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Background: Both ezetimibe and phytosterols inhibit cholesterol absorption. We tested the hypothesis that the combination of ezetimibe and phytosterols is more effective than ezetimibe alone in altering cholesterol metabolism.Methods and Results: Twenty-one mildly hypercholesterolemic subjects completed a randomized, double-blind, placebo-controlled, triple-crossover study. Each subject received a phytosterol-controlled diet plus (1) ezetimibe placebo+phytosterol placebo, (2) 10 mg/d ezetimibe+phytosterol placebo, and (3) 10 mg/d ezetimibe+2.5 g phytosterols for 3 weeks each. All meals were prepared in a metabolic kitchen. Primary outcomes were intestinal cholesterol absorption, fecal cholesterol excretion, and low-density lipoprotein cholesterol levels. The combined treatment resulted in significantly lower intestinal cholesterol absorption (598 mg/d; 95% confidence interval [CI], 368 to 828) relative to control (2161 mg/d; 95% CI, 1112 to 3209) and ezetimibe alone (1054 mg/d; 95% CI, 546 to 1561; both P<0.0001). Fecal cholesterol excretion was significantly greater (P<0.0001) with combined treatment (962 mg/d; 95% CI, 757 to 1168) relative to control (505 mg/d; 95% CI, 386 to 625) and ezetimibe alone (794 mg/d; 95% CI, 615 to 973). Plasma low-density lipoprotein cholesterol values during treatment with control, ezetimibe alone, and ezetimibe+phytosterols averaged 129 mg/dL (95% CI, 116 to 142), 108 mg/dL (95% CI, 97 to 119), and 101 mg/dL (95% CI, 90 to 112; (P<0.0001 relative to control).Conclusion: The addition of phytosterols to ezetimibe significantly enhanced the effects of ezetimibe on whole-body cholesterol metabolism and plasma low-density lipoprotein cholesterol. The large cumulative action of combined dietary and pharmacological treatment on cholesterol metabolism emphasizes the potential importance of dietary phytosterols as adjunctive therapy for the treatment of hypercholesterolemia.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00863265. [ABSTRACT FROM AUTHOR]

BACKGROUND: Phytosterol supplementation of 2 g/d is recommended by the National Cholesterol Education Program to reduce LDL cholesterol. However, the effects of different intakes of phytosterol on cholesterol metabolism are uncertain. OBJECTIVE: We evaluated the effects of 3 phytosterol intakes on whole-body cholesterol metabolism. DESIGN: In this placebo-controlled, crossover feeding trial, 18 adults received a phytosterol-deficient diet (50 mg phytosterols/2000 kcal) plus beverages supplemented with 0, 400, or 2000 mg phytosterols/d for 4 wk each, in random order. All meals were prepared in a metabolic kitchen; breakfast and dinner on weekdays were eaten on site. Primary outcomes were fecal cholesterol excretion and intestinal cholesterol absorption measured with stable-isotope tracers and serum lipoprotein concentrations. RESULTS: Phytosterol intakes (diet plus supplements) averaged 59, 459, and 2059 mg/d during the 3 diet periods. Relative to the 59-mg diet, the 459- and 2059-mg phytosterol intakes significantly (P < 0.01) increased total fecal cholesterol excretion (36 +/- 6% and 74 +/- 10%, respectively) and biliary cholesterol excretion (38 +/- 7% and 77 +/- 12%, respectively) and reduced percentage intestinal cholesterol absorption (-10 +/- 1% and -25 +/- 3%, respectively). Serum LDL cholesterol declined significantly only with the highest phytosterol dose (-8.9 +/- 2.3%); a trend was observed with the 459-mg/d dose (-5.0 +/- 2.1%; P = 0.077). CONCLUSIONS: Dietary phytosterols in moderate and high doses favorably alter whole-body cholesterol metabolism in a dose-dependent manner. A moderate phytosterol intake (459 mg/d) can be obtained in a healthy diet without supplementation. This trial was registered at clinicaltrials.gov as NCT00860054. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of a worksite health promotion program on improving cardiovascular disease risk factors.Methods: In St Louis, Missouri from 2005 to 2006, 151 employees (134 F, 17 M, 81% overweight/obese) participated in a cohort-randomized trial comparing assessments + intervention (worksite A) with assessments only (worksite B) for 1 year. All participants received personal health reports containing their assessment results. The intervention was designed to promote physical activity and favorable dietary patterns using pedometers, healthy snack cart, WeightWatchers(R) meetings, group exercise classes, seminars, team competitions, and participation rewards. Outcomes included BMI, body composition, blood pressure, fitness, lipids, and Framingham 10-year coronary heart disease risk.Results: 123 participants, aged 45+/-9 yr, with BMI 32.9+/-8.8 kg/m(2) completed 1 year. Improvements (P< or =0.05) were observed at both worksites for fitness, blood pressure, and total-, HDL-, and LDL-cholesterol. Additional improvements occurred at worksite A in BMI, fat mass, Framingham risk score, and prevalence of the metabolic syndrome; only the changes in BMI and fat mass were different between worksites.Conclusion: A multi-faceted worksite intervention promoted favorable changes in cardiovascular disease risk factors, but many of the improvements were achieved with worksite health assessments and personalized health reports in the absence of an intervention. [ABSTRACT FROM AUTHOR]

