Acute effects of a ketone monoester, whey protein, or their coingestion on mTOR trafficking and protein-protein colocalization in human skeletal muscle.

We recently demonstrated that acute oral ketone monoester intake induces a stimulation of postprandial myofibrillar protein synthesis rates comparable to that elicited following the ingestion of 10 g whey protein or their coingestion. The present investigation aimed to determine the acute effects of ingesting a ketone monoester, whey protein, or their coingestion on mechanistic target of rapamycin (mTOR)-related protein-protein colocalization and intracellular trafficking in human skeletal muscle. In a randomized, double-blind, parallel group design, 36 healthy recreationally active young males (age: 24.2 ± 4.1 yr) ingested either: 1) 0.36 g·kg-1 bodyweight of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET + PRO). Muscle biopsies were obtained in the overnight postabsorptive state (basal conditions), and at 120 and 300 min in the postprandial period for immunofluorescence assessment of protein translocation and colocalization of mTOR-related signaling molecules. All treatments resulted in a significant (Interaction: P < 0.0001) decrease in tuberous sclerosis complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) colocalization at 120 min versus basal; however, the decrease was sustained at 300 min versus basal (P < 0.0001) only in KET + PRO. PRO and KET + PRO increased (Interaction: P < 0.0001) mTOR-Rheb colocalization at 120 min versus basal; however, KET + PRO resulted in a sustained increase in mTOR-Rheb colocalization at 300 min that was greater than KET and PRO. Treatment intake increased mTOR-wheat germ agglutinin (WGA) colocalization at 120 and 300 min (Time: P = 0.0031), suggesting translocation toward the fiber periphery. These findings demonstrate that ketone monoester intake can influence the spatial mechanisms involved in the regulation of mTORC1 in human skeletal muscle.NEW & NOTEWORTHY We explored the effects of a ketone monoester (KET), whey protein (PRO), or their coingestion (KET + PRO) on mTOR-related protein-protein colocalization and intracellular trafficking in human muscle. All treatments decreased TSC2-Rheb colocalization at 120 minutes; however, KET + PRO sustained the decrease at 300 min. Only PRO and KET + PRO increased mTOR-Rheb colocalization; however, the increase at 300 min was greater in KET + PRO. Treatment intake increased mTOR-WGA colocalization, suggesting translocation to the fiber periphery. Ketone bodies influence the spatial regulation of mTOR.

A multimodal exercise countermeasure prevents the negative impact of head-down tilt bed rest on muscle volume and mitochondrial health in older adults.

Mitochondrial dysfunctions are thought to contribute to muscle atrophy and weakness that develop during ageing and mechanical unloading caused by immobilization, bed rest and microgravity. Older adults are at greater risk of developing muscle and mitochondrial dysfunctions in response to unloading. Although exercise is well known to promote muscle and mitochondrial health, its protective effect during mechanical unloading in older adults remains largely unexplored. Here, we investigated the impact of 14 days of head-down tilt bed rest (HDBR) with and without a multimodal exercise countermeasure in older men and women (55-65 years). Leg muscle volume was assessed using magnetic resonance imaging. Biopsies of the vastus lateralis were performed to assess markers of mitochondrial content, respiration, reactive oxygen species (ROS) production and calcium retention capacity (mCRC). Indices of mitochondrial quality control (MQC), including markers of fusion (MFN1 and 2), fission (Drp1), mitophagy (Parkin) and autophagy (p62 and LC3I and II) were measured using immunoblots. Muscle cross-sections were stained for neural cell adhesion molecule (NCAM, a marker of denervation). HDBR triggered muscle atrophy, decreased mitochondrial content and respiration and increased mitochondrial ROS production. HDBR had no impact on mCRC or MQC markers but increased markers of autophagy and denervation. Exercise prevented the deleterious effects of HDBR on leg muscle volume, mitochondrial ROS production and markers of autophagy and denervation. Exercise also increased mitochondrial content and respiration without altering mCRC and MQC markers. Collectively, our results indicate that an exercise countermeasure that can be performed in bed is effective in protecting muscle and mitochondrial health during HDBR in older adults. KEY POINTS: Conditions associated with muscle unloading, such as immobilization, bed rest or microgravity, result in muscle atrophy and weakness, particularly in older adults. Mitochondrial dysfunctions are thought to contribute to muscle atrophy caused by unloading and ageing. However, whether exercise can counteract the deleterious effects of unloading in older adults remains largely unexplored. Here, we report that older adults exposed to 14 days of head-down tilt bed rest (HDBR) displayed upper leg muscle atrophy, a decrease in mitochondrial content and respiration, an increase in H2O2 emission, and an increase in autophagy and denervation markers. No impact of HDBR on mitochondrial quality control was observed. A multimodal exercise countermeasure prevented the deleterious effects of HDBR on upper leg muscle volume, mitochondrial reactive oxygen species emission, and markers of autophagy and denervation and increased mitochondrial content and respiration. These findings highlight the effectiveness of exercise in promoting muscle and mitochondrial health in older adults undergoing bed rest.

