Navigating the Landscape of Translational Geroscience in Canada: A Comprehensive Evaluation of Current Progress and Future Directions.

The inaugural Canadian Conferences on Translational Geroscience were held as two complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This manuscript summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada.

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.

Acute ingestion of a ketone monoester, whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of myofibrillar protein synthesis rates in young males: a double-blind randomized trial.

BACKGROUND: Ketone bodies may have anabolic effects in skeletal muscle via their capacity to stimulate protein synthesis. Whether orally ingested exogenous ketones can stimulate postprandial myofibrillar protein synthesis (MyoPS) rates with and without dietary protein co-ingestion is unknown. OBJECTIVES: This study aimed to evaluate the effects of ketone monoester intake and elevated blood ß-hydroxybutyrate (ß-OHB) concentration, with and without dietary protein co-ingestion, on postprandial MyoPS rates and mechanistic target of rapamycin complex 1 (mTORC1) pathway signaling. METHODS: In a randomized, double-blind, parallel group design, 36 recreationally active healthy young males (age: 24.2 ± 4.1 y; body fat: 20.9% ± 5.8%; body mass index: 23.4 ± 2 kg/m2) received a primed continuous infusion of L-[ring-2H5]-phenylalanine and ingested one of the following: 1) the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KET), 2) 10 g whey protein (PRO), or 3) the combination of both (KET+PRO). Blood and muscle biopsy samples were collected during basal and postprandial (300 min) conditions to assess ß-OHB, glucose, insulin, and amino acid concentrations, MyoPS rates, and mTORC1 pathway signaling. RESULTS: Capillary blood ß-OHB concentration increased similarly during postprandial conditions in KET and KET+PRO, with both being greater than PRO from 30 to 180 min (treatment × time interaction: P < 0.001). Postprandial plasma leucine and essential amino acid (EAA) incremental area under the curve (iAUC) over 300 min was greater (treatment: both P < 0.001) in KET+PRO compared with PRO and KET. KET, PRO, and KET+PRO stimulated postprandial MyoPS rates (0-300 min) higher than basal conditions [absolute change: 0.020%/h; (95% CI: 0.013, 0.027%/h), 0.014%/h (95% CI: 0.009, 0.019%/h), 0.019%/h (95% CI: 0.014, 0.024%/h), respectively (time: P < 0.001)], with no difference between treatments (treatment: P = 0.383) or treatment × time interaction (interaction: P = 0.245). mTORC1 pathway signaling responses did not differ between treatments (all P > 0.05). CONCLUSIONS: Acute oral intake of a ketone monoester, 10 g whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of postprandial MyoPS rates in healthy young males. This trial was registered at clinicaltrials.gov as NCT04565444 (https://clinicaltrials.gov/study/NCT04565444).

Associations between circulating cardiovascular disease risk factors and cognitive performance in cognitively healthy older adults from the NuAge study.

Introduction: Cardiovascular disease risk factors (CVRFs) contribute to the development of cognitive impairment and dementia. Methods: This study examined the associations between circulating CVRF biomarkers and cognition in 386 cognitively healthy older adults (mean age = 78 ± 4 years, 53% females) selected from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). Memory, executive function, and processing speed were assessed at baseline and 2-year follow-up. CVRF biomarkers included total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides, glucose, insulin, high sensitivity C-reactive protein (hs-CRP), homocysteine, protein carbonyls, and cortisol. Linear mixed models were used to determine associations between individual CVRF biomarkers and cognition at both time points. Results: HDL-C was most consistently associated with cognition with higher values related to better performance across several domains. Overall, stronger and more consistent relationships between CVRF biomarkers and cognition were observed in females relative to males. Discussion: Findings suggest that increases in the majority of circulating CVRFs are not associated with worse cognition in cognitively healthy older adults.

Predictive Strategies to Reduce the Risk of Rehospitalization with a Focus on Frail Older Adults: A Narrative Review.

