Search

Background: Muscle weakness and obesity are two significant threats to mobility facing the increasing number of older adults. To date, there are no studies that have examined the association of strength and body mass index (BMI) on event rates on a widely used performance measure of major mobility disability.Methods: This study was a secondary analysis of a randomized controlled trial in which sedentary functionally limited participants (70-89 years, Short Physical Performance Battery ≤ 9) who were able to complete a 400-m walk test at baseline were randomized to a physical activity or health education intervention and reassessed for major mobility disability every 6 months for up to 18 months. We evaluated whether baseline grip strength and BMI predicted failure to complete the 400-m walk test in 15 minutes or less (major mobility disability).Results: Among N = 406 participants with baseline measures, lower grip strength was associated with an increased risk for developing major mobility disability, with and without covariate adjustment (p < .01): The hazard ratio (95% confidence interval) for the lowest versus high sex-specific quartile of grip strength was 6.11 (2.24-16.66). We observed a U-shaped relationship between baseline BMI and the risk of developing major mobility disability, such that the risk for participants with a BMI of 25-29 kg/m(2) was approximately half that of participants with BMI less than 25 or 30 kg/m(2) or more (p = .04 in fully adjusted analyses).Conclusions: Our data highlight the importance of muscle weakness, low BMI, and obesity as risk factors for major mobility disability in older adults. Being overweight may be protective for major mobility disability. [ABSTRACT FROM AUTHOR]

Background: As the number of older adults in the United States rises, maintaining functional independence among older Americans has emerged as a major clinical and public health priority. Older people who lose mobility are less likely to remain in the community; demonstrate higher rates of morbidity, mortality, and hospitalizations; and experience a poorer quality of life. Several studies have shown that regular physical activity improves functional limitations and intermediate functional outcomes, but definitive evidence showing that major mobility disability can be prevented is lacking. A Phase 3 randomized controlled trial is needed to fill this evidence gap.Methods: The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase 3 multicenter randomized controlled trial designed to compare a supervised moderate-intensity physical activity program with a successful aging health education program in 1,600 sedentary older persons followed for an average of 2.7 years.Results: LIFE's primary outcome is major mobility disability, defined as the inability to walk 400 m. Secondary outcomes include cognitive function, serious fall injuries, persistent mobility disability, the combined outcome of major mobility disability or death, disability in activities of daily living, and cost-effectiveness.Conclusions: Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: This study investigated whether high-velocity high-power training (POW) improved lower extremity muscle power and quality in functionally-limited elders greater than traditional slow-velocity progressive resistance training (STR). METHODS: Fifty-seven community-dwelling older adults aged 74.2+/-7 (range 65-94 yrs), Short Physical Performance Battery score 7.7+/-1.4, were randomized to either POW (n=23) (12 females), STR (n=22) (13 females) or a control group of lower extremity stretching (CON) (n=12) (6 females). Training was performed three times per week for 12 weeks and subjects completed three sets of double leg press and knee extension exercises at 70% of the one repetition maximum (1RM). Outcome measures included 1RM strength and peak power (PP). Total leg lean mass was determined using dual-energy X-ray absorptiometry to estimate specific strength and specific PP. RESULTS: During training, power output was consistently higher in POW compared to STR for knee extension (approximately 2.3-fold) and leg press (approximately 2.8-fold) exercises (p<0.01). Despite this, PP and specific PP of the knee extensors increased similarly from baseline in POW and STR compared to CON (p<0.01), and no significant time-group interaction occurred for PP of the leg extensors. However, gains in leg press specific PP were significantly greater in POW compared to both STR and CON (p<0.05). Total leg lean mass did not change within any group. CONCLUSIONS: A short-term intervention of high-velocity power training and traditional slow-velocity progressive resistance training yielded similar increases of lower extremity power in the mobility-impaired elderly. Neuromuscular adaptations to power training, rather than skeletal muscle hypertrophy, may have facilitated the improvements in muscle quality. Additional studies are warranted to test the efficacy of power training in older individuals with compromised physical functioning. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: The purpose of this study was to assess the reliability and concurrent validity of a new methodology to evaluate lower extremity muscle power in older, functionally limited men and women. METHODS: A cross sectional evaluation was performed on 58 older men (n=27) and women (n=31) (74.2+/-0.9 years). Knee and hip (leg press) and knee extensor power were evaluated on pneumatic and isokinetic resistance equipment. Incremental single attempt power (IP) testing utilized a single attempt at attaining maximum power at each of six external resistances and was compared to multiple attempt pneumatic power (MP) testing determined by the highest of 5 attempts at achieving maximum power at two set resistances and also with power determined by isokinetic dynamometry. RESULTS: Leg press extension MP yielded significantly greater power than IP at both low (mean=225.3+/-11.85 and 183.9+/-11.52 watts respectively, p<0.001) and high (mean=249.7+/-15.25 and 201.7+/-13.18 watts respectively, p<0.001) external resistances. Knee extension MP also produced significantly greater power when compared to IP at low (mean=82.4+/-4.45 and 69.7+/-4.28 watts respectively, p<0.001) and high (mean=93.7+/-6.3 and 83.2+/-5.93 watts respectively, p<0.001) external resistances. MP testing exhibited excellent reliability at both low (leg press extension: Intra Class Correlation (ICC)=0.93, knee extension: ICC=0.87) and high (Leg press extension: ICC=0.85, Knee Extension: ICC=0.91) external resistances. MP knee extension at 70% 1 RM also showed good agreement with average isokinetic power (R2=0.636). CONCLUSIONS: These findings support the reliability and concurrent validity of MP for the evaluation of muscle power in older individuals. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that elevated intramyocellular triacylglycerol concentrations are associated with diminished insulin sensitivity in skeletal muscle. This lipid accumulation is most likely due to enhanced fatty acid uptake into the muscle coupled with diminished mitochondrial lipid oxidation. The excess fatty acids are esterified and either stored or metabolized to various molecules that may participate or interfere with normal cellular signaling, particularly insulin-mediated signal transduction, thus altering cellular and, subsequently, whole-body glucose metabolism. Impaired insulin responsiveness, if not managed, can further progress to type 2 diabetes mellitus, an all too common condition. For most of the human population this is avoidable, given that causes of intramyocellular lipid deposition are predominantly lifestyle-mediated. Chronic overconsumption of calories coupled with deleterious intakes of saturated or trans-unsaturated fatty acids inconsistent with the recommendations outlined in the Dietary Guidelines for Americans have been shown to increase the risk of insulin resistance. Furthermore, lack of exercise, which can have a profound effect on skeletal muscle lipid turnover, is implicated in this lipid-induced insulin resistance. This review summarizes the current understanding of the effects of elevated intramyocellular lipids on insulin signaling and how these effects may be altered by varying dietary fat composition and exercise. Copyright © 2007 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: Chronic renal insufficiency leads to muscle wasting, which may be exacerbated by low-protein diets prescribed to delay disease progression. Resistance training increases protein utilization and muscle mass.Objective: To determine the efficacy of resistance training in improving protein utilization and muscle mass in patients with chronic renal insufficiency treated with a low-protein diet.Design: Randomized, controlled trial.Setting: Tufts University, Boston, Massachusetts.Patients: 26 older patients with moderate renal insufficiency (17 men, 9 women) who had achieved stabilization on a low-protein diet.Intervention: During a run-in period of 2 to 8 weeks, patients were instructed and their adherence to the low-protein diet (0.6 g/kg of body weight per day) was evaluated. They were randomly assigned to a low-protein diet plus resistance training (n = 14) or a low-protein diet alone (n = 12) for 12 weeks.Measurements: Total body potassium, mid-thigh muscle area, type I and II muscle-fiber cross-sectional area, and protein turnover.Results: Mean protein intake was 0.64 +/- 0.07 g/kg per day after stabilization. Total body potassium