Myths and Methodologies: Understanding the health impact of head down bedrest for the benefit of older adults and astronauts. Study protocol of the Canadian Bedrest Study.

Weightlessness during spaceflight can harm various bodily systems, including bone density, muscle mass, strength and cognitive functions. Exercise appears to somewhat counteract these effects. A terrestrial model for this is head-down bedrest (HDBR), simulating gravity loss. This mirrors challenges faced by older adults in extended bedrest and space environments. The first Canadian study, backed by the Canadian Space Agency, Canadian Institutes of Health Research, and Canadian Frailty Network, aims to explore these issues. The study seeks to: (1) scrutinize the impact of 14-day HDBR on physiological, psychological and neurocognitive systems, and (2) assess the benefits of exercise during HDBR. Eight teams developed distinct protocols, harmonized in three videoconferences, at the McGill University Health Center. Over 26 days, 23 participants aged 55-65 underwent baseline measurements, 14 days of -6° HDBR, and 7 days of recovery. Half did prescribed exercise thrice daily combining resistance and endurance exercise for a total duration of 1 h. Assessments included demographics, cardiorespiratory fitness, bone health, body composition, quality of life, mental health, cognition, muscle health and biomarkers. This study has yielded some published outcomes, with more forthcoming. Findings will enrich our comprehension of HDBR effects, guiding future strategies for astronaut well-being and aiding bedrest-bound older adults. By outlining evidence-based interventions, this research supports both space travellers and those enduring prolonged bedrest.

Impact of 14 Days of Bed Rest in Older Adults and an Exercise Countermeasure on Body Composition, Muscle Strength, and Cardiovascular Function: Canadian Space Agency Standard Measures.

INTRODUCTION: Head-down bed rest (HDBR) has long been used as an analog to microgravity, and it also enables studying the changes occurring with aging. Exercise is the most effective countermeasure for the deleterious effects of inactivity. The aim of this study was to investigate the efficacy of an exercise countermeasure in healthy older participants on attenuating musculoskeletal deconditioning, cardiovascular fitness level, and muscle strength during 14 days of HDBR as part of the standard measures of the Canadian Space Agency. METHODS: Twenty-three participants (12 males and 11 females), aged 55-65 years, were admitted for a 26-day inpatient stay at the McGill University Health Centre. After 5 days of baseline assessment tests, they underwent 14 days of continuous HDBR followed by 7 days of recovery with repeated tests. Participants were randomized to passive physiotherapy or an exercise countermeasure during the HDBR period consisting of 3 sessions per day of either high-intensity interval training (HIIT) or low-intensity cycling or strength exercises for the lower and upper body. Peak aerobic power (V̇O2peak) was determined using indirect calorimetry. Body composition was assessed by dual-energy X-ray absorptiometry, and several muscle group strengths were evaluated using an adjustable chair dynamometer. A vertical jump was used to assess whole-body power output, and a tilt test was used to measure cardiovascular and orthostatic challenges. Additionally, changes in various blood parameters were measured as well as the effects of exercise countermeasure on these measurements. RESULTS: There were no differences at baseline in main characteristics between the control and exercise groups. The exercise group maintained V̇O2peak levels similar to baseline, whereas it decreased in the control group following 14 days of HDBR. Body weight significantly decreased in both groups. Total and leg lean masses decreased in both groups. However, total body fat mass decreased only in the exercise group. Isometric and isokinetic knee extension muscle strength were significantly reduced in both groups. Peak velocity, flight height, and flight time were significantly reduced in both groups with HDBR. CONCLUSION: In this first Canadian HDBR study in older adults, an exercise countermeasure helped maintain aerobic fitness and lean body mass without affecting the reduction of knee extension strength. However, it was ineffective in protecting against orthostatic intolerance. These results support HIIT as a promising approach to preserve astronaut health and functioning during space missions, and to prevent deconditioning as a result of hospitalization in older adults.

Factors partitioning physical frailty in people aging with HIV: A classification and regression tree approach.

