Inhibition of GIP signaling extends lifespan without caloric restriction

Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic β-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue. Gipr-/- and Gipr+/+ mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid. We observed that GIP receptor-knockout (Gipr-/-) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr-/- mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes. Although maintenance of CR is difficult, food intake and muscle endurance of Gipr-/- mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients. •Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation.•Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on extra-pancreatic tissues.•GIP receptor-knockout (Gipr−/-) mice fed normal diet showed an extended lifespan, increased exploratory behaviors.•Gipr−/- mice showed increased Sirt1 and Nampt expression in the adipose tissue.•Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients.