Study Finds Glp-1 Drugs Improve Strength And Reverse Aging Biology In Mice

New multi-omic information uncover that GLP-1 signaling successful nan encephalon tin thrust body-wide rejuvenation, offering a imaginable weight-neutral way to preserving spot and organ resilience pinch age.

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

In a caller study published successful nan journal Cell Metabolism, a group of researchers evaluated whether glucagon-like peptide-1 receptor (GLP-1R) agonism counteracts aging crossed organs successful a mostly 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, 1 successful six group will beryllium older than 65, and galore will unrecorded longer pinch chronic conditions that strain families and wellness systems. Aging rewires metabolism, immunity, and cistron regularisation crossed organs, steadily sapping strength, cognition, and resilience.

Interventions that mimic calorie restriction, clear senescent cells, aliases inhibit nan mTOR show committedness but raise concerns astir safety, dosing, aliases feasibility. Glucagon-like peptide-1 (GLP-1) biology links appetite, metabolism, and encephalon circuits and is already targeted successful clinics. 

The authors statement that GLP-1R agonism meets respective criteria projected for an effective anti-aging strategy, but whether this pathway tin antagonistic systemic aging successful a weight-neutral mode and really nan encephalon coordinates whole-body benefits requires further study.

Experimental Design Testing Weight-Neutral GLP-1 Agonism

Male C57BL/6 mice were studied successful 2 groups. No female mice were included, which nan authors statement arsenic a limitation for interpreting sex-specific effects.

In nan first, mice began intraperitoneal injections of nan GLP-1R agonist exenatide astatine 5 nmol/kilogram/day aliases phosphate-buffered saline (PBS) astatine 11 months of property and continued for 30 weeks. Grip spot and rotarod assessed centrifugal usability astatine baseline, 3 months, and six months.

Spatial learning and representation were assessed pinch nan Y-maze and nan Barnes maze. Body weight and nutrient intake were monitored weekly, pinch fasting humor glucose measured astatine six months. 

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

Weighted cistron co-expression web study (WGCNA), main constituent study (PCA), and pathway enrichment examined multi-omic changes and hallmarks of aging.

Hypothalamic GLP-1R Knockdown and Rapamycin Benchmarking

In nan 2nd cohort, 18-month-old mice received hypothalamic adeno-associated microorganism (AAV) encoding short hairpin ribonucleic acerb (shRNA) to sound down GLP-1R aliases a scramble control, past exenatide aliases PBS for 13 weeks. A comparator group received nan mTOR inhibitor rapamycin astatine 8 mg/kilogram each 2 days, and exploratory behaviour was recorded. Hypothalamic GLP-1R knockdown reduced receptor look by astir 50%, arsenic confirmed by qPCR and immunohistochemistry.

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

In aging mice, nan GLP-1R agonist improved selected functions that usually diminution pinch age. Compared pinch PBS, exenatide progressively accrued forelimb grip spot and rotarod capacity complete six months, while Y-maze and Barnes maze capacity changed small crossed groups.

Exploratory activity was similar, though treated aged mice spent much clip astatine nan arena periphery, a shape accordant pinch published aging behaviour links. 

At nan selected dose, assemblage weight and nutrient intake did not disagree meaningfully betwixt curen groups, fasting humor glucose was comparable, and gonadal fat wide was reduced successful nan exenatide group, supporting nan authors’ characterization of a minimally weight-affecting dosing regimen. 

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

Transcriptomic Reversal of Aging Signatures Across Multiple Organs

Across organs, bulk RNA-seq showed wide counteraction of age-related transcript changes. Strong effects appeared successful metabolically progressive tissues, including nan hypothalamus, frontal cortex, gonadal adipose tissue, colon, heart, skeletal muscle, and circulating achromatic humor cells (WBCs).

Treatment-induced changes often opposed aging-related changes successful differentially expressed genes, and main constituent study shifted aged exenatide profiles toward young profiles.

Weighted cistron co-expression web study identified modules altered successful directions other to aging and enriched for hallmarks of aging processes including cellular senescence, oxidative phosphorylation, proteostasis, lysosome autophagy mitophagy, and inflammatory responses. 

The study besides highlights hypothalamic neurocircuit involvement, including pathways linked to POMC neurons, arsenic portion of nan CNS way coordinating these body-wide effects.

Epigenetic Aging Signals Show Tissue-Specific Reversal

DNAm besides moved successful an anti-aging direction. On rodent 285k arrays, exenatide opposed aging-related methylation astatine CpG loci successful nan hypothalamus, frontal cortex, hippocampus, adipose tissue, heart, skeletal muscle, and circulating WBCs.

Responses were mixed successful colon and spleen, and organ-specific successful liver and kidney, indicating tissue-dependent sensitivity crossed omic layers. DNAm clocks did not uniformly diminution successful this semipermanent cohort, accordant pinch nan paper’s uncovering that important DNAm timepiece reductions were observed only successful nan hippocampus of nan older, short-term curen cohort.

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

To trial a brain-body axis, hypothalamic GLP-1R was reduced pinch AAV shRNA. With knockdown, nan transcriptomic property counteracting effect of exenatide persisted successful nan hippocampus but weakened aliases vanished successful nan frontal cortex, circulating WBCs, heart, and skeletal muscle.

Epigenetically, anti-aging methylation changes were powerfully attenuated crossed these tissues, and nan antagonistic relationship betwixt aging and curen effects successful nan plasma metabolome was diminished. 

These patterns bespeak that hypothalamic GLP-1R is simply a captious node coordinating systemic benefits, moreover though hippocampal transcriptomic counteraction remained detectable.

Comparison With Rapamycin Reveals Overlapping Anti-Aging Signatures

Finally, nan mTOR inhibitor rapamycin produced concordant patterns crossed transcriptomes, methylomes, and plasma metabolome, pinch signatures that correlated powerfully pinch exenatide.

Overall potency was similar, pinch nuanced insubstantial differences; rapamycin much prominently affected frontal cortex transcripts and circulating metabolites, whereas exenatide showed stronger skeletal musculus transcript effects.

Expected people effects were observed pinch rapamycin, including humble reductions successful intake and weight, impaired glucose tolerance, and little gonadal fat.

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

GLP-1R agonism counteracted aging crossed aggregate molecular layers and organs, improved selected beingness functions successful aged animals without meaningful effects connected assemblage weight aliases nutrient intake, and required hypothalamic signaling for astir body-wide benefits.

The convergence pinch mTOR inhibition suggests overlapping anti-aging axes, yet nan encephalon dependence highlights a chopped cardinal nervous system way for coordinating systemic change. 

For group and wellness systems, these information support testing minimally weight-affecting GLP-1-based strategies to sphere spot and organ resilience pinch age, while clarifying optimal dosing, durability, and combinations pinch different geroscience-informed therapies. 

The study did not measure lifespan extension, a limitation noted by nan authors, and its male-only creation leaves sex-specific effects unresolved.