Metformin effects on plasma zonulin levels correlate with enhanced physical performance in osteoarthritis patients with diabetes.

PURPOSE: Metformin (MTF) shows promise in protecting against physical decline in osteoarthritis (OA), but how it works remains unclear. We studied MTF's effects on gut permeability and its link to physical performance in OA patients. METHODS: We studied four groups: control (n = 72), OA non-diabetic (n = 58), OA diabetic on MTF (n = 55), and OA diabetic on other anti-diabetics (n = 57). We measured zonulin levels, as intestinal permeability marker, hand-grip strength (HGS), Oxford knee scoring (OKS) to determine OA severity, and short performance physical battery (SPPB) to determine physical functions. RESULTS: Patients suffering from OA showed a reduction in HGS and SPPB scores with raised plasma zonulin than controls, irrespective of disease severity. MTF decreased plasma zonulin levels and improved OKS, gait speed, HGS, and SPPB scores in OA patients. However, OA patients taking other anti-diabetic medications demonstrated higher levels of plasma zonulin, reduced HGS, and SPPB scores. Furthermore, a robust correlation of plasma zonulin and HGS, OKS, gait speed, and SPPB scores in OA patients on MTF was observed. Moreover, we found reduced oxidative stress and inflammation associated with these alterations in OA patients treated with MTF. CONCLUSION: MTF improves HGS and physical performance by lowering zonulin levels, preserving gut permeability in OA patients.

Gut matters in microgravity: potential link of gut microbiota and its metabolites to cardiovascular and musculoskeletal well-being.

The gut microbiota and its secreted metabolites play a significant role in cardiovascular and musculoskeletal health and diseases. The dysregulation of the intestinal microbiota poses a significant threat to cardiovascular and skeletal muscle well-being. Nonetheless, the precise molecular mechanisms underlying these changes remain unclear. Furthermore, microgravity presents several challenges to cardiovascular and musculoskeletal health compromising muscle strength, endothelial dysfunction, and metabolic changes. The purpose of this review is to critically examine the role of gut microbiota metabolites on cardiovascular and skeletal muscle functions and dysfunctions. It also explores the molecular mechanisms that drive microgravity-induced deconditioning in both cardiovascular and skeletal muscle. Key findings in this review highlight that several alterations in gut microbiota and secreted metabolites in microgravity mirror characteristics seen in cardiovascular and skeletal muscle diseases. Those alterations include increased levels of Firmicutes/Bacteroidetes (F/B) ratio, elevated lipopolysaccharide levels (LPS), increased in para-cresol (p-cresol) and secondary metabolites, along with reduction in bile acids and Akkermansia muciniphila bacteria. Highlighting the potential, modulating gut microbiota in microgravity conditions could play a significant role in mitigating cardiovascular and skeletal muscle diseases not only during space flight but also in prolonged bed rest scenarios here on Earth.

Predictors of the onset of low handgrip strength in Europe: a longitudinal study of 42,183 older adults from 15 countries.

OBJECTIVES: A low handgrip strength (HGS) is a significant risk factor for multiple diseases. However, most relevant studies investigate the complications of a low HGS, while the risk potential of causative factors of low HGS remain poorly characterized. METHODS: We investigated the potentials of quality of life, depression, dyslipidaemia, diabetes mellitus, cancer, Alzheimer's disease, stroke, frailty, and difficulties performing daily activities in predicting low HGS (≤ 27 kg for men, ≤ 16 kg for women) in European older adults aged 50 or above from 15 countries (n = 42,183). All data was collected from four successive waves of survey of health, ageing, and retirement in Europe (SHARE) conducted between 2013 and 2020. Logistic models are applied, and estimated effects are presented as odds ratios and probabilities. RESULTS: Collectively, 3016 participants (men; n = 1395; 7.38%, women; n = 1621, 6.97%) developed low HGS during the 6.5 years study period. After adjusting for covariables, we identified an advancing age (1.6-48.1% points higher risk of low HGS), male gender (1.0%-point higher risk of low HGS), lower quality of life (1.6%-point higher), and stroke (1.5%-points) as significant risk factors for low HGS. We also found a dose-dependent association of Euro-D depression scores with the risk of low HGS, as the higher scores were associated with between 0.6- and 2.3%-points higher risk of developing low HGS than participants without depression. Among physical performance indicators, difficulty climbing stairs (2.0%-points higher low HGS risk) or rising from a chair (0.7%-points) were significantly associated with developing low HGS. Lastly, frailty (0.9%-points higher risk of low HGS) and the fear of falling down (1.6%-points higher risk) also increased the risk of developing low HGS. CONCLUSION: Altogether, we report several risk factors for developing low HGS. Our observations may help evaluating and monitoring high-risk population for developing low HGS in pre-clinical settings.

