Masoud Isanejad

Background: Handgrip strength (HGS) and Timed Up and Go (TUG) tests are established measures of physical capacity and widely utilized in geriatric assessments. We aimed to assess their independent and combined association with activity of daily living (ADL) and psychological life satisfaction (LS). Methods: Data were analysed from 684 community-dwelling aging women (mean age 81.2 years [SD 2.5]) in the 30-year follow-up (2019) of the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE). Relationships of physical capacity measures (HGS: low < 16 kg vs. normal ≥ 16 kg; TUG: slow ≥ 20 s vs. normal < 20 s; both also analyzed continuously) with ADL and LS were examined using independent-samples t-tests, multiple linear regression and restricted cubic spline models. Combined associations were assessed using a four-level combined HGS–TUG variable. Results: After adjustments, both low HGS and slow TUG were associated with lower ADL scores (HGS: B = -1.97; TUG: B = -2.98; both p < 0.001) and worse LS (HGS: B = 0.69; TUG: B = 0.96; both p < 0.05). Combined physical capacity impairments (i.e. HGS and TUG) showed the largest deficits in ADL (B = -4.09, p < 0.001) and LS (B = 1.42, p < 0.05). Conclusions: Among women in their eighties, reduced HGS and slower TUG were associated with poorer functional independence and subjective well-being, with the largest effect estimates observed when both were impaired. Longitudinal and intervention studies are needed to clarify the direction and clinical relevance of these associations.

Background: Sarcopenia is prevalent in heart failure (HF), but its role in incident HF and underlying metabolic mechanisms remains unclear. We examined the interplay between sarcopenia phenotypes, circulating metabolic profiles, and incident HF. Methods: We analyzed UK Biobank participants without baseline HF. Associations between sarcopenia phenotypes and HF incidence were assessed using Cox regression. Nuclear magnetic resonance metabolomics was used to characterize sarcopenia‐related profiles. Cox regression was applied to test metabolite–HF associations, and least absolute shrinkage and selection operator regression was further used to refine predictors. Incremental predictive value beyond clinical risk factors was evaluated using discrimination and reclassification metrics. Results: During a median 15.3 years, 10 233 of 267 335 participants (mean age 56.5 ± 8.1 years; 44.6% men) developed HF. Groups with confirmed sarcopenia (n=1993) and low handgrip strength (normalized to body mass index) only (n=18 796) were associated with higher HF risk (hazard ratio [HR], 1.63 [95% CI, 1.44–1.85]; HR, 1.76 [95% CI, 1.66–1.85]) compared with the reference group, with stronger effects observed in younger adults and women. Metabolomic profiling revealed sarcopenia‐related alterations (higher glycoprotein acetyls, glucose–lactate, phenylalanine, tyrosine, 3‐hydroxybutyrate; lower omega‐3 fatty acids, docosahexaenoic acid, glycine, glutamine, histidine), which also predicted higher HF risk (Bonferroni‐adjusted P < 0.05). Selected metabolites are significant mediators and modestly improved HF prediction (15‐year net reclassification improvement 14%–15%; integrated discrimination improvement 0.9%–1.0%). Conclusions: Sarcopenia, particularly reduced handgrip strength, was a strong predictor for incident HF. Lipid‐, amino acid‐, and energy metabolism–related alterations modestly improved risk prediction and partially mediated the association.