and type I and II muscle-fiber cross-sectional areas increased in patients who performed resistance training by a mean (+/-SD) of 4% +/- 8%, 24% +/- 31%, and 22% +/- 29%, respectively, compared with those who did not. Leucine oxidation and serum prealbumin levels also improved significantly. Patients assigned to resistance training maintained body weight compared with those who were not. Improvement in muscle strength was significantly greater with resistance training (32% +/- 14%) than without (-13% +/- 20%) (P < 0.001).Conclusion: By improving muscle mass, nutritional status, and function, resistance training seems to be effective against the catabolism of a low-protein diet and uremia in patients with renal failure. [ABSTRACT FROM AUTHOR]

Background: Identification of the physiologic factors most relevant to functional independence in the elderly population is critical for the design of effective interventions. It has been suggested that muscle power may be more directly related to impaired physical performance than muscle strength in elderly persons. We tested the hypothesis that peak muscle power is closely associated with self-reported functional status in sedentary elderly community-dwelling women.Methods: We used baseline data that were collected as part of a 1-year randomized controlled clinical trial of a combined program of strength, power, and endurance training in 80 elderly women (mean age 74.8 +/- 5.0 years) with 3.2 +/- 1.9 chronic diseases, selected for baseline functional impairment and/or falls.Results: Functional status at baseline was related in univariate analyses to physiologic capacity, habitual physical activity level, neuropsychological status, and medical diagnoses. Leg power had the strongest univariate correlation to self-reported functional status (r = -.47, p < .0001) of any of the physiologic factors we tested. In a forward stepwise regression model, leg press power and habitual physical activity level were the only two factors that contributed independently to functional status (r = .64, p < .0001), accounting for 40% of the variance in functional status.Conclusions: Leg power is a strong predictor of self-reported functional status in elderly women. [ABSTRACT FROM AUTHOR]

Obesity accelerates the onset and progression of age-related conditions. In preclinical models, obesity drives cellular senescence, a cell fate that compromises tissue health and function, in part through a robust and diverse secretome. In humans, components of the secretome have been used as senescence biomarkers that are predictive of age-related disease, disability, and mortality. Here, using biospecimens and clinical data from two large and independent cohorts of older adults, we tested the hypothesis that the circulating concentrations of senescence biomarkers are influenced by body mass index (BMI). After adjusting for age, sex, and race, we observed significant increases in activin A, Fas, MDC, PAI1, PARC, TNFR1, and VEGFA, and a significant decrease in RAGE, from normal weight, to overweight, to obesity BMI categories by linear regression in both cohorts (all p < 0.05). These results highlight the influence of BMI on circulating concentrations of senescence biomarkers., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Sarcopenia is the accelerated loss of skeletal muscle mass and function commonly, but not exclusively, associated with advancing age. It is observed across many species including humans in whom it can lead to decline in physical function and mobility as well as to increased risk of adverse outcomes including falls, fractures and premature mortality. Although prevalence estimates vary because sarcopenia has been defined in different ways, even using a conservative approach, the prevalence is between 5% and 10% in the general population. A life course framework has been proposed for understanding not only the occurrence of sarcopenia in later life but also influences operating at earlier life stages with potentially important implications for preventive strategies. Harnessing progress in understanding the hallmarks of ageing has been key to understanding sarcopenia pathophysiology. Considerable convergence in approaches to diagnosis of sarcopenia has occurred over the last 10 years, with a growing emphasis on the central importance of muscle strength. Resistance exercise is currently the mainstay of treatment; however, it is not suitable for all. Hence, adjunctive and alternative treatments to improve quality of life are needed. An internationally agreed approach to definition and diagnosis will enable a step change in the field and is likely to be available in the near future through the Global Leadership Initiative in Sarcopenia., (© 2024. Springer Nature Limited.)

