Effects of Intrinsic Cardiorespiratory Fitness and Caloric Restriction on Metabolites in Plasma and Skeletal Muscle and Skeletal Muscle Mitochondrial DNA

[摘要] Individuals with higher cardiorespiratory fitness (CRF), most often assessed by measuring maximal oxygen consumption while performing incremental exercise, have a decreased risk of a wide variety of metabolic diseases and a reduced mortality rate. Rats selected for increased CRF show improved metabolic status and longevity and a higher mitochondrial capacity for fatty acid (FA) and branched-chain amino acid (BCAA) catabolism as they age. To determine whether these findings are associated with CRF-induced delayed metabolic aging in humans, we assessed CRF reported as VO2max (ml/min/kg fat free mass), fasting plasma metabolites that are related to FA and amino acids (AA) metabolism, as well as 2 hr-postprandial skeletal muscle metabolites levels in lean (n = 28 plasma, n = 15 muscle) and obese (n = 124 plasma, n = 99 muscle) individuals, the latter before and after 4-6 months of caloric restriction (CR) by 800 kcal/day of high-protein liquid diet.VO2max fell with age, but was higher at any age in lean compared to obese. Multiple linear regression analysis of plasma metabolites demonstrated that FA-derived acylcarnitines and the ratio of BCAA intermediates to their substrates increased with age, suggesting that aging reduces capacity for fatty acid oxidation (FAO) and BCAA catabolism. Regardless of age, higher CRF was associated with lower levels of FA-derived acylcarnitines. In addition, CRF counteracted the age-associated increase in FA-derived acylcarnitines, suggesting that higher CRF directly mitigates age-associated incomplete FAO.CR also decreased FA-derived acylcarnitine levels and decreased the ratio of BCAA intermediates to their substrates, suggesting that CR decreases metabolic markers of aging. Multiple linear regression analysis of skeletal muscle metabolites showed that most phospholipids decreased with age and polyunsaturated phospholipids increased with age, consistent with the age-induced increase in susceptibility to lipid peroxidative damage of mitochondria. AAs and a ratio of valine intermediate to valine were negatively correlated with VO2max, but FA-derived acylcarnitines were positively correlated with VO2max, suggesting that higher CRF is associated with improved mitochondrial capacity for AA catabolism and FAO. VO2max was also positively correlated with glutathione (the most abundant endogenous antioxidant), DHEAS and UDP-n-acetyl glucosamine, all of which decrease with age, suggesting that higher CRF is associated with lessened oxidative stress which may play a role in slowing aging.Unlike plasma metabolites, CRF was not statistically associated with age-related changes in skeletal muscle metabolite levels. Rather, CRF was directly associated with changes in skeletal muscle metabolites independent of age and its effect was in part mediated by mitochondrial DNA (mtDNA) count number, suggesting an expansion of mitochondria with CRF. CR decreased isoleucine+leucine-to-their-substrates ratio and increased FA-derived acylcarnitines, suggesting that CR improves mitochondrial capacity for AA catabolism and FAO as well. CR also decreased the levels of polyunsaturated FAs (PUFAs), and increased levels of glycocholic acid, a metabolite inversely related to lifespan in humans, again supporting the notion that CR delays metabolic aging. Because both high CRF and CR can improve substrate utilization of mitochondria and show evidence of delayed metabolic aging, the effects of high CRF and CR are comparable. Both appear to induce metabolite profiles consistent with a ;;younger’ metabolic state, offering insight into the mechanisms by which they are associated with enhanced metabolic health and longevity.

[发布机构] University of Michigan

[效力级别] Physiology

[关键词] Cardiorespiratory fitness and metabolic aging;Physiology;Health Sciences;Molecular and Integrative Physiology