Predictors of hip fracture in 15 European countries: a longitudinal study of 48,533 geriatric adults using SHARE dataset.

We investigated the risk factors for hip fracture in 48,533 European older adults for 8 years from 2013 onward. We identified female gender, age above 80, low handgrip strength, and depression as significant risk factors for hip fracture. Our findings may help identify high-risk populations for hip fractures in pre-clinical settings. OBJECTIVES: Hip fracture is a major cause of functional disability, mortality, and health costs. However, the identification and characterization of its causative factors remain poor. METHODS: We investigated demography, handgrip strength (HGS), depression, and multiple age-associated comorbidities for predicting future hip fracture in individuals aged 50 or above from 15 European countries (n = 48,533). All participants were evaluated from 2013 to 2020 using four successive waves of the Survey of Health, Aging, and Retirement in Europe (SHARE). RESULTS: Altogether, 1130 participants developed hip fractures during the study period. We identified female gender, an advancing age from quinquagenarians onward, and a poor socioeconomic status as critical risk factors for future hip fracture. Having mobility difficulty, a low HGS (< 27 kg in men, < 16 kg in women) and higher scores on Euro-D depression scales were also significant risk factors for hip fracture. Summated scales of hypertension, diabetes mellitus, cancer, Alzheimer's disease, and stroke did not appear as risk factors. CONCLUSION: Collectively, we report advancing age, female gender, low HGS, and depression as independent risk factors for hip fracture. Our findings are useful in identifying high-risk populations for hip fractures in pre-clinical settings before rigorous evaluation and treatment in clinics.

Tracking the Plasma C-Terminal Agrin Fragment as a Biomarker of Neuromuscular Decline in 18- to 87-Year-Old Men.

OBJECTIVES: Plasma C-terminal agrin-fragment-22 (CAF22), a breakdown product of neuromuscular junction, is a potential biomarker of muscle loss. However, its levels from adolescence to octogenarians are unknown. METHODS: We evaluated young (18-34 years, n = 203), middle-aged (35-59 years, n = 163), and old men (60-87 years, n = 143) for CAF22, handgrip strength (HGS), appendicular skeletal-mass index (ASMI), and gait speed. RESULTS: We found an age-associated increase in CAF22 from young (100.9 ± 29 pmol) to middle-aged (128.3 ± 38.7 pmol) and older men (171.5 ± 35.5 pmol) (all p<0.05). This was accompanied by a gradual reduction in HGS (37.7 ± 6.1 kg, 30.2 ± 5.2 kg, and 26.6 ± 4.7 kg, for young, middle-aged, and old men, respectively), ASMI (8.02 ± 1.02 kg/m2, 7.65 ± 0.92 kg/m2, 6.87 ± 0.93 kg/m2, for young, middle-aged, and old men, respectively), and gait speed (1.29 ± 0.24 m/s, 1.05 ± 0.16 m/s, and 0.81 ± 0.13 m/s, for young, middle-aged, and old men, respectively). After adjustment for age, we found negative regressions of CAF22 with HGS (- 0.0574, p < 0.001) and gait speed (- 0.0162, p < 0.001) in the cumulative cohort. The receiver operating characteristics analysis revealed significant efficacy of plasma CAF22 in diagnosing muscle weakness (HGS < 27 kg) (middle-aged men; AUC = 0.731, 95% CI = 0.629-0.831, p < 0.001, Older men; AUC = 0.816, 95% CI = 0.761-0.833, p < 0.001), and low gait speed (0.8 m/s) (middle-aged men; AUC = 0.737, 95% CI = 0.602-0.871, p < 0.001, older men; AUC = 0.829, 95% CI = 0.772-0.886, p < 0.001), and a modest efficacy in diagnosing sarcopenia (middle-aged men; AUC = 0.701, 95% CI = 0.536-0.865, p = 0.032, older men; AUC = 0.822, 95% CI = 0.759-0.884, p < 0.001) in middle-aged and older men. CONCLUSION: Altogether, CAF22 increases with advancing age and may be a reliable marker of muscle weakness and low gait speed.