Frailty is a geriatric syndrome that has physical, cognitive, psychological, social, and environmental components and is characterized by a decrease in physiological reserves. Frailty is associated with several adverse health outcomes such as an increase in rehospitalization rates, falls, delirium, incontinence, dependency on daily living activities, morbidity, and mortality. Older adults may become frailer with each hospitalization; thus, it is beneficial to develop and implement preventive strategies. The present review aims to highlight the epidemiological importance of frailty in rehospitalization and to compile predictive strategies and related interventions to prevent hospitalizations. Firstly, it is important to identify pre-frail and frail older adults using an instrument with high validity and reliability, which can be a practically applicable screening tool. Comprehensive geriatric assessment-based care is an important strategy known to reduce morbidity, mortality, and rehospitalization in older adults and aims to meet the needs of frail patients with a multidisciplinary approach and intervention that includes physiological, psychological, and social domains. Moreover, effective multimorbidity management, physical activity, nutritional support, preventing cognitive frailty, avoiding polypharmacy and anticholinergic drug burden, immunization, social support, and reducing the caregiver burden are other recommended predictive strategies to prevent post-discharge rehospitalization in frail older adults.

What Do Older Canadians Think They Need to Walk Well?

Purpose: To identify older Canadians' perception of the importance of expert-generated elements of walking quality, and the contributors to and consequences of perceived walking quality. Method: Cross-sectional survey of 649 adults was conducted through a commercial participant panel, Hosted in Canada Surveys. Results: Of the 649 respondents, 75% were between 65 and 74 years old (25% ≥ 75) and 49% were women. The most important elements were foot, ankle, hip, and knee mobility with little difference in ranks across walking perception (Fr χ12 = 5.0, p > 0.05). People who were older by a decade were more likely to report poorer walking (POR: 1.4; 95% CI: 1.0, 1.7), as were women compared to men, and people who used a walking aid compared to none. Lung disease showed the highest association with a perception of not walking well (POR: 7.2; 95% CI: 3.7, 14.2). The odds of being willing to pay more for a technology to improve walking were always greater for those with a lower perception of their walking quality. Conclusions: People who perceived their walking quality as poor were more likely to report poorer health and were willing to pay more for a technology to improve walking. This supports the opportunity of leveraging wearable technologies to improve walking.

Objectif : déterminer la perception des Canadiens âgés à l'égard de l'importance des éléments relatifs à la qualité de la marche produits par des experts et établir les incitatifs à la perception de la qualité de la marche, de même que les conséquences s'y rapportant. Méthodologie : sondage transversal auprès de 649 adultes au moyen de Hosted in Canada Surveys, un groupe commercial de participants. Résultats : sur les 649 répondants, 75 % étaient âgés de 65 à 74 ans (25 % ≥ 75 ans), et 49 % étaient des femmes. La mobilité du pied, de la cheville, de la hanche et du genou constituait les éléments les plus importants, et le niveau hiérarchique de chacun différait peu en matière de perceptions de la marche (test de Friedman [Fr] χ2 = 5,0, degré de liberté [ddl] 12, p > 0,05). Les personnes âgées d'une décennie de plus risquaient davantage de déclarer moins bien marcher (rapport de cotes proportionnel [RCP] : 1,4; IC à 95 % : 1,0 à 1,7), tout comme les femmes et les personnes qui utilisaient une aide à la marche. La maladie pulmonaire était la plus liée à la perception de moins bien marcher (RCP : 7,2; IC à 95 % : 3,7, 14,2). La probabilité d'être prêt à payer plus cher pour disposer d'une technologie destinée à améliorer la marche était toujours plus forte chez les personnes qui avaient une moins bonne perception de leur qualité de marche. Conclusion : les personnes qui avaient une moins bonne perception de leur qualité de marche étaient plus susceptibles de se déclarer en moins bonne santé et étaient prêtes à payer plus cher pour disposer d'une technologie destinée à améliorer la marche. Cette constatation confirme la possibilité de mettre à profit des technologies portables pour améliorer la marche.

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.

Serum metabolomic adaptations following a 12-week high-intensity interval training combined to citrulline supplementation in obese older adults.

