Long-term Changes in Body Composition and Exercise Capacity Following Calorie Restriction and Exercise Training in Older Patients with Obesity and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Obesity combined with heart failure with preserved ejection fraction (HFpEF) is the dominant form of HF among older persons. In a randomized trial, we previously showed that a 5-month calorie restriction (CR) program, with or without aerobic exercise training (AT), resulted in significant weight and fat loss and improved exercise capacity. However, little is known regarding the long-term effects of these outcomes after a short-term (5-month) intervention of CR with or without AT in older patients with obesity and HFpEF. METHODS: Sixteen participants from either the CR or CR+AT who experienced significant weight loss ≥ 2 kg were reexamined after a long-term follow-up endpoint (28.0 ± 10.8 months) without intervention. The follow-up assessment included body weight and composition via dual-energy X-ray absorptiometry and exhaustive cardiopulmonary treadmill exercise testing. RESULTS: Compared to the 5-month time-point intervention endpoint, at the long-term follow-up endpoint, mean body weight increased +5.2 ± 4.0 kg (90.7 ± 11.2 kg vs 95.9 ± 11.9; P < 0.001) due to increased fat mass (38.9 ± 9.3 vs 43.8 ± 9.8; P < 0.001) with no change in lean mass (49.6 ± 7.1 vs 49.9±7.6; P = 0.67), resulting in worse body composition (decreased lean-to-fat mass). Change in total mass was strongly and significantly correlated with change in fat mass (r = 0.75; P < 0.001), whereas there appeared to be a weaker correlation with change in lean mass (r = 0.50; P = 0.051). Additionally, from the end of the 5-month time-point intervention endpoint to the long-term follow-up endpoint, there were large, significant decreases in VO2peak (-2.2 ± 2.1 mL/kg/min; P = 0.003) and exercise time (-2.4 ± 2.6 min; P = 0.006). There appeared to be an inverse correlation between the change in VO2peak and the change in fat mass (r = -0.52; P = 0.062). CONCLUSION: Although CR and CR+AT in older patients with obesity and HFpEF can improve body composition and exercise capacity significantly, these positive changes diminish considerably during long-term follow-up endpoints, and regained weight is predominantly adipose, resulting in worsened overall body composition compared to baseline. This suggests a need for long-term adherence strategies to prevent weight regain and maintain improvements in body composition and exercise capacity following CR in older patients with obesity and HFpEF.

The impact of Dietary Weight loss, Aerobic Exercise, and Daylong Movement on Social Cognitive Mediators of Long-term Weight loss.

This report contrasts the impact of a dietary weight loss intervention (WL) paired with aerobic exercise (EX) and/or sitting less and moving throughout the day (SL) on self-efficacy for walking (hereafter walking self-efficacy) and satisfaction with physical functioning (hereafter satisfaction). Additional analyses examined dose-response associations between change in weight and changes in these key outcomes. Older adults (N = 112; age = 70.21[Formula: see text]4.43) were randomized to 6 months of WL+EX, WL+SL, or WL+EX+SL followed by a 12-month maintenance period. All groups reported increases in walking self-efficacy at month 6 with greater improvements in WL+EX and WL + EX+SL. Only WL+SL demonstrated improved walking self-efficacy at month 18. All conditions demonstrated improved satisfaction scores at both time points. Changes in walking self-efficacy and satisfaction were negatively associated with change in weight over the 6-month intervention and after the maintenance period. These results support the utility of WL + SL for improving key social cognitive outcomes in aging.

Effects of Exercise and Weight Loss on Proximal Aortic Stiffness in Older Adults With Obesity.