BACKGROUND: Weight loss, through calorie restriction or increases in energy expenditure via exercise, improves glucose tolerance and insulin action. However, exercise-induced energy expenditure may further improve glucoregulation through mechanisms independent of weight loss. OBJECTIVE: The objective was to assess the hypothesis that weight loss through exercise-induced energy expenditure improves glucoregulation and circulating factors involved in insulin action to a greater extent than does similar weight loss through calorie restriction. DESIGN: Sedentary men and women aged 50-60 y with a body mass index (kg/m(2)) of 23.5-29.9 were randomly assigned to 1 of 2 weight-loss interventions [12 mo of exercise training (EX group; n = 18) or calorie restriction (CR group; n = 18)] or to a healthy lifestyle (HL) control group (n = 10). The insulin sensitivity index and areas under the curve for glucose and insulin were assessed with an oral-glucose-tolerance test. Adiponectin and tumor necrosis factor alpha concentrations were measured in fasting serum. Fat mass was measured by dual-energy X-ray absorptiometry. RESULTS: Yearlong energy deficits were not significantly different between the EX and CR groups, as evidenced by body weight and fat mass changes. The insulin sensitivity index increased and the glucose and insulin areas under the curve decreased in the EX and CR groups, remained unchanged in the HL group, and did not differ significantly between the EX and CR groups. Marginally significant increases in adiponectin and decreases in the ratio of tumor necrosis factor alpha to adiponectin occurred in the EX and CR groups but not in the HL group. CONCLUSIONS: Weight loss induced by exercise training or calorie restriction improves glucose tolerance and insulin action in nonobese, healthy, middle-aged men and women. However, it does not appear that exercise training-induced weight loss results in greater improvements than those that result from calorie restriction alone. Copyright © 2006 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: Caloric restriction (CR) increases maximal life span in short-lived organisms, and its effects are being explored in nonhuman primates. The objectives of this study were to determine the feasibility of prolonged CR in nonobese adults and to compare the effects of CR- and exercise-induced weight loss on body composition and abdominal adiposity.Methods: A randomized, controlled trial was conducted with 48 healthy, nonobese women and men, aged 57 +/- 1 (mean +/- standard error [SE]) years, with body mass index 27.3 +/- 0.3 kg/m2. Participants were randomly assigned to a 20% calorically-restricted diet (CR, n = 19), exercise designed to produce a similar energy deficit (EX, n = 19), or a healthy lifestyle control group (HL, n = 10) for 1 year. Assessments included weight, body composition by dual-energy x-ray absorptiometry, abdominal adipose tissue by magnetic resonance imaging, and energy intake by doubly labeled water.Results: The average level of CR achieved by the CR group was 11.5 +/- 2.1%, and the EX group completed 59 +/- 6.7% of their prescribed exercise. Weight changes were greater (p Conclusions: CR for 1 year was feasible, but the level of CR achieved was less than prescribed. CR and exercise were equally effective in reducing weight and adiposity. [ABSTRACT FROM AUTHOR]

Weight gain and behavioral patterns during college may contribute to overweight and obesity in adulthood. The aims of this study were to assess weight, exercise, and dietary patterns of 764 college students (53% women, 47% men) during freshman and sophomore years. Students had their weight and height measured and completed questionnaires about their recent exercise and dietary patterns. At the beginning of freshman year, 29% of students reported not exercising, 70% ate fewer than 5 fruits and vegetables daily, and more than 50% ate fried or high-fat fast foods at least 3 times during the previous week. By the end of their sophomore year, 70% of the 290 students who were reassessed had gained weight (4.1+/-3.6 kg, p < .001), but there was no apparent association with exercise or dietary patterns. Future research is needed to assess the contributions of fat, muscle, and bone mass to observed weight gain and to determine the health implications of these findings. [ABSTRACT FROM AUTHOR]

