Importance:Severe burn injury triggers systemic inflammation that can lead to multiple organ dysfunctions and death. High-dose intravenous vitamin C has been proposed to mitigate these effects, but strong evidence in patients with burn injury is lacking. Objective:To evaluate the efficacy of high-dose intravenous vitamin C in patients with severe burn injury. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled phase 3 trial conducted across 24 burn centers in North, Central, and South America; Europe; and Asia. Adults (≥18 years) with deep second- and/or third-degree burns covering 20% or more of total body surface area and requiring skin grafting were enrolled between August 18, 2020, and September 12, 2025. Final follow-up was completed in March 2026. The trial was stopped early after the first prespecified interim analysis for futility/harm. Interventions:Patients were randomly assigned (1:1) to receive intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) or matched placebo. Main Outcomes and Measures:The primary outcome was a composite of 28-day mortality and persistent organ dysfunction (defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28). The main secondary outcome was time to discharge alive from hospital within 90 days. Results:Among 238 patients enrolled (mean age, 48.9 [SD, 19.1] years; 79% male; mean total body surface area, 37.0% [SD, 14.6%]), 120 were assigned to vitamin C and 118 to placebo. The primary composite outcome occurred in 49 patients (40.8%) in the vitamin C group and 35 patients (29.7%) in the placebo group (adjusted risk ratio [RR], 1.28 [95% CI, 0.99-1.65]; P = .06), crossing the prespecified futility/harm threshold and prompting early trial termination. Time to discharge alive from hospital within 90 days was not improved (adjusted subdistribution hazard ratio, 0.85 [95% CI, 0.62-1.16]; P = .31). Twenty-eight-day mortality was higher in the vitamin C group (15.0% vs 7.6%; adjusted RR, 1.96 [95% CI, 1.32-2.90]; P = .001), as was hospital mortality (23.3% vs 16.1%; adjusted RR, 1.44 [95% CI, 1.03-2.00]; P = .03). Conclusions and Relevance:Among patients with severe burn injury, high-dose intravenous vitamin C did not reduce 28-day mortality and persistent organ dysfunction and is possibly harmful. Trial Registration:ClinicalTrials.gov Identifier: NCT04138394.

OBJECTIVE:Dietary protein reduction increases plasma fibroblast growth factor 21 (FGF21) and energy requirements in lean men under eucaloric conditions. Whether these metabolic effects translate to weight loss during isocaloric conditions in men with overweight or obesity remains unclear. METHODS:Seventeen men with overweight or obesity were randomly allocated to two different highly controlled, isocaloric diets for 5 weeks, receiving either a protein-reduced diet (0.9 g kg-1 BW day-1) substituted with increased carbohydrates or a habitual diet (1.8 g kg-1 BW day-1). RESULTS:Protein reduction induced a 2.0 ± 0.6 kg weight loss and increased plasma FGF21 concentration compared with higher protein intake, without caloric restriction. Changes in plasma FGF21 concentration were inversely associated with changes in body weight (r = -0.59, p = 0.02). Expression of key components in the FGF21 receptor complex, FGFR1 and β-klotho, and downstream targets in subcutaneous adipose tissue remained unchanged. Markers of skeletal muscle mitochondrial oxidative phosphorylation were also unaltered. Fat mass decreased significantly, whereas this level of protein reduction only tended to lower lean body mass. CONCLUSIONS:These findings suggest that reducing protein intake (0.9 g kg-1 BW day-1), substituted with increased carbohydrates, compared with a habitual protein intake (1.8 g kg-1 BW day-1), can induce weight loss without restricting total energy intake in men with overweight or obesity. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT06263725.