BACKGROUND: Obesity may accelerate age-related increases in aortic stiffness. Although aerobic exercise training generally has favorable effects on aortic structure and function, exercise alone may not be sufficient to improve aortic stiffness in older adults with obesity. We determined the effects of aerobic exercise training with and without moderate- to high-caloric restriction (CR) on the structure and function of the proximal aorta in 160 older (65-79 years) men and women with obesity (body mass index=30-45 kg/m2). METHODS: Participants were randomly assigned to 1 of 3 groups: aerobic exercise training only (treadmill 4 days/week for 30 minutes at 65% to 70% of heart rate reserve; n=56), aerobic exercise training plus moderate CR (n=55), or aerobic exercise training plus more intensive CR (n=49) for 20 weeks. Aortic pulse wave velocity, aortic distensibility, and other measures of aortic structure and function were assessed by cardiovascular magnetic resonance imaging. Pearson correlation coefficients were examined to assess associations between changes in proximal aortic stiffness and changes in fitness, fatness, and other potential confounders. RESULTS: Weight loss in the aerobic exercise training plus moderate CR (-8.0 kg [95% CI, -9.17 to -6.87]) and aerobic exercise training plus more intensive CR (-8.98 kg [95% CI, -10.23 to -7.73) groups was significantly greater compared with the aerobic exercise training-only group (-1.66 kg [95% CI, -2.94 to -0.38]; P<0.017 for both). There were significant treatment effects for descending aorta distensibility (P=0.008) and strain (P=0.004) and aortic arch pulse wave velocity (P=0.01) with the aerobic exercise training plus moderate CR group having a 21% increase in distensibility (P=0.016) and an 8% decrease in pulse wave velocity (P=0.058). None of the aortic stiffness measures changed significantly in the aerobic exercise training-only or aerobic exercise training plus more intensive CR groups, and there were no significant changes in any other measure of aortic structure or function in these groups. Overall, increases in aortic distensibility were correlated with improvements in body weight and body fat distribution, but these associations were not statistically significant after adjustment for multiple comparisons. CONCLUSIONS: In older adults with obesity, combining aerobic exercise with moderate CR leads to greater improvements in proximal aortic stiffness than exercise alone. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01048736.

Six-month changes in ghrelin and glucagon-like peptide-1 with weight loss are unrelated to long-term weight regain in obese older adults.

BACKGROUND AND OBJECTIVE: Weight loss (WL) and subsequent regain are complex physiologic processes, and our understanding of the hormonal changes associated with these processes continues to evolve. We aimed to examine the effects of behavioral WL on 6-month changes in ghrelin and GLP-1 and evaluate the effects of these changes in gut hormones on weight regain among older adults. SUBJECTS AND METHODS: One hundred seventy-seven obese (BMI: 33.5 (3.5) kg/m2) older adults (66.9 ± 4.7 years, 71.2% female, 67.6% white) were randomized to WL (WL; n = 68), WL plus aerobic training (n = 79), or WL plus resistance training (n = 75) for 18 months. Ghrelin, GLP-1, power of food scale (PFS), and weight were measured at baseline, 6 months, and 18 months. RESULTS: There was no differential treatment effect on change in either gut hormone, however, there was a significant time effect across all groups (p < 0.001), with increases in ghrelin (∆ = +106.77 pg/ml; 95% CI = + 84.82, +128.71) and decreases in GLP-1 (∆ = -4.90 pM; 95% CI = -6.27, -3.51) at 6-month. Ratings on the PFS decreased from baseline to 6-month and there was significant loss of weight from baseline to either 6- or 18-month, ∆ = -7.96 kg; 95% CI = -7.95, -8.78 and ∆ = -7.80 kg; 95% CI = -8.93, -6.65, respectively (p < 0.001). Changes in ghrelin and GLP-1 at 6-month did not predict weight regain from 6- to 18-month. DISCUSSION AND CONCLUSION: Among older adults with obesity and cardiometabolic disease, the intensive phase of dietary WL results in increasing levels of ghrelin and decreasing levels of GLP-1 that are unrelated to weight regain a year later. Registered with ClinicalTrials.gov (NCT01547182).

Effect of High-Intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Adults With Knee Osteoarthritis: The START Randomized Clinical Trial.

Importance: Thigh muscle weakness is associated with knee discomfort and osteoarthritis disease progression. Little is known about the efficacy of high-intensity strength training in patients with knee osteoarthritis or whether it may worsen knee symptoms. Objective: To determine whether high-intensity strength training reduces knee pain and knee joint compressive forces more than low-intensity strength training and more than attention control in patients with knee osteoarthritis. Design, Setting, and Participants: Assessor-blinded randomized clinical trial conducted at a university research center in North Carolina that included 377 community-dwelling adults (≥50 years) with body mass index (BMI) ranging from 20 to 45 and with knee pain and radiographic knee osteoarthritis. Enrollment occurred between July 2012 and February 2016, and follow-up was completed September 2017. Interventions: Participants were randomized to high-intensity strength training (n = 127), low-intensity strength training (n = 126), or attention control (n = 124). Main Outcomes and Measures: Primary outcomes at the 18-month follow-up were Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) knee pain (0 best-20 worst; minimally clinically important difference [MCID, 2]) and knee joint compressive force, defined as the maximal tibiofemoral contact force exerted along the long axis of the tibia during walking (MCID, unknown). Results: Among 377 randomized participants (mean age, 65 years; 151 women [40%]), 320 (85%) completed the trial. Mean adjusted (sex, baseline BMI, baseline outcome values) WOMAC pain scores at the 18-month follow-up were not statistically significantly different between the high-intensity group and the control group (5.1 vs 4.9; adjusted difference, 0.2; 95% CI, -0.6 to 1.1; P = .61) or between the high-intensity and low-intensity groups (5.1 vs 4.4; adjusted difference, 0.7; 95% CI, -0.1 to 1.6; P = .08). Mean knee joint compressive forces were not statistically significantly different between the high-intensity group and the control group (2453 N vs 2512 N; adjusted difference, -58; 95% CI, -282 to 165 N; P = .61), or between the high-intensity and low-intensity groups (2453 N vs 2475 N; adjusted difference, -21; 95% CI, -235 to 193 N; P = .85). There were 87 nonserious adverse events (high-intensity, 53; low-intensity, 30; control, 4) and 13 serious adverse events unrelated to the study (high-intensity, 5; low-intensity, 3; control, 5). Conclusions and Relevance: Among patients with knee osteoarthritis, high-intensity strength training compared with low-intensity strength training or an attention control did not significantly reduce knee pain or knee joint compressive forces at 18 months. The findings do not support the use of high-intensity strength training over low-intensity strength training or an attention control in adults with knee osteoarthritis. Trial Registration: ClinicalTrials.gov Identifier: NCT01489462.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty.

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age.

Impact of Diet and/or Exercise Intervention on Infrapatellar Fat Pad Morphology: Secondary Analysis from the Intensive Diet and Exercise for Arthritis (IDEA) Trial.

OBJECTIVES: The infrapatellar fat pad (IPFP) represents intra-articular adipose tissue that may contribute to intra-articular inflammation and pain by secretion of proinflammatory cytokines. Here we examined the impact of weight loss by diet and/or exercise interventions on the IPFP volume. METHODS: Intensive Diet and Exercise for Arthritis (IDEA) was a single-blinded, single-center, 18-month, prospective, randomized controlled trial that enrolled 454 overweight and obese older adults with knee pain and radiographic osteoarthritis. Participants were randomized to 1 of 3 groups: exercise-only control (E), diet-induced weight loss (D), and diet-induced weight loss + exercise (D+E). In a subsample (n = 106; E: n = 36, D: n = 35, and D+E: n = 35), magnetic resonance images were acquired at baseline and at the 18-month follow-up, from which we analyzed IPFP volume, surface areas, and thickness in this secondary analysis. RESULTS: The average weight loss amounted to 1.0% in the E group, 10.5% in the D group, and 13.0% in the D+E group. A significant (p < 0.01) reduction in IPFP volume was observed in the E (2.1%), D (4.0%), and D+E (5.2%) groups. The IPFP volume loss in the D+E group was significantly greater than that in the E group (p < 0.05) when not adjusting for parallel comparisons. Across intervention groups, there were significant correlations between IPFP volume change, individual weight loss (r = 0.40), and change in total body fat mass (dual-energy X-ray absorptiometry; r = 0.44, n = 88) and in subcutaneous thigh fat area (computed tomography; r = 0.32, n = 82). CONCLUSIONS: As a potential link between obesity and knee osteoarthritis, the IPFP was sensitive to intervention by diet and/or exercise, and its reduction was correlated with changes in weight and body fat.

Gait speed response to aerobic versus resistance exercise training in older adults.

