Summary Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.
The signaling molecule p66Shc is often described as a longevity protein. This conclusion is based on a single life span study that used a small number of mice. The purpose of the present studies was to measure life span in a sufficient number of mice to determine if longevity is altered in mice with decreased Shc levels (ShcKO). Studies were completed at UC Davis and the European Institute of Oncology (EIO). At UC Davis, male C57BL/6J WT and ShcKO mice were fed 5% or 40% calorie-restricted (CR) diets. In the 5% CR group, there was no difference in survival curves between genotypes. There was also no difference between genotypes in prevalence of neoplasms or other measures of end-of-life pathology. At 40% calorie restriction group, 70th percentile survival was increased in ShcKO, while there were no differences between genotypes in median or subsequent life span measures. At EIO, there was no increase in life span in ShcKO male or female mice on C57BL/6J, 129Sv, or hybrid C57BL/6J-129Sv backgrounds. These studies indicate that p66Shc is not a longevity protein. However, additional studies are needed to determine the extent to which Shc proteins may influence the onset and severity of specific age-related diseases.
Calorie restriction (CR) without malnutrition extends life span in several animal models. It has been proposed that a decrease in the amount of polyunsaturated fatty acids (PUFAs), and especially n-3 fatty acids, in membrane phospholipids may contribute to life span extension with CR. Phospholipid PUFAs are sensitive to dietary fatty acid composition, and thus, the purpose of this study was to determine the influence of dietary lipids on life span in CR mice. C57BL/6J mice were assigned to four groups (a 5% CR control group and three 40% CR groups) and fed diets with soybean oil (high in n-6 PUFAs), fish oil (high in n-3 PUFAs), or lard (high in saturated and monounsaturated fatty acids) as the primary lipid source. Life span was increased (p < .05) in all CR groups compared to the Control mice. Life span was also increased (p < .05) in the CR lard mice compared to animals consuming either the CR fish or soybean oil diets. These results indicate that dietary lipid composition can influence life span in mice on CR, and suggest that a diet containing a low proportion of PUFAs and high proportion of monounsaturated and saturated fats may maximize life span in animals maintained on CR.
Dysregulation of mitochondrial energy metabolism is a major hallmark of mammalian aging. Calorie restriction (CR) has been shown to effectively increase lifespan and is associated with a metabolic shift toward a decrease in glycolysis and an increase in fatty acid oxidation. This shift in fuel utilization that occurs with CR relies heavily on mitochondrial energy metabolism. Thus, a diet that can mimic the metabolic reprogramming that occurs with CR may reduce age‐related decline in mitochondrial function and energy metabolism, and contribute to healthy aging and longevity. A ketogenic diet, which is depleted in carbohydrates, would drive the utilization of fat as a fuel and increase mitochondrial fatty acid oxidation. By chronically stimulating pathways in mitochondrial oxidative metabolism, the ketogenic diet could influence mitochondrial function and biogenesis, and may prevent age‐related decreases in mitochondrial content. In this study, mice were fed an isocaloric control (CLT), low carbohydrate (low‐CHO), or ketogenic diet (KD) from the age of 12 months. Tissues were collected after 1 month and 14 months of dietary treatment for evaluation of mitochondrial content. The results showed that the low‐CHO and KD increase markers of mitochondrial content in skeletal muscle in old mice (age of 26 months). The activities of both Complex I and IV were increased (p<0.05) in the low CHO and KD diet compared to the CTL diet. Old mice fed a KD also maintained activity of Complex I compared to the young mice, while mice fed the CLT and low‐CHO diets showed a decline (p<0.05) in Complex I activity with aging. Mice fed a KD also showed increased muscle citrate synthase activity with age. However, these changes are tissue specific with liver showing only an increase in Complex IV activity with aging in the KD group. In summary, the study demonstrates that long‐term ketogenic diet may prevent age related decline in mitochondrial content in some tissues in adult mice.Support or Funding InformationNIH Grant PO1AGO25532
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