OBJECTIVE: To estimate the extent to which comorbidity and lifestyle factors were associated with physical frailty in middle-aged and older Canadians living with HIV. DESIGN: Cross-sectional analysis of 856 participants from the Canadian Positive Brain Health Now cohort. METHODS: The frailty indicator phenotype was adapted from Fried's criteria using self-report items. Univariate logistic regression and classification and regression tree (CaRT) models were used to identify the most relevant independent contributors to frailty. RESULTS: In all, 100 men (14.0%) and 26 women (19.7%) were identified as frail (≥ 3/5 criteria) for an overall prevalence of 15.2%. Nine comorbidities showed an influential association with frailty. The most influential comorbidities were hypothyroidism [odds ratio (OR) = 2.55, 95% confidence interval (CI): 1.29-5.03] and arthritis (OR = 2.54, 95% CI: 1.58-4.09). Additionally, tobacco (OR = 1.79, 95% CI: 1.05-3.04) showed an association. Any level of alcohol consumption showed a protective effect for frailty. The CaRT model showed nine pathways that led to frailty. Arthritis was the most discriminatory variable followed by alcohol, hypothyroidism, tobacco, cancer, cannabis, liver disease, kidney disease, osteoporosis, lung disease and peripheral vascular disease. The prevalence of physical frailty for people with arthritis was 27.4%; with additional cancer or tobacco and alcohol the prevalence rates were 47.1% and 46.1%, respectively. The protective effect of alcohol consumption evident in the univariate model appeared again in the CaRT model, but this effect varied. Cognitive frailty (19.5% overall) and emotional frailty (37.9% overall) were higher than the prevalence of physical frailty. CONCLUSIONS: Specific comorbidities and tobacco use were implicated in frailty, suggesting that it is comorbidities causing frailty. However, some frailty still appears to be HIV-related. The higher prevalence of cognitive and emotional frailty highlights the fact that physical frailty should not be the only focus in HIV.

A reliable, reproducible flow cytometry protocol for immune cell quantification in human adipose tissue.

The ability to accurately identify and quantify immune cell populations within adipose tissue is important in understanding the role of immune cells in metabolic disease risk. Flow cytometry is the gold standard method for immune cell quantification. However, quantification of immune cells from adipose tissue presents a number of challenges because of the complexities of working with an oily substance and the rapid deterioration of immune cell viability before analysis can be performed. Here we present a highly reproducible flow cytometry protocol for the quantification of immune cells in human adipose tissue, which overcomes these issues.

Early Mobilization in Older Adults with Acute Cardiovascular Disease.

BACKGROUND: Early mobilization (EM) is beneficial in critical care units and in older hospitalized patients, but little is known about EM in older adults with acute cardiovascular disease. METHODS: Consecutive admissions of adults ≥80 years old to a Cardiac Intensive Care Unit (CICU) prior to and following implementation of a nurse-driven EM program were reviewed. Mobility was measured using the Level of Function (LOF) Mobility Scale, which ranges from 0 (bed immobile) to 5 (able to walk >20 meters). The primary outcome was discharge home. RESULTS: There were 412 patients included (N = 234, intervention; N = 178, preintervention). There was no difference in age between groups (overall 86.3 ± 4.8 years old) or sex (overall female N = 215, 52.2%). In the intervention group, functional impairment was present in 89 patients (38.0%) prehospitalization and in 209 patients (89.3%) on admission. Nearly half of patients (N = 107; 45.7%) improved their LOF by ≥1 during admission. Mobilization occurred during nearly all opportunities (838/850; 98.6%), and most mobility activities were completed (2,207/2,553; 86.4%). Adverse events were rare (5/2,207 activities [0.2% adverse event rate]) and transient. Patients in the intervention group were more likely than patients in the preintervention group to be discharged home (74.4 vs. 65.7%, P = 0.047, respectively) and had a lower rate of in-hospital death (6.4 vs. 14.6%, P = 0.006, respectively). There was no difference in mean length of hospital stay, 30-day emergency department visit or hospital re-admission. CONCLUSION: EM is safe in older adults in the CICU and is associated with reduced discharge to healthcare facility and in-hospital mortality.

Motoric cognitive risk syndrome and incident dementia in older adults from the Québec NuAge cohort.

BACKGROUND: The co-occurrence of slow walking speed and subjective cognitive complaint (SCC) in non-demented individuals defines motoric cognitive risk syndrome (MCR), which is a pre-dementia stage. There is no information on the association between MCR and incident dementia in Québec's older population. OBJECTIVE: The study aims to examine the association of MCR and its individual components (i.e. SCC and slow walking speed) with incident dementia in community-dwelling older adults living in the province of Québec (Canada). DESIGN: Québec older people population-based observational cohort study with 3 years of follow-up. SETTING: Community dwellings. SUBJECTS: A subset of participants (n = 1,098) in 'Nutrition as a determinant of successful aging: The Québec longitudinal study' (NuAge). METHODS: At baseline, participants with MCR were identified. Incident dementia was measured at annual follow-up visits using the Modified Mini-Mental State (≤79/100) test and Instrumental Activity Daily Living scale (≤6/8) score values. RESULTS: The prevalence of MCR was 4.2% at baseline and the overall incidence of dementia was 3.6%. MCR (Hazard Ratio (HR) = 5.18, with 95% confidence interval (CI) = [2.43-11.03] and P ≤ 0.001) and SCC alone (HR = 2.54, with 95% CI = [1.33-4.85] and P = 0.005) were associated with incident dementia, but slow walking speed was not (HR = 0.81, with 95%CI = [0.25-2.63] and P = 0.736). CONCLUSIONS: MCR and SCC are associated with incident dementia in NuAge study participants.

