Combination therapy of glycation lowering compounds reduces caloric intake, improves insulin sensitivity and extends lifespan.

Wimer, L.; Kaneshiro, K. R.; Ramirez, J.; Contreras, M. V.; Shanmugam, M.; Gaffney, D.; Singh, P.; Beck, J.; Sellegounder, D.; Newman, J.; Galligan, J.; Koliwad, S.; Kapahi, P.

doi:10.1101/2022.08.10.503411

bioRxiv · 10.1101/2022.08.10.503411

Combination therapy of glycation lowering compounds reduces caloric intake, improves insulin sensitivity and extends lifespan.

Wimer, L.·Kaneshiro, K. R.·Ramirez, J.·Contreras, M. V.·Shanmugam, M.·Gaffney, D.·Singh, P.·Beck, J.·Sellegounder, D.·Newman, J.·Galligan, J.·Koliwad, S.·Kapahi, P.

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Abstract

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, -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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/503411v3_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1beedc4org.highwire.dtl.DTLVardef@1ec1933org.highwire.dtl.DTLVardef@16a7ad2org.highwire.dtl.DTLVardef@1a5a608_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wimer, L., Kaneshiro, K. R., Ramirez, J., Contreras, M. V., Shanmugam, M., Gaffney, D., Singh, P., Beck, J., Sellegounder, D., Newman, J., Galligan, J., Koliwad, S., Kapahi, P.. 2022-08-13. Combination therapy of glycation lowering compounds reduces caloric intake, improves insulin sensitivity and extends lifespan.. https://doi.org/10.1101/2022.08.10.503411

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