Dysregulated metabolomic profiles (dysmetabolism) have been observed in patients with heart failure (HF). In this study, we investigated metabolomic profiling differences in HF with reduced physical-functional capacity, hereafter termed reduced "muscle health" for brevity (HF-RM) compared to preserved muscle health (HF-PM) and healthy adults (NonHF). The HF-RM label denotes a screening-level functional phenotype consistent with EWGSOP2 "probable sarcopenia" and Fried physical-frailty constructs and is not intended to imply primary skeletal myopathy independent of cardiac limitation. Exploratory objectives included compared HFrEF and HFpEF subtypes to detangle muscle and metabolomic phenotype from cardiac markers. Twenty-five patients with HF (67.9 ± 10.0 years) and 29 NonHF (67.8 ± 11.1 years) underwent body composition, muscle strength, and lifestyle habits assessments. Reduced muscle health was defined based on low physical activity and sex-specific cut-offs for handgrip strength (HGS) and/or 30-s chair stand test (30CST). Energy and inflammatory metabolites were assessed via untargeted plasma metabolomic profiling. Statistical analyses were conducted using SPSS and MetaboAnalyst. Agnostic principal component analysis revealed elevated branched-chain amino acids (BCAA) and reduced glutamine, methionine and tryptophan in HF-RM vs. NonHF-PM controls (p < 0.05). Compared to HF-PM, HF-RM had lower galacturonic acid-1-phosphate, methionine, indole-3-propionic acid, and pyruvic and malic acid (p < 0.05). Significant negative correlations were found between N-terminal pro-B-type natriuretic peptide, tumour necrosis factor-alpha, GDF-15, HGS/BMI, appendicular lean soft tissue index (ALSTI)/BMI, and 30CST (p < 0.05). Among HF, higher HGS/body mass index (BMI) was linked to longer 6MWD (β = 0.677, p < 0.001) and shorter walking speed (β = -0.532, p = 0.006). HF-RM compared to NonHF-PM had significantly elevated growth differentiation factor-15 (GDF-15) levels (median 1202 vs. 344 pg/ml, p < 0.01). HF-RM is marked by impaired energy and fatty acid metabolism, and elevated BCAA catabolism, inflammation, and GDF-15. These biomarkers may represent candidate therapeutic targets to mitigate functional decline in HF, although the present cross-sectional design precludes causal inference. Also, HGS/BMI shows promise as a body-load-normalised functional indicator in HF; given the absence of group differences in absolute strength and the predominantly sarcopenic-obesity phenotype of this cohort, this exploratory finding requires confirmation in larger and HFrEF/HFpEF-balanced studies.

Growth differentiation factor-15 (GDF-15) is an established marker of oxidative stress and a general stress-response mitokines. In this study, we aim to investigate the association of GDF-15 with the metabolic signature of gut and mitochondrial activity in HF and ageing population. A total of 25 HF (67.9 ± 10.0 years) and 29 age-matched healthy participants (HPs) (67.8 ± 11.1 years) were recruited and underwent detailed body composition assessment via dual X-ray absorptiometry; total fat mass and appendicular lean soft tissue index (ALSTI/body mass index (BMI)) were calculated. Utilizing semi-targeted Gas Chromatography–Mass Spectrometry on fasting plasma, a panel of gut microbial-derived (e.g., hippuric acid, indole derivatives, and sarcosine) and tricarboxylic acid cycle metabolites was identified. Results showed higher GDF-15 tertiles were associated with greater HF prevalence, fat mass, NT-proBNP, and TNF-α (p < 0.05). Gut-derived metabolites exhibited phenotype-specific patterns; 3-hydroxyindole predicted higher fat mass in HP; hippuric acid was inversely related in HF; and sarcosine correlated with GDF-15 only in HP. In HF, GDF-15 was strongly driven by pyruvic and fumaric acid, indicating disease-specific mitochondrial stress. In conclusion, these observed associations could be evaluated in future mechanistic studies as sensitive biomarkers of systemic oxidative stress markers, informing potential microbiome-targeted therapeutic avenues.

Resistance training (RT) is an effective intervention for improving muscle health and metabolism in ageing, but the degree of responsiveness (hypertrophy) to RT varies substantially. We examined muscle metabolomic profiles before and after 10-weeks RT in older adults classified into upper (UPPER) and lower (LOWER) tertiles of hypertrophy to identify key metabolic adaptation differences. Fifty older adults (23 males, 27 females, mean 68.2 years old) completed 10 weeks of RT combined with whey protein supplementation. Quadriceps cross-sectional area (CSA) was assessed via magnetic resonance imaging before and after RT. Participants were grouped into UPPER (n = 25, 10.3 ± 2% CSA increase) or LOWER (n = 25, 3.3 ± 2% CSA increase) based on ranked CSA changes. We profiled skeletal muscle tissues from the UPPER and LOWER groups using a metabolomics platform. Over 2,500 metabolites were mapped to 104 metabolic pathways. In the UPPER group, upregulation of tryptophan-indole metabolites and the kynurenine pathway suggests a potential role of gut function and anti-inflammatory effect on RT-induced hypertrophy. Also, leucine, isoleucine and valine were significantly upregulated in the absence of their catabolites. Enrichment of urea cycle/amino group metabolism alongside mitochondria-matrix metabolites in the UPPER group indicates improved amino acids and energy homeostasis. Our findings highlight distinct RT-induced skeletal muscle metabolic profiles between UPPER and LOWER in older adults, underscoring the value of metabolic data. These metabolic pathways are important for understanding what contributes to the heterogeneity of hypertrophic response to RT in older adults. Graphical Abstract