Background: Doubly labeled water is gold standard for measuring total energy expenditure (TEE). Measurements using the method are sensitive to the isotope dilution space ratio (DSR). Accuracy and precision of the method might be improved if we could identify factors influencing DSR., Objectives: We evaluated the potential associations of age, sex, ethnicity, anthropometry, body composition, turnover rates of the isotopes, and geographical elevation with DSR., Methods: We used univariate regression analysis to explore the relationships between the continuous variables and analysis of variance to test the relationships between the categorical variables with DSR. Subsequently, we used general linear model (GLM) and 1-way analysis of variance to evaluate the simultaneous associations of age, sex, ethnicity, fat-free mass (FFM) and fat mass (FM) on DSR., Results: From 5678 measurements complied from studies around the world with diverse ethnicity and living at various elevations, the mean DSR was 1.0364 ± 0.0141. No meaningful physiologic effect of any of the continuous and categorical variable on DSR was detected. General linear model analysis revealed no effect of FFM and FM (P > 0.33) on DSR, but DSR decreased with age (P < 0.001) among those aged 60 y and older regardless of sex. Among the Whites who were younger than 60 y, DSR was not related to FFM and FM (P = 0.73) but was affected by both age and sex (P < 0.001)., Conclusions: Previous estimates of age-related decline in TEE may have overestimated TEE at age 90 y. Validation studies on older participants are required to confirm this finding., Competing Interests: Conflict of interest WWW reports administrative support was provided by Baylor College of Medicine. JRS reports administrative support and article publishing charges were provided by University of Aberdeen. MLN is a Deputy Editor of the Journal of Nutrition but played no role in the Journal’s evaluation of the manuscript. The other authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Peak oxygen consumption (V̇O 2peak ) is used to predict outcomes and the timing of transplantation in patients with heart failure with reduced ejection fraction (HFrEF); V̇O 2peak also has predictive utility in patients with adult congenital heart disease (ACHD). However, the predictive value of a given V̇O 2peak in patients with ACHD compared to those with HFrEF, especially after adjustment for age and sex, is not clear., Methods: To address this, we performed a longitudinal cohort study comparing patients with ACHD to patients with HFrEF. The ACHD and HFrEF cohorts were matched for sex and age (+/- 10 y). V̇O 2peak tests were conducted between 1993 and 2012. Events were defined as death, cardiac transplantation, or left ventricular assist device placement. Outcome data were obtained via electronic medical record, Social Security Death Index, and phone interview. Cox proportional-hazard regressions were used to evaluate relationships of event-free survival with predictor variables., Results: Patients with ACHD (N=137) and HFrEF (N=137) with a median follow-up time of 14.5 (13.4-15.6) y in the ACHD cohort and 19 (14.8-21.1) y in the HFrEF cohort. Higher V̇O 2peak was associated with lower risk for a cardiac outcome, independent of age and sex, in both ACHD (HR 0.89, 95% CI 0.83-0.96, P =0.002) and HFrEF (HR 0.85, 95% CI 0.81-0.89, P <0.001Male sex was associated with greater risk of a cardiac outcome ( P =0.001) in ACHD (HR 3.34) and HFrEF (HR 1.83). After multivariable adjustment (that included age, sex, and V̇O 2peak ) having ACHD conferred a 66% lower risk of a cardiovascular event compared to a HFrEF diagnosis (HR 0.34, 95% CI 0.22-0.53, P <0.001)., Conclusions: V̇O 2peak independently predicts event-free survival among adults with ACHD or HFrEF and has clinical utility in the outpatient setting. Patients with ACHD, however, have a better prognosis for any given V̇O 2peak compared to those with HFrEF., What Is New?: In an age- and sex-matched longitudinal cohort study with over 7 y of follow-up, adults with congenital heart disease (ACHD) were found to have a better event-free (no transplant or LVAD) survival than adults with heart failure with reduced ejection fraction (HFrEF) even after multivariable adjustment that included age, sex, and V̇O 2peak . Thus, for any given V̇O 2peak a better event-free survival would be expected in ACHD compared with HFrEF. For both groups, a higher V̇O 2peak did still confer an improved event-free survival and male sex conferred a worse event-free survival., What Are the Clinical Implications?: Patients with HFrEF commonly undergo V̇O 2peak testing to evaluate clinical status, exercise capabilities, and timing for transplantation. Less commonly, patients with ACHD undergo V̇O 2peak testing. This study confirmed that a higher V̇O 2peak is still an excellent predictor of freedom from cardiac events and survival in both groups; however, for a given V̇O 2peak , a patient with ACHD would be expected to have a markedly improved event-free survival vs. a patient with HFrEF even after adjusting for age and sex. Moreover, our analysis adds to the understanding of how much of an advantage a higher V̇O 2peak confers for each mL·min -1 ·kg -1 confers in each group, with a slightly greater incremental benefit for the ACHD group. This finding has implications for timing of referral to cardiac transplantation for patients with ACHD. Future studies are needed to determine the optimal V̇O 2peak cut-off for transplantation for those with ACHD. Furthermore, more studies are needed to investigate the potential mechanism(s) for the ACHD survival advantage.

Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular disease (CVD) risk. Compared with males, females are twice as likely to develop PTSD after trauma exposure, and cardiovascular reactivity to stress is a known risk factor for CVD. We aimed to examine hemodynamic responses to acute mental stress in trauma-exposed females with and without a clinical diagnosis of PTSD. We hypothesized that females with PTSD would have higher heart rate (HR), blood pressure (BP), and lower blood flow velocity (BFV) responsiveness compared with controls. We enrolled 21 females with PTSD and 21 trauma-exposed controls. We continuously measured HR using a three-lead electrocardiogram, BP using finger plethysmography, and brachial BFV using Doppler ultrasound. All variables were recorded during 10 min of supine rest, 5 min of mental arithmetic, and 5 min of recovery. Females with PTSD were older, and had higher BMI and higher resting diastolic BP. Accordingly, age, BMI, and diastolic BP were covariates for all repeated measures analyses. Females with PTSD had a blunted brachial BFV response to mental stress (time × group, p = 0.005) compared with controls, suggesting greater vasoconstriction. HR and BP responses were comparable. In conclusion, our results suggest early impairment of vascular function in premenopausal females with PTSD., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21-50y; BMI 22.0-27.9 kg/m 2 ), to 25% CR or ad-libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE™ participants' blood chemistries, immunology, and epigenetic data suggest the 2-year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere length (TL) attrition. TL was quantified in blood samples collected at baseline, 12-, and 24-months by quantitative PCR (absolute TL; aTL) and a published DNA-methylation algorithm (DNAmTL). Intent-to-treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect-of-Treatment-on-the-Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12-month weight-loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period. No differences were observed when considering TL change across the study duration from baseline to 24-months, leaving it unclear whether CR-related effects reflect long-term detriments to telomere fidelity, a hormesis-like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE™ analyses and trials., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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