The emerging roles of necroptosis in skeletal muscle health and disease.

Necroptosis is a regulated form of cell death with implications in various physiological and pathological processes in multiple tissues. However, the relevant findings from post-mitotic tissues, such as skeletal muscle, are scarce. This review summarizes the potential contributions of necroptosis to skeletal muscle health and diseases. It first discusses the physiological roles of necroptosis in muscle regeneration and development. It then summarizes the contributions of necroptosis to the pathogenesis of multiple muscle diseases, including muscular dystrophies, inflammatory myopathies, cachexia, and neuromuscular disorders. Lastly, it unravels the gaps in our understanding and therapeutic challenges of inhibiting necroptosis as a potential intervention for muscle diseases. Specifically, the findings from the transgenic animal models and the use of pharmacological inhibitors of necroptosis are discussed with relevance to improving the structure and/or function of skeletal muscle in various diseases. Recent developments from experimental animal models and clinical data are presented to discuss the roles of necroptosis in skeletal muscle health and diseases.

Metformin improves skeletal muscle and physical capacity by stabilizing neuromuscular junction in older adults.

OBJECTIVES: Metformin is an anti-diabetic drug with protective effects on skeletal muscle and physical capacity. However, the relevant mechanisms of action on skeletal muscle remain poorly understood. We investigated the potential contribution of neuromuscular junction (NMJ) degradation to skeletal muscle and physical capacity in geriatric men taking metformin. METHOD: We recruited geriatric men for placebo (Age=73.1 ± 4.2 years, n = 70) and metformin (Age=70.1 ± 4.5 years, n = 62) groups. The patients in the metformin group received 1700 mg of metformin twice a day for 16 weeks. We measured plasma c-terminal agrin-fragment-22 (CAF22) and neurofilament light chain (NfL) as markers of neuromuscular junction (NMJ) degradation and neurodegeneration, respectively, with relevance to handgrip strength (HGS) and short physical performance battery (SPPB; a marker of physical capacity) in older adults taking metformin. These findings were associated with reduced oxidative stress in the metformin group. RESULTS: At baseline, both groups had similar HGS, gait speed, SPPB scores, and plasma biochemistry. Metformin improved HGS, gait speed, and cumulative SPPB scores in geriatric men (all p < 0.05). Metformin also reduced plasma CAF22 and NfL levels when compared to baseline. Similar observations were not found in the placebo group. Correlation analysis revealed significant correlations of plasma CAF22 with HGS, gait speed, and cumulative SPPB scores in the metformin group. These observations were associated with reduced oxidative stress in the metformin group. CONCLUSION: Altogether, the restorative effects of metformin on skeletal muscle and physical capacity involve NMJ stabilization. Our data is clinically relevant for geriatric men with functional disabilities.

Retinal vascular changes and arterial stiffness during 8-month isolation and confinement: the SIRIUS-21 space analog mission.

Introduction: Isolation and confinement are significant stressors during space travel that can impact crewmembers' physical and mental health. Space travel has been shown to accelerate vascular aging and increase the risk of cardiovascular and cerebrovascular disorders. However, the effect of prolonged isolation and confinement on microvascular function has not yet been thoroughly investigated. Methods: Retinal vascular imaging was conducted on four crewmembers during- and post-8-month SIRIUS-21 space analog mission. Central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and arteriovenous ratio (AVR) were measured. Pulse wave velocity (PWV), an indicator of arterial stiffness, was also measured. Results: Data from 4 participants was analyzed. These participants had a mean age of 34.75 ± 5.44 years, height of 170.00 ± 2.00 cm, weight of 74.50 ± 12.53 kg, and average BMI of 25.47 ± 3.94 kg/m2. During- and post-isolation, average CRVE showed an upward trend (Pearson's r 0.784, R-square 0.62), suggesting a dilation of retinal venules, while AVR showed a downward trend (Pearson's r -0.238, R-square 0.057), which is suggestive of a higher risk of cardiovascular and cerebrovascular dysfunctions. But neither of these trends were statistically significant. Additionally, the average PWV showed an upward trend during- and after-isolation across all crew members. Conclusion: Isolation and confinement appear to contribute towards retinal vascular damage and arterial stiffness. This cautiously suggests an increased risk of cardiovascular and cerebrovascular disorders due to the contribution of the isolation in space flight. Further studies are needed to confirm and expand on these results as we prepare for future manned missions to the Moon and Mars.