Physical activity and nutrition play important roles in preventing adverse health outcomes that accompany aging. It has been shown that high-intensity interval training (HIIT) combined with citrulline (CIT) supplementation can improve physical and functional capacities. The aim of this study was to evaluate serum metabolites following a 12-week HIIT combined or not with CIT in obese older adults, and to correlate the metabolic changes with clinico-biological parameters changes. Eighty-six obese older adults completed a 12-week HIIT program combined with a 10 g daily supplementation of either CIT or placebo (PLA) during a double-blinded randomized interventional trial. Only participants with blood samples at T0 (before the intervention) and/or T12 (after the intervention) were included in our sub-analysis (HIIT-PLA-T0: n = 44 and HIIT-PLA-T12: n = 28; HIIT-CIT-T0: n = 39 and HIIT-CIT-T12: n = 42). Serum samples were analyzed by different liquid or gas phase chromatography methods coupled to mass spectrometry. Among the identified metabolites, 44 changed significantly following the 12-week intervention (Time effect), and 10 of them were more affected when HIIT was combined with CIT (Time × Supp effect). Arginine increased significantly due to the 12-week intervention. Correlation analyses demonstrated that decreased triglyceride (TG) (16:1/18:1/16:0) and aspartic acid significantly correlated with a reduction of adiposity-related parameters (fat mass, leg lean mass, leptin, total triglycerides and low-density lipoprotein). Arginine, TG (16:1/18:1/16:0) and aspartic acid might constitute biomarkers of cardiometabolic health and adiposity. Further studies are needed to confirm these associations and understand the underlying mechanisms.Highlights A 12-week intervention involving high-intensity interval training (HIIT) with or without citrulline (CIT) supplementation induced adaptations in the serum metabolome of obese older adults through significant changes in 44 metabolites.Changes in 23 metabolites were observed when a CIT supplementation was administered along with a 12-week HIIT intervention.TG (16:1/18:1/16:0) correlated with several adiposity parameters including leptin, triglycerides, legs lean mass.Aspartic acid correlated with several adiposity parameters including leptin, LDL cholesterol as well as android, arms and trunk fat mass.

Senescence markers in subcutaneous preadipocytes differ in childhood- versus adult-onset obesity before and after weight loss.

OBJECTIVE: The aim of this study was to determine the effect of age of obesity onset on senescence-related markers in abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) before and after moderate (~10%) weight loss. METHODS: AB and FEM SAT were collected from human females with childhood-onset obesity (CO) or adult-onset obesity (AO) before and after diet- and exercise-induced weight loss. Immunofluorescence analysis of γH2AX/RAD51 (DNA damage/repair markers) and p53/p21 (senescence markers) was conducted in cultured preadipocytes, and senescence-associated ß-galactosidase (SA-ß-gal) activity was measured in SAT. RESULTS: CO had proportionately more AB and FEM preadipocytes with DNA damage (γH2AX+ ) and senescence markers (p53+ and/or p21+ ) than AO at baseline. The proportion of γH2AX+ FEM preadipocytes declined with weight loss in CO and was similar between groups after weight loss. The number of γH2AX foci in γH2AX+ preadipocytes decreased similarly between groups and regions with weight loss in parallel with an increase in RAD51. The proportion of p53+ and p21+ preadipocytes and SA-ß-gal+ cells in SAT did not change with weight loss, but the total p21 intensity in p53+ /p21+ FEM preadipocytes declined in AO. CONCLUSIONS: These results provide preliminary evidence that females with CO have an accelerated preadipocyte aging state that improves with weight loss in terms of DNA damage but not senescence.

MYTHO is a novel regulator of skeletal muscle autophagy and integrity.

Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.

Personalized Telehealth: Redesigning Complex Care Delivery for the 65+ During the COVID Pandemic: a Survey of Patients, Caregivers, and Health-care Providers.

Background: In the context of the ongoing COVID-19 pandemic, rapid transitions have been made towards telehealth. Optimal use of telehealth in elderly patients remains poorly understood and adaptation challenges persist. Our study aimed at identifying perceptions, barriers, and possible facilitators to telehealth use amongst elderly patients with comorbidities, their caregivers, and health-care providers (HCPs). Methods: Health-care providers, patients 65 years and older with multiple comorbidities, and caregivers were recruited from outpatient clinics and invited to complete an electronic self-administered or telephone-administered survey on their perceptions of telehealth and of barriers to its implementation. Results: A total of 39 health-care providers, 40 patients, and 22 caregivers responded to the survey. Most patients (90%), caregivers (82%), and HCPs (97%) had experienced telephone visits, but few were conducted via videoconference platforms. Patients and caregivers showed interest in pursuing some future telehealth visits (68%, 86%, respectively), but felt they lacked access to technology and skills (n=8, 20%), and some felt that telehealth visits may be inferior to in-person visits (n=9, 23%). HCPs showed interest in incorporating telehealth visits into practice (n=32, 82%), but identified challenges in lack of administrative support (n=37), lack of HCP (n=28) and patient (n=37) technological skills, and limited infrastructure (n=37)/internet access (n=33). Conclusions: Older patients, caregivers, and HCPs show interest in pursuing future telehealth visits but elucidate similar barriers. Facilitating access to technology, as well as to administrative and technology support guides, could promote high quality and equal access to virtual care for the older adult.