Glucose and protein metabolic responses to an energy- but not protein- restricted diet in type 2 diabetes.

AIMS: To test the effect of energy restriction with maintained protein intake on body composition and on insulin sensitivity of glucose and protein metabolism in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: After 3 days of an isoenergetic diet with 1.2 g/kg/d protein, obese adults with T2D (three women, two men) followed a 5-week diet providing 60% of energy requirements with 45% carbohydrate, and with protein maintained at pre-intervention level. Isotopic tracers were used to quantify whole-body glucose (3-3 H-glucose) and protein (13 C-leucine) metabolism pre- (day 4) and post-intervention (day 39), in the postabsorptive state and during a hyperinsulinaemic, isoglycaemic, isoaminoacidaemic clamp. Body composition was measured using dual-energy x-ray absorptiometry. RESULTS: After energy restriction, 6% weight loss occurred via total body (11%) and visceral fat losses (25%), but lean mass was preserved. Fasting glucose level, serum insulin level, homeostatic model assessment of insulin resistance index and C-peptide level decreased significantly (29%, 38%, 54% and 38%, respectively) as did other cardiometabolic risk factors. Between clamp studies, postabsorptive protein turnover and oxidation rates decreased (12% and 32%), resulting in less negative net balance, consistent with protein conservation. The rates of glucose turnover decreased, and glucose metabolic clearance rate improved (24%). During the clamp, protein flux was lower (9%) and breakdown suppressed (12%), and net balance became less negative but not different. Although glucose turnover did not differ, metabolic clearance improved by 47%. CONCLUSIONS: In obese adults with T2D, an energy-restricted diet with maintained protein intake of ~1.2 g/kg/d improved the kinetics of protein metabolism (particularly in the postabsorptive state), and preserved lean body mass and increased glucose metabolic clearance rate.

Sex differences in the relationship between dietary pattern adherence and cognitive function among older adults: findings from the NuAge study.

BACKGROUND: Consumption of a prudent dietary pattern rich in healthy nutrients is associated with enhanced cognitive performance in older adulthood, while a Western dietary pattern low in healthy nutrients is associated with poor age-related cognitive function. Sex differences exist in dietary intake among older adults; however, there is a paucity of research examining the relationship between sex-specific dietary patterns and cognitive function in later life. METHODS: The current study aimed to investigate sex differences in the relationship between sex-specific dietary pattern adherence and global cognitive function at baseline and over a 3-year follow-up in 1268 community-dwelling older adults (Mage = 74 years, n = 664 women, n = 612 men) from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). A 78-item Food Frequency Questionnaire was used to estimate dietary intake over the previous year. Sex-specific dietary pattern scores were derived using principal component analysis. Global cognition was assessed using the Modified Mini-Mental State Examination (3MS). RESULTS: Adjusted linear mixed effects models indicated that a healthy, prudent dietary pattern was not associated with baseline cognitive performance in men or women. No relationship was found between Western dietary pattern adherence and baseline cognitive function in women. Among men, adherence to an unhealthy, Western dietary pattern was associated with poorer baseline cognitive function (ß = - 0.652, p = 0.02, 95% CI [- 1.22, - 0.65]). No association was found between prudent or Western dietary patterns and cognitive change over time in men or women. CONCLUSIONS: These findings highlight the importance of conducting sex-based analyses in aging research and suggest that the relationship between dietary pattern adherence and cognitive function in late life may be sex-dependent.

Revisiting the hypothesis of syndromic frailty: a cross-sectional study of the structural validity of the frailty phenotype.

