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

PURPOSE: Cardiorespiratory fitness (CRF) measured by peak oxygen consumption (VO 2 peak) 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 is unclear. Our objective was to design and implement a dependable, safe and reliable CPET protocol in older adults. METHODS: VO 2 peak was measured by CPET, performed using treadmill exercise in 875 adults ≥70 years 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 [VO 2 peak < 12.0 ml/kg/min; maximum heart rate (HR) <100 bpm; respiratory exchange ratio (RER) <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 VO 2 peak 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 VO 2 peak was 20.2 ± 4.8 mL/kg/min, peak HR 142 ± 18 bpm, and peak RER 1.14 ± 0.09. Adjudication was indicated in 47 tests; 20 were evaluated as valid, 27 as invalid (18 data collection errors, 9 did not reach VO 2 peak). Reproducibility of VO 2 peak 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.

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.

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.

Usual-Paced 400m Long Distance Corridor Walk Estimates Cardiorespiratory Fitness among Older Adults: The Study of Muscle, Mobility and Aging (SOMMA).

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 400m long-distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF among populations unable to complete maximal intensity testing. The purpose of this study was to develop and validate an estimating equation to estimate VO 2 peak from average 400m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA). Methods: At baseline, participants (N=820, 76.2±4.9 years, 58% Women, 86% Non-Hispanic White) completed a 400m LDCW (400m WS=400m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO 2 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 400m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%). Results: Mean VO 2 peak was 20.2±4.8 mL/kg/min and mean 400m WS was 1.06±0.2 m/s. Each 0.05 m/s increment in 400m WS was associated with a 0.40 mL/kg/min higher VO 2 peak after adjustment for covariates. An estimating equation including 400m 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 VO 2 peak values. Bland-Altman plot and regression analyses indicated predicted VO 2 peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among those with CPET VO 2 peak ≥25 mL/kg/min. Conclusions: Usual-paced 400m LDCW strongly correlates with direct measures of cardiorespiratory fitness during CPET in older adults with lower fitness and can be used to test both fitness and function.

Cardiopulmonary Exercise Testing in a Prospective Multicenter Cohort of Older Adults: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Cardiorespiratory fitness (CRF) measured by peak oxygen consumption (VO2peak) declines with aging and correlates with mortality and morbidity. Cardiopulmonary Exercise Testing (CPET) has long been the criterion method to assess CRF, but its feasibility, efficacy and reliability in older adults is unclear. The large, multicenter Study of Muscle, Mobility and Aging (SOMMA) employed CPET to evaluate the mechanisms underlying declines in mobility with aging among community-dwelling older adults. Our primary objective was to design and implement a CPET protocol in older adults that was dependable, safe, scientifically valuable, and methodologically reliable. METHODS: CPET was performed using treadmill exercise in 875 adults ≥70 years. A composite protocol included a symptom-limited peak exercise phase and two submaximal phases to assess cardiopulmonary ventilatory indices during 1) participants' preferred walking speed and 2) at slow walking speed of 1.5 mph (0.67 m/s). An adjudication process was in place to review tests for validity if they met any prespecified criteria (VO2peak <12.0 ml/kg/min; maximum heart rate (HR) <100 bpm; respiratory exchange ratio (RER) <1.05 and a rating of perceived exertion <15). A repeat test was performed in a subset (N=30) to assess reproducibility. RESULTS: CPET was safe and well tolerated, with 95.8% of participants able to complete the VO2peak phase of the protocol. Only 56 (6.4%) participants had a risk alert during any phase of testing and only two adverse events occurred during the peak phase: a fall and atrial fibrillation. The average ± standard deviation for VO2peak was 20.2 ± 4.8 mL/kg/min, peak HR 142 ± 18 bpm, and peak RER 1.14 ± 0.09. VO2peak and RER were slightly higher in men than women. Adjudication was indicated in 47 participants; 20 were evaluated as valid, 27 as invalid (18 had a data collection error, 9 did not reach VO2peak). Reproducibility of VO2peak was high (intraclass correlation coefficient=0.97). CONCLUSIONS: CPET was feasible, effective and safe for community-dwelling older adults, many of whom had multimorbidity and frailty. These data support a broader implementation of CPET to provide important insight into the role of CRF and its underlying determinants in aging and age-related conditions and diseases. Clinical Perspective: What Is New?: Performing cardiopulmonary exercise testing in a community dwelling older adult with multimorbidities or frailty is feasible and exceptionally safe under highly trained exercise physiologists and physician supervision.Reproducibility of VO2peak among community-dwelling older adults with significant clinical complexity was high (intraclass correlation coefficient=0.97).The VO2peak observed was comparable to established normative data for older adults, and adds merit to the limited data collected on VO2peak norms in older adults.What Are the Clinical Implications?: Ventilatory gas collection during clinical cardiac stress testing may be valuable to plan of care in routine management of older adults due to the important role of aerobic fitness on morbidity and mortality.Cardiopulmonary exercise testing can provide insight into the role of cardiorespiratory fitness and its underlying determinants in aging and age-related conditions and diseases.