Development of a Frailty Ladder Using Rasch Analysis: If the Shoe Fits.

Background: The current measurement approach to frailty is to create an index of frailty status, rather than measure it. The purpose of this study is to test the extent to which a set of items identified within the frailty concept fit a hierarchical linear model (e.g., Rasch model) and form a true measure reflective of the frailty construct. Methods: A sample was assembled from three sources: community organization for at-risk seniors (n=141); colorectal surgery group assessed post-surgery (n=47); and hip fracture assessed post-rehabilitation (n=46). The 234 individuals (age 57 to 97) contributed 348 measurements. The frailty construct was defined according to the named domains within commonly used frailty indices, and items drawn to reflect the frailty came from self-report measures. Performance tests were tested for the extent to which they fit the Rasch model. Results: Of the 68 items, 29 fit the Rasch model: 19 self-report items on physical function and 10 performance tests, including one for cognition; patient reports of pain, fatigue, mood, and health did not fit; nor did body mass index (BMI) nor any item representing participation. Conclusion: Items that are typically identified as reflecting the frailty concept fit the Rasch model. The Frailty Ladder would be an efficient and statistically robust way of combining results of different tests into one outcome measure. It would also be a way of identifying which outcomes to target in a personalized intervention. The rungs of the ladder, the hierarchy, could be used to guide treatment goals.

Serum Metabolome Adaptations Following 12 Weeks of High-Intensity Interval Training or Moderate-Intensity Continuous Training in Obese Older Adults.

Physical activity can be effective in preventing some of the adverse effects of aging on health. High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are beneficial interventions for the quality of life of obese older individuals. The understanding of all possible metabolic mechanisms underlying these beneficial changes has not yet been established. The aim of this study was to analyze changes in the serum metabolome after 12 weeks of HIIT and MICT in obese older adults. Thirty-eight participants performed either HIIT (n = 26) or MICT (n = 12) three times per week for 12 weeks. Serum metabolites as well as clinical and biological parameters were assessed before and after the 12-week intervention. Among the 364 metabolites and ratio of metabolites identified, 51 metabolites changed significantly following the 12-week intervention. Out of them, 21 significantly changed following HIIT intervention and 18 significantly changed following MICT. Associations with clinical and biological adaptations revealed that changes in acyl-alkyl-phosphatidylcholine (PCae) (22:1) correlated positively with changes in handgrip strength in the HIIT group (r = 0.52, p < 0.01). A negative correlation was also observed between 2-oxoglutaric acid and HOMA-IR (r = -0.44, p < 0.01) when considering both groups together (HIIT and MICT). This metabolite also correlated positively with quantitative insulin-sensitivity check index (QUICKI) in both groups together (r = 0.46, p < 0.01) and the HIIT group (r = 0.51, p < 0.01). Additionally, in the MICT group, fumaric acid was positively correlated with triglyceride levels (r = 0.73, p < 0.01) and acetylcarnitine correlated positively with low-density lipoprotein (LDL) cholesterol (r = 0.81, p < 0.01). These four metabolites might represent potential metabolites of interest concerning muscle strength, glycemic parameters, as well as lipid profile parameters, and hence, for a potential healthy aging. Future studies are needed to confirm the association between these metabolites and a healthy aging.

The Implementation of a Geriatrics Co-Management Model of Care Reduces Hospital Length of Stay.

(1) Background: Older adults comprise a large proportion of hospitalized patients. Many are frail and require complex care. Geriatrics has developed models of care specific to this inpatient population. Our objective was to demonstrate the effect of a geriatric co-management team on clinical administrative indicators of care in Clinical Teaching Units (CTUs) that have adopted the Age-friendly Hospital (AFH) principles in Brazilian hospitals. (2) Methods: Following 3 months of implementation of the AFH principles in CTUs, two periods of the same 6 months of two consecutive years were compared. (3) Results: The total number of participants in the study was 641 and 743 in 2015 and 2016, respectively. Average length of patient-stay (length of stay: 8.7 ± 2.7 vs. 5.4 ± 1.7 days) and number of monthly complaints (44.2 ± 6.5 vs. 13.5 ± 2.2) were significantly lower with the co-management model. Number of homecare service referrals/month was also significantly higher (2.5 ± 1 vs. 38.3 ± 6.3). The 30-day readmission rates and total hospital costs per patient remained unchanged. (4) Conclusion: The presence of a geriatric co-management team in CTUs is of added benefit to increase the efficiency of the AFH for vulnerable older inpatients with reduced LOS and increased referrals to homecare services without increasing hospital costs.