The Association of Intestinal Leak with Sarcopenia and Physical Disability in Patients with Various Stages of Chronic Kidney Disease.

Sarcopenia is related to disease severity in chronic kidney disease (CKD) patients; however, its pathophysiology remains poorly known. We investigated the associations of biomarkers of intestinal leak with sarcopenia in various stages of CKD. We recruited 61-76-year-old male controls and patients with various stages of CKD (n = 36-57/group) for measuring plasma lipopolysaccharide-binding protein (LBP) and zonulin (markers of intestinal leak), handgrip strength (HGS), skeletal mass index (SMI), and gait speed (markers of sarcopenia), and short physical performance battery (SPPB; marker of physical capacity). CKD stages 4 and 5 were associated with lower HGS, SMI, gait speed, and cumulative SPPB scores and a higher sarcopenia prevalence than controls and patients with CKD stages 1 and 2 (all p < 0.05). CKD patients (stages 1 and 2) had elevated plasma zonulin and LBP when compared with CKD stages 4 and 5. Plasma zonulin and LBP exhibited significant correlations with renal function, HGS, gait speed, SPPB scores, and oxidative stress markers in CKD stages 4 and 5 (all p < 0.05). However, similar relations were not found in early CKD. Collectively, intestinal leak may be contributing to sarcopenia and physical disability in the advanced stages of CKD.

Resistance Exercise Reduces Sarcopenia by Repairing Leaky Gut in Patients with Alzheimer's Disease.

PURPOSE: Sarcopenia or age-associated muscle loss is common in patients with Alzheimer's disease (AD). We have previously demonstrated the contribution of a leaky gut to sarcopenia in AD. Here, we asked whether resistant exercise (RE) reduces the sarcopenia phenotype by repairing intestinal leakage in patients with AD. METHOD: A prospective, single-center study of older adults, including healthy controls and patients with AD (n = 44-51/group), was conducted to measure plasma zonulin and claudin-3 (markers of intestinal leakage), handgrip strength (HGS), and short physical performance battery (SPPB) as a measure of functional capacity. Measurements in patients with AD were performed at baseline and after 12 weeks of RE. RESULTS: At baseline, patients with AD had higher plasma zonulin and claudin-3 and lower HGS, gait speed, and SPPB scores than controls. RE reduced plasma zonulin and claudin-3 levels and improved HGS, SPPB scores, and gait speed. Regression analysis revealed robust relationships between changes in plasma zonulin and claudin-3 with HGS. Plasma zonulin was also positively associated with SPPB scores. In addition, RE downregulated plasma markers of inflammation and oxidative stress. However, the prevalence of sarcopenia based on low HGS and muscle atrophy or low SPPB was not affected by RE. CONCLUSION: Taken together, disruption of the intestinal mucosal barrier may contribute to functional decline and sarcopenia in AD, which is incompletely recovered by RE. Circulating levels of zonulin and claudin-3 may be valuable in predicting sarcopenia and functional capacity in older adults with AD.

A leaky gut contributes to postural imbalance in male patients with chronic obstructive pulmonary disease.

AIMS: Patients with chronic obstructive pulmonary disease (COPD) frequently exhibit an inability to maintain postural balance. However, the contribution of increased intestinal permeability or leaky gut to the postural imbalance in COPD is not known. METHODS: We measured plasma zonulin, a marker of leaky gut, with relevance to postural balance in male controls (n = 70) and patients with mild (n = 67), moderate (n = 66), and severe (n = 58) COPD. We employed a short physical performance battery to evaluate postural balance in supine, tandem, and semi-tandem positions. We also measured handgrip strength (HGS), gait speed, plasma c-reactive proteins (CRP), and 8-isoprostanes as potential mechanistic connections between postural imbalance and leaky gut. RESULTS: COPD patients demonstrated higher plasma zonulin, CRP, and 8-isoprostanes levels and lower balance, HGS, and gait speed than controls (all p < 0.05). These findings were more robust in patients with moderate and severe than mild COPD. In addition, plasma zonulin exhibited significant potential in diagnosing poor balance, low HGS, and gait speed in COPD patients (all p < 0.05). We also found significant correlations of plasma zonulin with CRP and 8-isoprostanes, providing heightened inflammation and oxidative stress as mechanistic connections between leaky gut and postural imbalance. CONCLUSION: Plasma zonulin may be helpful in evaluating postural imbalance in COPD patients. Repairing intestinal leaks can be a therapeutic target to improve postural control in COPD.

