Ying Li

Oxidative stress accompanies aging, but whether a defined endogenous oxidant source can initiate tissue-to-organism aging remains unclear. We investigated xanthine oxidase (XO), an enzyme coupling purine catabolism to superoxide and hydrogen peroxide generation, using a human cross-sectional cohort and Drosophila genetic models. Among 442 adults, higher serum XO activity was independently associated with shorter relative leukocyte telomere length. Ubiquitous overexpression of xdh, the Drosophila xanthine oxidoreductase gene, shortened lifespan, accelerated locomotor decline, disrupted metabolic homeostasis, reduced antioxidant enzyme activities, and remodeled redox-, immune-, and metabolism-related transcriptional programs. Intestine-specific xdh overexpression was sufficient to reproduce organismal lifespan shortening and functional decline in both sexes. Intestinal xdh elevation increased intestinal DCF fluorescence and reduced total superoxide dismutase activity before detectable barrier leakage or expansion of culturable intestinal bacteria. These early redox abnormalities were followed by progressive barrier failure, increased bacterial burden, and reduced survival during hydrogen peroxide challenge. Intestinal transcriptomics further revealed early and persistent enrichment of oxidoreductase, glutathione, immune, and lipid-metabolic programs, with shared functional signatures across intestinal xdh overexpression, systemic xdh overexpression, and chronological aging. Collectively, these findings identify intestinal XO as a defined metabolic source of redox disruption capable of producing effects beyond the gut. They support a model in which sustained intestinal oxidative stress precedes and amplifies the loss of gut homeostasis, linking local redox disturbance to organismal aging phenotypes.

Multi-organ ionomics analysis reveals that zinc deficiency induces organ-specific disruptions in mineral homeostasis by affecting mineral intake, absorption, excretion, and distribution.

Vitamin K2 (VK2) significantly rescues the multi-organ transcriptome and restores tissue-specific pathways in high-fat diet-induced obese mice.

Background: Skeletal muscle atrophy and insulin resistance (IR) aggravate each other. Vitamin K2 (VK2) exhibits beneficial effects on IR, but whether it improves IR associated skeletal muscle atrophy remains insufficiently understood. This study aims to investigate the effects of VK2 on IR associated skeletal muscle atrophy in high‐fat diet (HFD) mice and type 2 diabetes mellitus (T2DM) patients and explore the potential mechanisms.Methods: VK2 was administered to HFD‐fed C57BL/6 mice for 16 weeks. Grip strength, exercise capacity, oral glucose tolerance test (OGTT) and body fat rate were measured. Animals were sacrificed, and skeletal muscle and serum samples were collected to analyse muscle atrophy, glucose and lipid levels. The gene expression profile of skeletal muscle was determined by RNA sequencing. C2C12 cells were cultured for gene knockdown and overexpression experiments. For the randomized controlled trial (RCT), a total of 102 T2DM patients aged 50–80 years were recruited and randomly assigned to receive yogurt (one cup per day) with or without VK2 fortification (90 μg/day) for 6 months. Grip strength, skeletal muscle mass (SM), skeletal muscle mass index (SMI), 6‐m gait speed (6‐m GS), glycated haemoglobin (HbA1c), fasting blood glucose (FBG), fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA‐IR) were measured at 0, 3 and 6 months, respectively.Results: VK2 significantly improved grip strength (p < 0.01) and exercise capacity (all p < 0.05) in HFD‐fed mice. At the tissue level, VK2 increased skeletal muscle mass (p < 0.05) and cross‐sectional area of muscle fibres (p < 0.05), while reducing the proportion of fast‐twitch fibres (p < 0.01). VK2 treatment decreased body fat rate (p < 0.01) accompanied by enhanced whole‐body energy metabolism. VK2 also diminished the glucolipid metabolism parameters, including glucose (p < 0.01), HOMA‐IR (p < 0.01) and serum lipid levels. Regarding the mechanism, VK2 promoted the phosphorylation of proteins in the FAK‐AKT–mTOR‐P70S6K pathway by targeting Ccn2, thereby enhancing protein synthesis of C2C12 myotubes. In the RCT study, VK2 supplementation significantly increased grip strength (p_{treatment × time} = 0.017), SM (p_{treatment × time} = 0.001), SMI (p_{treatment × time} < 0.001) and decreased HbA1c (p_{treatment × time} < 0.001), FBG (p_{treatment × time} = 0.056), FINS (p_{treatment × time} < 0.001), and HOMA‐IR (p_{treatment × time} < 0.001) in T2DM subjects.Conclusions: Our findings demonstrated the beneficial effects of VK2 on insulin resistance related skeletal muscle atrophy by promoting protein synthesis via the AKT/mTOR pathway.

The timing of dietary total fat intake influences glucose homeostasis, however, the impact of unsaturated fat (USFA) intake has yet to be explored. This 12-week, double-blind, randomized, controlled, 2 × 2 factorial-designed feeding trial investigated the effects of timing (lunch or dinner) and types of dietary USFA (high monounsaturated fat or polyunsaturated fat diet) intake on glucose metabolism in seventy prediabetes participants (mean age, 57 years). Sixty participants with completed fecal samples were included in the final analysis (n = 15 for each group). Postprandial serum glucose was first primary outcome, postprandial insulin levels and insulin sensitivity indices were co-primary outcomes Secondary outcomes were continuous glucose levels, serum fatty acid profile, gut microbiome (metagenomic sequencing) and fecal metabolites. Results showed no significant differences in postprandial glucose between groups. However, USFA intake at lunch (vs. dinner) improved insulin sensitivity and reduced postprandial insulin and serum free saturated fatty acid (P_timing < 0.05, P_type > 0.05, P_interaction > 0.05), which was associated with alterations in gut microbiome and bile acid metabolism, regardless of USFA type. In summary, these results suggest that advancing timing of USFA intake improves insulin sensitivity through the gut microbiome and bile acid metabolism. Trial registration: ChiCTR2100045645.