathway can counter systemic aging in a weight-neutral manner and how the brain coordinates whole-body benefits requires further study.

Experimental Design Testing Weight-Neutral GLP-1 Agonism

Male C57BL/6 mice were studied in two groups. No female mice were included, which the authors note as a limitation for interpreting sex-specific effects.

In the first, mice began intraperitoneal injections of the GLP-1R agonist exenatide at 5 nmol/kilogram/day or phosphate-buffered saline (PBS) at 11 months of age and continued for 30 weeks. Grip strength and rotarod assessed motor function at baseline, three months, and six months.

Spatial learning and memory were assessed with the Y-maze and the Barnes maze. Body weight and food intake were monitored weekly, with fasting blood glucose measured at six months. 

At study end, organs and blood were collected for bulk ribonucleic acid sequencing (RNA-seq), deoxyribonucleic acid methylation (DNAm) microarrays covering 285,000 mouse Cytosine-phosphate-Guanine (CpG) sites and imputed mammalian-conserved sites, and plasma metabolomics.

Weighted gene co-expression network analysis (WGCNA), principal component analysis (PCA), and pathway enrichment examined multi-omic changes and hallmarks of aging.

Hypothalamic GLP-1R Knockdown and Rapamycin Benchmarking

In the second cohort, 18-month-old mice received hypothalamic adeno-associated virus (AAV) encoding short hairpin ribonucleic acid (shRNA) to knock down GLP-1R or a scramble control, then exenatide or PBS for 13 weeks. A comparator group received the mTOR inhibitor rapamycin at 8 mg/kilogram every two days, and exploratory behavior was recorded. Hypothalamic GLP-1R knockdown reduced receptor expression by approximately 50%, as confirmed by qPCR and immunohistochemistry.

GLP-1 Agonism Improved Strength and Motor Aging Without Weight Loss

In aging mice, the GLP-1R agonist improved selected functions that usually decline with age. Compared with PBS, exenatide progressively increased forelimb grip strength and rotarod performance over six months, while Y-maze and Barnes maze performance changed little across groups.

Exploratory activity was similar, although treated aged mice spent more time at the arena periphery, a pattern consistent with published aging behavior links. 

At the selected dose, body weight and food intake did not differ meaningfully between treatment groups, fasting blood glucose was comparable, and gonadal fat mass was reduced in the exenatide group, supporting the authors’ characterization of a minimally weight-affecting dosing regimen. 

In young adult mice, functional gains were minimal, suggesting age-selective benefits.

Transcriptomic Reversal of Aging Signatures Across Multiple Organs

Across organs, bulk RNA-seq showed widespread counteraction of age-related transcript changes. Strong effects appeared in metabolically active tissues, including the hypothalamus, frontal cortex, gonadal adipose tissue, colon, heart, skeletal muscle, and circulating white blood cells (WBCs).

Treatment-induced changes frequently opposed aging-related changes in differentially expressed genes, and principal component analysis shifted aged exenatide profiles toward young profiles.

Weighted gene co-expression network analysis identified modules altered in directions opposite to aging and enriched for hallmarks of aging processes including cellular senescence, oxidative phosphorylation, proteostasis, lysosome autophagy mitophagy, and inflammatory responses. 

The study also highlights hypothalamic neurocircuit involvement, including pathways linked to POMC neurons, as part of the CNS route coordinating these body-wide effects.

Epigenetic Aging Signals Show Tissue-Specific Reversal

DNAm also moved in an anti-aging direction. On mouse 285k arrays, exenatide opposed aging-related methylation at CpG loci in the hypothalamus, frontal cortex, hippocampus, adipose tissue, heart, skeletal muscle, and circulating WBCs.

Responses were mixed in colon and spleen, and organ-specific in liver and kidney, indicating tissue-dependent sensitivity across omic layers. DNAm clocks did not uniformly decline in this long-term cohort, consistent with the paper’s finding that significant DNAm clock reductions were observed only in the hippocampus of the older, short-term treatment cohort.

Hypothalamic GLP-1R Required for Systemic Anti-Aging Effects

To test a brain-body axis, hypothalamic GLP-1R was reduced with AAV shRNA. With knockdown, the transcriptomic age counteracting impact of exenatide persisted in the hippocampus but weakened or disappeared in the frontal cortex, circulating WBCs, heart, and skeletal muscle.

Epigenetically, anti-aging methylation changes were strongly attenuated across these tissues, and the negative correlation between aging and treatment effects in the plasma metabolome was diminished. 

These patterns indicate that hypothalamic GLP-1R is a critical node coordinating systemic benefits, even though hippocampal transcriptomic counteraction remained detectable.

Comparison With Rapamycin Reveals Overlapping Anti-Aging Signatures

Finally, the mTOR inhibitor rapamycin produced concordant patterns across transcriptomes, methylomes, and plasma metabolome, with signatures that correlated strongly with exenatide.

Overall potency was similar, with nuanced tissue differences; rapamycin more prominently affected frontal cortex transcripts and circulating metabolites, whereas exenatide showed stronger skeletal muscle transcript effects.

Expected class effects were observed with rapamycin, including modest reductions in intake and weight, impaired glucose tolerance, and lower gonadal fat.

GLP-1R Agonism Shows CNS-Dependent, Multi-Omic Reversal of Aging

GLP-1R agonism counteracted aging across multiple molecular layers and organs, improved selected physical functions in aged animals without meaningful effects on body weight or food intake, and required hypothalamic signaling for most body-wide benefits.

The convergence with mTOR inhibition suggests overlapping anti-aging axes, yet the brain dependence highlights a distinct central nervous system route for coordinating systemic change. 

For people and health systems, these data support testing minimally weight-affecting GLP-1-based strategies to preserve strength and organ resilience with age, while clarifying optimal dosing, durability, and combinations with other geroscience-informed therapies. 

The study did not assess lifespan extension, a limitation noted by the authors, and its male-only design leaves sex-specific effects unresolved.