Glycation-lowering compounds inhibit ghrelin signaling to reduce food intake, lower insulin resistance, and extend lifespan.

Non-enzymatic reactions in glycolysis produce methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity, diabetes, and aging-associated pathologies. A combination of nicotinamide, α-lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low) lowers the deleterious effects of glycation by reducing MGO and the MGO-derived AGE, MG-H1, in mice. Gly-Low supplementation in the diet reduces food consumption, decreases body weight while preserving muscle mass, improves insulin sensitivity, and increases survival in leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Transcriptional, protein, and functional analyses demonstrate that Gly-Low inhibits appetite stimulation through ghrelin and AMP-activated protein kinase (AMPK) signaling pathways in the hypothalamus, leading to reduced hunger responses. Consistent with these molecular findings, Gly-Low inhibits ghrelin-mediated hunger responses. As a late-life intervention, Gly-Low slows hypothalamic aging signatures, improves glucose homeostasis and motor coordination, and increases lifespan, suggesting its potential benefits in ameliorating age-associated decline.