Associations between skeletal muscle energetics and accelerometry-based performance fatigability: Study of Muscle, Mobility and Aging.

Performance fatigability is typically experienced as insufficient energy to complete daily physical tasks, particularly with advancing age, often progressing toward dependency. Thus, understanding the etiology of performance fatigability, especially cellular-level biological mechanisms, may help to delay the onset of mobility disability. We hypothesized that skeletal muscle energetics may be important contributors to performance fatigability. Participants in the Study of Muscle, Mobility and Aging completed a usual-paced 400-m walk wearing a wrist-worn ActiGraph GT9X to derive the Pittsburgh Performance Fatigability Index (PPFI, higher scores = more severe fatigability) that quantifies percent decline in individual cadence-versus-time trajectory from their maximal cadence. Complex I&II-supported maximal oxidative phosphorylation (max OXPHOS) and complex I&II-supported electron transfer system (max ETS) were quantified ex vivo using high-resolution respirometry in permeabilized fiber bundles from vastus lateralis muscle biopsies. Maximal adenosine triphosphate production (ATPmax ) was assessed in vivo by 31 P magnetic resonance spectroscopy. We conducted tobit regressions to examine associations of max OXPHOS, max ETS, and ATPmax with PPFI, adjusting for technician/site, demographic characteristics, and total activity count over 7-day free-living among older adults (N = 795, 70-94 years, 58% women) with complete PPFI scores and ≥1 energetics measure. Median PPFI score was 1.4% [25th-75th percentile: 0%-2.9%]. After full adjustment, each 1 standard deviation lower max OXPHOS, max ETS, and ATPmax were associated with 0.55 (95% CI: 0.26-0.84), 0.39 (95% CI: 0.09-0.70), and 0.54 (95% CI: 0.27-0.81) higher PPFI score, respectively. Our findings suggested that therapeutics targeting muscle energetics may potentially mitigate fatigability and lessen susceptibility to disability among older adults.

Validation of the Pittsburgh Performance Fatigability Index in the Study of Muscle, Mobility and Aging.

BACKGROUND: The Pittsburgh Performance Fatigability Index (PPFI) quantifies the percent decline in cadence using accelerometry during standardized walking tasks. Although PPFI has shown strong correlations with physical performance, the developmental sample was relatively homogenous and small, necessitating further validation. METHODS: Participants from the Study of Muscle, Mobility and Aging (N = 805, age = 76.4 ±â€…5.0 years, 58% women, 85% White) wore an ActiGraph GT9X on the nondominant wrist during usual-paced 400 m walk. Tri-axial accelerations were analyzed to compute PPFI (higher score = greater fatigability). To evaluate construct and discriminant validity, Spearman correlations (rs) between PPFI and gait speed, Short Physical Performance Battery (SPPB), chair stand speed, leg peak power, VO2peak, perceived fatigability, and mood were examined. Sex-specific PPFI cut-points that optimally discriminated gait speed using classification and regression tree were then generated. Their discriminate power in relation to aforementioned physical performance were further evaluated. RESULTS: Median PPFI score was 1.4% (25th-75th percentile range: 0%-21.7%), higher among women than men (p < .001). PPFI score was moderate-to-strongly correlated with gait speed (rs = -0.75), SPPB score (rs = -0.38), chair stand speed (rs = -0.36), leg peak power (rs = -0.34) and VO2peak (rs = -0.40), and less strongly with perceived fatigability (rs = 0.28-0.29), all p < .001. PPFI score was not correlated with mood (|rs| < 0.08). Sex-specific PPFI cut-points (no performance fatigability: PPFI = 0%; mild performance fatigability: 0% < PPFI < 3.5% [women], 0% < PPFI < 5.4% [men]; moderate-to-severe performance fatigability: PPFI ≥ 3.5% [women], PPFI ≥ 5.4% [men]) discriminated physical performance (all p < .001), adjusted for demographics and smoking status. CONCLUSION: Our work underscores the utility of PPFI as a valid measure to quantify performance fatigability in future longitudinal epidemiologic studies and clinical/pharmaceutical trials.

Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: The pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved. Objective: To evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance. Design, Setting, and Participants: In this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I-linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021. Main Outcomes and Measures: Skeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery. Results: Of 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001). Conclusions and Relevance: In this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I-linked and complex II-linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

Associations of interleukin-6 with functional trajectories in older adults with cancer: Findings from the Health, Aging, and Body Composition Study.

BACKGROUND: Elevated markers of inflammation, such as interleukin-6 (IL-6), are associated with aging, cancer, and functional decline. We assessed the association of pre-diagnosis IL-6 levels with post-diagnosis functional trajectories among older adults with cancer. Black and White participants experience different social structures, therefore we sought to understand whether these associations differ between Black and White participants. METHODS: We conducted secondary analysis of the Health Aging, Body, and Composition (ABC) prospective longitudinal cohort study. Participants were recruited from 4/1997 to 6/1998. We included 179 participants with a new cancer diagnosis and IL-6 level measured within 2 years before diagnosis. Primary endpoint was functional measures (self-reported ability to walk 1/4, 20-meter gait speed). Nonparametric longitudinal models were used to cluster the trajectories; multinomial and logistic regressions to model associations. FINDINGS: Mean age was 74 (SD 2.9); 36 % identified as Black. For self-reported functional status, we identified 3 clusters: high stable, decline, low stable. For gait speed, we identified 2 clusters: resilient, decline. The relationship between cluster trajectory and IL-6 was different between Black and White participants (p for interaction<0.05). For gait speed, among White participants, a greater log IL-6 level was associated with greater odds of being in the decline vs. resilient cluster [Adjusted Odds Ratio (AOR): 4.31, 95 % CI: 1.43, 17.46]. Among Black participants, a greater log IL-6 levels were associated with lower odds of being in the decline vs. resilient cluster (AOR: 0.49, 95 % CI: 0.10, 2.08). Directionality was similar for self-reported ability to walk » mile (high stable vs. low stable). Among White participants, a higher log IL-6 level was associated numerically with greater odds of being in the low stable vs. high stable cluster (AOR: 1.99, 95 % CI: 0.82, 4.85). Among Black participants, a higher log IL-6 level was associated numerically with lower odds of being in the low stable cluster vs. high stable cluster (AOR: 0.78, 95 % CI: 0.30, 2.00). INTERPRETATION: The association between IL-6 levels and functional trajectories of older adults differed by race. Future analyses exploring stressors faces by other minoritized racial backgrounds are needed to determine the association between IL-6 and functional trajectories. PANEL: RESEARCH IN CONTEXT: Evidence before this study: Previous research has shown that aging is the greatest risk factor for cancer and older adults with cancer experience a higher burden of comorbidities, increasing their risk of functional decline. Race has also been shown to be associated with increased risk for functional decline. Black individuals are exposed to more chronic negative social determinants, compared to White individuals. Previous work has shown that chronic exposure to negative social determinants leads to elevated levels of inflammatory markers, such as IL-6, but studies investigating the relationship between inflammatory markers and functional decline are limited. Added value of this study: Authors of this study sought to understand the association between pre-diagnosis IL-6 levels and functional trajectories post-diagnosis in older adults with cancer, and whether these associations differed between Black and White participants with cancer. Authors decided to utilize the data from the Health, Aging and Body Composition (Health ABC) Study. The Health ACB study was a prospective longitudinal cohort study that has a high representation of Black older adults and collected inflammatory cytokines and physical function data over time. Implications of all available evidence: This work adds to the literature by providing an opportunity to study the difference in the relationships between IL-6 levels and functional trajectories between older Black and White participants with cancer. Identifying factors associated with functional decline and its trajectories may inform treatment decision making and guide development of supportive care interventions to prevent functional decline. Additionally, given the disparities in clinical outcomes for Black individuals, a better understanding of the difference in functional decline based on race will allow more equitable care to be distributed.