BACKGROUND: Fried's Phenotype Model of Frailty (PMF) postulates that frailty is a syndrome. Features of a syndrome are a heterogeneous population that can be split into at least two classes, those presenting and those not presenting the syndrome. Syndromes are characterized by a specific mixture of signs and symptoms which increase in prevalence, from less to more severe classes. So far, the null hypothesis of homogeneity - signs and symptoms of frailty cannot identify at least two classes - has been tested using Latent Class Analysis (LCA) on the five dichotomized components of PMF (unintentional weight loss, exhaustion, weakness, slowness, and low physical activity). The aim of this study is to investigate further the construct validity of frailty as a syndrome using the extension offered by Factor Mixture Models (FMM). METHODS: LCA on dichotomized scores and FMM on continuous scores were conducted to test homogeneity on the five PMF components in a sample of 1643 community-dwelling older adults living in Québec, Canada (FRéLE). RESULTS: With dichotomized LCA, three frailty classes were found: robust, prefrail and frail, and the hypothesis of homogeneity was rejected. However, in FMM, frailty was better represented as a continuous variable than as latent heterogeneous classes. Thus, the PMF measurement model of frailty did not meet the features of a syndrome in this study. CONCLUSION: Using the FRéLE cohort, the PMF measurement model validity is questioned. Valid measurement of a syndrome depends on an understanding of its etiological factors and pathophysiological processes, and on a modelling of how the measured components are linked to these processes. Without these features, assessing frailty in a clinical setting may not improve patient health. Research on frailty should address these issues before promoting its use in clinical settings.

Effect of two different pre-operative exercise training regimens before colorectal surgery on functional capacity: A randomised controlled trial.

BACKGROUND: Multimodal prehabilitation, including exercise training, nutritional therapy and anxiety reduction, has been shown to attenuate functional decline associated with surgery. Due to the growing interest in functional status as a targeted surgical outcome, a better understanding of the optimal prescription of exercise is critical. OBJECTIVE: The objective is to compare peri-operative functional trajectory in response to two different exercise training protocols within a 4-week, supervised, multimodal prehabilitation programme. DESIGN: This was a single blinded, single centre, randomised controlled study. Participants performed four assessments: at baseline, after prehabilitation (just before surgery), and at 1 and 2 months after surgery. PATIENTS: Adult patients scheduled for elective resection of nonmetastatic colorectal cancer were included provided there were no absolute contraindications to exercise nor poor language comprehension. INTERVENTION: Patients followed either high-intensity interval training (HIIT), or moderate intensity continuous training (MICT), as part of a 4-week multimodal prehabilitation programme. Both groups followed the same supervised resistance training, nutritional therapy and anxiety reduction interventions. All patients followed standardised peri-operative management. MAIN OUTCOME MEASURE: Changes in oxygen consumption at anaerobic threshold, measured with sequential cardio-pulmonary exercise testing, were assessed and compared between groups. RESULTS: Forty two patients were included in the primary analysis (HIIT n = 21 vs. MICT n = 21), with mean ±â€ŠSD age 64.5 ±â€Š11.2 years and 62% were men. At 2 months after surgery, 13/21 (62%) in HIIT and 11/21 (52%) in MICT attended the study visits. Both protocols significantly enhanced pre-operative functional capacity, with no difference between groups: mean (95% confidence interval) oxygen consumption at anaerobic threshold 1.97 (0.75 to 3.19) ml kg min in HIIT vs. 1.71 (0.56 to 2.85) in MICT, P = 0.753. At 2 months after surgery, the HIIT group showed a higher improvement in physical fitness: 2.36 (0.378 to 4.34) ml kg min, P = 0.021. No adverse events occurred during the intervention. CONCLUSION: Both MICT and HIIT enhanced pre-operative functional capacity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03361150.

Fidelity of muscle fibre reinnervation modulates ageing muscle impact in elderly women.

KEY POINTS: Susceptibility to age-related muscle atrophy relates to the degree of muscle denervation and the capacity of successful reinnervation. However, the specific role of denervation as a determinant of the severity of muscle aging between populations with low versus high physical function has not been addressed. We show that prefrail/frail elderly women exhibited marked features of muscle denervation, whereas world class octogenarian female master athletes showed attenuated indices of denervation and greater reinnervation capacity. These findings suggest that the difference in age-related muscle impact between low- and high-functioning elderly women is the robustness of the response to denervation of myofibers. ABSTRACT: Ageing muscle degeneration is a key contributor to physical frailty; however, the factors responsible for exacerbated vs. muted ageing muscle impact are largely unknown. Based upon evidence that susceptibility to neurogenic impact is an important determinant of the severity of ageing muscle degeneration, we aimed to determine the presence and extent of denervation in pre-frail/frail elderly (FE, 77.9 ± 6.2 years) women compared to young physically inactive (YI, 24.0 ± 3.5 years) females, and contrast these findings to high-functioning world class octogenarian female masters athletes (MA, 80.9 ± 6.6 years). Muscle biopsies from vastus lateralis muscle were obtained from all three groups to assess denervation-related morphological and transcriptional markers. The FE group displayed marked grouping of slow fibres, accumulation of very small myofibres, a severe reduction in type IIa/I size ratio, highly variable inter-subject accumulation of neural cell adhesion molecule (NCAM)-positive myofibres, and an accumulation of pyknotic nuclei, indicative of recurring cycles of denervation/reinnervation and persistent denervation. The MA group exhibited a smaller decline in type IIa/I size ratio and fewer pyknotic nuclei, accompanied by a higher degree of type I fibre grouping and larger fibre group size, suggesting a greater reinnervation of denervated fibres. Consistent with this interpretation, MA had higher mRNA levels of the reinnervation-promoting cytokine fibroblast growth factor binding protein 1 (FGFBP1) than FE. Our results indicate that the muscle of FE women has significant neurogenic atrophy, whereas MA muscle exhibit superior reinnervation capacity, suggesting that the difference in age-related muscle impact between low- and high-functioning elderly women is the robustness of the response to denervation of myofibres.