Aims: While physical frailty is a common feature in heart failure (HF), less is known about how frailty is linked to impaired clinical biomarkers and metabolic dysregulation in HF. Methods: We recruited 25 patients with HF (67.9 ± 10.0 years) and 29 adults without HF (NonHF) (67.8 ± 11.1 years). Physical frailty was assessed using low physical activity levels with low handgrip strength (HGS) and/or 30-second chair stand test (30CST). Untargeted plasma metabolomic profiling was performed via gas chromatography-mass spectrometry. Statistical analyses were conducted via SPSS and MetaboAnalyst. Results: HF-Frail (n=25) compared to NonHF-NonFrail (n=18), had lower 6-minute walking distance (386.4 vs. 501.3 meters, P<0.01) and weaker HGS/body mass index (BMI) (1.05 vs. 1.41, P=0.04). HF-Frail compared to NonHF-NonFrail had significantly elevated plasma N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) (241.2 vs. 117.1 pg/ml, P=0.007) and growth differentiation factor-15 (GDF-15) levels (1227.2 vs. 382.5 pg/ml, P<0.01). Agnostic principal component analysis revealed elevated plasma branched chain amino acids and reduced glutamine, methionine and tryptophan in HF-Frail vs. NonHF-NonFrail controls (P<0.05). Compared to HF-NonFrail (n=7), HF-Frail had lower galacturonic acid-1-phosphate, methionine, indole-3-acetamide, pyruvic and malic acid (P<0.05). Significant negative correlations were found between NT-proBNP, tumour necrosis factor-alpha (TNF-α), GDF-15, and frailty outcomes (HGS/BMI, 30CST; P<0.05). Conclusions: In HF, physical frailty is linked to impaired energy and amino acid metabolism, along with elevated inflammation and GDF-15. These findings warrant for longitudinal studies to unravel clinical biomarkers that could serve as therapeutic agents, targeting frailty progression in HF. Lay Summary: This study investigated the association between physical frailty, clinical biomarkers, and metabolic dysregulation in patients with heart failure (HF), revealing significant impairments in physical performance and metabolic profiles compared to non-frail HF and non-HF controls. Patients with HF and frailty exhibited reduced 6-minute walk distance and 30-second chair stand repetitions, had weaker handgrip strength, and elevated levels of N-terminal pro-B-type natriuretic peptide and growth differentiation factor-15 compared to non-frail controls (P<0.05). Metabolomic analysis showed increased plasma branched-chain amino acids, reduced glutamine and methionine, and altered energy metabolism intermediates (i.e., pyruvic acid) (P<0.05) in HF with frailty, indicating significant metabolic disruptions.