Age-related changes in gait biomechanics and their impact on the metabolic cost of walking: Report from a National Institute on Aging workshop.

Changes in old age that contribute to the complex issue of an increased metabolic cost of walking (mass-specific energy cost per unit distance traveled) in older adults appear to center at least in part on changes in gait biomechanics. However, age-related changes in energy metabolism, neuromuscular function and connective tissue properties also likely contribute to this problem, of which the consequences are poor mobility and increased risk of inactivity-related disease and disability. The U.S. National Institute on Aging convened a workshop in September 2021 with an interdisciplinary group of scientists to address the gaps in research related to the mechanisms and consequences of changes in mobility in old age. The goal of the workshop was to identify promising ways to move the field forward toward improving gait performance, decreasing energy cost, and enhancing mobility for older adults. This report summarizes the workshop and brings multidisciplinary insight into the known and potential causes and consequences of age-related changes in gait biomechanics. We highlight how gait mechanics and energy cost change with aging, the potential neuromuscular mechanisms and role of connective tissue in these changes, and cutting-edge interventions and technologies that may be used to measure and improve gait and mobility in older adults. Key gaps in the literature that warrant targeted research in the future are identified and discussed.

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.

A Randomized, Controlled Trial of Resistance Training Added to Caloric Restriction Plus Aerobic Exercise Training in Obese Heart Failure With Preserved Ejection Fraction.

BACKGROUND: We have shown that combined caloric restriction (CR) and aerobic exercise training (AT) improve peak exercise O2 consumption (VO2peak), and quality-of-life in older patients with obese heart failure with preserved ejection fraction. However, ≈35% of weight lost during CR+AT was skeletal muscle mass. We examined whether addition of resistance training (RT) to CR+AT would reduce skeletal muscle loss and further improve outcomes. METHODS: This study is a randomized, controlled, single-blind, 20-week trial of RT+CR+AT versus CR+AT in 88 patients with chronic heart failure with preserved ejection fraction and body mass index (BMI) ≥28 kg/m2. Outcomes at 20 weeks included the primary outcome (VO2peak); MRI and dual X-ray absorptiometry; leg muscle strength and quality (leg strength ÷ leg skeletal muscle area); and Kansas City Cardiomyopathy Questionnaire. RESULTS: Seventy-seven participants completed the trial. RT+CR+AT and CR+AT produced nonsignificant differences in weight loss: mean (95% CI): -8 (-9, -7) versus -9 (-11, -8; P=0.21). RT+CR+AT and CR+AT had non-significantly differences in the reduction of body fat [-6.5 (-7.2, -5.8) versus -7.4 (-8.1, -6.7) kg] and skeletal muscle [-2.1 (-2.7, -1.5) versus -2.1 (-2.7, -1.4) kg] (P=0.20 and 0.23, respectively). RT+CR+AT produced significantly greater increases in leg muscle strength [4.9 (0.7, 9.0) versus -1.1 (-5.5, 3.2) Nm, P=0.05] and leg muscle quality [0.07 (0.03, 0.11) versus 0.02 (-0.02, 0.06) Nm/cm2, P=0.04]. Both RT+CR+AT and CR+AT produced significant improvements in VO2peak [108 (958, 157) versus 80 (30, 130) mL/min; P=0.001 and 0.002, respectively], and Kansas City Cardiomyopathy Questionnaire score [17 (12, 22) versus 23 (17, 28); P=0.001 for both], with no significant between-group differences. Both RT+CR+AT and CR+AT significantly reduced LV mass and arterial stiffness. There were no study-related serious adverse events. CONCLUSIONS: In older obese heart failure with preserved ejection fraction patients, CR+AT produces large improvements in VO2peak and quality-of-life. Adding RT to CR+AT increased leg strength and muscle quality without attenuating skeletal muscle loss or further increasing VO2peak or quality-of-life. REGISTRATION: URL: https://ClincalTrials.gov; Unique identifier: NCT02636439.

Estimating heterogeneity of physical function treatment response to caloric restriction among older adults with obesity.