BACKGROUND: Little is known about the comparative effect of aerobic training (AT) versus resistance training (RT) on gait speed, a strong predictor of disability. AIMS: To compare the effect of AT versus RT on gait speed and other functional measures. METHODS: Overweight and obese [body mass index (BMI) ≥27.0 kg/m2] sedentary men and women aged 65-79 years engaged in 5 months of either 4 days/weeks moderate-intensity treadmill walking, AT, (n = 44) or 3 days/weeks moderate-intensity RT (n = 56). Usual-pace gait speed, fast-pace gait speed and short physical performance battery (SPPB) were evaluated in all participants before and after training. Peak oxygen consumption (VO2peak) was assessed in AT participants only, and knee extensor strength was assessed in RT participants. RESULTS: Both AT and RT resulted in clinically significant improvements in usual-pace gait speed (0.08 ± 0.14 and 0.08 ± 0.17 m/s, respectively, both p < 0.05) and SPPB (0.53 ± 1.40 and 0.53 ± 1.20 points, both p < 0.05) and chair rise time (-1.2 ± 3.2 and -1.7 ± 3.0 s, p < 0.05). Only AT improved fast-pace gait speed (0.11 ± 0.10 m/s, p < 0.05). In the RT participants, lower baseline knee strength was associated with less improvement in usual-pace gait speed. In AT participants, lower baseline VO2peak was associated with less improvement in chair rise time and self-reported disability. DISCUSSION: While both AT and RT improved usual-pace gait speed, only AT improved fast-pace gait speed. Lower baseline fitness was associated with less improvement with training. CONCLUSION: Research to directly compare which mode of training elicits the maximum improvement in older individuals with specific functional deficits could lead to better intervention targeting.

Impact of methods used to express levels of circulating fatty acids on the degree and direction of associations with blood lipids in humans.

Numerous studies have examined relationships between disease biomarkers (such as blood lipids) and levels of circulating or cellular fatty acids. In such association studies, fatty acids have typically been expressed as the percentage of a particular fatty acid relative to the total fatty acids in a sample. Using two human cohorts, this study examined relationships between blood lipids (TAG, and LDL, HDL or total cholesterol) and circulating fatty acids expressed either as a percentage of total or as concentration in serum. The direction of the correlation between stearic acid, linoleic acid, dihomo-γ-linolenic acid, arachidonic acid and DHA and circulating TAG reversed when fatty acids were expressed as concentrations v. a percentage of total. Similar reversals were observed for these fatty acids when examining their associations with the ratio of total cholesterol:HDL-cholesterol. This reversal pattern was replicated in serum samples from both human cohorts. The correlations between blood lipids and fatty acids expressed as a percentage of total could be mathematically modelled from the concentration data. These data reveal that the different methods of expressing fatty acids lead to dissimilar correlations between blood lipids and certain fatty acids. This study raises important questions about how such reversals in association patterns impact the interpretation of numerous association studies evaluating fatty acids and their relationships with disease biomarkers or risk.

Aerobic Exercise for Reducing Migraine Burden: Mechanisms, Markers, and Models of Change Processes.

BACKGROUND: Engagement in regular exercise routinely is recommended as an intervention for managing and preventing migraine, and yet empirical support is far from definitive. We possess at best a weak understanding of how aerobic exercise and resulting change in aerobic capacity influence migraine, let alone the optimal parameters for exercise regimens as migraine therapy (eg, who will benefit, when to prescribe, optimal types, and doses/intensities of exercise, level of anticipated benefit). These fundamental knowledge gaps critically limit our capacity to deploy exercise as an intervention for migraine. OVERVIEW: Clear articulation of the markers and mechanisms through which aerobic exercise confers benefits for migraine would prove invaluable and could yield insights on migraine pathophysiology. Neurovascular and neuroinflammatory pathways, including an effect on obesity or adiposity, are obvious candidates for study given their role both in migraine as well as the changes known to accrue with regular exercise. In addition to these biological pathways, improvements in aerobic fitness and migraine alike also are mediated by changes in psychological and sociocognitive factors. Indeed a number of specific mechanisms and pathways likely are operational in the relationship between exercise and migraine improvement, and it remains to be established whether these pathways operate in parallel or synergistically. As heuristics that might conceptually benefit our research programs here forward, we: (1) provide an extensive listing of potential mechanisms and markers that could account for the effects of aerobic exercise on migraine and are worthy of empirical exploration and (2) present two exemplar conceptual models depicting pathways through which exercise may serve to reduce the burden of migraine. CONCLUSION: Should the promise of aerobic exercise as a feasible and effective migraine therapy be realized, this line of endeavor stands to benefit migraineurs (including the many who presently remain suboptimally treated) by providing a new therapeutic avenue as an alternative or augmentative compliment to established interventions for migraine.

Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial.

IMPORTANCE: More than 80% of patients with heart failure with preserved ejection fraction (HFPEF), the most common form of heart failure among older persons, are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL). OBJECTIVE: To determine whether caloric restriction (diet) or aerobic exercise training (exercise) improves exercise capacity and QOL in obese older patients with HFPEF. DESIGN, SETTING, AND PARTICIPANTS: Randomized, attention-controlled, 2 × 2 factorial trial conducted from February 2009 through November 2014 in an urban academic medical center. Of 577 initially screened participants, 100 older obese participants (mean [SD]: age, 67 years [5]; body mass index, 39.3 [5.6]) with chronic, stable HFPEF were enrolled (366 excluded by inclusion and exclusion criteria, 31 for other reasons, and 80 declined participation). INTERVENTIONS: Twenty weeks of diet, exercise, or both; attention control consisted of telephone calls every 2 weeks. MAIN OUTCOMES AND MEASURES: Exercise capacity measured as peak oxygen consumption (V̇O2, mL/kg/min; co-primary outcome) and QOL measured by the Minnesota Living with Heart Failure (MLHF) Questionnaire (score range: 0-105, higher scores indicate worse heart failure-related QOL; co-primary outcome). RESULTS: Of the 100 enrolled participants, 26 participants were randomized to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 participants completed the trial. Exercise attendance was 84% (SD, 14%) and diet adherence was 99% (SD, 1%). By main effects analysis, peak V̇O2 was increased significantly by both interventions: exercise, 1.2 mL/kg body mass/min (95% CI, 0.7 to 1.7), P < .001; diet, 1.3 mL/kg body mass/min (95% CI, 0.8 to 1.8), P < .001. The combination of exercise + diet was additive (complementary) for peak V̇O2 (joint effect, 2.5 mL/kg/min). There was no statistically significant change in MLHF total score with exercise and with diet (main effect: exercise, -1 unit [95% CI, -8 to 5], P = .70; diet, -6 units [95% CI, -12 to 1], P = .08). The change in peak V̇O2 was positively correlated with the change in percent lean body mass (r = 0.32; P = .003) and the change in thigh muscle:intermuscular fat ratio (r = 0.27; P = .02). There were no study-related serious adverse events. Body weight decreased by 7% (7 kg [SD, 1]) in the diet group, 3% (4 kg [SD, 1]) in the exercise group, 10% (11 kg [SD, 1] in the exercise + diet group, and 1% (1 kg [SD, 1]) in the control group. CONCLUSIONS AND RELEVANCE: Among obese older patients with clinically stable HFPEF, caloric restriction or aerobic exercise training increased peak V̇O2, and the effects may be additive. Neither intervention had a significant effect on quality of life as measured by the MLHF Questionnaire. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00959660.

Standardized Rehabilitation and Hospital Length of Stay Among Patients With Acute Respiratory Failure: A Randomized Clinical Trial.

IMPORTANCE: Physical rehabilitation in the intensive care unit (ICU) may improve the outcomes of patients with acute respiratory failure. OBJECTIVE: To compare standardized rehabilitation therapy (SRT) to usual ICU care in acute respiratory failure. DESIGN, SETTING, AND PARTICIPANTS: Single-center, randomized clinical trial at Wake Forest Baptist Medical Center, North Carolina. Adult patients (mean age, 58 years; women, 55%) admitted to the ICU with acute respiratory failure requiring mechanical ventilation were randomized to SRT (n=150) or usual care (n=150) from October 2009 through May 2014 with 6-month follow-up. INTERVENTIONS: Patients in the SRT group received daily therapy until hospital discharge, consisting of passive range of motion, physical therapy, and progressive resistance exercise. The usual care group received weekday physical therapy when ordered by the clinical team. For the SRT group, the median (interquartile range [IQR]) days of delivery of therapy were 8.0 (5.0-14.0) for passive range of motion, 5.0 (3.0-8.0) for physical therapy, and 3.0 (1.0-5.0) for progressive resistance exercise. The median days of delivery of physical therapy for the usual care group was 1.0 (IQR, 0.0-8.0). MAIN OUTCOMES AND MEASURES: Both groups underwent assessor-blinded testing at ICU and hospital discharge and at 2, 4, and 6 months. The primary outcome was hospital length of stay (LOS). Secondary outcomes were ventilator days, ICU days, Short Physical Performance Battery (SPPB) score, 36-item Short-Form Health Surveys (SF-36) for physical and mental health and physical function scale score, Functional Performance Inventory (FPI) score, Mini-Mental State Examination (MMSE) score, and handgrip and handheld dynamometer strength. RESULTS: Among 300 randomized patients, the median hospital LOS was 10 days (IQR, 6 to 17) for the SRT group and 10 days (IQR, 7 to 16) for the usual care group (median difference, 0 [95% CI, -1.5 to 3], P = .41). There was no difference in duration of ventilation or ICU care. There was no effect at 6 months for handgrip (difference, 2.0 kg [95% CI, -1.3 to 5.4], P = .23) and handheld dynamometer strength (difference, 0.4 lb [95% CI, -2.9 to 3.7], P = .82), SF-36 physical health score (difference, 3.4 [95% CI, -0.02 to 7.0], P = .05), SF-36 mental health score (difference, 2.4 [95% CI, -1.2 to 6.0], P = .19), or MMSE score (difference, 0.6 [95% CI, -0.2 to 1.4], P = .17). There were higher scores at 6 months in the SRT group for the SPPB score (difference, 1.1 [95% CI, 0.04 to 2.1, P = .04), SF-36 physical function scale score (difference, 12.2 [95% CI, 3.8 to 20.7], P = .001), and the FPI score (difference, 0.2 [95% CI, 0.04 to 0.4], P = .02). CONCLUSIONS AND RELEVANCE: Among patients hospitalized with acute respiratory failure, SRT compared with usual care did not decrease hospital LOS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00976833.

