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Abstract People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. −10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed. Clinical Trials.gov registration: NCT03743636.

Background Overweight and obesity are associated with adverse functional outcomes in people with peripheral artery disease (PAD). The effects of weight loss in people with overweight/obesity and PAD are unknown. Methods The PROVE (Promote Weight Loss in Obese PAD Patients to Prevent Mobility Loss) Trial is a multicentered randomized clinical trial with the primary aim of testing whether a behavioral intervention designed to help participants with PAD lose weight and walk for exercise improves 6‐minute walk distance at 12‐month follow‐up, compared with walking exercise alone. A total of 212 participants with PAD and body mass index ≥25 kg/m2 will be randomized. Interventions are delivered using a Group Mediated Cognitive Behavioral intervention model, a smartphone application, and individual telephone coaching. The primary outcome is 12‐month change in 6‐minute walk distance. Secondary outcomes include total minutes of walking exercise/wk at 12‐month follow‐up and 12‐month change in accelerometer‐measured physical activity, the Walking Impairment Questionnaire distance score, and the Patient‐Reported Outcomes Measurement Information System mobility questionnaire. Tertiary outcomes include 12‐month changes in perceived exertional effort at the end of the 6‐minute walk, diet quality, and the Short Physical Performance Battery. Exploratory outcomes include changes in gastrocnemius muscle biopsy measures of mitochondrial cytochrome C oxidase activity, mitochondrial biogenesis, capillary density, and inflammatory markers. Conclusions The PROVE randomized clinical trial will evaluate the effects of exercise with an intervention of coaching and a smartphone application designed to achieve weight loss, compared with exercise alone, on walking performance in people with PAD and overweight/obesity. Results will inform optimal treatment for the growing number of patients with PAD who have overweight/obesity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04228978.

BackgroundThe prevention of mobility-related disability amongst adults is a global healthcare priority. Cost-effective community-based strategies to improve physical function and independence in older adults with mobility limitations are needed. This study investigated the effectiveness of the REtirement in ACTion (REACT) exercise intervention on individual markers of physical function at 6-and 12-months.MethodsThe REACT multicentre randomised controlled trial assigned 777 older adults (female, 514; male 263) (mean age 77·6 [SD 6·8] years) with reduced lower limb physical functioning (Short Physical Performance Battery [SPPB] score 4–9) to receive brief healthy ageing advice or a 12-month, group-based, multimodal exercise programme delivered in local communities. Estimated differences in the three individual component scores of the SPPB (strength, balance, gait speed) and physical functional outcomes recorded at 6- and 12-months were assessed.ResultsThe intervention group demonstrated significant improvements in strength (OR = 1.88, 95% CI = 1.36–2.59, p

Background: Mobility limitation in older age reduces quality of life, generates substantial health- and social-care costs, and increases mortality. Objective: The REtirement in ACTion (REACT) trial aimed to establish whether or not a community-based active ageing intervention could prevent decline in physical functioning in older adults already at increased risk of mobility limitation. Design: A multicentre, pragmatic, two-arm, parallel-group randomised controlled trial with parallel process and health economic evaluations. Setting: Urban and semi-rural locations across three sites in England. Participants: Physically frail or pre-frail older adults (aged ≥ 65 years; Short Physical Performance Battery score of 4–9). Recruitment was primarily via 35 primary care practices. Interventions: Participants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal exercise and behavioural maintenance programme delivered in fitness and community centres. Randomisation was stratified by site and used a minimisation algorithm to balance age, sex and Short Physical Performance Battery score. Data collection and analyses were blinded. Main outcome measures: The primary outcome was change in lower limb physical function (Short Physical Performance Battery score) at 24 months, analysed using an intention-to-treat analysis. The economic evaluation adopted the NHS and Personal Social Services perspective. Results: Between June 2016 and October 2017, 777 participants (mean age 77.6 years, standard deviation 6.8 years; 66% female; mean Short Physical Performance Battery score 7.37, standard deviation 1.56) were randomised to the intervention arm (n = 410) or the control arm (n = 367). Data collection was completed in October 2019. Primary outcome data at 24 months were provided by 628 (80.8%) participants. At the 24-month follow-up, the Short Physical Performance Battery score was significantly greater in the intervention arm (mean 8.08, standard deviation 2.87) than in the control arm (mean 7.59, standard deviation 2.61), with an adjusted mean difference of 0.49 (95% confidence interval 0.06 to 0.92). The difference in lower limb function between intervention and control participants was clinically meaningful at both 12 and 24 months. Self-reported physical activity significantly increased in the intervention arm compared with the control arm, but this change was not observed in device-based physical activity data collected during the trial. One adverse event was related to the intervention. Attrition rates were low (19% at 24 months) and adherence was high. Engagement with the REACT intervention was associated with positive changes in exercise competence, relatedness and enjoyment and perceived physical, social and mental well-being benefits. The intervention plus usual care was cost-effective compared with care alone over the 2 years of REACT; the price year was 2019. In the base-case scenario, the intervention saved £103 per participant, with a quality-adjusted life-year gain of 0.04 (95% confidence interval 0.006 to 0.074) within the 2-year trial window. Lifetime horizon modelling estimated that further cost savings and quality-adjusted life-year gains were accrued up to 15 years post randomisation. Conclusion: A relatively low-resource, 1-year multimodal exercise and behavioural maintenance intervention can help older adults to retain physical functioning over a 24-month period. The results indicate that the well-established trajectory of declining physical functioning in older age is modifiable. Limitations: Participants were not blinded to study arm allocation. However, the primary outcome was independently assessed by blinded data collectors. The secondary outcome analyses were exploratory, with no adjustment for multiple testing, and should be interpreted accordingly. Future work: Following refinements guided by the process evaluation findings, the REACT intervention is suitable for large-scale implementation. Further research will optimise implementation of REACT at scale. Trial registration: This trial is registered as ISRCTN45627165. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 14. See the NIHR Journals Library website for further project information.

Summary: Background: Mobility limitations in older populations have a substantial impact on health outcomes, quality of life, and social care costs. The Retirement in Action (REACT) randomised controlled trial assessed a 12-month community-based group physical activity and behaviour maintenance intervention to help prevent decline in physical functioning in older adults at increased risk of mobility limitation. We aimed to do an economic evaluation of the REACT trial to investigate whether the intervention is cost-effective. Methods: In this health economic evaluation, we did cost-effectiveness and cost-utility analyses of the REACT programme versus standard care on the basis of resource use, primary outcome, and health-related quality-of-life data measured in the REACT trial. We also developed a decision analytic Markov model that forecasts the mobility of recipients beyond the 24-month follow-up of the trial and translated this into future costs and potential benefit to health-related quality of life using the National Health Service and Personal Social Services perspective. Participants completed questionnaire booklets at baseline, and at 6, 12, and 24 months after randomisation, which included a resource use questionnaire and the EQ-5D-5L and 36-item short-form survey (SF-36) health-related quality-of-life instruments. The cost of delivering the intervention was estimated by identifying key resources, such as REACT session leader time, time of an individual to coordinate the programme, and venue hire. EQ-5D-5L and SF-36 responses were converted to preference-based utility values, which were used to estimate quality-adjusted life-years (QALYs) over the 24-month trial follow-up using the area-under-the-curve method. We used generalised linear models to examine the effect of the REACT programme on costs and QALYs and adjust for baseline covariates. Costs and QALYs beyond 12 months were discounted at 3·5% per year. This is a pre-planned analysis of the REACT trial; the trial itself is registered with ISRCTN (ISRCTN45627165). Findings: The 12-month REACT programme was estimated to cost £622 per recipient to deliver. The most substantial cost components are the REACT session leader time (£309 per participant), venue hire (£109), and the REACT coordinator time (£80). The base-case analysis of the trial-based economic evaluation showed that reductions in health and social care usage due to the REACT programme could offset the REACT delivery costs (£3943 in the intervention group vs £4043 in the control group; difference: –£103 [95% CI −£695 to £489]) with a health benefit of 0·04 QALYs (0·009–0·071; 1·354 QALYs in the intervention group vs 1·314 QALYs in the control group) within the 24-month timeframe of the trial. Interpretation: The REACT programme could be considered a cost-effective approach for improving the health-related quality of life of older adults at risk of mobility limitations. Funding: National Institute for Health Research Public Health Research Programme.

Summary: Background: Mobility limitations in old age can greatly reduce quality of life, generate substantial health and social care costs, and increase mortality. Through the Retirement in Action (REACT) trial, we aimed to establish whether a community-based active ageing intervention could prevent decline in lower limb physical functioning in older adults already at increased risk of mobility limitation. Methods: In this pragmatic, multicentre, two-arm, single-blind, parallel-group, randomised, controlled trial, we recruited older adults (aged 65 years or older and who are not in full-time employment) with reduced lower limb physical functioning (Short Physical Performance Battery [SPPB] score 4–9) from 35 primary care practices across three sites (Bristol and Bath; Birmingham; and Devon) in England. Participants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal physical activity (64 1-h exercise sessions) and behavioural maintenance (21 45-min sessions) programme delivered by charity and community or leisure centre staff in local communities. Randomisation was stratified by site and adopted a minimisation approach to balance groups by age, sex, and SPPB score, using a centralised, online, randomisation algorithm. Researchers involved in data collection and analysis were masked but participants were not because of the nature of the intervention. The primary outcome was change in SPPB score at 24 months, analysed by intention to treat. This trial is registered with ISRCTN, ISRCTN45627165. Findings: Between June 20, 2016, and Oct 30, 2017, 777 participants (mean age 77·6 [SD 6·8] years; 66% female; mean SPPB score 7·37 [1·56]) were randomly assigned to the intervention (n=410) and control (n=367) groups. Primary outcome data at 24 months were provided by 628 (81%) participants (294 in the control group and 334 in the intervention group). At the 24-month follow-up, the SPPB score (adjusted for baseline SPPB score, age, sex, study site, and exercise group) was significantly greater in the intervention group (mean 8·08 [SD 2·87]) than in the control group (mean 7·59 [2·61]), with an adjusted mean difference of 0·49 (95% CI 0·06–0·92; p=0·014), which is just below our predefined clinically meaningful difference of 0·50. One adverse event was related to the intervention; the most common unrelated adverse events were heart conditions, strokes, and falls. Interpretation: For older adults at risk of mobility limitations, the REACT intervention showed that a 12-month physical activity and behavioural maintenance programme could help prevent decline in physical function over a 24-month period. Funding: National Institute for Health Research Public Health Research Programme (13/164/51).

Background In people with lower‐extremity peripheral artery disease, the effects of exercise on patient‐reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6‐minute walk and the Walking Impairment Questionnaire distance score (score 0–100, 100=best) at baseline and 6‐month follow‐up. Compared with the control group, exercise improved 6‐minute walk distance by +39.8 m (95% CI, 26.8–52.8, P

Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2‐like macrophages positively correlated to satellite cell number (r=0.461 [P=0.023] and r=0.416 [P=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206− macrophages negatively correlated to 4‐meter walk tests at normal (r=−0.447, P=0.036) and fast pace (r=−0.510, P=0.014). Extracellular matrix occupied more muscle area in PAD compared with non‐PAD (8.72±2.19% versus 5.30±1.03%, P

Background Patients with peripheral artery disease (PAD) undergo frequent episodes of ischemia‐reperfusion in lower extremity muscles that may negatively affect mitochondrial health and are associated with impaired mobility. We hypothesized that skeletal muscle from PAD patients will show high mitochondrial DNA heteroplasmy, especially in regions more susceptible to oxidative damage, such as the displacement loop, and that the degree of heteroplasmy will be correlated with the severity of ischemia and mobility impairment. Methods and Results Mitochondrial mutations and deletions and their relative abundance were identified by targeted mitochondrial DNA sequencing in biopsy specimens of gastrocnemius muscle from 33 PAD (ankle brachial index 0.9) subjects aged ≥60 years. The probability of heteroplasmy per DNA base was significantly higher for PAD subjects than non‐PAD within each region. In adjusted models, PAD was associated with higher heteroplasmy than non‐PAD (P=0.003), but the association was limited to microheteroplasmy, that is heteroplasmy found in 1% to 5% of all mitochondrial genomes (P=0.004). Heteroplasmy in the displacement loop and coding regions were significantly higher for PAD than non‐PAD subjects after adjustment for age, sex, race, and diabetes mellitus (P=0.037 and 0.004, respectively). Low mitochondrial damage, defined by both low mitochondrial DNA copy number and low microheteroplasmy, was associated with better walking performance. Conclusions People with PAD have higher “low frequency” heteroplasmy in gastrocnemius muscle compared with people without PAD. Among people with PAD, those who had evidence of least mitochondrial damage, had better walking performance than those with more mitochondrial damage. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02246660.

Abstract Background The REtirement in ACTion (REACT) study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial (RCT) with an internal pilot phase. It aims to test the effectiveness and cost-effectiveness of a community, group-based physical activity intervention for reducing, or reversing, the progression of functional limitations in older people who are at high risk of mobility-related disability. Methods/design A sample of 768 sedentary, community-dwelling, older people aged 65 years and over with functional limitations, but who are still ambulatory (scores between 4 and 9 out of 12 in the Short Physical Performance Battery test (SPPB)) will be randomised to receive either the REACT intervention, delivered over a period of 12 months by trained facilitators, or a minimal control intervention. The REACT study incorporates comprehensive process and economic evaluation and a nested sub-study which will test the hypothesis that the REACT intervention will slow the rate of brain atrophy and of decline in cognitive function assessed using magnetic resonance imaging (MRI). Outcome data will be collected at baseline, 6, 12 and 24 months for the main study, with MRI sub-study data collected at baseline, 6 and 12 months. The primary outcome analysis (SPPB score at 24 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals. Discussion REACT represents the first large-scale, pragmatic, community-based trial in the UK to target the non-disabled but high-risk segment of the older population with an intervention to reduce mobility-related disability. A programme that can successfully engage this population in sufficient activity to improve strength, aerobic capacity, coordination and balance would have a major impact on sustaining health and independence. REACT is also the first study of its kind to conduct a full economic and comprehensive process evaluation alongside the RCT. If effective and cost-effective, the REACT intervention has strong potential to be implemented widely in the UK and elsewhere. Trial registration ISRCTN, ID:ISRCTN45627165. Retrospectively registered on 13 June 2016. Trial sponsor: University of Bath. Protocol Version 1.5.

Background: Physical performance in the older adult has been extensively studied. However, only a few studies have evaluated physical performance among older adults of high Andean populations and none have studied the factors associated with it. The objective of this study was to evaluate factors associated with poor physical performance by using the Short Physical Performance Battery (SPPB) in older adults living in 11 Peruvian high Andean communities. Methods: An analytical cross-sectional study was carried out in inhabitants aged 60 or over from 11 high-altitude Andean communities of Peru during 2013-2017. Participants were categorized in two groups according to their SPPB score: poor physical performance (0-6 points) and medium/good physical performance (7-12 points). Additionally, we collected socio-demographic, medical, functional and cognitive assessment information. Poisson regression models were constructed to identify factors associated with poor physical performance. Prevalence ratio (PR) with 95% confidence intervals (95 CI%) are presented. Results: A total of 407 older adults were studied. The average age was 73.0 ± 6.9 years (range: 60-94 years) and 181 (44.5%) participants had poor physical performance (0-6 points). In the adjusted Poisson regression analysis, the factors associated with poor physical performance were: female gender (PR=1.29; 95%CI: 1.03-1.61), lack of social support (PR=2.10; 95%CI: 1.17-3.76), number of drugs used (PR=1.09; 95%CI: 1.01-1.17), urinary incontinence (PR=1.45; 95%CI: 1.16-1.82), exhaustion (PR=1.35; 95%CI: 1.03-1.75) and cognitive impairment (PR=1.89; 95%CI: 1.40-2.55). Conclusions: Almost half of the population evaluated had poor physical performance based on the SPPB. Factors that would increase the possibility of suffering from poor physical performance were: female gender, lack of social support, number of drugs used, urinary incontinence, exhaustion and cognitive impairment. Future studies with a larger sample and longitudinal follow-up are needed to design beneficial interventions for the high Andean population.

Background/Aims: Clinical trials of older adults are increasingly common, but risks of serious adverse events (SAE) may vary. We describe the incidence of SAE in two randomized trials, one community-based and one nursing home-based. Methods: We performed a secondary data analysis from two randomized clinical trials at one academic health center and 21 nursing homes involving 200 sedentary community dwellers aged 70–89 years and 185 female nursing home residents aged 65 years or older. Interventions included structured physical activity to reduce mobility disability in the Lifestyle Interventions and Independence for Elders (LIFE) study and oral cranberry capsules to reduce bacteriuria plus pyuria in nursing home residents (CRANNY) trial. We measured SAE incidence per 100 person-years and incidence of protocol-related unanticipated SAE per 100 person-years in LIFE and CRANNY trials. Results: Mean age and proportion of patients with dementia in LIFE and CRANNY trials were 79.3 years and 86.4 years and 0% and 78%, respectively. There were 179 total SAE in LIFE including 8 (4%) deaths, and 116 total SAE in CRANNY including 33 (28%) deaths. SAE incidence was 33.7 (95% CI 27.2, 41.8) events per 100 person-years in LIFE and 69.4 (95% CI 49.1, 98.1) events per 100 person-years in CRANNY. No protocol-related unanticipated SAE occurred in either trial. Conclusions: The frequency and severity of SAE vary in older adults. While SAE are common in nursing home residents, protocol-related, unanticipated SAE are rare in nursing home residents and community dwellers. This finding can inform trial monitoring protocols. Trial registration: ClinicalTrials.gov identifiers: NCT01072500 and NCT01691430.

Abstract Background Improving physical functioning may be a future intervention to keep older adults driving safely longer as it can help maintain both physical and cognitive health longer. This systematic review assesses the evidence on the association between three physical functioning measures: the Short Physical Performance Battery, the Timed Up-and-Go test, and the Rapid Pace Walk with driving outcomes in older adults. Methods Older adult studies published between 1994 and 2015 that included the Short Physical Performance Battery, the Timed Up-and-Go test, or the Rapid Pace Walk as a measure of physical functioning and included a driving-related outcome were identified through a comprehensive search and reviewed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results Thirteen studies involving 5,313 older adults met the inclusion criteria. Lower Short Physical Performance Battery scores were associated with reduced driving exposure and increased cessation in all three Short Physical Performance Battery studies. The Timed Up-and-Go test was not associated with the driving outcomes (cessation, ability, crashes, and citations) in either of the two Timed Up-and-Go studies. Poorer Rapid Pace Walk scores were associated with decreased driving ability in two studies and with reduced driving exposure in one study, but not associated with driving ability, crashes, citations, or cessation in the remaining five Rapid Pace Walk studies. Conclusions The Timed Up-and-Go test measure appears not to be a useful measure of physical functioning for the driving outcomes included here. The Rapid Pace Walk may be useful in studies of driving ability and exposure. More driving studies should consider using the Short Physical Performance Battery to determine if it may be useful as a risk factor assessment for identifying individuals at risk of certain driving outcomes.

Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle‐brachial index

Aging is a primary risk factor for the progressive loss of function, disease onset, and increased vulnerability to negative health-related outcomes. These clinical manifestations arise in part from declines in mitochondrial, metabolic, and other processes considered to be hallmarks of aging. Collectively, these changes can be defined as age-associated cellular decline (AACD) and are often associated with fatigue, reduced strength, and low physical activity. This manuscript summarizes a recent Gerontological Society of America Annual Scientific Meeting symposium that explored mechanisms, clinical signs, and emerging cellular nutrition interventions for AACD. The session opened by highlighting results of an expert consensus that developed an initial framework to identify self-reported symptoms and observable signs of AACD in adults aged >50 years. Next, findings from the multi-ethnic molecular determinants of sarcopenia study were discussed, showing impaired mitochondrial bioenergetic capacity and NAD+ metabolism in skeletal muscle of older adults with sarcopenia. Lastly, recent clinical evidence was presented linking urolithin A, a natural mitophagy activator, to improved mitochondrial and cellular health. The virtual panel discussed how stimulation of mitochondrial function via biological pathways, such as mitophagy and NAD+ augmentation, could improve cellular function and muscle health, potentially impacting clinical signs of AACD and overall healthy aging.

Background: Physical performance in the older adult has been extensively studied. However, only a few studies have evaluated physical performance among older adults of high Andean populations and none have studied the factors associated with it. The objective of this study was to evaluate factors associated with poor physical performance by using the Short Physical Performance Battery (SPPB) in older adults living in 11 Peruvian high Andean communities. Methods: An analytical cross-sectional study was carried out in inhabitants aged 60 or over from 11 high-altitude Andean communities of Peru during 2013-2017. Participants were categorized in two groups according to their SPPB score: poor physical performance (0-6 points) and medium/good physical performance (7-12 points). Additionally, we collected socio-demographic, medical, functional and cognitive assessment information. Poisson regression models were constructed to identify factors associated with poor physical performance. Prevalence ratio (PR) with 95% confidence intervals (95 CI%) are presented. Results: A total of 407 older adults were studied. The average age was 73.0 ± 6.9 years (range: 60-94 years) and 181 (44.5%) participants had poor physical performance (0-6 points). In the adjusted Poisson regression analysis, the factors associated with poor physical performance were: female gender (PR=1.29; 95%CI: 1.03-1.61), lack of social support (PR=2.10; 95%CI: 1.17-3.76), number of drugs used (PR=1.09; 95%CI: 1.01-1.17), urinary incontinence (PR=1.45; 95%CI: 1.16-1.82), exhaustion (PR=1.35; 95%CI: 1.03-1.75) and cognitive impairment (PR=1.89; 95%CI: 1.40-2.55). Conclusions: Almost half of the population evaluated had poor physical performance based on the SPPB. Factors that would increase the possibility of suffering from poor physical performance were: female gender, lack of social support, number of drugs used, urinary incontinence, exhaustion and cognitive impairment. Future studies with a larger sample and longitudinal follow-up are needed to design beneficial interventions for the high Andean population.

Abstract Background Among older persons, disability is often precipitated by intervening illnesses and injuries leading to hospitalization. In the Lifestyle Interventions and Independence for Elders (LIFE) Study, a structured moderate-intensity physical activity program, compared with a health education program, was shown to significantly reduce the amount of time spent with major mobility disability (MMD) over the course of 3.5 years. We aimed to determine whether the benefit of the physical activity program in promoting independent mobility was diminished in the setting of intervening hospitalizations. Methods We analyzed data from a single-blinded, parallel group randomized trial (ClinicalTrials.gov: NCT01072500). In this trial, 1635 sedentary persons, aged 70–89 years, who had functional limitations but were able to walk 400 m, were randomized from eight US centers between February 2010 and December 2013: 818 to physical activity (800 received intervention) and 817 to health education (805 received intervention). Intervening hospitalizations and MMD, defined as the inability to walk 400 m, were assessed every 6 months for up to 3.5 years. Results For both the physical activity and health education groups, intervening hospitalizations were strongly associated with the initial onset of MMD and inversely associated with recovery from MMD, defined as a transition from initial MMD onset to no MMD. The benefit of the physical activity intervention did not differ significantly based on hospital exposure. For onset of MMD, the hazard ratios (HR) were 0.79 (95% confidence interval [CI] 0.58–1.1) and 0.77 (0.62–0.95) in the presence and absence of intervening hospitalizations, respectively (P-interaction, 0.903). For recovery of MMD, the magnitude of effect was modestly greater among participants who were hospitalized (HR 1.5, 95% CI 0.71–3.0) than in those who were not hospitalized (HR 1.2, 95% CI 0.88–1.7), but this difference did not achieve statistical significance (P-interaction, 0.670). Conclusions Intervening hospitalizations had strong deleterious effects on the onset of MMD and recovery from MMD, but did not diminish the beneficial effect of the LIFE physical activity intervention in promoting independent mobility. To achieve sustained benefits over time, structured physical activity programs should be designed to accommodate acute illnesses and injuries leading to hospitalizations given their high frequency in older persons with functional limitations. Trial registration ClinicalTrials.gov identifier NCT01072500 .

Abstract Background Continued automobile driving is important for the wellbeing and independence of older adults. Frailty has been associated with a variety of negative health outcomes, but studies are lacking on the potential association between frailty and driving status. The present study uses data from The National Health and Aging Trends Study (NHATS) to assess if the presence of frailty is associated with being a current non-driver. Methods NHATS is a nationally representative cohort study of Medicare beneficiaries (aged ≥65) that have been followed since 2011. We examined frailty status at baseline (Fried’s frailty phenotype) and driving status over 4 years (from 2011 to 2014) excluding never drivers at baseline. Multivariable Poisson regression was used to obtain incidence rate ratios, adjusting for covariates and clustering. To account for the repeated measures in the data collection, generalized estimating equations (GEE) were employed. Results A significant association between baseline frailty and driving status was observed at all four time points. At T4, frail participants at baseline had an incidence rate for becoming a current non-driver 1.80 times (or an 80% increase) that of non-frail participants at baseline (adjusted 95% confidence interval (CI) 1.56–2.07). Conclusions Frailty was associated with an increased rate of being a current non-driver. Based on this association, we posit that screening for and intervening on frailty may help certain older adults who are at risk for becoming a current non-driver to remain on the road longer.

Background The effects of race on response to medical therapy in people with peripheral artery disease (PAD) are unknown. Methods and Results In the PROPEL (Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD) Trial, PAD participants were randomized to 1 of 4 groups for 6 months: supervised treadmill exercise+granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) (Group 1), exercise+placebo (Group 2), attention control+GM‐CSF (Group 3), or attention control+placebo (Group 4). Change in 6‐minute walk distance was measured at 12‐ and 26‐week follow‐up. In these exploratory analyses, groups receiving GM‐CSF (Groups 1 and 3), placebo (Groups 2 and 4), exercise (Groups 1 and 2), and attention control (Groups 2 and 4) were combined, maximizing statistical power for studying the effects of race on response to interventions. Of 210 PAD participants, 141 (67%) were black and 64 (30%) were white. Among whites, GM‐CSF improved 6‐minute walk distance by +22.0 m (95% CI: −4.5, +48.5, P=0.103) at 12 weeks and +44.4 m (95% CI: +6.9, +82.0, P=0.020) at 26 weeks, compared with placebo. Among black participants, there was no effect of GM‐CSF on 6‐minute walk distance at 12‐week (P=0.26) or 26‐week (−5.0 m [−27.5, +17.5, P=0.66]) follow‐up, compared with placebo. There was an interaction of race on the effect of GM‐CSF on 6‐minute walk change at 26‐week follow‐up (P=0.018). Exercise improved 6‐minute walk distance in black (P=0.006) and white (P=0.034) participants without interaction. Conclusions GM‐CSF improved 6‐minute walk distance in whites with PAD but had no effect in black participants. Further study is needed to confirm racial differences in GM‐CSF efficacy in PAD. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01408901.

Background It is currently unknown whether 6 months of supervised treadmill exercise has a durable benefit on 6‐minute walk performance, even after exercise is completed, in people with peripheral artery disease. Methods and Results A total of 156 participants with peripheral artery disease were randomized to 1 of 3 groups: supervised treadmill exercise, supervised resistance training, or attention control. Participants received supervised sessions during months 1 to 6 and telephone contact during months 6 to 12. Primary outcomes were change in 6‐minute walk distance and short physical performance battery at 6‐month follow‐up and have been reported previously. Secondary outcomes were change in 6‐minute walk and short physical performance battery at 12‐month follow‐up and are reported here. A group of 134 participants (86%) completed the 12‐month follow‐up. At 6‐month follow‐up, compared with control, 6‐minute walk distance improved in the treadmill exercise group (+36.1 m, 95% CI=13.9‐58.3, P=0.001). Between 6‐ and 12‐month follow‐up, 6‐minute walk distance significantly declined (−28.6 m, 95% CI=−52.6 to −4.5, P=0.020) and physical activity declined −272 activity units (95% CI=−546 to +2, P=0.052) in the treadmill exercise group compared with controls. At 12‐month follow‐up, 6 months after completing supervised treadmill exercise, change in 6‐minute walk distance was not different between the treadmill exercise and control groups (+7.5, 95% CI=−17.5 to +32.6, P=0.56). There were no differences in short physical performance battery change between either exercise group and control at 6‐month or 12‐month follow‐up. Conclusions A 6‐month supervised treadmill exercise intervention that improved 6‐minute walk distance at 6‐month follow‐up did not have persistent benefit at 12‐month follow‐up. These results do not support a durable benefit of supervised treadmill exercise in peripheral artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Identifier: NCT00106327.

Physical capability (PC) is conventionally evaluated through performance-based clinical assessments. We aimed to transform a battery of sensor-based functional tests into a clinically applicable assessment tool. We used Exploratory Factor Analysis (EFA) to uncover the underlying latent structure within sensor-based measures obtained in a population-based study. Three hundred four community-dwelling older adults (163 females, 80.9 ± 6.4 years), underwent three functional tests (Quiet Stand, QS, 7-meter Walk, 7MW and Chair Stand, CST) wearing a smartphone at the lower back. Instrumented tests provided 73 sensor-based measures, out of which EFA identified a fifteen-factor model. A priori knowledge and the associations with health-related measures supported the functional interpretation and construct validity analysis of the factors, and provided the basis for developing a conceptual model of PC. For example, the “Walking Impairment„ domain obtained from the 7MW test was significantly associated with measures of leg muscle power, gait speed, and overall lower extremity function. To the best of our knowledge, this is the first time that a battery of functional tests, instrumented through a smartphone, is used for outlining a sensor-based conceptual model, which could be suitable for assessing PC in older adults and tracking its changes over time.

