Increased longevity in mice lacking DGAT1

The fat‐storing (or adipose) tissue of organisms has been implicated in modulating the rate of aging across the animal phyla. In mammals, leanness, whether the result of caloric restriction or genetic manipulations, is associated with increased longevity. Male mice lacking acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the terminal step in triacylglycerol synthesis, have enhanced insulin sensitivity and are protected from diet‐induced obesity, a result of increased energy expenditure. We hypothesized that the lean phenotype and improved metabolic state of DGAT1‐deficient mice would result in increased longevity. To test this hypothesis, we determined the lifespan of wild‐type and DGAT1‐deficient mice (n = 30 female mice of each genotype). Mice lacking DGAT1 had increased longevity, with mean lifespan increased by more than 20% (Table 1 , P < 0.005). DGAT1‐deficient mice also had reduced (33%) serum IGF‐1 levels and impaired fertility, consistent with other models of increased longevity. To examine the aging phenotype in more detail, young (3–4 month old) and middle‐aged (12–14 month old) female mice were further characterized. DGAT1‐deficient mice were protected from age‐related obesity, the result of increased energy expenditure. Food intake and serum insulin levels were not different, and serum leptin levels were significantly reduced in DGAT1‐deficient mice, suggesting enhanced leptin sensitivity. Furthermore, mouse embryonic fibroblasts lacking DGAT1 were protected from palmitate‐induced cytotoxicity, suggesting that DGAT1 deficiency may promote increased longevity by protecting from lipotoxic stress. In summary, DGAT1‐deficient mice have increased longevity, supporting the hypothesis that leanness promotes life extension.