Genetic influence on exercise-induced changes in physical function among mobility-limited older adults.

To date, physical exercise is the only intervention consistently demonstrated to attenuate age-related declines in physical function. However, variability exists in seniors' responsiveness to training. One potential source of variability is the insertion (I allele) or deletion (D allele) of a 287 bp fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. This polymorphism is known to influence a variety of physiological adaptions to exercise. However, evidence is inconclusive regarding the influence of this polymorphism on older adults' functional responses to exercise. This study aimed to evaluate the association of ACE I/D genotypes with changes in physical function among Caucasian older adults (n = 283) following 12 mo of either structured, multimodal physical activity or health education. Measures of physical function included usual-paced gait speed and performance on the Short Physical Performance Battery (SPPB). After checking Hardy-Weinberg equilibrium, we used using linear regression to evaluate the genotype*treatment interaction for each outcome. Covariates included clinic site, body mass index, age, sex, baseline score, comorbidity, and use of angiotensin receptor blockers or ACE inhibitors. Genotype frequencies [II (19.4%), ID (42.4%), DD (38.2%)] were in Hardy-Weinberg equilibrium (P > 0.05). The genotype*treatment interaction was statistically significant for both gait speed (P = 0.002) and SPPB (P = 0.020). Exercise improved gait speed by 0.06 ± 0.01 m/sec and SPPB score by 0.72 ± 0.16 points among those with at least one D allele (ID/DD carriers), but function was not improved among II carriers. Thus, ACE I/D genotype appears to play a role in modulating functional responses to exercise training in seniors.

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFPEF) is the most common form of HF in older persons. The primary chronic symptom in HFPEF is severe exercise intolerance, and its pathophysiology is poorly understood. To determine whether skeletal muscle abnormalities contribute to their severely reduced peak exercise O2 consumption (Vo2), we examined 22 older HFPEF patients (70 ± 7 yr) compared with 43 age-matched healthy control (HC) subjects using needle biopsy of the vastus lateralis muscle and cardiopulmonary exercise testing to assess muscle fiber type distribution and capillarity and peak Vo2. In HFPEF versus HC patients, peak Vo2 (14.7 ± 2.1 vs. 22.9 ± 6.6 ml·kg(-1)·min(-1), P < 0.001) and 6-min walk distance (454 ± 72 vs. 573 ± 71 m, P < 0.001) were reduced. In HFPEF versus HC patients, the percentage of type I fibers (39.0 ± 11.4% vs. 53.7 ± 12.4%, P < 0.001), type I-to-type II fiber ratio (0.72 ± 0.39 vs. 1.36 ± 0.85, P = 0.001), and capillary-to-fiber ratio (1.35 ± 0.32 vs. 2.53 ± 1.37, P = 0.006) were reduced, whereas the percentage of type II fibers was greater (61 ± 11.4% vs. 46.3 ± 12.4%, P < 0.001). In univariate analyses, the percentage of type I fibers (r = 0.39, P = 0.003), type I-to-type II fiber ratio (r = 0.33, P = 0.02), and capillary-to-fiber ratio (r = 0.59, P < 0.0001) were positively related to peak Vo2. In multivariate analyses, type I fibers and the capillary-to-fiber ratio remained significantly related to peak Vo2. We conclude that older HFPEF patients have significant abnormalities in skeletal muscle, characterized by a shift in muscle fiber type distribution with reduced type I oxidative muscle fibers and a reduced capillary-to-fiber ratio, and these may contribute to their severe exercise intolerance. This suggests potential new therapeutic targets in this difficult to treat disorder.