Natural compound screening predicts novel GSK-3 isoform-specific inhibitors.

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-3ß often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3ß, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50 = 2.26 µM) vs. GSK-3ß (IC50 = 4.23 µM) while Rosmarinic acid was found to be more potent against GSK-3ß (IC50 = 2.24 µM) than GSK-3α (IC50 = 5.14 µM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3ß isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers.

GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia.

Dysregulated autophagy/mitophagy is one of the major causes of cardiac injury in ischemic conditions. Glycogen synthase kinase-3alpha (GSK-3α) has been shown to play a crucial role in the pathophysiology of cardiac diseases. However, the precise role of GSK-3α in cardiac mitophagy remains unknown. Herein, we investigated the role of GSK-3α in cardiac mitophagy by employing AC16 human cardiomyocytes under the condition of acute hypoxia. We observed that the gain-of-GSK-3α function profoundly induced mitophagy in the AC16 cardiomyocytes post-hypoxia. Moreover, GSK-3α overexpression led to increased ROS generation and mitochondrial dysfunction in cardiomyocytes, accompanied by enhanced mitophagy displayed by increased mt-mKeima intensity under hypoxia. Mechanistically, we identified that GSK-3α promotes mitophagy through upregulation of BNIP3, caused by GSK-3α-mediated increase in expression of HIF-1α and FOXO3a in cardiomyocytes post-hypoxia. Moreover, GSK-3α displayed a physical interaction with BNIP3 and, inhibited PINK1 and Parkin recruitment to mitochondria was observed specifically under hypoxia. Taken together, we identified a novel mechanism of mitophagy in human cardiomyocytes. GSK-3α promotes mitochondrial dysfunction and regulates FOXO3a -mediated BNIP3 overexpression in cardiomyocytes to facilitate mitophagy following hypoxia. An interaction between GSK-3α and BNIP3 suggests a role of GSK-3α in BNIP3 recruitment to the mitochondrial membrane where it enhances mitophagy in stressed cardiomyocytes independent of the PINK1/Parkin.

Lipid-Lowering Medications are Associated with Reduced Sarcopenia-Related Quality of Life in Older Adults with Hyperlipidemia.

PURPOSE: Statins medications negatively affect age-associated loss of muscle mass and strength, termed sarcopenia, and neuromuscular junction (NMJ) integrity. However, their association with the sarcopenia-related-quality-of-life (SarQoL) is unknown. METHODS: In this cross-sectional, case control study, we recruited male nonusers (n = 75 and age 75.2 ± 5.9 years) and users (n = 77 and age 77.1 ± 6.2 years) of statins to evaluate SarQoL and handgrip strength (HGS). We also measured plasma C-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation. RESULTS: Statin users had higher CAF22, and lower HGS, and cumulative SarQoL scores than non-users (all p < 0.05). Plasma CAF22 exhibited negative correlations with SarQoL scores for physical and mental health, locomotion, functionality, activities-of-daily-living, and cumulative SarQoL in statins users and non-users (all p < 0.05). Lastly, the cumulative SarQoL scores exhibited positive associations with HGS and gait speed in the study participants (all p < 0.05). CONCLUSIONS: Collectively, statin usage was associated with NMJ degradation and reduced SarQoL. Statins should be cautiously prescribed in patients with sarcopenia with reduced QoL.

Probiotics Supplements Improve the Sarcopenia-Related Quality of Life in Older Adults with Age-Related Muscle Decline.