Fatty acids (FAs) are categorized by chain length into short-, medium-, and long-chain FAs. This classification shapes nutrition guidelines and stipulates that saturated FAs within one class share biological functions. We compared acute metabolic, transcriptional, and metabolomic effects in obese mice of three saturated MCFAs: caproic (C6:0), octanoic (C8:0), and decanoic (C10:0) acid. Despite similar glycemic effects, MCFAs produced distinct phenotypes. C6:0 and C8:0 were strongly ketogenic, and C8:0 uniquely reduced food intake and body weight while increasing circulating GDF15. C6:0 and C10:0 oppositely altered carbohydrate oxidation. Liver RNA sequencing and plasma metabolomics identified chain-length-specific molecular programs, with C8:0 eliciting the strongest hepatic response, C6:0 selectively regulating indoles in the portal vein, and C8:0 altering systemic tryptophan metabolism. The intriguing effects of C8:0 on tryptophan metabolism were also present in humans. Thus, MCFAs engage distinct physiological and molecular pathways, challenging chain-length-based nutritional and biochemical classification and supporting a molecule-resolved framework.

QuestionDoes high-dose intravenous vitamin C reduce a composite of 28-day mortality and persistent organ dysfunction in patients with severe burn injury?FindingsIn this randomized clinical trial that included 238 patients with severe burns, the primary composite outcome of 28-day mortality and persistent organ dysfunction occurred in 40.8% of patients in the intravenous vitamin C group compared with 29.7% in the placebo group. At the first prespecified interim analysis, this result crossed the futility/harm threshold, prompting early termination of the trial.MeaningHigh-dose intravenous vitamin C did not reduce mortality and organ dysfunction and may be associated with harm in patients with severe burn injury. ImportanceSevere burn injury triggers systemic inflammation that can lead to multiple organ dysfunctions and death. High-dose intravenous vitamin C has been proposed to mitigate these effects, but strong evidence in patients with burn injury is lacking.ObjectiveTo evaluate the efficacy of high-dose intravenous vitamin C in patients with severe burn injury.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled phase 3 trial conducted across 24 burn centers in North, Central, and South America; Europe; and Asia. Adults (>= 18 years) with deep second- and/or third-degree burns covering 20% or more of total body surface area and requiring skin grafting were enrolled between August 18, 2020, and September 12, 2025. Final follow-up was completed in March 2026. The trial was stopped early after the first prespecified interim analysis for futility/harm.InterventionsPatients were randomly assigned (1:1) to receive intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) or matched placebo.Main Outcomes and MeasuresThe primary outcome was a composite of 28-day mortality and persistent organ dysfunction (defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28). The main secondary outcome was time to discharge alive from hospital within 90 days.ResultsAmong 238 patients enrolled (mean age, 48.9 [SD, 19.1] years; 79% male; mean total body surface area, 37.0% [SD, 14.6%]), 120 were assigned to vitamin C and 118 to placebo. The primary composite outcome occurred in 49 patients (40.8%) in the vitamin C group and 35 patients (29.7%) in the placebo group (adjusted risk ratio [RR], 1.28 [95% CI, 0.99-1.65]; P = .06), crossing the prespecified futility/harm threshold and prompting early trial termination. Time to discharge alive from hospital within 90 days was not improved (adjusted subdistribution hazard ratio, 0.85 [95% CI, 0.62-1.16]; P = .31). Twenty-eight-day mortality was higher in the vitamin C group (15.0% vs 7.6%; adjusted RR, 1.96 [95% CI, 1.32-2.90]; P = .001), as was hospital mortality (23.3% vs 16.1%; adjusted RR, 1.44 [95% CI, 1.03-2.00]; P = .03).Conclusions and RelevanceAmong patients with severe burn injury, high-dose intravenous vitamin C did not reduce 28-day mortality and persistent organ dysfunction and is possibly harmful.Trial RegistrationClinicalTrials.gov Identifier: NCT04138394 This international randomized clinical trial evaluates the efficacy of high-dose intravenous vitamin C in reducing 28-day mortality and persistent organ dysfunction (dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28) in patients with severe burn injury.