The effects of a long-term physical activity intervention on serum uric acid in older adults at risk for physical disability.

Observational studies show a relationship between elevated serum uric acid (UA) and better physical performance and muscle function. The purpose of this paper was to determine whether regular participation in an exercise intervention, known to improve physical functioning, would result in increased serum UA. For this study, 424 older adults at risk for physical disability were randomized to participate in either a 12-mo moderate-intensity physical activity (PA) or a successful aging (SA) health education intervention. UA was measured at baseline, 6, and 12 mo (n = 368, 341, and 332, respectively). Baseline UA levels were 6.03 ± 1.52 mg/dl and 5.94 ± 1.55 mg/dl in the PA and SA groups, respectively. The adjusted mean UA at month 12 was 4.8% (0.24 mg/dl) higher in the PA compared with the SA group (p = .028). Compared with a health education intervention, a 1-yr PA intervention results in a modest increase in systemic concentration of UA in older adults at risk for mobility disability.

Serum factors mediate changes in mitochondrial bioenergetics associated with diet and exercise interventions.

Mitochondrial improvements resulting from behavioral interventions, such as diet and exercise, are systemic and apparent across multiple tissues. Here, we test the hypothesis that factors present in serum, and therefore circulating throughout the body, can mediate changes in mitochondrial function in response to intervention. To investigate this, we used stored serum from a clinical trial comparing resistance training (RT) and RT plus caloric restriction (RT + CR) to examine effects of blood borne circulating factors on myoblasts in vitro. We report that exposure to dilute serum is sufficient to mediate bioenergetic benefits of these interventions. Additionally, serum-mediated bioenergetic changes can differentiate between interventions, recapitulate sex differences in bioenergetic responses, and is linked to improvements in physical function and inflammation. Using metabolomics, we identified circulating factors associated with changes in mitochondrial bioenergetics and the effects of interventions. This study provides new evidence that circulating factors play a role in the beneficial effects of interventions that improve healthspan among older adults. Understanding the factors that drive improvements in mitochondrial function is a key step towards predicting intervention outcomes and developing strategies to countermand systemic age-related bioenergetic decline.

Caloric Restriction Intervention Alters Specific Circulating Biomarkers of the Senescence-Associated Secretome in Middle-Aged and Older Adults With Obesity and Prediabetes in an 18-Week Randomized Controlled Trial.

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n = 31) or Control (n = 27) in 58 middle-aged/older adults (57.6 ±â€…5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost -10.8 ±â€…0.9 kg (-11.3% ±â€…5.4%) over 18 weeks compared with +0.5 ±â€…0.9 kg (+0.03% ±â€…3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F = 4.17, p ≤ .05) and associated with the degree of weight loss (R2 = 0.12, p ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions.

Cardiopulmonary Exercise Testing in a Prospective Multicenter Cohort of Older Adults.