Implementation of exercise countermeasures during spaceflight and microgravity analogue studies: Developing countermeasure protocols for bedrest in older adults (BROA).

Significant progress has been made in the development of countermeasures to attenuate the negative consequences of prolonged exposure to microgravity on astronauts' bodies. Deconditioning of several organ systems during flight includes losses to cardiorespiratory fitness, muscle mass, bone density and strength. Similar deconditioning also occurs during prolonged bedrest; any protracted time immobile or inactive, especially for unwell older adults (e.g., confined to hospital beds), can lead to similar detrimental health consequences. Due to limitations in physiological research in space, the six-degree head-down tilt bedrest protocol was developed as ground-based analogue to spaceflight. A variety of exercise countermeasures have been tested as interventions to limit detrimental changes and physiological deconditioning of the musculoskeletal and cardiovascular systems. The Canadian Institutes of Health Research and the Canadian Space Agency recently provided funding for research focused on Understanding the Health Impact of Inactivity to study the efficacy of exercise countermeasures in a 14-day randomized clinical trial of six-degree head-down tilt bedrest study in older adults aged 55-65 years old (BROA). Here we will describe the development of a multi-modality countermeasure protocol for the BROA campaign that includes upper- and lower-body resistance exercise and head-down tilt cycle ergometry (high-intensity interval and continuous aerobic exercise training). We provide reasoning for the choice of these modalities following review of the latest available information on exercise as a countermeasure for inactivity and spaceflight-related deconditioning. In summary, this paper sets out to review up-to-date exercise countermeasure research from spaceflight and head-down bedrest studies, whilst providing support for the proposed research countermeasure protocols developed for the bedrest study in older adults.

Association of Low Muscle Mass With Cognitive Function During a 3-Year Follow-up Among Adults Aged 65 to 86 Years in the Canadian Longitudinal Study on Aging.

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. Results: Of 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 ß: -0.032; P = .03) only. Low ALM was not associated with memory. Conclusions and Relevance: This cohort study found longitudinal associations between low ALM 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.

Clinical and Biological Adaptations in Obese Older Adults Following 12-Weeks of High-Intensity Interval Training or Moderate-Intensity Continuous Training.

Sarcopenia and obesity are considered a double health burden. Therefore, the implementation of effective strategies is needed to improve the quality of life of older obese individuals. The aim of this study was to compare the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on functional capacities, muscle function, body composition and blood biomarkers in obese older adults. Adipose tissue gene expression and markers of muscle mitochondrial content and quality control involved in exercise adaptations were also investigated. Sixty-eight participants performed either HIIT (n = 34) on an elliptical trainer or MICT (n = 34) on a treadmill, three times per week for 12 weeks. HIIT produced significantly higher benefits on some physical parameters (six-minute walking test (HIIT: +12.4% vs. MICT: +5.2%); step test (HIIT: +17.02% vs. MICT: +5.9%); ten-repetition chair test (HIIT: -17.04% vs. MICT: -4.7%)). Although both HIIT and MICT led to an improvement in lower limb power (HIIT: +25.2% vs. MICT: +20.4%), only MICT led to higher improvement in lower limb muscle strength (HIIT: +4.3% vs. MICT: +23.2%). HIIT was more beneficial for increasing total lean body mass (HIIT: +1.58% vs. MICT: -0.81%), while MICT was more effective for decreasing relative gynoid fat mass (HIIT: -1.09% vs. MICT: -4.20%). Regarding adipose tissue gene expression, a significant change was observed for cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) in the HIIT group (A.U; HIIT at T0: 32.10 ± 39.37 vs. HIIT at T12: 48.2 ± 59.2). Mitochondrial transcription factor A (TFAM) content, a marker of mitochondrial biogenesis, increased significantly following HIIT (+36.2%) and MICT (+57.2%). A significant increase was observed in the HIIT group for Translocase of Outer Membrane 20 (TOM20; +54.1%; marker of mitochondrial content), Mitofusin-2 (MFN2; +71.6%; marker of mitochondrial fusion) and Parkin RBR E3 Ubiquitin Protein Ligase (PARKIN; +42.3%; marker of mitophagy). Overall, our results indicate that even though MICT (walking on treadmill) and HIIT (on an elliptical) are effective intervention strategies in obese older adults, HIIT appears to have slightly more beneficial effects. More specifically, HIIT led to higher improvements than MICT on functional capacities, lean mass and skeletal muscle markers of mitochondrial content, fusion, and mitophagy. Thus, MICT but also HIIT (time-efficient training) could be recommended as exercise modalities for obese older adults to maintain or improve mobility, health and quality of life.

