We investigate the age-related metabolic changes that occur in aged and rejuvenated myoblasts using in vitro and in vivo models of aging. Metabolic and signaling experiments reveal that human senescent myoblasts and myoblasts from a mouse model of premature aging suffer from impaired glycolysis, insulin resistance, and generate Adenosine triphosphate by catabolizing methionine via a methionine adenosyl-transferase 2A-dependant mechanism, producing significant levels of ammonium that may further contribute to cellular senescence. Expression of the pluripotency factor NANOG downregulates methionine adenosyltransferase 2 A, decreases ammonium, restores insulin sensitivity, increases glucose uptake, and enhances muscle regeneration post-injury. Similarly, selective inhibition of methionine adenosyltransferase 2 A activates Akt2 signaling, repairs pyruvate kinase, restores glycolysis, and enhances regeneration, which leads to significant enhancement of muscle strength in a mouse model of premature aging. Collectively, our investigation indicates that inhibiting methionine metabolism may restore age-associated impairments with significant gain in muscle function.

The embryonic factor NANOG reverses aging hallmarks and rejuvenates senescent skeletal muscle progenitors.

Vitamin D insufficiency (serum 25-OH vitamin D > 10 ng/ml and < 30 ng/ml) is prevalent in the obese (body mass index (BMI) > 30 kg/m2), yet relationships between the two are poorly understood. Objectives of this study include identification of the impact of obesity on reducing serum 25-OH vitamin D concentration, particularly in response to altered vitamin D3 supplementation, and to elucidate the longitudinal impact of serum 25-OH vitamin D on body mass index. Twenty four-week-old lean and obese male C57BL/6 J mice were fed low, standard, or high levels of cholecalciferol supplementation and followed for 24 weeks. Longitudinal measurements include serum 25-OH and 1,25-(OH)2 vitamin D, intact PTH, and calcium concentrations, as well as BMI, bone density and body fat/lean mass. Baseline serum 25-OH concentrations were not different in lean and obese mice (lean 32.8 ± 4.4 ng/ml versus obese 30.9 ± 1.6 ng/ml p = 0.09). Lean mice receiving low supplementation exhibited rapid declines in serum 25-OH vitamin D concentrations, falling from 33.4 ± 5.4 ng/ml to 14.5 ± 3.4 ng/ml after 2 weeks, while obese mice declined at a lower rate, falling from 30.9 ± 1.5 to 19.0 ± 0.9 ng/ml within the same time period. Surprisingly, high vitamin D3 supplementation did not substantially increase serum vitamin D concentrations above standard supplementation, in either lean or obese mice. No differences in serum 1,25-(OH)2 vitamin D, intact parathyroid hormone (PTH) or serum calcium were observed between lean and obese mice within the same vitamin D supplementation group. Yet obese mice exhibited lower serum calcitriol, higher serum PTH, and lower bone mineral density (BMD) than did lean mice. Additionally, neither body mass index nor body fat % was significantly correlated with vitamin D concentrations. Interestingly, lean mice with high vitamin D supplementation consumed significantly more food than did lean mice with standard or low supplementation (14.6 ± 1.7 kcal/mouse/day versus 11.8 ± 1.4 and 12.3 ± 1.7 respectively, p < 0.0001 for both). Low cholecalciferol supplementation in both lean and obese mice significantly and sustainably reduces serum 25-OH vitamin D concentrations. Interestingly, obesity slowed the rate of decline. Over the period of the study, vitamin D insufficiency was not subsequently correlated with greater BMI/body fat, although lean mice with high supplementation consumed greater calories with no apparent BMI increase.

Low 25-OH serum vitamin D (VitD) is pervasive in older adults and linked to functional decline and progression of frailty. We have previously shown that chronic VitD insufficiency in “middle-aged” mice results in impaired anaerobic exercise capacity, decreased lean mass, and increased adiposity. Here, we examine if VitD insufficiency results in similar deficits and greater frailty progression in old-aged (24 to 28 months of age) mice. Similar to what we report in younger mice, older mice exhibit a rapid and sustained response in serum 25-OH VitD levels to differential supplementation, including insufficient (125 IU/kg chow), sufficient (1000 IU/kg chow), and hypersufficient (8000 IU/kg chow) groups. During the 4-month time course, mice were assessed for body composition (DEXA), physical performance, and frailty using a Fried physical phenotype-based assessment tool. The 125 IU mice exhibited worse grip strength (p = 0.002) and inverted grip hang time (p = 0.003) at endpoint and the 8000 IU mice transiently displayed greater rotarod performance after 3 months (p = 0.012), yet other aspects including treadmill performance and gait speed were unaffected. However, 125 and 1000 IU mice exhibited greater frailty compared to baseline (p = 0.001 and p = 0.038, respectively), whereas 8000 IU mice did not (p = 0.341). These data indicate targeting higher serum 25-OH vitamin D levels may attenuate frailty progression during aging.