Objective: We investigated whether the associations of serum adiponectin, leptin, and resistin with adiposity differ with menopausal age., Methods: In this cross-sectional study, we included 751 postmenopausal women from the Multi-Ethnic Study of Atherosclerosis (MESA) who reported their menopausal age (<45, 45-49, 50-54 and ≥55 y) and had anthropometrics, serum adipokines, and abdominal computed tomography measures of visceral and subcutaneous adipose tissue (VAT and SAT) obtained at MESA exam 2 or 3. Linear regression models were used for analysis., Results: The mean ± SD age was 65.1 ± 9.0 years for all participants. The median (interquartile range) values for serum adiponectin, leptin and resistin, VAT, and SAT were 21.9 (14.8-31.7) ng/L, 24.3 (12.5-42.4) pg/L, 15.3 (11.8-19.5) pg/L, 183.9 (130.8-251.1) cm2, and 103.7 (65.6-151.5) cm2, respectively. The mean ± SD values for body mass index, waist circumference, and waist-to-hip ratio were 28.3 ± 5.81 kg/m2, 96.6 ± 15.9 cm, and 0.91 ± 0.078, respectively. Adiponectin was inversely associated with all adiposity measures, with similar patterns across menopausal age categories. Leptin was positively associated with all adiposity measures, and the strength of associations varied across menopausal age categories for body mass index, waist circumference, and SAT (Pinteraction ≤ 0.01 for all). The associations of resistin with adiposity measures were mostly nonsignificant except in the 45- to 49-year menopausal age category., Conclusions: Menopausal age category had no influence on the association of serum adiponectin with adiposity. The association of serum leptin and resistin differed according to menopausal age category for generalized adiposity but was inconsistent for measures of abdominal adiposity., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2024 by The Menopause Society.)

The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high-depth RNA-Seq (387-618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12- and 24-month follow-up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein-coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Traditional cardiac rehabilitation (CR) improves cardiovascular outcomes and reduces mortality, but less is known about the relative benefit of intensive CR (ICR) which incorporates greater lifestyle education through 72 sessions (versus 36 in CR). Our objective was to determine whether ICR is associated with a mortality and cardiovascular benefit compared with CR., Methods: Retrospective cohort study of Medicare Fee-For-Service beneficiaries in a 100% sample, claims data set. Qualifying events were captured from May 1, 2016 to December 31, 2019 and ICR/CR utilization captured from May 1, 2016 to December 31, 2020. Among patients attending at least 1 day of either CR or ICR, Cox proportional hazards models using a 1 to 5 propensity score match were used to compare utilization and the association of ICR versus CR participation with (1) all-cause mortality and (2) cardiovascular-related hospitalizations or nonfatal cardiac events. Dose-response was assessed by the number of days attended., Results: From 2016 to 2019, 1 277 358 unique patients met at least one qualifying indication for ICR/CR from 2016 to 2019. Of these, 262 579 (20.6%) and 4452 (0.4%) attended at least one session of CR or ICR, respectively (mean [SD] age, 73.2 [7.8] years; 32.3% female). In the matched sample, including 26 659 total patients (median, 2.4-year follow-up), ICR was associated with 12% lower all-cause mortality (multivariable adjusted hazard ratio, 0.88 [95% CI, 0.78-0.99]; P =0.036) compared with CR but no significant difference for cardiovascular-related hospitalization or nonfatal cardiac events. The mortality benefit was seen for both ICR and CR per day strata, with each modality demonstrating a clear dose-response benefit., Conclusions: ICR is associated with lower mortality than traditional CR among Medicare beneficiaries but no difference in cardiovascular-related hospitalization or nonfatal cardiac events. Moreover, ICR and CR demonstrate a dose-response relationship for mortality. Additional studies are needed to confirm these observations and to better understand the mechanisms by which ICR may lead to a reduction in mortality., Competing Interests: Disclosures Dr Husaini received research support from Pritikin intensive cardiac rehabilitation (ICR), LLC through the Foundation for Barnes-Jewish Hospital and has received honoraria from Bristol Meyers Squibb. Dr Racette receives research support from the National Institutes of Health (NIH; R01 AG070717, R01 AG060499, R61 HL155858, R34 HL158947, R33 AG070455, R25 HL105400), and the Foundation for Barnes-Jewish Hospital. Dr Rich receives support from the NIH (R01 AG060499, R01 AG078153, R01 HL147862, R01 HL151431). Dr Joynt Maddox receives research support from the National Heart, Lung, and Blood Institute (R01HL143421 and R01HL164561), National Institute of Nursing research (U01NR020555), and National Institute on Aging (R01AG060935, R01AG063759, and R21AG065526), and from Humana. She also serves on the Health Policy Advisory Council for the Centene Corporation (St Louis, MO). Dr Peterson has stock holdings in Medtronic, Johnson and Johnson and receives research support from the NIH (R61/R33 HL155858, R01 AG060499-01, R01 HL 165238), the American Heart Association (No. 23SCISA1145192), the Children’s Discovery Institute, the Clinical and Translational Research Funding Program (CTRFP), and the Foundation for Barnes-Jewish Hospital in Saint Louis, MO. The other authors report no conflicts.

Background: Heart failure (HF) is a debilitating and often fatal disease that affects millions of people worldwide. Diminished nitric oxide synthesis, signaling, and bioavailability are believed to contribute to poor skeletal muscle function and aerobic capacity. The aim of this clinical trial (iNIX-HF) is to determine the acute and longer-term effectiveness of inorganic nitrate supplementation on exercise performance in patients with HF with reduced ejection fraction (HFrEF)., Methods: This clinical trial is a double-blind, placebo-controlled, randomized, parallel-arm design study in which patients with HFrEF (n = 75) are randomized to receive 10 mmol potassium nitrate (KNO 3 ) or a placebo capsule daily for 6 wk. Primary outcome measures are muscle power determined by isokinetic dynamometry and peak aerobic capacity (VO 2 peak) determined during an incremental treadmill exercise test. Endpoints include the acute effects of a single dose of KNO 3 and longer-term effects of 6 wk of KNO 3 . The study is adequately powered to detect expected increases in these outcomes at P < 0.05 with 1-β>0.80., Discussion: The iNIX-HF phase II clinical trial will evaluate the effectiveness of inorganic nitrate supplements as a new treatment to ameliorate poor exercise capacity in HFrEF. This study also will provide critical preliminary data for a future 'pivotal', phase III, multi-center trial of the effectiveness of nitrate supplements not only for improving exercise performance, but also for improving symptoms and decreasing other major cardiovascular endpoints. The potential public health impact of identifying a new, relatively inexpensive, safe, and effective treatment that improves overall exercise performance in patients with HFrEF is significant., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Inc.)