Clinical trials conventionally test aggregate mean differences and assume homogeneous variances across treatment groups. However, significant response heterogeneity may exist. The purpose of this study was to model treatment response variability using gait speed change among older adults participating in caloric restriction (CR) trials. Eight randomized controlled trials (RCTs) with five- or six-month assessments were pooled, including 749 participants randomized to CR and 594 participants randomized to non-CR (NoCR). Statistical models compared means and variances by CR assignment and exercise assignment or select subgroups, testing for treatment differences and interactions for mean changes and standard deviations. Continuous equivalents of dichotomized variables were also fit. Models used a Bayesian framework, and posterior estimates were presented as means and 95% Bayesian credible intervals (BCI). At baseline, participants were 67.7 (SD = 5.4) years, 69.8% female, and 79.2% white, with a BMI of 33.9 (4.4) kg/m2. CR participants reduced body mass [CR: -7.7 (5.8) kg vs. NoCR: -0.9 (3.5) kg] and increased gait speed [CR: +0.10 (0.16) m/s vs. NoCR: +0.07 (0.15) m/s] more than NoCR participants. There were no treatment differences in gait speed change standard deviations [CR-NoCR: -0.002 m/s (95% BCI: -0.013, 0.009)]. Significant mean interactions between CR and exercise assignment [0.037 m/s (95% BCI: 0.004, 0.070)], BMI [0.034 m/s (95% BCI: 0.003, 0.066)], and IL-6 [0.041 m/s (95% BCI: 0.009, 0.073)] were observed, while variance interactions were observed between CR and exercise assignment [-0.458 m/s (95% BCI: -0.783, -0.138)], age [-0.557 m/s (95% BCI: -0.900, -0.221)], and gait speed [-0.530 m/s (95% BCI: -1.018, -0.062)] subgroups. Caloric restriction plus exercise yielded the greatest gait speed benefit among older adults with obesity. High BMI and IL-6 subgroups also improved gait speed in response to CR. Results provide a novel statistical framework for identifying treatment heterogeneity in RCTs.

Longitudinal relationship of baseline functional brain networks with intentional weight loss in older adults.

OBJECTIVE: The goal of this study was to determine whether the degree of weight loss after 6 months of a behavior-based intervention is related to baseline connectivity within two functional networks (FNs) of interest, FN1 and FN2, in a group of older adults with obesity. METHODS: Baseline functional magnetic resonance imaging data were collected following an overnight fast in 71 older adults with obesity involved in a weight-loss intervention. Functional brain networks in a resting state and during a food-cue task were analyzed using a mixed-regression framework to examine the relationships between baseline networks and 6-month change in weight. RESULTS: During the resting condition, the relationship of baseline brain functional connectivity and network clustering in FN1, which includes the visual cortex and sensorimotor areas, was significantly associated with 6-month weight loss. During the food-cue condition, 6-month weight loss was significantly associated with the relationship between baseline brain connectivity and network global efficiency in FN2, which includes executive control, attention, and limbic regions. CONCLUSION: These findings provide further insight into complex functional circuits in the brain related to successful weight loss and may ultimately aid in developing tailored behavior-based treatment regimens that target specific brain circuitry.

Evaluation of a blood-based geroscience biomarker index in a randomized trial of caloric restriction and exercise in older adults with heart failure with preserved ejection fraction.