A pathological increase in intestinal leak is implicated in age-associated muscle loss, termed sarcopenia, and reduced sarcopenia-related quality-of-life (SarQoL). However, the potential therapies remain elusive. We investigated the effects of probiotic supplementation on sarcopenia and SarQoL in geriatric older adults. We randomized sarcopenic men into placebo (age = 71.4 ± 3.9 years, n = 63) and probiotic (age = 73 ± 4.1 years, n = 60) groups for 16 weeks. The probiotic used was one capsule daily of Vivomix 112 billion for 16 weeks. We measured sarcopenia parameters of handgrip strength (HGS) and skeletal mass index (SMI), plasma zonulin (marker of the intestinal leak), and SarQoL using a targeted questionnaire. Probiotics improved the SarQoL scores for locomotion, functionality, and activities of daily living and prevented a decline in cumulative SarQoL observed in the placebo group (all p < 0.05). Probiotic supplementation also reduced plasma zonulin and marker of systemic bacterial load. These changes were accompanied by an increase in HGS and maintenance of gait speed in the probiotic group compared to the placebo group. Correlation analysis revealed significant associations of cumulative SarQoL scores with plasma zonulin and HGS in the probiotic group. Collectively, probiotics improved SarQoL and HGS by repairing pathological intestinal leak. Future studies may further dissect the relation between intestinal leak and SarQoL in older adults taking probiotics.

Plasma levels of Neurofilament light chain correlate with handgrip strength and sarcopenia in patients with chronic obstructive pulmonary disease.

BACKGROUND: Age-associated muscle decline, termed sarcopenia, is a common systemic effect of chronic obstructive pulmonary disease (COPD). Circulating Neurofilament light chain (NfL) levels reflect neuronal degradation and may be relevant to sarcopenia phenotype. However, such an association in COPD patients remains elusive. METHODS: We investigated male, 60-76 years old controls (n = 50) and COPD patients (n = 139) for plasma NfL levels in relation to sarcopenia and physical capacity markers. We measured handgrip strength (HGS), body composition, and short physical performance battery (SPPB) to evaluate sarcopenia and physical capacity. RESULTS: COPD patients had higher plasma NfL and lower HGS and SPPB performance than controls. Plasma NfL levels demonstrated negative associations with HGS and gait speed in COPD patients (all p < 0.05). Further, NfL levels were negatively associated with total SPPB scores in controls and patients with advanced COPD (p < 0.05). Plasma NfL also demonstrated an acceptable accuracy in diagnosing sarcopenia in controls (AUC = 0.757, p < 0.05) and COPD (AUC = 0.806, p < 0.05) patients. CONCLUSION: Collectively, plasma NfL may be helpful in evaluating sarcopenia phenotype and physical capacity in geriatric patients with COPD.

Metformin Improves Sarcopenia-Related Quality of Life in Geriatric Adults: A Randomized Controlled Trial.

OBJECTIVES: Metformin protects against age-related muscle decline, termed sarcopenia. However, the effects on sarcopenia quality-of-life (SarQoL) are unknown. We investigated the effects of metformin on SarQoL and associated mechanisms in older adults. METHOD: This double-blind randomized, placebo-controlled trial included geriatric adult men, divided into non-sarcopenic controls (age = 72.2 ± 4.3 years, n = 52) and two groups of patients with sarcopenia randomized into placebo (age at baseline = 74.4 ± 5.7 years, n = 54) and metformin (age at baseline = 71.2 ± 3.9 years, n = 47) groups. Patients in the metformin group received 1.7 grams twice daily for four months. We evaluated SarQoL, handgrip strength (HGS), plasma zonulin, c-reactive protein (CRP), and 8-isoprostanes. RESULTS: Patients with sarcopenia had lower HGS and SarQoL than controls (both p <0.05). Metformin improved the HGS and the SarQoL domains related to physical and mental health, locomotion, and leisure activities, as well as cumulative SarQoL scores (all p <0.05). Metformin also prevented the decline in the SarQoL domains for functionality and fear. Among plasma biomarkers, metformin reduced the levels of zonulin, CRP, 8-isoprostanes, and creatine kinase. We also found a significant correlation of plasma zonulin with cumulative SarQoL in patients with sarcopenia taking metformin, suggesting a role for intestinal repair in improving SarQoL. Finally, metformin did not affect body composition and gait speed. CONCLUSION: Overall, metformin improved HGS and SarQoL by repairing intestinal leakage. Our data have clinical relevance for improving the quality of life in older adults with sarcopenia.

