We generated mice that overexpress the sirtuin, SIRT1. Transgenic mice have been generated by knocking in SIRT1 cDNA into the beta-actin locus. Mice that are hemizygous for this transgene express normal levels of beta-actin and higher levels of SIRT1 protein in several tissues. Transgenic mice display some phenotypes similar to mice on a calorie-restricted diet: they are leaner than littermate controls; are more metabolically active; display reductions in blood cholesterol, adipokines, insulin and fasted glucose; and are more glucose tolerant. Furthermore, transgenic mice perform better on a rotarod challenge and also show a delay in reproduction. Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity.