Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice

Aging is associated with the development of chronic diseases such as insulin resistance and type 2 diabetes. A reduction in mitochondria! fat oxidation is postulated to be a key factor contributing to the progression of these diseases. Our aim was to investigate the contribution of impaired mitochondria! fat oxidation toward age-related disease. Mice deficient for malonyl CoA decarboxylase (MCD-/-), a mouse model of reduced fat oxidation, were allowed to age while life span and a number of physiological parameters (glucose tolerance, insulin tolerance, indirect calorimetry) were assessed. Decreased fat oxidation in MCD-/- mice resulted in the accumulation of lipid intermediates in peripheral tissues, but this was not associated with a worsening of age-associated insulin resistance and, conversely, improved longevity. This improvement was associated with reduced oxidative stress and reduced acetylation of the antioxidant enzyme superoxide dismutase 2 in muscle but not the liver of MCD-/- mice. These findings were recapitulated in aged mice treated with an MCD inhibitor (CBM-3001106), and these mice also demonstrated improvements in glucose and insulin tolerance. Therefore, our results demonstrate that in addition to decreasing fat oxidation, MCD inhibition also has novel effects on protein acetylation. These combined effects protect against age-related metabolic dysfunction, demonstrating that MCD inhibitors may have utility in the battle against chronic disease in the elderly.