Glucose tolerance progressively declines with age in humans and is often accompanied by insulin resistance and a high prevalence of type 2 diabetes. Little is known about the mechanism underlying the age-related changes in glucose metabolism. Here we reported that acid-sensing ion channel 3 (ASIC3) is functionally expressed in adipose cells. ASIC3(-/-) mice were protected against age-dependent glucose intolerance with enhanced insulin sensitivity. Acute administration of ASIC3-selective blocker APETx2 improved the glucose control and increased the insulin sensitivity in older (25-27 weeks) ASIC3(+/+) mice. Moreover, the enhanced glucose control in aging ASIC3(-/-) mice was associated with high baseline levels of Akt phosphorylation and high copy number of mitochondrial DNA in adipose tissues. Taken together, our data suggest that ASIC3 signaling might be involved in the control of age-dependent glucose intolerance and insulin resistance. (c) 2008 Elsevier Inc. All rights reserved.