While the relationship between total cholesterol (TC) and cardiovascular disease (CVD) progressively weakens with aging, several studies have shown that low TC is associated with increased mortality in older individuals. However, the possible additive/synergic contribution of the two most important cholesterol rich fractions (LDL-C and HDL-C) to mortality risk has not been previously investigated. Our study aimed to investigate the relationship between baseline LDL-C and HDL-C, both separately and combined, and 9-years mortality in a sample of community dwelling older individuals from the InCHIANTI study.1044 individuals over 64 years were included. CVD and cancer mortality were defined by ICD-9 codes 390-459 and 140-239, respectively. LDL-C

Understanding the minimal dose of physical activity required to achieve improvement in physical functioning and reductions in disability risk is necessary to inform public health recommendations. To examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability in The Lifestyle Interventions and Independence for Elders (LIFE) Study. We conducted a multicenter single masked randomized controlled trial that enrolled participants in 2010 and 2011 and followed them for an average of 2.6 years. 1,635 sedentary men and women aged 70-89 years who had functional limitations were randomized to a structured moderate intensity walking, resistance, and flexibility physical activity program or a health education program. Physical activity dose was assessed by 7-day accelerometry and self-report at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery (SPPB), assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and SPPB from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability (overall P < 0.001) (highest versus the lowest quartile of physical activity change HR 0.23 ((95% CI:0.10-0.52) P = 0.001) in the physical activity arm. We observed a dose-dependent effect of objectively monitored physical activity on physical functioning and onset of major mobility disability. Relatively small increases (> 48 minutes per week) in regular physical activity participation had significant and clinically meaningful effects on these outcomes.ClinicalsTrials.gov NCT00116194.

BackgroundWe compared the incidence of depression, defined by a Geriatric Depression Score (GDS) ≥6, between people with versus without peripheral artery disease (PAD). We determined whether depressive symptoms were associated with increased mortality in people with and without PAD. Methods and ResultsNine hundred and fifty‐one PAD patients and 478 non‐PAD patients were recruited from Chicago medical centers and followed prospectively. At baseline and annually, participants completed the GDS (0–15 scale, score ≥6=depression) and 6‐minute walk. Cause of death was confirmed with death certificates. The prevalence of a GDS ≥6 at baseline was 186/951 (19.6%) among PAD versus 63/478 (13.2%) among non‐PAD participants (P=0.003). During a mean follow‐up of 2.7±1.2 years, 122/712 (17.1%) of participants with PAD versus 51/403 (12.7%) without PAD developed a GDS ≥6 (P=0.047). Adjusting for age, sex, race, comorbidities, and other confounders, PAD participants had an increased rate of developing a GDS ≥6 compared to non‐PAD participants (hazard ratio=1.54 (95% CI=1.05–2.25, P=0.026). This association was not statistically significant after adjusting for 6‐minute walk (P=0.258). Among PAD participants, a baseline GDS ≥6 was associated with increased all‐cause mortality, adjusting for confounders (hazard ratio=1.57, 95% CI=1.12–2.21, P=0.009). This association was not significant after adjusting for 6‐minute walk (P=0.224). ConclusionsPeople with PAD have a higher incidence of depressive symptoms than people without PAD. In PAD, depressive symptoms are associated with increased all‐cause and cardiovascular mortality. These associations are explained in part by poorer 6‐minute walk among people with PAD and among depressed people with PAD, respectively.

Background Few medical therapies improve lower extremity functioning in people with lower extremity peripheral artery disease (PAD). Among people with PAD, we studied whether a group‐mediated cognitive behavioral intervention promoting home‐based unsupervised exercise prevented mobility loss and improved functional performance compared to control. Methods and Results One hundred ninety‐four PAD participants were randomized. During months 1 to 6, the intervention group met weekly with other PAD participants and a facilitator. Group support and self‐regulatory skills were used to help participants adhere to walking exercise. Ninety‐percent of exercise was conducted at or near home. The control group attended weekly lectures. During months 6 to 12, each group received telephone contact only. Primary outcomes have been reported. Here we compare changes in exploratory outcomes of mobility loss (the inability to climb a flight of stairs or walk one‐quarter mile without assistance), walking velocity, and the Short Physical Performance Battery. Compared to controls, fewer participants randomized to the intervention experienced mobility loss at 6‐month follow‐up: 6.3% versus 26.5%, P=0.002, odds ratio=0.19 (95% CI=0.06 to 0.58) and at 12‐month follow‐up: 5.2% versus 18.5%, P=0.029, odds ratio=0.24 (95% CI=0.06 to 0.97). The intervention improved fast‐paced 4‐m walking velocity at 6‐month follow‐up (P=0.005) and the Short Physical Performance Battery at 12‐month follow‐up (P=0.027), compared to controls. Conclusions In exploratory analyses, a group‐mediated cognitive behavioral intervention promoting unsupervised walking exercise prevented mobility loss and improved functioning at 6‐ and 12‐month follow‐up in PAD patients. Clinical Trial Registration URL: http://clinicaltrials.gov. Unique identifier: NCT00693940.