The motoric cognitive risk syndrome (MCR) is a syndrome characterized by subjective memory complaints and slow walking speeds that can identify older adults at increased risk for developing Alzheimer's disease or a related dementia (ADRD). To date, the feasibility of community-based physical activity (PA) programs for improving outcomes in MCR have yet to be examined. To address this knowledge gap, we conducted a translational randomized controlled trial (RCT) comparing 24-weeks of PA to a healthy aging education (HE) control intervention delivered within the infrastructure of an urban senior center in Greater Boston (clincaltrials.gov identifier: NCT03750682). An existing senior center employee was trained to administer the multimodal group-based PA program that included moderate-intensity aerobic walking, strength, flexibility and balance training. A total of 79 older adults attended the senior center for a screening visit, of whom 29 met the MCR criteria and 25 were randomized to PA or HE (mean age: 74.4 ± 7 years; BMI: 32.4 ± 7 kg/m 2 ; 85% female; 3MSE score: 92.4 ± 7; gait speed: 0.52 ± 0.1 m/s; SPPB score 4.8 ± 1.9). Due to the Covid-19 pandemic the study was stopped prematurely. Participants could successfully adhere to the study interventions (overall attendance rate: PA: 69% vs. HE:70% at study termination). Participants also successfully completed baseline and follow-up study assessments that included a computerized cognitive testing battery and objective tests of physical performance and functional exercise capacity. No study-related adverse events occurred. Notable trends for improved cognitive performance, gait speed and 6-min walk distance were exhibited in PA compared to HE. Our study provides important preliminary information to aid the design of larger-scale RCTs of PA that may help to preserve the independence of vulnerable older adults at high risk for ADRD in community-based settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer OJ declared a shared affiliation with the author JV to the handling editor at the time of review. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hernon, Singh, Ward, Kramer, Travison, Verghese, Fielding, Kowaleski and Reid.)

Motoric cognitive risk syndrome (MCR) is a pre-dementia syndrome characterized by subjective memory complaints and gait impairments that may be related to lower prefrontal cortex (PFC) function. Acute bouts of aerobic exercise are shown to improve PFC function, however, the acute effects of exercise on PFC oxygenation have not yet been examined in MCR. This study aims to characterize the PFC oxygenation responses during acute exercise in older adults with MCR. Nineteen older adults with MCR performed a submaximal cycling exercise protocol. Functional near-infrared spectroscopy (fNIRS) is used to measure concentrations of oxygenated (OxyHb) and deoxygenated (DeoxyHb) hemoglobin from the PFC. There is a trend for increased OxyHb concentrations and decreased DeooxyHb concentrations during exercise. Exercise also induced significant increases in ratings of perceived exertion (RPEs) and heart rate. A significant, positive correlation between PFC OxyHb and RPEs during the cycling exercise are also observed. The findings reveal that PFC oxygenation increases during exercise in an intensity-dependent manner and the subjective perception of exertion is associated with the magnitude of PFC oxygenation. These results suggest that moderate-intensity cycling exercise may have beneficial effects on increasing cerebral blood flow in the PFC of older adults with MCR., (© 2024 Wiley‐VCH GmbH.)

Background: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited., Aim: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors., Methods: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index)., Results: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed., Conclusions: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors., (© 2024. The Author(s).)

Previous studies have identified a role for the gut microbiome and its metabolic products, short-chain fatty acids (SCFAs), in the maintenance of muscle mass and physical function (i.e., the gut-muscle axis), but interventions aimed at positively impacting the gut-muscle axis during aging are sparse. Gut bacteria ferment soluble fiber into SCFAs, and accordingly, to evaluate the impact of a high-soluble-fiber diet (HSFD) on the gut-muscle axis, we fed a whole-food, 3×-higher-soluble fiber-containing diet (relative to standard chow) to aged (98 weeks) C57BL/6J mice for 10 weeks. The HSFD significantly altered gut bacterial community structure and composition, but plasma SCFAs were not different, and a positive impact on muscle-related measures (when normalized to body weight) was not identified. However, when evaluating sex differences between dietary groups, female (but not male) HSFD-fed mice had significant increases for SCFAs, the quadriceps/body weight (BW) ratio, and treadmill work performance (distance run × BW), which suggests that an HSFD can positively impact the gut-muscle axis. In contrast, consistent effects in both male and female HSFD-fed mice included weight and fat loss, which suggests a positive role for an HSFD on the gut-adipose axis in aged mice.

