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 and aging-associated pathologies. A combination of nicotinamide, lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low), was identified to lower glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Administration of Gly-Low reduced food consumption, lowered body weight, improved insulin sensitivity, and increased survival in both leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Unlike caloric restriction, Gly-Low modulated hypothalamic signaling by upregulating mTOR pathway signaling to inhibit ghrelin-mediated hunger response. Gly-Low also slowed hypothalamic aging and increased survival when administered as a late-life intervention, suggesting its potential benefits in ameliorating age-associated decline by inducing voluntary caloric restriction and reducing glycation. We profiled hypothalamic transcripts from male C57BL/6J mice at three ages under different treatment paradigms: 1) young (4-month-old) male C57BL/6J mice fed a control or glycation-lowering (Gly-Low) diet for 1 week, 2) aged (25-month-old) male C57BL/6J mice fed a control or glycation-lowering (Gly-Low) diet for 5 months and 3) young (3-month-old) male C57BL/6J mice fed a control diet for 1 week. We used differential expression anaysis to assess genes and pathways that change under acute treatment (1 week) in young mice and to assess how genes that change with age (old control vs young control) are influenced by prolonged (5 month) Gly-Low treatment of old mice (old Gly-Low vs old control).