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

Non-enzymatic reactions in glycolysis lead to the accumulation of 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) lowered deleterious effects of glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Gly-Low supplementation in the diet reduced food consumption, decreased body weight, improved insulin sensitivity, and increased survival in leptin receptor-deficient ( Leprdb ) and wild-type C57B6/J mice. Transcriptional, protein, and functional analyses demonstrated that Gly-Low inhibited appetite-stimulating ghrelin signaling and enhanced the appetite-satiating mTOR pathways within the hypothalamus. Consistent with these molecular findings, Gly-Low inhibited ghrelin-mediated hunger responses. When administered as a late-life intervention, Gly-Low slowed hypothalamic aging signatures, improved glucose homeostasis and motor coordination, and increased lifespan, suggesting its potential benefits in ameliorating age-associated decline. ![Figure][1] ### Competing Interest Statement Lauren Wimer, Neelanjan Bose, and Pankaj Kapahi are patent holders of GLYLOTM, a supplenement licensed to Juvify Bio by the Buck Instutute. Dr. Pankaj Kapahi is the founder of Juvify Bio. The remaining authors have no conflicts of interest to declare. The remaining authors have no conflicts of interest to declare The data supporting this study’s findings are available from the corresponding author upon request. [1]: pending:yes