Objectives: Prior research suggested that loss of appetite (LOA) among adults with Medicare fee-for-service (FFS) insurance in the United States increased the risk of mortality within 1 year; those findings were not adjusted for risk factors and confounders. The objective of this study was to compare the risk of mortality among Medicare FFS beneficiaries with LOA to a control group without LOA while controlling or adjusting for age, comorbidities, body mass index (BMI), and weight loss., Design: Retrospective and observational analysis of Medicare FFS health insurance claims data from October 1, 2015 to December 31, 2021., Setting: Claims from all settings (e.g., hospital inpatient/outpatient, office, assisted living facility, skilled nursing facility, hospice, rehabilitation facility, home) were included in these analyses., Participants: The LOA group included all individuals aged 65-115 years with continuous Medicare FFS medical coverage (Parts A and/or B) for at least 12 months before a claim with ICD-10 diagnosis code "R63.0 Anorexia". The control group was drawn from individuals aged 65-115 years with continuous Medicare FFS coverage who did not have a diagnosis of R63.0. Individuals with LOA were matched 1:3 to those in the control group based on age, sex, and race/ethnicity., Measurements: Mortality in the LOA group was compared to mortality in the control group using Kaplan-Meier and Cox regression analyses and stratified or adjusted in terms of Charlson Comorbidity Index (CCI), claims-based frailty index (CFI), BMI, and weight loss., Results: The study population of 1,707,031 individuals with LOA and 5,121,093 controls without LOA was 61.7% female and 82.2% White. More individuals with LOA compared with the control group had a CCI score 5+ (52.4% vs. 19.4%), CFI score 5+ (31.6% vs. 6.4%), and BMI < 20 kg/m 2 (11.2% vs. 2.1%). Median follow-up was 12 months (individuals with LOA) and 49 months (control group). In a matched population, the risk of mortality was significantly higher (unadjusted hazard ratio 4.40, 95% confidence interval 4.39-4.42) for individuals with LOA than the control group. Median survival time was 4 months (individuals with LOA) and 26 months (control group); differences in survival time remained when stratifying by CCI, BMI, and weight loss., Conclusion: Individuals with LOA had a substantially increased risk of death even after matching for age, sex, race/ethnicity, and adjusting for comorbidities. These findings highlight the burden of illness in older adults with LOA and the need for therapies., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Sarcopenia, the age-related loss of muscle mass and strength/function, is an important clinical condition. However, no international consensus on the definition exists., Objective: The Global Leadership Initiative in Sarcopenia (GLIS) aimed to address this by establishing the global conceptual definition of sarcopenia., Design: The GLIS steering committee was formed in 2019-21 with representatives from all relevant scientific societies worldwide. During this time, the steering committee developed a set of statements on the topic and invited members from these societies to participate in a two-phase International Delphi Study. Between 2022 and 2023, participants ranked their agreement with a set of statements using an online survey tool (SurveyMonkey). Statements were categorised based on predefined thresholds: strong agreement (>80%), moderate agreement (70-80%) and low agreement (<70%). Statements with strong agreement were accepted, statements with low agreement were rejected and those with moderate agreement were reintroduced until consensus was reached., Results: 107 participants (mean age: 54 ± 12 years [1 missing age], 64% men) from 29 countries across 7 continents/regions completed the Delphi survey. Twenty statements were found to have a strong agreement. These included; 6 statements on 'general aspects of sarcopenia' (strongest agreement: the prevalence of sarcopenia increases with age (98.3%)), 3 statements on 'components of sarcopenia' (muscle mass (89.4%), muscle strength (93.1%) and muscle-specific strength (80.8%) should all be a part of the conceptual definition of sarcopenia)) and 11 statements on 'outcomes of sarcopenia' (strongest agreement: sarcopenia increases the risk of impaired physical performance (97.9%)). A key finding of the Delphi survey was that muscle mass, muscle strength and muscle-specific strength were all accepted as 'components of sarcopenia', whereas impaired physical performance was accepted as an 'outcome' rather than a 'component' of sarcopenia., Conclusion and Relevance: The GLIS has created the first global conceptual definition of sarcopenia, which will now serve to develop an operational definition for clinical and research settings., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Context: Anamorelin, a ghrelin receptor agonist known to stimulate the pulsatile release of GH from the pituitary, has the potential to improve musculoskeletal health in adults with osteosarcopenia., Objective: To determine the effect of anamorelin treatment for 1 year on muscle mass and strength and on biochemical markers of bone turnover in adults with osteosarcopenia (OS)., Design: Randomized, placebo-controlled, 1-year anamorelin intervention trial., Setting: The Bone Metabolism Laboratory at the USDA Nutrition Center at Tufts University., Participants: 26 men and women, age 50 years and older, with OS., Main Outcome Measures: Muscle mass by D3-creatine dilution and lean body mass (LBM) and bone mineral density (BMD) by dual-energy X-ray absorptiometry, muscle strength, serum IGF-1, and bone turnover markers, serum procollagen 1 intact N-terminal (P1NP), and C-terminal telopeptide (CTX)., Results: Anamorelin did not have a significant effect on muscle mass or LBM; it significantly increased knee flexion torque at 240°/s by 20% (P = .013) and had a similar nonstatistically significant effect on change in knee extension; it increased bone formation (P1NP) by 75% (P = .006) and had no significant effect on bone resorption (CTX) or BMD. Serum IGF-1 increased by 50% in the anamorelin group and did not change in the placebo group (P = .0001 for group difference)., Conclusion: In this pilot study, anamorelin did not significantly alter muscle mass; however, it may potentially improve lower extremity strength and bone formation in addition to increasing circulating IGF-1 levels in adults with OS. Further study of anamorelin in this population is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young-to-middle-aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

