Extending healthspan via GLP-1 receptor agonist: Insights and perspectives

Aging is characterized by chronic inflammation, oxidative stress, and mitochondrial dysfunction. Glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs), developed for type 2 diabetes and obesity, may modulate the hallmarks of aging. This review summarizes mechanistic and therapeutic evidence that GLP‑1 RAs improve mitochondrial function, reduce oxidative stress, enhance autophagy, and attenuate inflammaging. Preclinical and clinical data indicate neuroprotective, cardioprotective, and metabolic benefits. GLP‑1 RAs affect all 12 hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, insulin resistance, and dysbiosis. Although long‑term safety requires further evaluation, GLP‑1 RAs are promising gerotherapeutics with potential to extend healthspan.

Introduction
Aging involves progressive physiological decline and increased chronic disease risk. The twelve hallmarks of aging provide a framework for understanding molecular mechanisms. GLP‑1 is an incretin hormone that enhances insulin secretion, suppresses glucagon, and delays gastric emptying. GLP‑1 RAs resist DPP‑4 degradation and have shown benefits beyond glycemic control, including cardiovascular and neuroprotective effects. This review explores how GLP‑1R signaling may influence aging pathways and promote healthy aging.

GLP‑1R Signaling in Healthy Aging
GLP‑1R is a G‑protein‑coupled receptor in pancreas, brain, gut, and other tissues. Activation triggers cAMP/PKA, Epac/PI3K/Akt, and ERK/MAPK pathways. These pathways enhance mitochondrial biogenesis, autophagy, cell survival, and stress resistance. GLP‑1R also modulates sirtuins (SIRT1), NAD⁺ metabolism, and the HPA axis, linking metabolic health to neuroendocrine resilience. Cardiovascular benefits include improved endothelial function, reduced arterial stiffness, and lower MACE risk (~14% reduction in meta‑analyses).

GLP‑1 RAs and the Hallmarks of Aging
GLP‑1 RAs affect all twelve hallmarks:

• Genomic instability: Reduce oxidative DNA damage via AMPK and enhance DNA repair.

• Telomere attrition: May preserve telomere length by reducing metabolic stress and upregulating SIRT1.

• Epigenetic alterations: Reverse aberrant DNA methylation of the GLP‑1R gene and influence histone modifiers.

• Loss of proteostasis: Enhance autophagy (AMPK/mTOR pathway) to clear misfolded proteins.

• Deregulated nutrient sensing: Improve insulin sensitivity, suppress mTOR overactivation, and mimic caloric restriction effects.

• Mitochondrial dysfunction: Promote biogenesis (PGC‑1α), increase respiration, and reduce ROS.

• Cellular senescence: Lower oxidative stress and inflammation, reducing senescent cell burden.

• Stem cell exhaustion: Protect stem cell function via reduced inflammation and improved vascular niche.

• Altered intercellular communication: Reduce inflammatory cytokines (TNF‑α, IL‑6) and improve endothelial function.

• Inflammaging: Decrease systemic and neuroinflammation.

• Dysbiosis: Modify gut microbiota composition, increasing beneficial bacteria and reducing gut permeability.

• Disabled macroautophagy: Restore autophagic flux.

Clinical trials (STEP, SURMOUNT, SELECT) show GLP‑1 RAs induce weight loss, improve cardiovascular outcomes, and reduce all‑cause mortality. However, lean mass loss occurs (2–4 kg in major trials), necessitating protein intake (1.0–1.2 g/kg/day) and resistance exercise, especially in older adults. The SEMALEAN study found improved muscle function despite initial lean mass loss.

Emerging Hypotheses and Limitations
GLP‑1R activation may have organ‑specific effects due to differential aging rates (e.g., brain, kidney, heart). Individual variability in aging trajectories requires personalized dosing and monitoring. Chronic use may lead to receptor desensitization or gastrointestinal adverse events. Long‑term safety data in healthy, non‑obese older adults are lacking. Evidence for healthspan extension beyond metabolic benefits remains indirect; functional endpoints (frailty, cognition, mobility) need more study.

Clinical Uses and Obesity Link
Obesity accelerates aging via inflammation and metabolic dysfunction. GLP‑1 RAs reduce weight, improve insulin sensitivity, and lower biological age (epigenetic clocks). In HIV‑associated lipohypertrophy, semaglutide slowed epigenetic aging. Tirzepatide reduced left ventricular mass in heart failure. Ongoing trials are evaluating physical function and frailty outcomes.

Future Directions

• Standardize biomarkers of aging (epigenetic, proteomic clocks).

• Conduct long‑term RCTs in older adults with functional endpoints (cognition, gait speed, frailty).

• Develop precision medicine approaches based on organ‑specific aging profiles.

• Investigate combination with exercise and nutritional support to preserve lean mass.

• Address global access and health equity.

Conclusions
GLP‑1 RAs exert pleiotropic effects across all 12 hallmarks of aging. They improve mitochondrial function, reduce inflammation, enhance autophagy, and support metabolic and cardiovascular health. While long‑term safety and efficacy in healthy aging populations require further validation, current evidence positions GLP‑1 RAs as promising gerotherapeutics to extend healthspan and mitigate age‑related decline.

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https://www.xiahepublishing.com/2472-0712/ERHM-2025-00036

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

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