Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster

The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1—a Dynamin-related protein that promotes mitochondrial fission—in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1-mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1-mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife

AMPK α1 Activation Is Required for Stimulation of Glucose Uptake by Twitch Contraction, but Not by H2O2, in Mouse Skeletal Muscle

BACKGROUND: AMPK is a promising pharmacological target in relation to metabolic disorders partly due to its non-insulin dependent glucose uptake promoting role in skeletal muscle. Of the 2 catalytic alpha-AMPK isoforms, alpha(2) AMPK is clearly required for stimulation of glucose transport into muscle by certain stimuli. In contrast, no clear function has yet been determined for alpha(1) AMPK in skeletal muscle, possibly due to alpha-AMPK isoform signaling redundancy. By applying low-intensity twitch-contraction and H(2)O(2) stimulation to activate alpha(1) AMPK, but not alpha(2) AMPK, in wildtype and alpha-AMPK transgenic mouse muscles, this study aimed to define conditions where alpha(1) AMPK is required to increase muscle glucose uptake. METHODOLOGY/PRINCIPAL FINDINGS: Following stimulation with H(2)O(2) (3 mM, 20 min) or twitch-contraction (0.1 ms pulse, 2 Hz, 2 min), signaling and 2-deoxyglucose uptake were measured in incubated soleus muscles from wildtype and muscle-specific kinase-dead AMPK (KD), alpha(1) AMPK knockout or alpha(2) AMPK knockout mice. H(2)O(2) increased the activity of both alpha(1) and alpha(2) AMPK in addition to Akt phosphorylation, and H(2)O(2)-stimulated glucose uptake was not reduced in any of the AMPK transgenic mouse models compared with wild type. In contrast, twitch-contraction increased the activity of alpha(1) AMPK, but not alpha(2) AMPK activity nor Akt or AS160 phosphorylation. Glucose uptake was markedly lower in alpha(1) AMPK knockout and KD AMPK muscles, but not in alpha(2) AMPK knockout muscles, following twitch stimulation. CONCLUSIONS/SIGNIFICANCE: These results provide strong genetic evidence that alpha(1) AMPK, but not alpha(2) AMPK, Akt or AS160, is necessary for regulation of twitch-contraction stimulated glucose uptake. To our knowledge, this is the first report to show a major and essential role of alpha(1) AMPK in regulating a physiological endpoint in skeletal muscle. In contrast, AMPK is not essential for H(2)O(2)-stimulated muscle glucose uptake, as proposed by recent studies

Effects of Chronic Calorie Restriction or Dietary Resveratrol Supplementation on Insulin Sensitivity Markers in a Primate, Microcebus murinus

The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR) without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV), a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL) animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus) were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day−1·kg−1). Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic changes

Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals

Background: Circulating soluble transferrin receptor (sTfR) has been recently found to be associated negatively with insulin sensitivity. Objective: To evaluate circulating sTfR concentration after changing insulin sensitivity in obese individuals. Design: Circulating sTfR concentration was evaluated after diet-induced weight loss in obese women (diet (D) group, n=8); after diet-induced weight loss plus resistance training (D+RT group, n=11); and after follow-up without weight loss (control (C) group, n=7). Results: After 16 weeks, insulin sensitivity (HOMA (Homeostasis Model Assessment) value) significantly improved in parallel to weight loss (−7.3%) and reduced total fat mass (evaluated using magnetic resonance imaging) in the D group. Thigh muscle mass decreased significantly (P=0.03). Serum sTfR concentration did not change significantly. In the D+RT group, weight loss (−8.7%) and improvement of insulin sensitivity were of similar magnitude. Thigh muscle mass was preserved (P=0.8). Serum sTfR concentration decreased significantly (P=0.001). Interestingly, higher the thigh muscle volume after weight loss, higher the decrease in circulating sTfR concentration. We also found that higher the increases in leg force at week 16, higher the decrease in circulating sTfR concentration in all individuals as a whole. No significant changes were observed in insulin sensitivity, sTfR concentration or thigh muscle mass in the C group. Conclusion: These findings suggest a long-term regulation of serum sTfR concentration by exercise-induced improvement of insulin ensitivity in obese individuals