Impact of hormonal and metabolic disturbances on aging: evaluation of GLP-1 mimetics, DPP-4 inhibitors, nutraceutical compounds, and exercise-like interventions in Caenorhabditis elegans

Metabolic and hormonal disturbances—including obesity, insulin resistance, hypogonadism, and chronic low-grade inflammation—accelerate aging and increase risk for type 2 diabetes, cardiovascular disease, and neurodegeneration. Pharmacological strategies such as metformin, DPP-4 inhibition (e.g., sitagliptin), and incretin-based therapies (GLP-1/GIP agonists such as semaglutide/tirzepatide) improve metabolic control and may influence longevity-related biology. In parallel, nutraceuticals (geniposide, taurine, astilbin) exhibit antioxidant, anti-inflammatory, and metabolic effects that converge on conserved stress-response pathways. Here, we propose an integrated Caenorhabditis elegans platform to model “premature metabolic aging” and test whether metabolic drugs, nutraceuticals, sex-hormone modulation, and exercise-like training can restore healthspan and lifespan through coordinated activation of FOXO/DAF-16, Nrf2/SKN-1, and AMPK/AAK-2 signaling. We will induce metabolic dysfunction using high-glucose diets (2–4%) and complementary genetic perturbations in insulin/IGF-1 and AMPK pathways (e.g., daf-2, aak-2). In Phase 1 (screening), wild-type N2 worms under normal and high-glucose conditions will receive metformin, sitagliptin, geniposide, taurine, astilbin, testosterone (and/or estrogen), semaglutide, tirzepatide, and/or an exercise-like protocol (forced swimming in M9). Primary endpoints will include lifespan (Kaplan–Meier survival), locomotor performance (thrashing/crawling), acute oxidative stress resistance (paraquat, H₂O₂), and lipid storage (Oil Red O/Nile Red). In Phase 2 (mechanisms and combinations), top-performing interventions will be evaluated in pathway mutants (daf-16(mu86), skn-1(zu67), aak-2(ok524)) and reporter strains (DAF-16::GFP, SKN-1::GFP) to quantify nuclear translocation, intracellular ROS (H2DCF-DA), lipofuscin accumulation, and transcriptional responses (qPCR targets including sod-3, gst-4, hsp-16.2). This project will deliver a scalable, mechanistically grounded framework to dissect how metabolic therapies and lifestyle-mimetic interventions modulate aging biology, identify synergistic combinations (e.g., metformin + exercise-like; drug + nutraceutical), and define translational boundaries of incretin-based agents in a model lacking canonical mammalian receptors.