The Agouti-related protein (AgRP) is a central orexigenic peptide leading to increased food intake when ubiquitously overexpressed. AgRP-deficient (AgRP-/-) mice have either no phenotype or present an age-related leanness. In this study, AgRP-/- mice were fed alternate high fat or low fat diets in an effort to determine whether AgRP is a mediating factor for the effects of dietary fat on metabolic parameters. There were no striking metabolic differences between AgRP-/- and the equally obese wild type littermates but AgRP(-/-)mice displayed a significantly longer lifespan. The point estimate of median survival for the AgRP-/- group was 9.8% greater while the significantly low hazard ratio (0.494) suggests that mortality incidence of AgRP-/-mice is less than one-half that of the wild type reference population. It is concluded that although AgRP-/- mice become morbidly obese consuming a high fat diet (a landmark feature for a shortened lifespan), they seem to overcome obesity- and age-related pathologies and live significantly longer than their metabolically similar wild type littermates. (c) 2006 Elsevier Inc. All rights reserved.