PURPOSE: Cardiorespiratory fitness (CRF) measured by peak oxygen consumption (V̇O 2peak ) declines with aging and correlates with mortality and morbidity. Cardiopulmonary exercise testing (CPET) is the criterion method to assess CRF, but its feasibility, validity, and reliability in older adults are unclear. Our objective was to design and implement a dependable, safe, and reliable CPET protocol in older adults. METHODS: V̇O 2peak was measured by CPET, performed using treadmill exercise in 875 adults ≥70 yr in the Study of Muscle, Mobility and Aging (SOMMA). The protocol included a symptom-limited peak (maximal) exercise and two submaximal walking speeds. An adjudication process was in place to review tests for validity if they met any prespecified criteria (V̇O 2peak <12.0 mL·kg -1 ·min -1 ; maximum heart rate <100 bpm; respiratory exchange ratio <1.05 and a rating of perceived exertion <15). A subset ( N = 30) performed a repeat test to assess reproducibility. RESULTS: CPET was safe and well tolerated, with 95.8% of participants able to complete the V̇O 2peak phase of the protocol. Only 56 (6.4%) participants had a risk alert and only two adverse events occurred: a fall and atrial fibrillation. Mean ± SD V̇O 2peak was 20.2 ± 4.8 mL·kg -1 ·min -1 , peak heart rate 142 ± 18 bpm, and peak respiratory exchange ratio 1.14 ± 0.09. Adjudication was indicated in 47 tests; 20 were evaluated as valid and 27 as invalid (18 data collection errors, 9 did not reach V̇O 2peak ). Reproducibility of V̇O 2peak was high (intraclass correlation coefficient = 0.97). CONCLUSIONS: CPET was feasible, effective, and safe for older adults, including many with multimorbidity or frailty. These data support a broader implementation of CPET to provide insight into the role of CRF and its underlying determinants of aging and age-related conditions.

Usual-paced 400 m long distance corridor walk estimates cardiorespiratory fitness among older adults: The Study of Muscle, Mobility and Aging.

BACKGROUND: Cardiopulmonary exercise testing (CPET), the gold-standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual-paced 400 m long distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF. The purpose of this study was to develop and validate an estimating equation to estimate VO2 peak from average 400 m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA). METHODS: At baseline, women (58%) and men age 70 years and older enrolled in SOMMA (N = 820, 76.2 ± 4.9 years, 86% Non-Hispanic White) completed a 400 m LDCW (400 m WS = 400 m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO2 peak (mL/kg/min) was considered the highest 30-second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7-day wrist-worn accelerometer), physical function (Short Physical Performance Battery, range 0-12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0-50), and Borg Rating of Perceived Exertion (RPE, range 6-20) at completion of the 400 m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%). RESULTS: Mean VO2 peak was 20.2 ± 4.8 mL/kg/min and mean 400 m WS was 1.06 ± 0.2 m/s. Each 0.05 m/s increment in 400 m WS was associated with a 0.40 mL/kg/min higher VO2 peak after covariate adjustment. An estimating equation including 400 m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (-0.26) and strong correlation (r = 0.71) between predicted and measured VO2 peak values. Bland-Altman plot and regression analyses indicated predicted VO2 peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among the highly fit. CONCLUSIONS: Usual-paced 400 m LDCW strongly correlates with direct measures of CRF during CPET in older adults with lower fitness and can be used to test both fitness and function.

Role of Walking Energetics and Perceived Fatigability Differs by Gait Speed: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Slower gait speed may be driven by greater energy deficits and fatigability among older adults. We examined associations of walking energetics and perceived physical fatigability with gait speed among slower and faster walkers. Additionally, we used statistical mediation to examine the role of fatigability in the associations of walking energetics and gait speed using the Study of Muscle, Mobility and Aging (SOMMA). METHODS: Perceived physical fatigability was assessed using the Pittsburgh Fatigability Scale (PFS) Physical score (range 0-50, higher = greater). A 3-phase cardiopulmonary exercise treadmill test collected peak oxygen consumption (VO2peak, mL/kg/min), energetic cost of walking (ECW, mL/kg/m), and cost-capacity ratio (VO2/VO2peak*100, %). Slower (<1.01 m/s) versus faster (≥1.01 m/s) walkers were classified using median 4-m gait speed. Linear regressions and statistical mediation analyses were conducted. RESULTS: Slower walkers had lower VO2peak, higher ECW at preferred walking speed (PWS), and greater PFS Physical score compared to faster walkers (all p < .05; N = 849). One standard deviation (1-SD) higher VO2peak was associated with 0.1 m/s faster gait speed, while 1-SD higher ECW PWS, cost-capacity ratio at PWS and slow walking speed (SWS), and PFS Physical score were associated with 0.02-0.23 m/s slower gait speed. PFS Physical score was a significant statistical mediator in the associations between VO2peak (15.2%), SWS cost-capacity ratio (15.9%), and ECW PWS (10.7%) with gait speed and was stronger among slower walkers. CONCLUSIONS: Slower walkers may be more influenced by perceptions of fatigue in addition to walking energetics. Our work highlights the importance of targeting both energetics and perceived fatigability to prevent mobility decline.