Biomarkers of Physical and Mental Health for Prediction of Parkinson's Disease: A Population-Based Study from 15 European Countries.

OBJECTIVES: Early diagnosis of Parkinson's disease (PD) is critical for optimal treatment. However, the predictive potential of physical and mental health in PD is poorly characterized. METHODS: We evaluated the potential of multiple demographic, physical, and mental factors in predicting the future onset of PD in older adults aged 50 years or older from 15 European countries. Individual study participants were followed over four waves of the Survey of Health, Ageing, and Retirement in Europe (SHARE) from 2013-2020. RESULTS: Of 57,980 study participants, 442 developed PD during the study period. We identified male sex and advancing age from the sixth decade of life onward as significant predictors of future PD. Among physical factors, a low handgrip strength (HGS; men <27 kg, women <16 kg), being bothered by frailty, and recent falls were significantly associated with future PD. Among mental factors, a higher depression (Euro-D depression score >6) emerged as an independent predictor of future PD. Finally, the presence of hypertension or Alzheimer's disease (AD) increases the risk of future PD. CONCLUSIONS: Altogether, male sex, advancing age, low HGS, frailty, depression, hypertension, and AD were identified as critical risk factors for future PD. Our results may be useful in the early identification and treatment of populations at risk for PD.

Association between handgrip strength and metabolic syndrome in relation to gender and adiposity among middle aged and older Saudi populations.

AIM: This cross-sectional study investigated the association between metabolic syndrome (MetS) and handgrip strength (HGS) with respect to sex and adiposity in Saudi men (n = 287) and women (n = 268). MATERIAL AND METHODS: Anthropometry, body composition, HGS, and blood biochemistry were measured. The average age of the study population was 57.65 ± 9.3 years (men = 55.1 ± 9.3 years, women = 60.4 ± 9.3 years). We report that HGS/body mass index (BMI), HGS/weight, and HGS/fat (%) were significantly higher in controls than in patients with MetS in men but not in women. According to the ROC analysis, relative HGS (RHGS) was higher than HGS alone in the association with MetS, which was significant for men (p < 0.01). At lower quartiles of HGS, the probability of MetS was higher in women, and the same was found in men in the lower quartiles of HGS/%Fat. Multinomial regression revealed significant associations between age and adiposity and MetS in men and HGS in women. Additionally, the linear regression of age, HGS, and weight exhibited significant associations between HGS with WC in both sexes. CONCLUSION: A higher risk of MetS in the lower quartiles of HGS was found in women, and adiposity moderated the relationship between HGS and MetS in men.

Pharmacological inhibition of endoplasmic reticulum stress mitigates osteoporosis in a mouse model of hindlimb suspension.

Hindlimb suspension (HLS) mice exhibit osteoporosis of the hindlimb bones and may be an excellent model to test pharmacological interventions. We investigated the effects of inhibiting endoplasmic reticulum (ER) stress with 4-phenyl butyrate (4-PBA) on the morphology, physicochemical properties, and bone turnover markers of hindlimbs in HLS mice. We randomly divided 21 male C57BL/6J mice into three groups, ground-based controls, untreated HLS group and 4-PBA treated group (HLS+4PBA) (100mg/kg/day, intraperitoneal) for 21 days. We investigated histopathology, micro-CT imaging, Raman spectroscopic analysis, and gene expression. Untreated HLS mice exhibited reduced osteocyte density, multinucleated osteoclast-like cells, adipocyte infiltration, and reduced trabecular striations on micro-CT than the control group. Raman spectroscopy revealed higher levels of ER stress, hydroxyproline, non-collagenous proteins, phenylalanine, tyrosine, and CH2Wag as well as a reduction in proteoglycans and adenine. Furthermore, bone alkaline phosphatase and osteocalcin were downregulated, while Cathepsin K, TRAP, and sclerostin were upregulated. Treatment with 4-PBA partially restored normal bone histology, increased collagen crosslinking, and mineralization, promoted anti-inflammatory markers, and downregulated bone resorption markers. Our findings suggest that mitigating ER stress with 4-PBA could be a therapeutic intervention to offset osteoporosis in conditions mimicking hindlimb suspension.