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IMPORTANCEAging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans. OBJECTIVE To investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cellular health. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 years was conducted at a medical center and a cancer research center
IMPORTANCEAging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans. OBJECTIVE To investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cellular health. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 years was conducted at a medical center and a cancer research center
IMPORTANCE Cross-sectional studies have shown that combined low muscle mass and strength are associated with cognitive impairment. Whether low muscle mass, reflective of physiologic reserve, is independently associated with faster cognitive decline remains unknown. OBJECTIVE To investigate the associations between low muscle mass and cognitive decline in 3 distinct domains among adults aged at least 65 years. DESIGN, SETTING, AND PARTICIPANTS The Canadian Longitudinal Study on Aging is a prospective population-based cohort study of community-dwelling adults. Enrollment occurred from 2011 to 2015 with a 3-year follow-up. Analyses for this study were conducted on those aged at least 65 years from April 24 to August 12, 2020. EXPOSURE Appendicular lean soft tissue mass (ALM) was assessed by dual energy x-ray absorptiometry. Low ALM was identified using the sex-specific Canadian cut points. MAIN OUTCOMES AND MEASURES Memory was assessed using the Rey auditory verbal learning test. Executive function was assessed using the mental alternation test, Stroop high interference (words/dot) test, the animal fluency test, and the controlled oral word association test. Psychomotor speed was assessed using computer-administered choice reaction time. Composite scores by domain were created. RESULTSOf 8279 participants, 4003 (48%) were female, 8005 (97%) were White, and the mean (SD) age was 72.9 (5.6) years. A total of 1605 participants (19.4%) had low ALM at baseline.Participants with low ALM were older, had lower body mass index and physical activity level. The presence of low ALM at baseline was associated with faster 3-year cognitive decline in executive functions and psychomotor speed from multiple linear regressions. After adjusting for covariates including age, level of education, percentage body fat, and handgrip strength, low ALM remained independently associated with executive function decline (standardized β: −0.032; P = .03) only.Low ALM was not associated with memory. CONCLUSIONS AND RELEVANCE This cohort study found longitudinal associations between lowALM and cognition in aging. Identification of older adults with low muscle mass, a targetable modifiable factor, may help estimate those at risk for accelerated executive function decline. Further longer-term investigation of associations is warranted.
ImportanceKidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker (cystatin C level) associates more closely with future risk of cardiovascular disease (CVD) and mortality.ObjectivesTo evaluate whether testing concordance between estimated glomerular filtration rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age.Design, Setting, and ParticipantsA prospective population-based cohort study (UK Biobank), with participants recruited between 2006-2010 with median follow-up of 11.5 (IQR, 10.8-12.2) years; data were collected until August 31, 2020. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m2, albuminuria (albumin <30 mg/g), and no preexisting CVD or kidney failure.ExposuresChronic kidney disease status was categorized by concordance between eGFRcr and eGFRcys across the threshold for hronic kidney disease (CKD) diagnosis (60 mL/min/1.73 m2).Main Outcomes and MeasuresTen-year probabilities of CVD, mortality, and kidney failure were assessed according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification. Analyses were stratified by older (age 65-73 years) and younger (age <65 years) age.ResultsThere were 428 402 participants: median age was 57 (IQR, 50-63) years and 237 173 (55.4%) were women. Among 76 629 older participants, there were 9335 deaths and 5205 CVD events. Among 351 773 younger participants, there were 14 776 deaths and 9328 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was greater than or equal to 60 mL/min/1.73 m2; conversely, with eGFRcys less than 60 mL/min/1.73 m2, 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5% 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%-0.8%) in older people and 0.7% (95% CI, 0.7%-0.8%) in younger people; eGFRcr did not add to CVD risk estimation.Conclusions and RelevanceThe findings of this study suggest that eGFRcr 45 to 59 mL/min/1.73 m2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of individuals at high-risk for CVD and mortality. The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD.
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