With the increasing number of elderly individuals worldwide, the prevalence of age-related loss of muscle mass, referred to as sarcopenia, is expected to increase. Sarcopenia is a relatively new recognized syndrome, which is thought to affect 13% individuals worldwide, and the significant efforts made by different groups have advanced our understanding of the diagnosis, treatment, and natural history of this condition. However, the challenge is now to standardize its measurement and diagnosis to facilitate research in this area and a greater understanding of this condition and its management between clinicians and researchers. The Global Leadership Initiative on Sarcopenia (GLIS) is at the forefront of an international effort to produce standardized definition of sarcopenia. Setting a definition for sarcopenia entails several considerations and trade-offs. In this critical review, we have addressed key challenges driving the process of standardizing the definition, while delving into future avenues in sarcopenia research. Establishing a clear consensus on the working definition of sarcopenia is essential not only for advancing research in this field but also for assessing the prognostic implications of diagnosing sarcopenia and determining the most suitable treatment for affected patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation., Competing Interests: Declaration of interests K.G.A. has received consulting fees on SARS-CoV-2 and the COVID-19 pandemic., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death., (© 2023 Mayo Clinic. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Rationale & Objective: In the Lifestyle Interventions and Independence for Elders (LIFE) trial, a structured exercise intervention slowed kidney function decline in sedentary older adults. Biomarkers of kidney health could distinguish potential mechanisms for this beneficial effect., Study Design: Randomized controlled trial., Setting & Population: A total of 1,381 sedentary adults aged 70-89 years enrolled in the LIFE trial., Intervention: Structured, 2-year, moderate-intensity exercise intervention versus health education., Outcomes: Physical activity was measured by step count. Primary outcomes were changes in 14 serum and urine biomarkers of kidney health collected at baseline, year 1, and year 2. We determined the effect of randomization on changes in kidney measures and then evaluated observational associations of achieved activity on each measure., Results: Participants assigned to exercise walked on average 291 more steps per day than participants assigned to health education. The intervention was not significantly associated with changes in biomarkers of kidney health. In observational analyses, persons in the highest versus lowest quartile of activity (≥3,470 vs <1,568 steps/day) had significant improvement in urine albumin (mean, -0.22 mg albumin/g urine creatinine [interquartile range (IQR), -0.37 to -0.06]), alpha-1-microglobulin (-0.18 mg/L [-0.28 to -0.08]), trefoil factor-3 (-0.24 pg/mL [-0.35 to -0.13]), epidermal growth factor (0.19 pg/mL [0.06-0.32]), uromodulin (0.06 pg/mL [0.00-0.12]), interleukin 18 (-0.09 pg/mL [-0.15 to -0.03]), neutrophil gelatinase-associated lipocalin (-0.16 pg/mL [-0.24 to -0.07]), monocyte chemoattractant protein-1 (-0.25 pg/mL [-0.36 to -0.14]), clusterin (-0.16 pg/mL [-0.30 to -0.02]), serum tumor necrosis factor receptor-1 (-0.25 mg/dL [-0.39 to -0.11]) and tumor necrosis factor receptor-2 (-0.30 mg/dL [-0.44 to -0.16]). In sensitivity analyses, incremental changes in activity were most impactful on urine interleukin 18 and serum tumor necrosis factor-1., Limitations: The original study was not designed to assess the impact on kidney health. Non-white individuals and patients with advanced chronic kidney disease are underrepresented., Conclusions: Randomization to structured exercise did not improve kidney health at a group level. However, higher exercise was associated with concurrent improvements in biomarkers of glomerular injury, tubular function/repair, tubular injury, generalized inflammation, and tubulointerstitial repair/fibrosis., Plain-Language Summary: In the Lifestyle Interventions For Elders (LIFE) study, randomization to an exercise and physical activity intervention improved the slope of estimated glomerular filtration rate over 2 years compared with health education among older adults. In this study, we sought to determine whether there were specific biomarkers of kidney health that were affected by the exercise and physical activity intervention to investigate potential mechanisms for this positive impact on kidney decline. We found that randomization to the intervention did not improve any of the 14 measures of kidney tubule health. However, in observational analyses, higher activity was independently associated with improvements in several domains, especially tubular injury and generalized inflammation. These results help to clarify the impact of physical activity on kidney health.

