Aims/introduction: 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 beta-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue. Materials and methods: 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 Sirtl and Nampt expression followed by treatment with GIP and alpha-lipoic acid. Results: 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 Sirtl and Nampt expression in the adipose tissue. GIP suppressed alpha-lipoic acid-induced Sirtl expression and activity in differentiated adipocytes. Conclusions: 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. (C) 2019 Elsevier Inc. All rights reserved.