Purpose

This longitudinal study examined the major physiological mechanisms that determine the age-related loss of lower extremity muscle power in two distinct groups of older humans. We hypothesized that after ~3 years of follow-up, mobility-limited older adults (mean age: 77.2 ± 4, n = 22, 12 females) would have significantly greater reductions in leg extensor muscle power compared to healthy older adults (74.1 ± 4, n = 26, 12 females).

Methods

Mid-thigh muscle size and composition were assessed using computed tomography. Neuromuscular activation was quantified using surface electromyography and vastus lateralis single muscle fibers were studied to evaluate intrinsic muscle contractile properties.

Results

At follow-up, the overall magnitude of muscle power loss was similar between groups: mobility-limited: -8.5 % vs. healthy older: -8.8 %, P > 0.8. Mobility-limited elders had significant reductions in muscle size (-3.8 %, P < 0.01) and strength (-5.9 %, P < 0.02), however, these parameters were preserved in healthy older (P ≥ 0.7). Neuromuscular activation declined significantly within healthy older, but not in mobility-limited participants. Within both groups, the cross-sectional areas of type I and IIA muscle fibers were preserved while substantial increases in single fiber peak force (>30 %), peak power (>200 %) and unloaded shortening velocity (>50 %) were elicited at follow-up.

Conclusion

Different physiological mechanisms contribute to the loss of lower extremity muscle power in healthy older and mobility-limited older adults. Neuromuscular changes may be the critical early determinant of muscle power deficits with aging. In response to major whole muscle decrements, major compensatory mechanisms occur within the contractile properties of surviving single muscle fibers in an attempt to restore overall muscle power and function with advancing age.

Age-related impairment of neuromuscular activation has been shown to contribute to weakness in older adults. However, it is unclear to what extent impaired neuromuscular activation independently accounts for decline of mobility function. The hypothesis of this study is that the capability to produce rapid neuromuscular activation during maximal effort leg muscle contractions will be shown to be an independent predictor of mobility function in older men and women after accounting for muscle size and adiposity, body composition and age. Twenty six older men and eighteen older women (aged 70-85years) participated in this study. Mobility function was assessed by the 400-m walk test. Neuromuscular activation of the quadriceps muscle group was assessed by surface electromyography ("rate of EMG rise"). Thigh muscle cross sectional area and adiposity were assessed by computed tomography. In males, univariate regression analysis revealed strong associations between walking speed and a number of predictors including age (p<0.01), muscle area (p<0.01), intermuscular adipose tissue area (p<0.01), and rate of EMG rise (p<0.001). Subsequent multiple regression analysis with all variables accounted for 72% of the variability in walking speed (p<.0001), with age and rate of EMG rise as the dominant variables in the model. In females, univariate analysis showed a significant association only between walking speed and subcutaneous adipose tissue area (p<0.05). Multiple regression analysis accounted for only 44% of the variability in walking speed, and was not statistically significant (p=0.18). The present findings indicate that the capability to rapidly activate the quadriceps muscle group is an important factor accounting for inter-individual variability of walking speed among older men, but not among older women. This research is important for informing the design of assessments and interventions that seek to detect and prevent impairments that contribute to age-related mobility disability.

Background

We compared the effects of two uniquely different lower extremity power training interventions on changes in muscle power, physical performance, neuromuscular activation, and muscle cross sectional area in mobility-limited older adults.

Methods

Fifty-two subjects (78±5 years, short physical performance battery score: 8.1±1) were randomized to either 16 weeks of progressive high velocity resistance training performed at low external resistance (40% of the 1-repetition maximum [1-RM] [LO]) or high external resistance (70% of 1RM [HI]). Both groups completed three sets of leg and knee extension exercises at maximum voluntary velocity, two times per week. Neuromuscular activation was assessed using surface electromyography and muscle cross sectional area (CSA) was measured using computed tomography.

Results

At 16 weeks, LO and HI exhibited significant and similar within-group increases of leg extensor peak power (~34% vs ~42%), strength (~13% vs ~19%), and SPPB score (1.4±0.3 vs 1.8±0.3 units), respectively (all P < .03). Improvements in neuromuscular activation occurred in LO (P = .03) while small gains in mid-thigh muscle CSA were detected in LO (1.6%, P = .35) and HI (2.1%, P = .17). No significant between-group differences were evident for any measured parameters (all P > .25).

Conclusions

High velocity resistance training with low external resistance yields similar improvements in muscle power and physical performance compared to training with high external resistance in mobility-limited elders. These findings may have important implications for optimizing exercise interventions for older adults with mobility limitations.

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.

Objective

Obesity, defined by anthropometric measures, is a well-known risk factor for knee osteoarthritis (OA), but there is a relative paucity of data regarding the association of body composition (fat and muscle mass) with risk of knee OA. We undertook this study to examine the longitudinal association of body composition categories based on fat and muscle mass with risk of incident knee OA.

