The organic solute transporter OSTα-OSTβ is a key transporter for the efflux of bile acids across the basolateral mem-brane of ileocytes and the subsequent re-turn of bile acids to the liver. Ostα^-/- mice exhibit reduced bile acid pools and im-paired lipid absorption. In this study, wild type and Ostα^-/- mice were characterized at 5 and 12 months. Ostα^-/- mice were re-sistant to age-related weight gain, body fat accumulation, and liver and muscle lipid accumulation, and the males lived slightly longer than wild type mice. Caloric intake and activity levels were similar for Ostα^-/- and wild type males. Fecal lipid excretion was increased in Ostα^-/- mice, indicating that a defect in lipid absorption contributes to decreased fat accumulation. Analysis of genes involved in intestinal lipid absorption revealed changes consistent with de-creased dietary lipid absorption in Ostα^-/- animals. Hepatic expression of cholesterol synthetic genes was upregulated in the Ostα^-/- mice, showing that reduced dietary cholesterol absorption was partially compen¬sated for by increased cholesterol synthesis. Male Ostα^-/- mice had improved glucose tolerance and both male and fe-male knockout mice had improved insulin sensitivity. Akt phosphorylation was meas-ured in liver and muscle tissue from mice after acute administration of insulin. Male and female Ostα^-/- mice showed signifi-cantly larger insulin responses than wild type mice. These findings indicate that loss of OSTα-OSTβ protects against age-related weight gain and insulin resistance.