BACKGROUND Insulin resistance (IR) is closely linked to multiple chronic diseases, but the comparative associations and discriminatory performance of different IR surrogate indices for multimorbidity in postmenopausal women remain unclear. METHODS We analyzed postmenopausal women from NHANES and CHARLS. Eleven IR surrogate indices were evaluated using weighted logistic regression in NHANES and Cox proportional hazards models in CHARLS. Dose-response relationships were examined using restricted cubic splines. Discriminatory performance was assessed using ROC analyses, including time-dependent ROC analyses for CHARLS. Machine learning models were additionally developed using NHANES data to classify prevalent multimorbidity. RESULTS In NHANES, most IR surrogate indices were positively associated with prevalent multimorbidity, whereas estimated glucose disposal rate (eGDR) showed a strong inverse association (OR = 0.28, 95% CI 0.21-0.37, p < 0.001). In CHARLS, eGDR was also inversely associated with incident multimorbidity in both baseline (HR = 0.78, 95% CI 0.73-0.84, p < 0.001) and cumulative analyses (HR = 0.67, 95% CI 0.58-0.77, p < 0.001). eGDR showed the highest discrimination among the evaluated indices in NHANES (AUC = 0.809) and in the CHARLS cumulative analysis (AUC = 0.634). Machine learning analysis in NHANES identified eGDR as the most important feature, and the optimal support vector machine model achieved an AUC of 0.835. Sensitivity analyses excluding hypertension, diabetes, and dyslipidemia attenuated the eGDR associations in CHARLS. CONCLUSIONS Multiple IR surrogate indices were associated with multimorbidity among postmenopausal women, with eGDR showing the most consistent inverse association across analyses. These indices may assist population-level risk stratification, although their clinical utility requires further external validation.
OBJECTIVE To evaluate whether intervention-induced changes in epigenetic clocks correspond to changes in clinical outcomes in human geroscience intervention studies. METHODS We systematically reviewed studies reporting pre-post changes in at least one DNA-methylation clock and one clinical outcome. Study-level concordance was classified from paired clock and clinical effects. Individual-level change associations, mediation analyses, risk of bias, and certainty of evidence were also assessed. RESULTS Twenty-six independent studies were included: 13 comparative and 13 single-arm pre-post studies. Fifteen were mixed, six indeterminate, four jointly inconclusive, and one uncontrolled study uniformly concordant for intermediate outcomes; no comparative study or study of patient-important outcomes was uniformly concordant. Eleven studies assessed individual-level associations, responder differences, or mediation, but clear findings were isolated and not replicated across independent studies. No intervention-clock-clinical outcome combination met the criteria for meta-analysis, and no trial-level surrogate-endpoint validation was identified. Certainty was very low across all assessed evidence bodies. CONCLUSION Concordance between epigenetic-clock and clinical-outcome changes was inconsistent, with favorable signals concentrated mainly in selected intermediate outcomes. Epigenetic clocks should currently be considered exploratory or adjunctive biomarkers of intervention response rather than validated clinical surrogate endpoints.
Background Myonectin is a nutrient-responsive myokine implicated in systemic lipid handling, yet whether acute carbohydrate availability modifies exercise-induced myonectin responses in postmenopausal obesity remains unclear. This randomized crossover study examined the effects of sucrose ingestion before and during high-intensity interval exercise (HIIT) on circulating myonectin and related metabolic–myokine responses in postmenopausal women with obesity. Methods Fifteen postmenopausal women with obesity completed two experimental trials in randomized order: sucrose ingestion before and during HIIT and a non-caloric control trial. Trials were separated by a 7-day washout period. Venous blood samples were obtained before exercise, immediately after exercise, and 2 h after exercise. Circulating myonectin was the primary outcome; glucose, insulin, free fatty acids, glycerol, lactate, and interleukin-6 were secondary outcomes used to characterize the accompanying metabolic and myokine environment. Linear mixed-effects models included condition, time, condition × time, period, and treatment sequence. Results Significant condition × time interactions were observed for myonectin, glucose, insulin, free fatty acids, glycerol, lactate, and interleukin-6. Myonectin increased in both conditions, but the 2 h increase was greater following sucrose ingestion than control (between-condition difference: 0.543 ng/mL, 95% CI 0.346–0.741, p < 0.001). Sucrose produced higher glucose, insulin, and lactate responses, while attenuating free fatty acid and glycerol responses during early recovery. Although interleukin-6 increased in both trials, the 2 h interleukin-6 response was lower in the sucrose condition. No period or sequence effect was observed for myonectin. Conclusion Under a common HIIT stimulus, the sucrose condition was associated with a greater recovery-phase increase in circulating myonectin and distinct metabolic responses compared with the non-caloric control condition. Without non-exercise conditions or another carbohydrate comparator, these findings cannot establish an effect independent of exercise, an exercise × sucrose interaction, or specificity to sucrose. Circulating measurements also do not establish altered myonectin production or secretion.
BACKGROUND Age-related anabolic resistance has been proposed as one contributor to skeletal muscle loss in older adults, although its magnitude varies substantially among individuals and experimental conditions. Whey protein stimulates muscle protein synthesis (MPS) through increased circulating amino acid availability and activation of mechanistic target of rapamycin complex 1 (mTORC1), whereas fermented whey protein may exert greater anabolic effects due to enhanced bioactivity. However, its effects on skeletal muscle anabolic and metabolic responses during aging remain unclear. METHODS This randomized, double-blind, placebo-controlled, crossover study investigated the effects of fermented whey protein ingestion on serum-mediated anabolic and metabolic responses in cultured skeletal muscle cells from young and older males. Participants consumed fermented whey protein (Fermentis) and conventional non-fermented protein (control whey) on separate occasions. Differentiated C2C12 myotubes were cultured in medium containing 10% postprandial human serum to evaluate MPS, mitochondrial-related signaling, and myotube hypertrophy. RESULTS Serum obtained after Fermentis ingestion increased myotube diameter compared with serum obtained after conventional whey protein, with no age × protein interaction. For MPS, we observed a significant age × protein interaction, and MPS was greater in myotubes treated with post-Fermentis serum from older donors than from young donors. In addition, serum obtained after Fermentis ingestion markedly enhanced S6K1 Thr389 phosphorylation and oxidative metabolism-related signaling molecules compared with non-fermented protein treatment. CONCLUSIONS The present findings may provide mechanistic insights into the development of nutritional strategies to attenuate age-associated anabolic resistance and improve skeletal muscle oxidative metabolic function.
