Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis.

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/m2 ), 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.

Dietary Sodium and Potassium Patterns in Adults with Food Insecurity in the Context of Hypertension Risk.

Background: Food insecurity (FIS), characterized by the lack of consistent access to nutritious food, is associated with hypertension and adverse health outcomes. Despite evidence of a higher prevalence of hypertension (HTN) in patients living with FIS, there is limited data exploring the underlying mechanism. Methods: We conducted a cross-sectional analysis of 17,015 adults aged 18-65 years, using dietary recall data from the National Health and Nutrition Examination Survey (2011-2018). Univariate and multivariable analyses were used to examine the association between FIS, HTN, and dietary sodium and potassium levels. Results: Individuals reporting FIS had a significantly lower mean intake of potassium (2.5±0.03 gm) compared to those in food-secure households (2.74±0.02 gm). No significant difference was found in the mean dietary sodium intake based on food security status. Non-Hispanic Black participants showed a high prevalence of HTN and FIS. While Non-Hispanic White and Hispanic participants had a high prevalence of FIS, it did not appear to influence their risk of HTN. Conclusions: Adults with FIS and HTN were more likely to report a lower dietary potassium intake. Increasing access to healthy foods, particularly potassium-rich foods, for individuals facing FIS, may contribute to reducing the HTN prevalence and improving cardiovascular outcomes.

Adipokines and adiposity among postmenopausal women of the Multi-Ethnic Study of Atherosclerosis.

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.

Calorie restriction reduces biomarkers of cellular senescence in humans.

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.

Intensive Versus Traditional Cardiac Rehabilitation: Mortality and Cardiovascular Outcomes in a 2016-2020 Retrospective Medicare Cohort.

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.

The inorganic NItrate and eXercise performance in Heart Failure (iNIX-HF) phase II clinical trial: Rationale and study design.

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 (KNO3) or a placebo capsule daily for 6 wk. Primary outcome measures are muscle power determined by isokinetic dynamometry and peak aerobic capacity (VO2peak) determined during an incremental treadmill exercise test. Endpoints include the acute effects of a single dose of KNO3 and longer-term effects of 6 wk of KNO3. The study is adequately powered to detect expected increases in these outcomes at P < 0.05 with 1-ß>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.

Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study.

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.

Prospective Study of the Impact of Outpatient Intensive Cardiac Rehabilitation on Diet Quality, Health-related Quality of Life, and Cardiovascular Health Indices.

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.

A prospective cohort study of the impact of outpatient Intensive Cardiac Rehabilitation on depression and cardiac self-efficacy.

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.

Benefits of the First Pritikin Outpatient Intensive Cardiac Rehabilitation Program.

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 < .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.

Human total, basal and activity energy expenditures are independent of ambient environmental temperature.

Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta 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 Ta (-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 Ta 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 Ta 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.

Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial.

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/m2) 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.

Comparison of Bioelectrical Impedance Analysis with DXA in Adolescents with Cystic Fibrosis before and after a Resistance Training Intervention.

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.

Relationship Between Age at Menopause, Obesity, and Incident Heart Failure: The Atherosclerosis Risk in Communities Study.

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, Pinteraction 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.

Feasibility and Efficacy of Telehealth-Based Resistance Exercise Training in Adolescents with Cystic Fibrosis and Glucose Intolerance.

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/m2) 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 V̇O2peak (0.1 L/min p = 0.01), V̇CO2peak (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.

Challenges in defining successful adherence to calorie restriction goals in humans: Results from CALERIE™ 2.

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.

Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial.

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/m2, 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 PCRvsAL ≤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 PCRvsAL ≤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).

Intensive Cardiac Rehabilitation Is Markedly Underutilized by Medicare Beneficiaries: RESULTS FROM A 2012-2016 NATIONAL SAMPLE.

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.

Modified Application of Cardiac Rehabilitation in Older Adults (MACRO) Trial: Protocol changes in a pragmatic multi-site randomized controlled trial in response to the COVID-19 pandemic.

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.

Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: Exploratory analyses from CALERIE™ phase 2.

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/m2) 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.