Unbiased proteomics, histochemistry, and mitochondrial DNA copy number reveal better mitochondrial health in muscle of high-functioning octogenarians.

Background: Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear. Methods: We performed muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochondrial DNA (mtDNA) copy number, and proteomics by liquid-chromatography mass spectrometry. Results: MA exhibited markedly better performance on clinical function tests and greater cross-sectional area of the vastus lateralis muscle. Proteomics analysis revealed marked differences, where most of the ~800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage-dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and that are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA. Conclusions: We conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with underrepresentation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging. Funding: Funding for this study was provided by operating grants from the Canadian Institutes of Health Research (MOP 84408 to TT and MOP 125986 to RTH). This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, USA.

Impact of high-intensity interval training with or without l-citrulline on physical performance, skeletal muscle, and adipose tissue in obese older adults.

BACKGROUND: Aging is associated with a progressive decline in skeletal muscle mass and strength as well as an increase in adiposity. These changes may have devastating impact on the quality of life of older adults. Mitochondrial dysfunctions have been implicated in aging-related and obesity-related deterioration of muscle function. Impairments in mitochondrial quality control processes (biogenesis, fusion, fission, and mitophagy) may underlie this accumulation of mitochondrial dysfunction. High-intensity interval training (HIIT) was shown to improve muscle and mitochondrial function in healthy young and old adults and to improve body composition in obese older adults. Recent studies also positioned citrulline (CIT) supplementation as a promising intervention to counter obesity-related and aging-related muscle dysfunction. In the present study, our objectives were to assess whether HIIT, alone or with CIT, improves muscle function, functional capacities, adipose tissue gene expression, and mitochondrial quality control processes in obese older adults. METHODS: Eighty-one-old and obese participants underwent a 12 week HIIT with or without CIT on an elliptical trainer [HIIT-CIT: 20 men/25 women, 67.2 ± 5.0 years; HIIT-placebo (PLA): 18 men/18 women, 68.1 ± 4.1 years]. Handgrip and quadriceps strength, lower limb muscle power, body composition, waist circumference, and functional capacities were assessed pre and post intervention. Vastus lateralis muscle biopsies were performed in a subset of participants to quantify markers of mitochondrial content (TOM20 and OXPHOS subunits), biogenesis (TFAM), fusion (MFN1&2, OPA1), fission (DRP1), and mitophagy (Parkin). Subcutaneous abdominal adipose tissue biopsies were also performed to assess the expression of genes involved in lipid metabolism. RESULTS: HIIT-PLA and HIIT-CIT displayed improvements in functional capacities (P < 0.05), total (mean ± SD: HIIT-PLA: +1.27 ± 3.19%, HIIT-CIT: +1.05 ± 2.91%, P < 0.05) and leg lean mass (HIIT-PLA: +1.62 ± 3.85%, HIIT-CIT: +1.28 ± 4.82%, P < 0.05), waist circumference (HIIT-PLA: -2.2 ± 2.9 cm, HIIT-CIT: -2.6 ± 2.5 cm, P < 0.05), and muscle power (HIIT-PLA: +15.81 ± 18.02%, HIIT-CIT: +14.62 ± 20.02%, P < 0.05). Only HIIT-CIT decreased fat mass (-1.04 ± 2.42%, P < 0.05) and increased handgrip and quadriceps strength (+4.28 ± 9.36% and +10.32 ± 14.38%, respectively, P < 0.05). Both groups increased markers of muscle mitochondrial content, mitochondrial fusion, and mitophagy (P < 0.05). Only HIIT-CIT decreased the expression of the lipid droplet-associated protein CIDEA (P < 0.001). CONCLUSIONS: High-intensity interval training is effective in improving functional capacities, lean mass, muscle power, and waist circumference in obese older adults. HIIT also increases markers of mitochondrial biogenesis, mitochondrial fusion, and mitophagy. Importantly, adding CIT to HIIT results in a greater increase in muscle strength and a significant decrease in fat mass. The present study therefore positions HIIT combined with CIT as an effective intervention to improve the health status of obese 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.