Malnutrition and Mortality in Frail and Non-Frail Older Adults Undergoing Aortic Valve Replacement.

BACKGROUND: Older adults undergoing aortic valve replacement (AVR) are at risk for malnutrition. The association between preprocedural nutritional status and midterm mortality has yet to be determined. METHODS: The FRAILTY-AVR (Frailty in Aortic Valve Replacement) prospective multicenter cohort study was conducted between 2012 and 2017 in 14 centers in 3 countries. Patients ≥70 years of age who underwent transcatheter or surgical AVR were eligible. The Mini Nutritional Assessment-Short Form was assessed by trained observers preprocedure, with scores ≤7 of 14 considered malnourished and 8 to 11 of 14 considered at risk for malnutrition. The Short Performance Physical Battery was simultaneously assessed to measure physical frailty, with scores ≤5 of 12 considered severely frail and 6 to 8 of 12 considered mildly frail. The primary outcome was 1-year all-cause mortality, and the secondary outcome was 30-day composite mortality or major morbidity. Multivariable regression models were used to adjust for potential confounders. RESULTS: There were 1158 patients (727 transcatheter AVR and 431 surgical AVR), with 41.5% females, a mean age of 81.3 years, a mean body mass index of 27.5 kg/m2, and a mean Society of Thoracic Surgeons-Predicted Risk of Mortality of 5.1%. Overall, 8.7% of patients were classified as malnourished and 32.8% were at risk for malnutrition. Mini Nutritional Assessment-Short Form scores were modestly correlated with Short Performance Physical Battery scores (Spearman R=0.31, P<0.001). There were 126 deaths in the transcatheter AVR group (19.1 per 100 patient-years) and 30 deaths in the surgical AVR group (7.5 per 100 patient-years). Malnourished patients had a nearly 3-fold higher crude risk of 1-year mortality compared with those with normal nutritional status (28% versus 10%, P<0.001). After adjustment for frailty, Society of Thoracic Surgeons-Predicted Risk of Mortality, and procedure type, preprocedural nutritional status was a significant predictor of 1-year mortality (odds ratio, 1.08 per Mini Nutritional Assessment-Short Form point; 95% CI, 1.01-1.16) and of the 30-day composite safety end point (odds ratio, 1.06 per Mini Nutritional Assessment-Short Form point; 95% CI, 1.001-1.12). CONCLUSIONS: Preprocedural nutritional status is associated with mortality in older adults undergoing AVR. Clinical trials are needed to determine whether pre- and postprocedural nutritional interventions can improve clinical outcomes in these vulnerable patients.

Leucine Supplementation Does Not Alter Insulin Sensitivity in Prefrail and Frail Older Women following a Resistance Training Protocol.

BACKGROUND: Frailty is a clinical condition associated with loss of muscle mass and strength (sarcopenia). Although sarcopenia has multifactorial causes, it might be partly attributed to a blunted response to anabolic stimuli. Leucine acutely increases muscle protein synthesis, and resistance training (RT) is the strongest stimuli to counteract sarcopenia and was recently shown to improve insulin sensitivity (IS) in frail older women. Discrepancies exist regarding whether chronic supplementation of leucine in conjunction with RT can improve muscle mass and IS. OBJECTIVE: The aim of this double-blinded placebo-controlled study was to determine the effects of leucine supplementation and RT on IS in prefrail and frail older women. METHODS: Using the Fried criteria, 19 nondiabetic prefrail (1-2 criteria) and frail (≥3 criteria) older women (77.5 ± 1.3 y; body mass index (kg/m2): 25.1 ± 0.9) underwent a 3-mo intervention of RT 3 times/wk with protein-optimized diet of 1.2 g·kg-1·d-1 and 7.5 g·d-1 of l-leucine supplementation compared with placebo l-alanine. Pre-/postintervention primary outcomes were fasting plasma glucose, serum insulin, and 4-h responses to a standard meal of complete liquid formula. Secondary outcomes of resting energy expenditure using indirect calorimetry and body composition using dual-energy X-ray absorptiometry were obtained. Paired t tests analyzed pooled data, and 2-factor repeated-measures ANOVA determined supplementation, training, and interaction effects. RESULTS: No significant time, group, or interaction effects were observed for postprandial areas under the curve of serum insulin or plasma glucose or for resting energy expenditure in l-leucine compared with l-alanine. Total lean body mass increased and percentage body fat decreased significantly for both groups postintervention (0.76 ± 0.13 and -0.92 ± 0.33 kg, respectively; time effect: P < 0.01). CONCLUSIONS: IS was not affected by RT and leucine supplementation in nondiabetic prefrail and frail older women. Therefore, leucine supplementation does not appear to influence IS under these conditions. This trial was registered at clinicaltrials.gov as NCT01922167.