Biomarkers of ageing are defined as age-related changes in body function or composition that could serve as a measure of 'biological' age and predict the onset of age-related diseases and/or residual life expectancy. We conducted the MARK-AGE Study, a European population study (3300 subjects aged 35-74) to identify a powerful set of biomarkers of ageing. A total of 362 clinical-chemistry, genetic, cellular or molecular biomarkers were analysed for each subject. Using statistical models as well as machine learning we derived mathematical formulas for females and for males that yield a 'bioage score' of an individual, based on sets of 10 biomarkers for females and 10 for males. Collectively, these biomarkers model chronological age of our study population and, thus yield the 'biological' age of a certain person. 'Age difference' (defined as biological minus chronological age) should then identify biologically older or younger individuals. Using our set of biomarkers, subjects with Down Syndrome and smoking females are biologically older, whereas postmenopausal females taking hormone replacement therapy are biologically younger. Strikingly, our data reveal that age difference of MARK-AGE subjects, but not chronological age, is linearly correlated with levels of HDL, 25-hydroxy-Vitamin D, and CD3+ CD4+/CD45+ ratio in such a way that biologically younger subjects display values that are favourable to good health, whereas other markers such as glucose and HbA1c are correlated with chronological age, but not age difference. This dichotomy of correlations may point to different roles of such markers, that is, drivers of the ageing process versus bystanders of ageing.

Menopause is characterized by hormonal decline, increasing susceptibility to osteoporosis, cardiovascular disease, cognitive impairment, and metabolic dysfunction. Phytoestrogens, plant-derived bioactive compounds with estrogenic and anti-inflammatory properties, have emerged as potential alternatives to hormone therapy for mitigating these risks. This review critically examines their molecular mechanisms, bioavailability challenges, and clinical applications. Their impact on bone mineral density, cardiovascular function, neuroprotection, and metabolic regulation is evaluated, alongside safety considerations. However, inconsistencies in clinical outcomes underscore the need for standardized dosing strategies and precision-based approaches informed by genetic and microbiome profiling. Beyond clinical utility, their role in sustainable nutrition and global health equity is also considered. By integrating molecular insights with translational applications, phytoestrogens represent a promising, non-hormonal strategy for improving menopausal health.

Gender disparities in later life cognition call for a deeper understanding of how social determinants interact to shape cognitive outcomes. This study investigates the gendered moderating role of the social network in the association between employment status (employed, retired, homemaker, unemployed) and cognitive functioning (episodic memory, verbal fluency) among adults aged 50+ in Europe. Using data from the Survey of Health, Ageing and Retirement in Europe (SHARE; waves 4 (2011-2012), 6 (2015-2016), 8 (2019-2020)), we apply linear multilevel models stratified by gender, with episodic memory and verbal fluency as outcomes (N = 145,107). Results indicate that a stronger social network may buffer negative effects of non-employment on episodic memory for women, whereas for men, benefits are primarily indicated at lower social network strength levels. Our findings highlight gender-specific cognitive advantages of social networks, suggesting that gender should be considered a structural factor, not merely a demographic characteristic, in studies of cognitive aging.

BackgroundSerum trace elements, anthropometric data, and oxidative stress markers are often altered in patients diagnosed with Alzheimer's disease (AD) or other types of dementia (OTD). However, these parameters are rarely examined together before disease onset in a single study population.ObjectiveThis nested case-control study aims to investigate anthropometric data, serum trace elements, exchangeable copper (CuEXC), and oxidative stress markers to identify early associations with the risk of AD or OTD.MethodsFrom the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort (DRKS-ID: DRKS00020593), the High Fat Diet, Microbiota, and Neuroinflammation in the Progression of Alzheimer study was generated. One hundred twenty-eight individuals who developed AD or OTD were identified, approximately 15.7 years after baseline data collection, and matched for age, sex, fasting status, and season of blood sampling with 512 controls. Serum levels of manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), selenium (Se), iodine (I), CuEXC, and plasma malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) were analyzed.ResultsCases and non-cases did not differ in anthropometric data or oxidative stress markers. Female cases exhibited a trend of elevated serum Cu and CuEXC levels compared to female non-cases. A higher Se/Cu ratio suggested an inverse association (OR = 0.72, 95% CI: 0.56-0.92), while an increased Cu/Zn ratio was positively associated (OR = 2.1, 95% CI: 1.1-4.1) with AD or OTD incidence.ConclusionsRatios of serum trace elements, rather than individual levels, show early associations with the risk of AD or OTD while anthropometric and oxidative stress markers did not.