Patient perspectives are now widely recognized as a key element in the evaluation of health interventions. Therefore, the provision of specific and validated Patient Reported Outcome Measures that emphasize the lived experience of patients suffering from specific diseases is very important. In the field of sarcopenia, the only validated specific health-related quality of life (HRQoL) instrument available is the Sarcopenia Quality of Life questionnaire (SarQoL). This self-administrated HRQoL questionnaire, developed in 2015, consists of 55 items arranged into 22 questions and has currently been translated into 35 languages. Nineteen validation studies performed on SarQoL have consensually confirmed the capacity of SarQoL to detect difference in HRQoL between older people with and without sarcopenia, its reliability and its validity. Two further observational studies have also indicated its responsiveness to change. A short form SarQoL, including only 14 items has further been developed and validated to reduce the potential burden of administration. Research on the psychometric properties of SarQoL questionnaire is still encouraged as the responsiveness to change of SarQoL has not yet been measured in the context of interventional studies, as limited prospective data currently exist and as there is still not cut-off score to define a low HRQoL. In addition, SarQoL has mainly been used in community-dwelling older individuals with sarcopenia and would benefit to be studied in other types of populations. This review aims to provide to researchers, clinicians, regulators, pharmaceutical industries and other stakeholders a clear summary of comprehensive evidence on the SarQoL questionnaire published up to January 2023Query., (© 2023. The Author(s).)

Background: Dysfunction in blood vessel dynamics may contribute to changes in muscle measures. Therefore, we examined associations of vascular health measures with grip strength and gait speed in adults from the Framingham Heart Study., Methods: The cross-sectional study (1998-2001) included participants with 1 measure of grip strength (kg, dynamometer) or gait speed (4-m walk, m/s) and at least 1 measure of aortic stiffness (carotid-femoral pulse wave velocity, brachial pulse pressure, and brachial flow pulsatility index) or brachial artery structure and function (resting flow velocity, resting brachial artery diameter, flow-mediated dilation %, hyperemic brachial blood flow velocity, and mean arterial pressure [MAP]) assessed by tonometry and brachial artery ultrasound. The longitudinal study included participants with ≥1 follow-up measurement of gait speed or grip strength. Multivariable linear regression estimated the association of 1 standard deviation (SD) higher level of each vascular measure with annualized percent change in grip strength and gait speed, adjusting for covariates., Results: In cross-sectional analyses (n = 2 498, age 61 ± 10 years; 56% women), higher resting brachial artery diameter (β ± standard error [SE] per 1 SD: 0.59 ± 0.24, p = .01) and MAP (β ± SE: 0.39 ± 0.17, p = .02) were associated with higher grip strength. Higher brachial pulse pressure (β ± SE: -0.02 ± 0.01, p = .07) was marginally associated with slower gait speed. In longitudinal analyses (n = 2 157), higher brachial pulse pressure (β ± SE: -0.19 ± 0.07, p = .005), was associated with slowing of gait speed but not with grip strength., Conclusions: Higher brachial artery pulse pressure (measure of aortic stiffness) was associated with loss of physical function over ~11 years, although we found no evidence that microvascular function contributed to the relation., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Several candidate molecules that may have application in treating physical limitations associated with aging and chronic diseases are in development. Challenges in the framing of indications, eligibility criteria, and endpoints and the lack of regulatory guidance have hindered the development of function-promoting therapies., Methods: Experts from academia, pharmaceutical industry, National Institutes of Health (NIH), and Food and Drug Administration (FDA) discussed optimization of trial design including the framing of indications, eligibility criteria, and endpoints., Results: Mobility disability associated with aging and chronic diseases is an attractive indication because it is recognized by geriatricians as a common condition associated with adverse outcomes, and it can be ascertained reliably. Other conditions associated with functional limitation in older adults include hospitalization for acute illnesses, cancer cachexia, and fall injuries. Efforts are underway to harmonize definitions of sarcopenia