Methods

We included participants from the Multicenter Osteoarthritis Study, a longitudinal cohort of individuals with or at risk of knee OA. Based on body composition (i.e., fat and muscle mass) from whole-body dual x-ray absorptiometry, subjects were categorized as obese nonsarcopenic (obese), sarcopenic obese, sarcopenic nonobese (sarcopenic), or nonsarcopenic nonobese (the referent category). We examined the relationship of baseline body composition categories with the risk of incident radiographic OA at 60 months using binomial regression with robust variance estimation, adjusting for potential confounders.

Results

Among 1,653 subjects without radiographic knee OA at baseline, significantly increased risk of incident radiographic knee OA was found among obese women (relative risk [RR] 2.29 [95% confidence interval {95% CI} 1.64-3.20]), obese men (RR 1.73 [95% CI 1.08-2.78]), and sarcopenic obese women (RR 2.09 [95% CI 1.17-3.73]), but not among sarcopenic obese men (RR 1.74 [95% CI 0.68-4.46]). Sarcopenia was not associated with risk of knee OA (for women, RR 0.96 [95% CI 0.62-1.49]; for men, RR 0.66 [95% CI 0.34-1.30]).

Conclusion

In this large longitudinal cohort, we found body composition-based obesity and sarcopenic obesity, but not sarcopenia, to be associated with risk of knee OA. Weight loss strategies for knee OA should focus on obesity and sarcopenic obesity.

Objective

Physical activity is recommended to mitigate functional limitations associated with knee osteoarthritis (OA). However, it is unclear whether walking on its own protects against the development of functional limitation.

Methods

Walking over 7 days was objectively measured as steps/day within a cohort of people with or at risk of knee OA from the Multicenter Osteoarthritis Study. Incident functional limitation over 2 years was defined by performance-based (gait speed <1.0 meter/second) and self-report (Western Ontario and McMaster Universities Osteoarthritis Index physical function score >28 of 68) measures. We evaluated the association of steps/day at baseline with developing functional limitation 2 years later by calculating risk ratios adjusted for potential confounders. The number of steps/day that best distinguished risk for developing functional limitation was estimated from the maximum distance from chance on receiver operating characteristic curves.

Results

Among 1,788 participants (mean age 67 years, mean body mass index 31 kg/m(2) , 60% women), each additional 1,000 steps/day was associated with a 16% and 18% reduction in incident functional limitation by performance-based and self-report measures, respectively. Walking <6,000 and <5,900 steps/day were the best thresholds to distinguish incident functional limitation by performance-based (sensitivity 67.3%, specificity 71.8%) and self-report (sensitivity 58.7%, specificity 68.9%) measures, respectively.

Conclusion

More walking was associated with less risk of functional limitation over 2 years. Walking >6,000 steps/day provides a preliminary estimate of the level of walking activity to protect against developing functional limitation in people with or at risk of knee OA.

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.

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.

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.

The 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and the Sarcopenia Definitions and Outcomes Consortium (SDOC) have recently proposed sarcopenia definitions. However, comparisons of the performance of these approaches in terms of thresholds employed, concordance in individuals and prediction of important health-related outcomes such as death are limited. We addressed this in a large multinational assembly of cohort studies that included information on lean mass, muscle strength, physical performance and health outcomes. White men from the Health Aging and Body Composition (Health ABC) Study, Osteoporotic Fractures in Men (MrOS) Study cohorts (Sweden, USA), the Hertfordshire Cohort Study (HCS) and the Sarcopenia and Physical impairment with advancing Age (SarcoPhAge) Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over courses of 2.4-6 m. Deaths were recorded and verified. Definitions of sarcopenia were as follows: EWGSOP2 (grip strength <27 kg and ALM index <7.0 kg/m2 ), SDOC (grip strength <35.5 kg and gait speed <0.8 m/s) and Modified SDOC (grip strength <35.5 kg and gait speed <1.0 m/s). Cohen's kappa statistic was used to assess agreement between original definitions (EWGSOP2 and SDOC). Presence versus absence of sarcopenia according to each definition in relation to mortality risk was examined using Cox regression with adjustment for age and weight; estimates were combined across cohorts using random-effects meta-analysis. Mean (SD) age of participants (n = 9170) was 74.3 (4.9) years; 5929 participants died during a mean (SD) follow-up of 12.1 (5.5) years. The proportion with sarcopenia according to each definition was EWGSOP2 (1.1%), SDOC (1.7%) and Modified SDOC (5.3%). Agreement was weak between EWGSOP2 and SDOC (κ = 0.17). Pooled hazard ratios (95% CI) for mortality for presence versus absence of each definition were EWGSOP2 [1.76 (1.42, 2.18), I2 : 0.0%]; SDOC [2.75 (2.28, 3.31), I2 : 0.0%]; and Modified SDOC [1.93 (1.54, 2.41), I2 : 58.3%]. There was low prevalence and poor agreement among recent sarcopenia definitions in community-dwelling cohorts of older white men. All indices of sarcopenia were associated with mortality. The strong relationship between sarcopenia and mortality, regardless of the definition, illustrates that identification of appropriate management and lifecourse intervention strategies for this condition is of paramount importance.