Intermediate endpoints are needed to evaluate the effect of interventions targeting the biology of aging in clinical trials. A working group identified five blood-based biomarkers that may serve such a purpose as an integrated index. We evaluated the responsiveness of the panel to caloric restriction or aerobic exercise in the context of a randomized clinical trial conducted in patients with heart failure with preserved ejection fraction (HFpEF) with obese phenotype who were predominantly female. Obese HFpEF is highly prevalent in women, and is a geriatric syndrome whose disease pathology is driven by non-cardiac factors and shared drivers of aging. We measured serum Interleukin-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-b-type natriuretic peptide at baseline and after 20 weeks in older participants with stable obese HFpEF participating in a randomized, controlled, 2 × 2 factorial trial of caloric restriction and/or aerobic exercise. We calculated a composite biomarker index, summing baseline quintile scores for each biomarker, and analyzed the effect of the interventions on the index and individual biomarkers and their associations with changes in physical performance. This post hoc analysis included 88 randomized participants (71 women [81%]). The mean ± SD age was 66.6 ± 5.3 years, and body mass index (BMI) was 39.3 ± 6.3 kg/m2. Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (- 0.82 [Formula: see text] 0.58 points, p = 0.05), but not with exercise (- 0.28 [Formula: see text] 0.59 points, p = [Formula: see text]), with no evidence of an interaction effect of CR [Formula: see text] EX [Formula: see text] time (p = 0.80) with adjustment for age, gender, and BMI. At baseline, the biomarker index was inversely correlated with 6-min walk distance, scores on the short physical performance battery, treadmill test peak workload and exercise time to exhaustion (all [Formula: see text] s = between - 0.21 and - 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed ([Formula: see text] s = - 0.31). Among older patients with chronic obese HFpEF, caloric restriction improved a biomarker index designed to reflect biological aging. Moreover, the index was associated with physical performance and exercise tolerance.

Cardiac troponin T and autoimmunity in skeletal muscle aging.

Age-related muscle mass and strength decline (sarcopenia) impairs the performance of daily living activities and can lead to mobility disability/limitation in older adults. Biological pathways in muscle that lead to mobility problems have not been fully elucidated. Immunoglobulin G (IgG) infiltration in muscle is a known marker of increased fiber membrane permeability and damage vulnerability, but whether this translates to impaired function is unknown. Here, we report that IgG1 and IgG4 are abundantly present in the skeletal muscle (vastus lateralis) of ~ 50% (11 out of 23) of older adults (> 65 years) examined. Skeletal muscle IgG1 was inversely correlated with physical performance (400 m walk time: r = 0.74, p = 0.005; SPPB score: r = - 0.73, p = 0.006) and muscle strength (r = - 0.6, p = 0.05). In a murine model, IgG was found to be higher in both muscle and blood of older, versus younger, C57BL/6 mice. Older mice with a higher level of muscle IgG had lower motor activity. IgG in mouse muscle co-localized with cardiac troponin T (cTnT) and markers of complement activation and apoptosis/necroptosis. Skeletal muscle-inducible cTnT knockin mice also showed elevated IgG in muscle and an accelerated muscle degeneration and motor activity decline with age. Most importantly, anti-cTnT autoantibodies were detected in the blood of cTnT knockin mice, old mice, and older humans. Our findings suggest a novel cTnT-mediated autoimmune response may be an indicator of sarcopenia.

A Randomized Controlled Pilot Study of Yoga Skills Training Versus an Attention Control Delivered During Chemotherapy Administration.

CONTEXT: It is important to address fatigue and co-occurring symptoms during chemotherapy to preserve quality of life in patients with gastrointestinal (GI) cancer. OBJECTIVE: To conduct a randomized controlled pilot study of a Yoga Skills Training (YST) intervention compared to an attention control (AC) among adults diagnosed with GI cancer. METHODS: YST consisted of four 30-minute sessions delivered individually during chemotherapy plus home practice. AC provided empathic attention plus home diaries. Patient-reported (PROMIS T-score) assessments of fatigue, depressive symptoms, sleep disturbances, and psychological stress (Perceived Stress Scale) were collected at chemotherapy visits: baseline, Week 8, Week 10 and Week 14, and analyzed using a mixed effects model. Inflammatory cytokines were assessed at baseline and Week 10. RESULTS: Forty-four of 77 adults approached agreed to participate (57%; YST n = 23; AC n = 21). Participants' mean age was 58 years and 48% were men. Participants randomized to YST reported a larger decline in fatigue (-2.4 difference, d = 0.30) and depressive symptoms (-2.5 difference, d = 0.30) than AC participants from baseline to Week 10 and sleep disturbances at Week 8 (-3.9 difference, d = 0.50). Differences in magnitude of change in symptoms were consistent with or exceeded a minimally important difference. Psychological stress decreased more in the AC at Week 10 (d = 0.30). Reductions in inflammatory cytokines (IL-6, sTNF R1) were larger in the YST group than AC. CONCLUSION: YST showed promise for improving fatigue, depressive symptoms, sleep disturbances, and inflammation. YST is also feasible and reaches patients underrepresented in yoga research (i.e., GI cancer, men), thus warranting further examination.