and frailty. Eligibility criteria should reconcile the goals of selecting participants with the condition and ensuring generalizability and ease of recruitment. An accurate measure of muscle mass (eg, D3 creatine dilution) could be a good biomarker in early-phase trials. Performance-based and patient-reported measures of physical function are needed to demonstrate whether treatment improves how a person lives, functions, or feels. Multicomponent functional training that integrates training in balance, stability, strength, and functional tasks with cognitive and behavioral strategies may be needed to translate drug-induced muscle mass gains into functional improvements., Conclusions: Collaborations among academic investigators, NIH, FDA, pharmaceutical industry, patients, and professional societies are needed to conduct well-designed trials of function-promoting pharmacological agents with and without multicomponent functional training., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In recent years, several new classes of therapies have been investigated with their potential for restoring or improving physical functioning in older adults. These have included Mas receptor agonists, regulators of mitophagy, skeletal muscle troponin activators, anti-inflammatory compounds, and targets of orphan nuclear receptors. The present article summarizes recent developments of the function-promoting effects of these exciting new compounds and shares relevant preclinical and clinical data related to their safety and efficacy. The development of novel compounds in this area is expanding and likely will need the advent of a new treatment paradigm for age-associated mobility loss and disability., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Functional limitations and physical disabilities associated with aging and chronic disease are major concerns for human societies and expeditious development of function-promoting therapies is a public health priority., Methods: Expert panel discussion., Results: The remarkable success of Operation Warp Speed for the rapid development of COVID-19 vaccines, COVID-19 therapeutics, and of oncology drug development programs over the past decade have taught us that complex public health problems such as the development of function-promoting therapies will require collaboration among many stakeholders, including academic investigators, the National Institutes of Health, professional societies, patients and patient advocacy organizations, the pharmaceutical and biotechnology industry, and the U.S. Food and Drug Administration., Conclusions: There was agreement that the success of well designed, adequately powered clinical trials will require careful definitions of indication/s, study population, and patient-important endpoints that can be reliably measured using validated instruments, commensurate resource allocation, and versatile organizational structures such as those used in Operation Warp Speed., (Published by Oxford University Press on behalf of The Gerontological Society of America 2023.)

Physical activity and exercise training exert multiple and varied beneficial effects on a wide array of human tissues, making them therapeutic modalities that can prevent and treat age-related decline in physical function. The Molecular Transducers of Physical Activity Consortium is currently working to elucidate the molecular mechanisms underlying how physical activity improves and preserves health. Exercise training, especially when task specific, is an effective intervention for improving skeletal muscle performance and physical function in everyday activities. As seen elsewhere in this supplement, its adjunctive use with pro-myogenic pharmaceuticals may prove to be synergistic in effect. Behavioral strategies aiming to promote exercise participation and sustain adherence are being considered as additional adjuncts to further improve physical function in comprehensive, multicomponent interventions. One application of this combined strategy may be to target multimodal pro-myogenic therapies in prehabilitation to optimize physical preoperative health to enhance functional recovery postsurgery. We summarize here recent progress on biological mechanisms of exercise training, behavioral approaches to exercise participation, and the role task-specific exercise plays in synergy with pharmacologic therapies with a particular focus on older adults. Physical activity and exercise training in multiple settings should serve as the baseline standard of care around which other therapeutic interventions should be considered when the goal is restoring or increasing physical function., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)