To understand the mechaisnm behind high respond (HighR) compared to low respond (LowR) to resistnace training (RT) and whey protein supplementation (20g/day), we analysied vastus laterails muscle biopsies from a total of 50 participants. Utilising the MRI muscle cross-sectional area (CSA) data, we defined responders as those who had hypertrophy exceeding the 1.7% method error. Quadriceps CSA in the lower responder (LowR) (n=25, mean age 69±5 years) and HighR (n=25, mean age 67±4 years) increased from 53.6 ± 12.1 cm ² to 55.4 ± 12.8 cm ² after 10 weeks of RET (3.3 ± 1.7%, P < 0.001) and increased the absolute CSA in the higher responders (HighR) from 53.7 ± 12.5 cm ² to 59.2 ± 13.6 cm ² (10.3 ± 2.0%, P < 0.001). Muscle biopsies were taken from the vastus lateralis before and after RT. We performed untargeted liquid chromatography-mass spectrometry metabolomics to investigate changes in muscle metabolic regulation. The partial least squares discriminant analysis (PLS-DA) yielded the best results using the polar extracts, achieving a 75% average correct classification rate for predicting HighR and LowR. There was no signifncat differences in metabolomic profile at the basline. Our findings revealed several metabolic pathways, including branched-chain amino acid catabolism, tryptophan metabolism (indole and kynurenine pathways), the TCA cycle, gut-derived metabolites, carnitine shuttle metabolism as prominent pathways disrupted in LowR. We provide new insights and has the potential to identify and enhance interventions targeting muscle metabolism, ultimately improving muscle mass and strength to reduce the risk of sarcopenia and frailty in older age.

Introduction Heart failure (HF) is one of the most common cardiovascular disorders, and its prevalence is increased due to age, genetics, and lifestyle factors. Emerging evidence suggests that the Mediterranean Diet (Med Diet) is linked to lower all-cause mortality in patients with increased cardiovascular disease risk, such as those with HF. Objective To conduct a systematic review and meta-analysis of observational studies into the relationship between the Med Diet on HF risk. Design Several databases (PubMed, Scopus, Web of Science and Cochrane Library) until the 01^st of May 2023 were searched. Our research was conducted based on the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were reported as risk ratios (RRs) with their 95% confidence intervals (CIs) as results of multivariate or univariate analyses. Results From the original 1206 studies collected, six observational prospective studies were included, with a total of 216,385 European participants without evidence of HF at baseline. Over a mean period of 11 years of follow-up, a 1-point increase in the Med Diet score was associated with a significantly lower risk of HF (RR = 0.940; 95% CI: 0.912–0.969, p < 0.0001; I² = 42.9%). Categorised by sex, a higher adherence to Med Diet was associated with a significantly lower incidence of HF in women (RR = 0.942; 95% CI: 0.912-0.973, p = 0.001; I² = 41.8%), but not in men. The overall quality of included studies was good. Conclusions Higher adherence to Med Diet across European countries is associated with lower risk of HF, particularly in women.

Objective Protein–energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly. Methods and analysis In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the ‘Joint Programming Initiative A healthy diet for a healthy life’. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9–1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics. Ethics and dissemination All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects’ regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals. Trial registration number NCT05343611.

Sarcopenia, a progressive disease characterized by a decline in muscle strength, quality, and mass, affects aging population worldwide, leading to increased morbidity and mortality. Besides resistance exercise, various nutritional strategies, including omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation, have been sought to prevent this condition. This narrative review summarizes the current evidence on the effect and mechanism of n-3 PUFA on musculoskeletal health. Despite conflicting evidence, n-3 PUFA is suggested to benefit muscle mass and volume, with more evident effects with higher supplementation dose (>2 g/day). n-3 PUFA supplementation likely improves handgrip and quadriceps strength in the elderly. Improved muscle functions, measured by walking speed and time-up-to-go test, are also observed, especially with longer duration of supplementation (>6 months), although the changes are small and unlikely to be clinically meaningful. Lastly, n-3 PUFA supplementation may positively affect muscle protein synthesis response to anabolic stimuli, alleviating age-related anabolic resistance. Proposed mechanisms by which n-3 PUFA supplementation improves muscle health include 1. anti-inflammatory properties, 2. augmented expression of mechanistic target of rapamycin complex 1 (mTORC1) pathway, 3. decreased intracellular protein breakdown, 4. improved mitochondrial biogenesis and function, 5. enhanced amino acid transport, and 6. modulation of neuromuscular junction activity. In conclusion, n-3 PUFAs likely improve musculoskeletal health related to sarcopenia, with suggestive effect on muscle mass, strength, physical performance, and muscle protein synthesis. However, the interpretation of the findings is limited by the small number of participants, heterogeneity of supplementation regimens, and different measuring protocols.