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at different life stages, along with several morphological traits: height, fat free mass and fat mass. Total EE, and to some degree also activity EE, exhibit considerable greater male variation (GMV) in young adults, and then a decreasing GMV in progressively older individuals. Arguably, basal EE, and also morphometrics, do not exhibit this pattern. These findings suggest that single male sexual characteristics may not exhibit peak GMV in young adulthood, however total and perhaps also activity EE, associated with many morphological and physiological traits combined, do exhibit GMV most prominently during the reproductive life stages.

Intensive cardiac rehabilitation (ICR) programs are approved by the Centers for Medicare & Medicaid Services on the basis of their expected benefits for cardiovascular disease (CVD) risk factors and health outcomes. However, the impact of outpatient ICR on diet quality, quality of life (QOL), and CVD risk factors has not been prospectively assessed. The aim of this cohort study was to test the hypothesis that patients enrolled in a Pritikin outpatient ICR program would show improved diet quality, QOL, and CVD health indexes, and that the improvements would be greater than those of patients in traditional cardiac rehabilitation (CR). Patients enrolled in ICR (n = 230) or CR (n = 62) were assessed at baseline and at visit 24. Diet quality was assessed using the Rate Your Plate questionnaire, and QOL was assessed through the Dartmouth COOP Functional Health Assessment questionnaire. Secondary end points included anthropometrics, CVD biomarkers, hemodynamics, and fitness. Patients in ICR programs displayed significant improvements at visit 24 versus baseline in Rate Your Plate and Dartmouth COOP Functional Health Assessment scores, weight, body mass index (BMI), waist circumference, fat mass, total and low-density lipoprotein cholesterol, 6-minute walk distance, and grip strength. Patients in ICR had greater improvements in diet quality (p = 0.001), weight (p = 0.001), and BMI (p <0.001) than did those in CR. In summary, this prospective study of Pritikin outpatient ICR revealed significant improvements in diet quality, QOL, adiposity, and other CVD risk factors. The improvements in diet quality, body weight, and BMI were greater than those observed with traditional CR., Competing Interests: Disclosures Dr. Peterson has received an honorarium from the American Association of Cardiovascular and Pulmonary Rehabilitation. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan 1-3 . Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients 4 , results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm) 5-7 , and is established to increase healthy lifespan in multiple species 8,9 . Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10 ). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health 11-13 . The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies 14-16 and contrasting with reports that biological aging may not be modifiable 17 . Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality 18-20 ., (© 2023. The Author(s).)

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lacks access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5604 people from the ages of 8 days to 96 years from 23 countries using isotope-tracking ( 2 H) methods. Age, body size, and composition were significantly associated with WT, as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People who lived in countries with a low human development index (HDI) had higher WT than people in high-HDI countries. On the basis of this extensive dataset, we provide equations to predict human WT in relation to anthropometric, economic, and environmental factors.

Purpose: Intensive cardiac rehabilitation (ICR) is a comprehensive, medically supervised exercise treatment program covered by Medicare for patients with approved cardiac diagnoses. The aim of this study was to determine the benefits of the first Pritikin outpatient ICR program., Methods: This retrospective analysis included patients referred to ICR or traditional cardiac rehabilitation (CR) during the first 7 yr (2013-2019) at the first facility to implement Pritikin ICR. Intensive cardiac rehabilitation is composed of 36 education sessions on nutrition, exercise, and a healthy mindset, in addition to 36 monitored exercise sessions that comprise traditional CR. Assessments included anthropometrics (weight, body mass index, and waist circumference), dietary patterns, physical function (6-min walk test, [6MWT] Short Physical Performance Battery [SPPB: balance, 4-m walk, chair rise], handgrip strength), and health-related quality of life (Dartmouth COOP, 36-item Short Form Survey). Baseline and follow-up measures were compared within and between groups., Results: A total of 1963 patients enrolled (1507 ICR, 456 CR, 66.1 ± 11.4 yr, 68% male, 82% overweight or obese); 1141 completed the program (58%). The ICR patients completed 22 exercise and 18 education sessions in 9.6 wk; CR patients completed 19 exercise sessions in 10.3 wk. ICR resulted in improvements ( P &lt; .001 pre vs post) in all anthropometric measures, dietary patterns, 6MWT distance, all SPPB components, grip strength, and health-related quality of life. The improvements in anthropometrics and dietary patterns were greater in ICR than in CR., Conclusions: The Pritikin outpatient ICR program promoted improvements in several cardiovascular health indices. Critical next steps are to assess long-term health outcomes after ICR, including cardiac events and mortality., Competing Interests: Dr Peterson has stock holdings in Johnson & Johnson, Shockwave Medical, and Medtronic. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aim was to determine the nutritional adequacy of calorie restricted (CR) diets during CR interventions up to 12 months., Methods: The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) phase 1 trial consisted of 3 single-site studies to test the feasibility and effectiveness of CR in adults without obesity. After baseline assessments, participants who were randomized to a CR intervention received education and training from registered dietitians on how to follow a healthful CR diet. Food diaries were completed at baseline and during the CR interventions (~6, 9, and 12 months) when participants were self-selecting CR diets. Diaries were analyzed for energy, macronutrients, fiber, 11 vitamins, and 9 minerals. Nutritional adequacy was defined by sex- and age-specific Estimated Average Requirement (EAR) or Adequate Intake (AI) criteria for each nutrient. Diet quality was evaluated using the PANDiet diet quality index., Results: Eighty-eight CR participants (67% women, age 40 ± 9 y, BMI 27.7 ± 1.5 kg/m 2 ) were included in the analysis. Dietary intake of fiber and most vitamins and minerals increased during CR. More than 90% of participants achieved 100% of EAR or AI during CR for 2 of 4 macronutrients (carbohydrate and protein), 6 of 11 vitamins (A, B1, B2, B3, B6, B12), and 6 of 9 minerals assessed (copper, iron, phosphorus, selenium, sodium, zinc). Nutrients for which <90% of participants achieved adequacy included fiber, omega-3 fatty acids, vitamins B5, B9, C, E, and K, and the minerals calcium, magnesium, and potassium. The PANDiet diet quality index improved from 72.9 ± 6.0% at baseline to 75.7 ± 5.2% during CR (p < 0.0001)., Conclusion: Long-term, calorie-restricted diets were nutritionally equal or superior to baseline ad libitum diets among adults without obesity. Our results support modest calorie restriction as a safe strategy to promote healthy aging without compromising nutritional adequacy or diet quality., (Copyright © 2022. Published by Elsevier Inc.)

Lower ambient temperature (T a ) requires greater energy expenditure to sustain body temperature. However, effects of T a on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of T a (-10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average T a and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p < 0.01) relationships between TEE, BEE and T a emerged in females but the effect sizes were not biologically meaningful. Temperatures inside buildings are regulated at 18-25°C independent of latitude. Hence, adults in the US modify their environments to keep TEE constant across a wide range of external ambient temperatures., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors.)

Background: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 trial tested the effects of two years of 25% calorie restriction (CR) on aging in humans. CALERIE 2 was one of the first studies to use a graph of predicted weight loss to: 1) provide a proxy of dietary adherence, and 2) promote dietary adherence. Assuming 25% CR, each participant's weight over time was predicted, with upper and lower bounds around predicted weights. Thus, the resulting weight graph included a zone or range of body weights that reflected adherence to 25% CR, and this was named the zone of adherence. Participants were considered adherent if their weight was in this zone. It is unlikely, however, that the entire zone reflects 25% CR., Objectives: To determine the level of CR associated with the zone of adherence and if the level of CR achieved by participants was within the zone., Methods: Percent CR associated with the upper and lower bounds of the zone were determined via the Body Weight Planner (https://www.niddk.nih.gov/bwp) for participants in the CALERIE 2 CR group (N = 143). Percent CR achieved by participants was estimated with the intake-balance method., Results: At month 24, the zone of adherence ranged from 10.4(0.0)% to 19.4(0.0)% CR [Mean(SEM)], and participants achieved 11.9(0.7)% CR and were in the zone., Conclusion: The results highlight the challenges of: 1) setting a single CR goal vs. a range of acceptable values, and 2) obtaining real-time and valid measures of CR adherence to facilitate adherence., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Intensive cardiac rehabilitation (ICR) was developed to enhance traditional cardiac rehabilitation (CR) by adding sessions focused on nutrition, lifestyle behaviors, and stress management. Intensive CR has been Medicare-approved since 2010, yet little is known about national utilization rates of ICR in the Medicare population or characteristics associated with its use., Methods: A 5% sample of Medicare claims data from 2012 to 2016 was used to identify beneficiaries with a qualifying indication for ICR/CR and to quantify utilization of ICR or CR within 1 yr of the qualifying diagnosis., Results: From 2012 to 2015, there were 107 246 patients with a qualifying indication. Overall, only 0.1% of qualifying patients participated in ICR and 16.2% in CR from 2012 to 2016, though utilization rates of both ICR and CR increased during this period (ICR 0.06 to 0.17%, CR 14.3 to 18.2%). The number of ICR centers increased from 15 to 50 over the same period. There were no differences between ICR and CR enrollees with respect to age, sex, race, discharge location, median income, dual enrollment, or number of comorbidities. Compared with eligible beneficiaries who did not attend ICR or CR, those who attended either program were younger, more likely to be male and White, and had higher median income., Conclusions: Although ICR and CR have a class 1 indication for the treatment of cardiovascular disease and the number of ICR centers has increased, ICR is not widely available and remains markedly underutilized. Continued research is needed to understand the barriers to program development and patient participation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background The mechanisms linking menopausal age and heart failure (HF) incidence are controversial. We investigated for heterogeneity by obesity on the relationship between menopausal age and HF incidence. Methods and Results Using postmenopausal women who attended the Atherosclerosis Risk in Communities Study Visit 4, we estimated hazard ratios of incident HF associated with menopausal age using Cox proportional hazards models, testing for effect modification by obesity and adjusting for HF risk factors. Women were categorized by menopausal age: <45 years, 45 to 49 years, 50 to 54 years, and ≥55 years. Among 4441 postmenopausal women, aged 63.5±5.5 years, there were 903 incident HF events over a mean follow-up of 16.5 years. The attributable risk of generalized and central obesity for HF incidence was greatest among women who experienced menopause at age ≥55 years: 11.09/1000 person-years and 7.38/1000 person-years, respectively. There were significant interactions of menopausal age with body mass index and waist circumference for HF incidence, P interaction 0.02 and 0.001, respectively. The hazard ratios of incident HF for a SD increase in body mass index was elevated in women with menopausal age <45 years [1.39 (1.05-1.84)]; 45-49 years [1.33, (1.06-1.67)]; and ≥55 years [2.02, (1.41-2.89)]. The hazard ratio of incident HF for a SD increase in waist circumference was elevated only in women with menopausal age ≥55 years [2.93, (1.85-4.65)]. Conclusions As obesity worsened, the risk of developing HF became significantly greater when compared with women with lower body mass index and waist circumference, particularly among those who had experienced menopause at age ≥55 years.

Background: The purpose of this pilot study was to compare body composition metrics obtained by two portable bioelectrical impedance analysis (BIA) devices with dual-energy X-ray absorptiometry (DXA) among adolescents with cystic fibrosis (CF) before and after a resistance exercise training program., Methods: Participants with CF were assessed using DXA, single-frequency BIA (SFBIA), and multiple-frequency BIA (MFBIA) to quantify percent body fat (%Fat), fat mass (FM), and fat-free mass (FFM) at baseline and after a home-based resistance training intervention comprised of 36, 1 h sessions completed in 12-14 weeks. Repeated measures analysis of variance, paired samples t -tests, Cohen's d effect sizes, and Pearson's correlations were used to compare differences between and within methods at baseline and post-intervention., Results: Ten participants (15.8 ± 2.2 yr, 60.1 ± 15.1 kg) completed the assessments. At baseline, both SFBIA and MFBIA scales significantly underestimated %Fat and FM and overestimated FFM, with small to moderate effect sizes. Post-intervention, small, non-significant differences were found between DXA and both BIA scales for all body composition metrics. Significant changes in %Fat and FFM were observed with DXA. MFBIA displayed less constant error than SFBIA when compared to DXA for pre- and post-intervention assessments for %Fat (MFBIA: pre and post -2.8 and -0.8 vs. SFBIA: -4.6 and -2.0), FM (-0.4 and -0.4 vs. -3.0 and -1.1), and FFM (+0.8 and +0.6 vs. +3.1 and +1.3). Near-perfect correlations were observed at both time points between DXA and each BIA scale. Conclusions: Portable BIA results should be interpreted with caution, and further validation studies in CF patients are needed prior to clinical use.

The aims of this study were to (1) determine the feasibility of a home-based resistance exercise training (RET) program in patients with cystic fibrosis and impaired glucose tolerance using virtual personal training and (2) observe the effects completion of the RET program had on glucose metabolism, pulmonary function, body composition, and physical fitness. The feasibility of the program was defined as 80% compliance. Ten participants (15.80 ± 2.20 yr, 25.1 ± 7.4 kg/m 2 ) began a home-based resistance training program consisting of 36 sessions supervised via online videoconferencing. Compliance scores of 78.9% (all participants) and 81.8% (without one outlier) were observed. A significant increase was observed in 2-h C-peptide levels (2.1 ng/mL; p = 0.04), with a moderate decrease in fasting glucose (-5.2 mg/dL; p = 0.11) and a moderate increase in 2-h insulin (35.0 U/mL; p = 0.10). A small decrease in the fat percentage (-1.3%; p = 0.03) was observed in addition to increases in fat-free mass (1.5 kg; p = 0.01) and the fat-free mass index (0.4; p = 0.01). Small, yet statistically significant increases were observed in V̇O 2peak (0.1 L/min p = 0.01), V̇CO 2peak (0.1 L/min; p = 0.01), and ventilation (5.3 L/min; p = 0.04). Telehealth-based RET is feasible in adolescents with CF and impaired glucose tolerance and elicits small yet favorable changes in insulin secretion, body composition, and exercise capacity.

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20-60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested., (© 2022. The Author(s).)

Background: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values within ranges considered normal for healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young (21-50 years), normal weight healthy population undergoing calorie restriction for two years., Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, multicenter, randomized controlled trial (May 2007-November 2012) in healthy, adults without obesity to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9 ± 7.2 years and body mass index (BMI) 25.1 ± 1.7 kg/m 2 , mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy., Findings: Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes-Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all P CRvsAL ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and low-density lipoprotein particles, a shift to larger high-density lipoprotein particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all P CRvsAL ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women., Interpretation: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ∼12% CR improved newly identified risk markers for atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These markers suggest that CR improves risks by reducing inflammation and BCAAs and shifting lipoproteins from atherogenic to cholesterol transporting. Additionally, these improvements are greater for men and for those with greater BMIs indicating sex and BMI-influences merit attention in future investigations of lifestyle-mediated improvements in disease risk factors., Funding: The CALERIE™ trial design and implementation were supported by a National Institutes of Health (NIH) U-grant provided to four institutions, the three intervention sites and a coordinating center (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480). For this secondary analysis including sample acquisition and processing, data analysis and interpretation, additional funding was provided by the NIH to authors as follows: R01 AG054840 (MO, VBK); R33 AG070455 (KMH, DCP, MB, SBR, CKM, LMR, SKD, CFP, CJR, WEK); P30 DK072476 (CKM, LMR); and U54 GM104940 (CKM, LMR)., Competing Interests: MAC, IS, and JDO are employees of Labcorp. All other authors have no conflicts interests., (© 2021 The Authors.)