Effect of a 12-week mixed power training on physical function in dynapenic-obese older men: does severity of dynapenia matter?

INTRODUCTION: Mobility disability affects nearly 15% of people aged 65 or over worldwide. Excess weight or obesity (OB), along with an accentuated loss of muscle strength (dynapenia), is recognized to be one of the most common risk factors for mobility impairment among the elderly. OBJECTIVE: To investigate the effect of a 12-week mixed power training (MPT high-velocity resistance training mixed with functional exercises) on physical function in obese older men exhibiting different severities of dynapenia. METHODS: Community-dwelling older men (69 ± 6 years) were assigned to the study if they were considered obese (OB, fat mass ≥ 25% body weight, BW) and to one of the two groups according to severity of dynapenia [(handgrip strength-HS)/BW]: type 1(OB-DY1) or type 2(OB-DY2), < 1 or 2SD from a young reference group. Participants followed a 12-week MPT, three times/week, 75 min/session. Main outcomes included the performance on the 4-m and 6-min walking tests, Timed Up and Go, stair and balance tests. RESULTS AND DISCUSSION: At baseline, OB-DY1 performed better than OB-DY2 in all functional tests (p < 0.05). Following the intervention, medium-to-large training effect size (ES) were observed for fat (ES = 0.21) and lean (ES = 0.32, p < 0.001) masses, functional performance (ES 0.11-0.54, p < 0.05), HS (ES = 0.10, p < 0.05) and lower limb muscle strength (ES = 0.67, p < 0.001) and power (ES = 0.60, p < 0.05). Training-by-group interaction showed that OB-DY1 lost more FM (ES = 0.11, p = 0.03) and OB-DY2 improved more HS (ES = 0.19, p = 0.006) than their counterparts. CONCLUSIONS: Seniors with obesity and severe dynapenia have poorer physical function than those in the early stage of dynapenia. Both seem to benefit from a high-velocity resistance training mixed with functional exercises, although by slightly different pathways.

Wireless measurement of rectal temperature during exercise: Comparing an ingestible thermometric telemetric pill used as a suppository against a conventional rectal probe.

Wireless measurement of rectal temperature during exercise may circumvent some limitations associated with the use of a conventional wired probe. We determined, for the first time, whether temperatures provided in vivo by wireless ingestible thermometric telemetric pills and a rectal probe compare favorably under conditions producing slow and rapid increases and decreases in rectal temperature. While wearing a rectal probe linked to a wireless ingestible thermometric telemetric pill, 13 participants completed the following phases: 1) 30 min sitting; 2) 45 min passive heat exposure (40-42 °C); 3) 45 min sitting while ingesting 7.5 g of ice slurry · kg body mass-1; 4) running exercise (38 °C) at 68% V˙O2max until a 39.5 °C increase in rectal probe temperature and; 5) cold-water (10 °C) immersion until a 1.5 °C decrease in rectal probe temperature. Acceptable differences between devices were taken as ≤ 0.3 °C. Mean differences within phases were all < 0.3 °C, whereas 95% limits of agreement ranged from ±0.2 °C to ±0.4 °C, coefficient of variations from ±0.3% to ±0.6% and typical error of measurements from ±0.1 °C to ±0.2°. Of the 14881 rectal temperature values measured over the experiment with the wireless ingestible thermometric telemetric pills and rectal probe, 91% of the differences between devices were found to be ≤ 0.3 °C. Results suggest that rectal temperatures provided by a wireless ingestible thermometric telemetric pill used as a suppository agree with those of a conventional wired probe. Hence, rectal temperature can reliably be measured using a wireless ingestible thermometric telemetric pill as a suppository.

Current Concepts in Healthy Aging and Physical Activity: A Viewpoint.

Physical activity plays an important role for achieving healthy aging by promoting independence and increasing the quality of life. However, current guidelines for physical activity in older adults may be difficult to achieve in an older population. Indeed, there is evidence to suggest that increasing exercise intensity in older adults may be associated with greater reductions in the risk of cardiovascular disease and mortality. Therefore, the idea prescribing high-intensity exercise protocols such as high-intensity interval training and high-intensity resistance training becomes an intriguing strategy for healthy aging. Collectively, the literature review in this viewpoint will briefly focus on summarizing alternative/novel time-efficient approaches in physical activity toward healthy aging. Our goal is to hopefully open a discussion on possibly revising the current physical activity guidelines in older adults.