Aging is associated with declines in skeletal muscle function, mitochondrial capacity, and changes in redox balance, which collectively contribute to frailty and chronic disease risk. This study investigated the effects of a 12-week resistance training (RT) program combined with a small dose of high-intensity interval training (HIIT), with or without polyphenol supplementation, on mitochondrial respiratory capacity (MRC) and oxidative stress in middle-aged and older adults (55–70 years). Forty-one participants were randomized to receive either a polyphenol supplement or a placebo for 30 days before the training intervention. Following the training intervention, aerobic capacity, lean mass, and strength improved significantly in both groups. Training also increased MRC in the placebo group but not in the polyphenol group, which displayed higher MRC following the supplementation phase, possibly reflecting either a supplement effect or baseline variation. The training resulted in a 20% decrease in skeletal muscle H2O2 emission across both groups, suggesting enhanced mitochondrial efficiency or antioxidant defenses. However, gene expression of selected antioxidants was unchanged, and plasma oxidative stress markers malondialdehyde (MDA) increased, and 3-nitrotyrosine (3-NT) remained unchanged. Circulating antioxidants showed distinct changes with training, as ascorbic acid increased with training in both groups, while α-tocopherol increased only in the placebo group and β-cryptoxanthin and retinol declined in the polyphenol group, suggesting potential supplement–nutrient interactions. Uric acid increased in both groups, likely reflecting exercise-induced purine turnover. In conclusion, combined RT and HIIT improved mitochondrial bioenergetics and muscle redox balance in middle-aged and older adults, whereas polyphenol supplementation did not augment these adaptations and may have blunted some vitamin-related responses. These findings underscore resistance-based exercise as a potent intervention for maintaining physical and mitochondrial health with age.

The MoKaRi study aims to evaluate the impact of two nutritional concepts on cardiometabolic risk factors. For our 20-week intervention study, 65 participants with moderate elevated low-density lipoprotein cholesterol (LDL-C; ≥ 3 mmol/l) and without lipid-lowering therapy were recruited. The intervention to improve nutritional behavior was based on individualized menu plans which were characterized by defined energy and nutrient intake. To improve compliance, individual nutritional counselling sessions were held every two weeks. In addition to motivation, cooking skills were strengthened and nutritional knowledge was imparted. Follow-up visits were carried out after 10 and 20 weeks. The MoKaRi diet lowered the concentrations of total cholesterol (menu plan group (MP): -15

Cardiac metabolism is highly adaptive, and distinct maladaptive remodeling processes may contribute to the development of cardiac dysfunction. Here, we compared the metabolic, structural, and functional adaptations of two murine models: C57BL/6J mice fed a high-fat, carbohydrate-free diet and New Zealand Obese mice maintained on a standard diet. Cardiac function was assessed by echocardiography, plasma metabolite profiles were analyzed, and cardiac proteomes were quantified by mass spectrometry. Proteomic data were computationally integrated into a kinetic model of cardiac central metabolism (CARDIOKIN1) to predict changes in substrate utilization and ATP production capacities under physiological nutrient conditions. Diet-induced metabolic stress led to cardiac dysfunction with preserved ejection fraction, characterized by mitochondrial dysfunction, impaired ATP production, inflammation, and reduced cardiac mass. Conversely, genetically induced obesity resulted in cardiac impairment with reduced ejection fraction associated with mild fibrosis, maintained ATP production, and substrate switching favoring fatty acid utilization. Proteomic and computational analyses revealed a coordinated downregulation of metabolic networks involved in oxidative phosphorylation, substrate transport, and energy production in both models, but with distinct profiles of metabolic inflexibility and mitochondrial efficiency. This study provides insights of how dietary versus genetic metabolic stress reprograms cardiac metabolism and structure, offering mechanistic insights into the diverse pathways leading to cardiac dysfunction. These insights may guide future strategies for metabolic intervention in heart failure subtypes.