Background: Older adults are at higher risk for cardiovascular disease and functional decline, often leading to deterioration and dependency. Cardiac rehabilitation (CR) provides opportunity to improve clinical and functional recovery, yet participation in CR decreases with age. Modified Application of CR in Older Adults (MACRO) is a National Institute on Aging (NIA)-funded pragmatic trial that responds to this gap by aiming to increase enrollment of older adults into CR and improving functional outcomes. This article describes the methodology and novel features of the MACRO trial., Methods: Randomized, controlled trial of a coaching intervention (MACRO-I) vs. usual care for older adults (age ≥ 70 years) eligible for CR after an incident cardiac hospitalization. MACRO-I incorporates innovations including holistic risk assessments, flexible CR format (i.e., helping patients to select a CR design that aligns with their personal risks and preferences), motivational prompts, nutritional emphasis, facilitated deprescription, enhanced education, and home visits. Key modifications were necessitated by the COVID-19 pandemic, including switching from a performance-based primary endpoint (Short Physical Performance Battery) to a patient-reported measure (Activity Measure for Post-Acute Care Computerized Adaptive Testing). Changes prompted by COVID-19 maintain the original intent of the trial and provide key methodologic advantages., Conclusions: MACRO is exploring a novel individualized coaching intervention to better enable older patients to participate in CR. Due to COVID-19 many aspects of the MACRO protocol required modification, but the primary objective of the trial is maintained and the updated protocol will more effectively achieve the original goals of the study., (Published by Elsevier Inc.)

Study Objective: To evaluate whether an Intensive Cardiac Rehabilitation (ICR) program improves depression and cardiac self-efficacy among patients with a qualifying cardiac diagnosis., Design: Prospective, longitudinal cohort design., Setting: Single-center, tertiary referral, outpatient cardiac rehabilitation center., Participants: Patients with a qualifying diagnosis for ICR., Interventions: Outpatient ICR., Main Outcome Measures: Mental health, as assessed using the Patient Health Questionnaire-9 (PHQ-9) and cardiac self-efficacy using the Cardiac Self-Efficacy (CSE) scale., Results: Of the 268 patients included (median age 69 y, 73% men), 70% had no depressive symptoms at baseline (PHQ-9 score <5). PHQ-9 scores improved in the overall sample (p < 0.0001), with greater improvements among patients with mild depressive symptoms at baseline (-4 points, p < 0.001) and those with moderate to severe depressive symptoms at baseline (-5.5 points, p < 0.001). Cardiac self-efficacy improved overall, and the two subsections of the cardiac self-efficacy questionnaire titled, "maintain function" and "control symptoms" improved (all p < 0.001)., Conclusions: Participation in an outpatient ICR program is associated with fewer depressive symptoms and greater cardiac self-efficacy among patients with CVD who qualify for ICR. The improvement in depression was greatest for those with moderate to severe depressive symptoms.

Background: Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass., Objectives: A study is presented of the association between FFM and physical activity in relation to age., Methods: In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution., Results: PAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males < 18 y old, and 32% and 47% of the variation in FFM in females and males ≥ 18 y old, respectively. In participants < 18 y old, mean FM-adjusted FFM was 1.7 kg (95% CI: 0.1, 3.2 kg) and 3.4 kg (95% CI: 1.0, 5.6 kg) higher in a very active participant with PAL = 2.0 than in a sedentary participant with PAL = 1.5, for females and males, respectively. At age 18 y, height and FM-adjusted FFM was 3.6 kg (95% CI: 2.8, 4.4 kg) and 4.4 kg (95% CI: 3.2, 5.7 kg) higher, and at age 80 y 0.7 kg (95% CI: -0.2, 1.7 kg) and 1.0 kg (95% CI: -0.1, 2.1 kg) higher, in a participant with PAL = 2.0 than in a participant with PAL = 1.5, for females and males, respectively., Conclusions: If these associations are causal, they suggest physical activity is a major determinant of body composition as reflected in peak FFM, and that a physically active lifestyle can only partly protect against loss of FFM in aging adults., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Caloric restriction (CR) improves markers of aging in humans; but it is not known if the fat mass and obesity-associated gene (FTO) rs9939609 single nucleotide polymorphism (SNP), which is associated with appetite and energy intake, influences adherence to prolonged CR. Utilizing data from the two-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 randomized controlled trial, we tested whether the FTO rs9939609 SNP was associated with adherence to CR in healthy adults without obesity. As secondary aims, we assessed whether the FTO rs9939609 SNP was associated with changes in body composition, biomarkers of aging, and eating behaviors. Participants were randomized into either a CR group that targeted a 25% reduction in energy intake compared to the habitual energy intake at baseline, or an ad libitum (AL) control group. Participants were genotyped for the FTO rs9939609 SNP. Dietary adherence was determined through changes in energy intake using doubly labeled water and changes in body composition at baseline, month 12, and month 24 in both the CR and AL condition. Weight, body composition, resting metabolic rate (RMR), adiponectin, insulin, leptin, and eating behaviors were measured at the same timepoints. A total of 144 participants (91 CR and 53 AL, age: 38.6 ± 7.1 years; body mass index: 25.3 ± 1.7 kg/m 2 ) were studied. Of these, 27 were homozygous for the 'obesity-risk' A allele (AA), while 44 were homozygous for the T allele (TT) and 73 were heterozygotes (AT). By design, the CR group exhibited greater percent CR compared to the AL group during the trial (P < 0.01), but no genotype-by-treatment interaction was observed for change in energy intake or percent CR (P ≥ 0.40). The FTO rs9939609 SNP was also negligibly associated with change in most other endpoints (P ≥ 0.13), though AAs showed a reduction in RMR adjusted for body composition change over the 24 months relative to TTs (genotype-by-treatment interaction: P = 0.03). In a two-year CR intervention delivered to healthy individuals without obesity, the FTO rs9939609 SNP was not associated with adherence to CR and did not alter improvements in most aging biomarkers., (Copyright © 2021 Elsevier Inc. All rights reserved.)