Smoke-induced neuromuscular junction degeneration precedes the fibre type shift and atrophy in chronic obstructive pulmonary disease.

KEY POINTS: Chronic obstructive pulmonary disease (COPD) is largely caused by smoking, and patient limb muscle exhibits a fast fibre shift and atrophy. We show that this fast fibre shift is associated with type grouping, suggesting recurring cycles of denervation-reinnervation underlie the type shift. Compared to patients with normal fat-free mass index (FFMI), patients with low FFMI exhibited an exacerbated fibre type shift, marked accumulation of very small persistently denervated muscle fibres, and a blunted denervation-responsive transcript profile, suggesting failed denervation precipitates muscle atrophy in patients with low FFMI. Sixteen weeks of passive tobacco smoke exposure in mice caused neuromuscular junction degeneration, consistent with a key role for smoke exposure in initiating denervation in COPD. ABSTRACT: A neurological basis for the fast fibre shift and atrophy seen in limb muscle of patients with chronic obstructive pulmonary disease (COPD) has not been considered previously. The objective of our study was: (1) to determine if denervation contributes to fast fibre shift and muscle atrophy in COPD; and (2) to assess using a preclinical smoking mouse model whether chronic tobacco smoke (TS) exposure could initiate denervation by causing neuromuscular junction (NMJ) degeneration. Vastus lateralis muscle biopsies were obtained from severe COPD patients [n = 10 with low fat-free mass index (FFMI), 65 years; n = 15 normal FFMI, 65 years) and healthy age- and activity-matched non-smoker control subjects (CON; n = 11, 67 years), to evaluate morphological and transcriptional markers of denervation. To evaluate the potential for chronic TS exposure to initiate these changes, we examined NMJ morphology in male adult mice following 16 weeks of passive TS exposure. We observed a high proportion of grouped fast fibres and a denervation transcript profile in COPD patients, suggesting that motor unit remodelling drives the fast fibre type shift in COPD patient limb muscle. A further exacerbation of fast fibre grouping in patients with low FFMI, coupled with blunted reinnervation signals, accumulation of very small non-specific esterase hyperactive fibres and neural cell adhesion molecule-positive type I and type II fibres, suggests denervation-induced exhaustion of reinnervation contributes to muscle atrophy in COPD. Evidence from a smoking mouse model showed significant NMJ degeneration, suggesting that recurring denervation in COPD is probably caused by decades of chronic TS exposure.

SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment.

BACKGROUND: Physical exercise, cognitive training, and vitamin D are low cost interventions that have the potential to enhance cognitive function and mobility in older adults, especially in pre-dementia states such as Mild Cognitive Impairment (MCI). Aerobic and progressive resistance exercises have benefits to cognitive performance, though evidence is somewhat inconsistent. We postulate that combined aerobic exercise (AE) and progressive resistance training (RT) (combined exercise) will have a better effect on cognition than a balance and toning control (BAT) intervention in older adults with MCI. We also expect that adding cognitive training and vitamin D supplementation to the combined exercise, as a multimodal intervention, will have synergistic efficacy. METHODS: The SYNERGIC trial (SYNchronizing Exercises, Remedies in GaIt and Cognition) is a multi-site, double-blinded, five-arm, controlled trial that assesses the potential synergic effect of combined AE and RT on cognition and mobility, with and without cognitive training and vitamin D supplementation in older adults with MCI. Two-hundred participants with MCI aged 60 to 85 years old will be randomized to one of five arms, four of which include combined exercise plus combinations of dual-task cognitive training (real vs. sham) and vitamin D supplementation (3 × 10,000 IU/wk. vs. placebo) in a quasi-factorial design, and one arm which receives all control interventions. The primary outcome measure is the ADAS-Cog (13 and plus modalities) measured at baseline and at 6 months of follow-up. Secondary outcomes include neuroimaging, neuro-cognitive performance, gait and mobility performance, and serum biomarkers of inflammation (C reactive protein and interleukin 6), neuroplasticity (brain-derived neurotropic factor), endothelial markers (vascular endothelial growth factor 1), and vitamin D serum levels. DISCUSSION: The SYNERGIC Trial will establish the efficacy and feasibility of a multimodal intervention to improve cognitive performance and mobility outcomes in MCI. These interventions may contribute to new approaches to stabilize and reverse cognitive-mobility decline in older individuals with MCI. TRIAL REGISTRATION: Identifier: NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676 .