Genomic instability markers are important hallmarks of aging, as previously evidenced within the European study of biomarkers of human aging, MARK-AGE; however, establishing the specific metabolic determinants of vascular aging is challenging. The objective of the present study was to evaluate the impact of the susceptibility to oxidation of serum LDL particles (LDLox) and the plasma metabolization products of nitric oxide (NOx) on relevant genomic instability markers. The analysis was performed on a MARK-AGE cohort of 1326 subjects (635 men and 691 women, 35–75 years old) randomly recruited from the general population. The Inverse Probability of Treatment Weighting causal inference algorithm was implemented in order to assess the potential causal relationship between the LDLox and NOx octile-based thresholds and three genomic instability markers measured in mononuclear leukocytes: the percentage of telomeres shorter than 3 kb, the initial DNA integrity, and the DNA damage after irradiation with 3.8 Gy. The results showed statistically significant telomere shortening for LDLox, while NOx yielded a significant impact on DNA integrity. Overall, the effect on the genomic instability markers was higher than for the confirmed vascular aging determinants, such as low HDL cholesterol levels, indicating a meaningful impact even for small changes in LDLox and NOx values.

Aging is a biological and degenerative process with numerous changes in molecular and cellular mechanisms in various organ systems. These changes result in a progressive loss of anatomical structures and physiological functions. Among others, they occur in the cardiovascular system, gastrointestinal tract, skin, muscles, bones, respiratory tract, immune system, endocrine systems, and the brain. The alterations in aging can lead to diseases such as coronary heart disease, sarcopenia, osteoporosis, Alzheimer's disease, and cancer. To delay these age-related alterations and thus prevent diseases, a healthy lifestyle with a balanced diet is important. An adequate diet includes the sufficient intake of micronutrients. This article first provides an overview of physiological characteristics of aging and then addresses the supply of micronutrients in old age.In older age, the supply of vitamin D, vitamin B12, magnesium, iron, folate, and calcium may be critical. These micronutrients play a role in the immune system, bone metabolism, cell metabolism, energy production, and many other metabolic processes. Micronutrient deficiencies can enhance the aging process. Healthy older people should use the German Nutrition Society (DGE) reference values to meet their daily micronutrient needs. Older people with illnesses should follow the reference values of the guidelines for their specific illnesses to cover their micronutrient needs.

Aging is associated with a decline in muscle mass and function, increasing the risk of adverse health outcomes. Amino acid profiling has emerged as a potential tool for assessing skeletal muscle health. This study examines the associations between fasting plasma amino acids, muscle function, and inflammation in healthy older and young adults. Data from 131 participants (101 older adults, 71.5±4.9 years; 30 young adults, 25.5±3.9 years) were analyzed. Skeletal muscle mass was assessed using bioimpedance analysis, and hand grip strength was measured with a dynamometer. Plasma amino acids, kynurenine, and inflammatory markers (CRP, IL-6) were quantified using ultraperformance liquid chromatography with tandem mass spectrometry and commercial immunosorbent assays, respectively. Older adults exhibited lower levels of glutamic acid, isoleucine, leucine, phenylalanine, kynurenine, and kynurenine-to-tryptophan (KYN:TRP) ratio compared to younger individuals (all p<0.05). In older adults, branched-chain and essential amino acids correlated positively with skeletal muscle index (SMI) and hand grip strength, whereas in young adults, only glutamic acid, proline, and KYN:TRP showed positive associations with SMI (all p<0.05). CRP and IL-6 were associated with several amino acids in older adults but not in younger individuals. These findings suggest that age-related shifts in amino acid profiles may reflect underlying changes in muscle metabolism and function, highlighting their potential as early indicators of muscle decline.

Amid global population ageing and evidence that health disparities in later life often stem from accumulated disadvantage, it is essential to assess health inequalities in older adults in an internationally comparable and comprehensive way. Addressing the shortcomings of analysing average health levels in a population while preserving the comparability of countries and subpopulations, we estimate Gini coefficients to examine inequalities in physical and cognitive functioning of older adults in 41 countries, stratified by gender and five-year age group. Utilising data from 11 nationally representative surveys on the health and ageing of older adults, we find substantial heterogeneities in physical and cognitive functioning inequalities across countries for both women and men. Notably, countries with higher median scores in cognitive functioning tend to exhibit significantly less pronounced inequalities. Furthermore, our results reveal a steep positive age gradient in both dimensions of cognitive functioning. Taken together, our descriptive results provide a valuable foundation for researchers and policymakers aiming to identify targeted interventions and policy measures to address health disparities.

BACKGROUND & AIMS:Disruptions in protein metabolism can impact health outcomes in older age, with amino acid metabolism playing a central role. Aging is associated with impaired muscle protein synthesis, insulin resistance, and inflammation, all of which may alter postprandial amino acid responses. METHODS:This study analyzed amino acid profiles in older (n = 40, female n = 32) and younger (n = 30, female n = 21) adults after consuming test meals with standard protein [NP; 16 energy percent (E%) protein, 68 E% carbohydrates] or high protein [HP; 77 E% protein, 17 E% carbohydrates; 450 kcal each]. Postprandial plasma amino acids were quantified at 0, 30, 60, 120, and 240 min using liquid chromatography coupled with tandem mass spectrometry, with plasma amino acids responses evaluated as the incremental area under the curve (iAUC). RESULTS:Fasting amino acid concentrations were similar between age groups, but significant postprandial changes (p < 0.05) were observed after both meals. Older adults exhibited altered branched-chain amino acids, proline, and tyrosine dynamics (all p < 0.05) after HP ingestion. Postprandial amino acid dynamics were comparable age between groups after NP ingestion, except for higher glutamine in older adults, but markedly higher postprandial amino acid concentrations occurred in older adults after HP. Regression analysis revealed insulin resistance, insulin response, and interleukin-6 as key determinants of amino acid iAUCs after NP, while skeletal muscle mass index, habitual protein intake and liver enzymes were significant factors after HP. CONCLUSIONS:These findings suggest that amino acid dynamics in older adults are shaped by habitual protein intake, muscle mass, insulin resistance, and inflammation rather than age alone. A more pronounced postprandial amino acid response to a high-protein meal in older adults may reflect reduced amino acid uptake due to lower muscle mass.

Das Altern ist ein biologischer und degenerativer Prozess, bei dem zahlreiche molekulare und zelluläre Mechanismen in den unterschiedlichsten Organsystemen wirken. Es kommt zu einem fortschreitenden Verlust anatomischer Strukturen und physiologischer Funktionen des Körpers. Die Veränderungen finden u. a. im Herz-Kreislauf-System, Magen-Darm-Trakt, in der Haut, Muskulatur, Knochen, Atemtrakt, Immunsystem, im endokrinen System und im Gehirn statt. Dieser Wandel im Alter kann zu Krankheiten wie koronarer Herzkrankheit, Sarkopenie, Osteoporose, Alzheimer-Demenz und Krebs führen. Um diese altersassoziierten Veränderungen hinauszuzögern und somit auch Krankheiten vorzubeugen, ist ein gesunder Lebensstil mit ausgewogener Ernährung wichtig. Eine adäquate Ernährung umfasst unter anderem die ausreichende Zufuhr von Mikronährstoffen. In diesem Artikel wird zunächst ein Überblick über physiologische Alterungsmerkmale gegeben und im Anschluss auf die Versorgung mit Mikronährstoffen im Alter eingegangen. Im Alter kann die Versorgung mit Vitamin D, Vitamin B12, Magnesium, Eisen, Folat und Calcium kritisch sein. Diese Mikronährstoffe wirken im Immunsystem, Knochenstoffwechsel, Zellstoffwechsel, in der Energieproduktion und vielen anderen Stoffwechselprozessen im Körper. Ein Mangel kann den Alterungsprozess beschleunigen. Gesunde Ältere können sich an den Referenzwerten der Deutschen Gesellschaft für Ernährung (DGE) orientieren, um ihren täglichen Mikronährstoffbedarf zu decken. Ältere Menschen mit Erkrankungen sollten sich an die Referenzwerte der Leitlinien zu den spezifischen Erkrankungen orientieren, um ihren nötigen Bedarf an Mikronährstoffen zu erreichen.