Background Genetic determinants of resilience remain poorly defined beyond family studies. Objectives The purpose of this study was to perform an unbiased study of individuals with discordance between clinical/genetic risk and atherosclerotic burden to discover novel genetic pathways underpinning atherosclerosis. Methods We used 2 genotyped cohorts with well-defined coronary anatomy: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) (discovery cohort: coronary computed tomography angiography) and CATHGEN (CATHeterization GENetics) (validation cohort: invasive angiography). Resilience was defined as high clinical and polygenic risk of coronary artery disease (CAD), yet without coronary plaque. Resilient individuals were compared to patients with obstructive CAD (oCAD) (stenosis ≥70%) using genome-wide association analyses at variant, gene, and pathway levels. Results In PROMISE (n = 605), 46 (8%) were resilient and 88 (15%) had oCAD. In CATHGEN (n = 3,236), 127 (4%) were resilient and 1,852 (57%) had oCAD. Clinical risk factors and polygenic risk scores were similar between resilient and oCAD patients in both cohorts. Variant- and gene-level analyses did not yield genome-wide significant signals. Pathway-level analyses identified 4 resilience-associated pathways in PROMISE that replicated in CATHGEN: adipocytokine signaling, fatty acid metabolism, fatty acid degradation, and vascular smooth muscle contraction. Conclusions Resilience to CAD—defined as the absence of coronary atherosclerosis despite high clinical and polygenic risk—is present in both lower- (PROMISE) and higher-risk (CATHGEN) cohorts and is linked to protective variants in metabolic and vascular pathways. This unbiased, proof-of-concept approach reveals biologically plausible targets for replication and mechanistic studies in larger imaging-based genetics cohorts.

Background:Caloric restriction (CR) improves markers of biological aging, yet long-term effects on the human metabolome remain unclear. Objective:This study examined the effects of CR (2 years) in healthy adults without obesity on circulating metabolites linked to aging and metabolic adaptations. Methods:Untargeted metabolomics was performed using fasted plasma samples collected at baseline, 12, and 24 months (BL, 12M, 24M) from CALERIE™ participants randomized to CR or ad libitum (AL) control. A total of 864 known metabolites were identified and grouped into nine biologically coherent super pathways to support pathway-level interpretation (amino acid, peptide, carbohydrate, energy, lipid, nucleotide, cofactors and vitamins, xenobiotics, and partially characterized molecules). Principal component analysis (PCA) summarized metabolite variation, and linear mixed models assessed intervention effects on each PC in group-by-time interactions. Results:Three principal components showed significant group-by-time interactions: PC2 (carbohydrate), PC5 (partially characterized molecules), and PC4 (lipid). Carbohydrate (PC2) and partially characterized metabolites (PC5) decreased from baseline to 12M in both groups; from 12M to 24M, levels stabilized in CR but increased in AL for PC2, while PC5 continued to decline in AL and increased in CR. Lipid metabolites (PC4) decreased in CR and increased in AL at 12M, with the pattern reversing from 12M to 24M. Key contributors included malto-saccharides and related carbohydrate intermediates for PC2, glutamine degradants and lactone sulfates for PC5, and sphingolipids for PC4. Conclusion:Calorie restriction produced distinct, time-dependent shifts in carbohydrate and lipid metabolism, with early reductions during the weight-loss phase followed by stabilization or compensatory responses during weight maintenance. These dynamic metabolic changes may relate to inflammation-linked mechanisms. Further work is needed to distinguish CR-specific adaptations from dietary influences and to clarify the functional significance of these metabolic responses for aging and long-term metabolic health.

Background:Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods:Seventy-three participants (71.3±7.2 years; 64% women; 77% White) completed Reunion assessments ∼11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results:Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ∼3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass ( p =0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association (β=0.84, p <0.0001). Conclusions:In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes - supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

Skeletal muscle is a central regulator of insulin sensitivity and glucose homeostasis. The ryanodine receptor 1 (RYR1) is highly expressed in skeletal muscle and plays a key role in myogenic differentiation. We hypothesize that RYR1+ extracellular vesicles (EVs) represent a skeletal muscle-derived EV subpopulation whose abundance and small RNA (smRNA) cargo are associated with aging, insulin action, and exercise responsiveness. We tested this hypothesis through in vitro analyses of smRNAs of skeletal muscle-derived EVs and in vivo evaluation of their exercise responsiveness and association with insulin action in older adults. Using an integrated workflow combining centrifugation, polymer-based precipitation, and single-EV sorting, we isolated RYR1+ and RYR− EVs secreted from myobundles—3D contractile skeletal muscle tissues engineered from primary muscle progenitor cells obtained from healthy donors (n = 6). We also isolated plasma EVs from 48 human participants and performed targeted high-resolution flow cytometry to evaluate EV biomarkers associated with aging, insulin action, and exercise responsiveness in older adults. By smRNA sequencing, compared to myobundle RYR− EVs, RYR1+ EVs contained three unique microRNAs (miRNAs) and an additional 21 miRNAs with significantly greater abundance (including canonical myoMiRs miR-206, miR-1-3p, and miR-208a-3p). Of the 24 RYR1+ EV-enriched miRNAs, experimentally-supported mRNA targets (n = 422) are involved in pathways governing cell proliferation, apoptosis, senescence, insulin and glucose signaling. In two independent cohorts, including older adults with prediabetes or unknown prediabetes status, frequencies of RYR1+ EV subsets were significantly upregulated by chronic exercise with greater RYR1+ EV frequencies associated with better insulin action. These complementary in vitro and in vivo data identify skeletal muscle-derived RYR1+ EVs as upregulated by exercise and as carriers of miRNAs linked to insulin action in older adults, including those with prediabetes. These results highlight skeletal muscle-derived EVs as novel biomarkers and potential mediators of systemic metabolic regulation and healthy aging.

OBJECTIVE:Recruiting participants in pediatric obesity research is challenging due to logistical and systemic barriers. This study evaluated the use of a best practice alert (BPA) within the electronic health record (EHR) to aid in recruitment for a randomized controlled trial testing a pediatric obesity treatment intervention. METHODS:The BPA was designed to identify eligible patients aged 5 to 17 years with a body mass index ≥95th percentile during their annual well-child visits. Between January 2018 and March 2020, the BPA was utilized in 4 primary care clinics. Patients were identified in the EHR and pre-screened by the study team. RESULTS:The BPA was deployed to 2121 individual patients, and providers responded to 85% of alerts. Over half (52%) of patients indicated interest in further contact by the study team. The BPA facilitated recruitment 68% (177/261) of participants or 16% of those who agreed to be contacted. CONCLUSIONS:Overall, the BPA was responsible for the majority of total enrollment in the trial. This study demonstrates the potential of BPAs to facilitate recruitment into pediatric obesity treatment studies.

Background Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. Objectives The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. Methods Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank.The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. Results The mean BMI was 29.2 ± 5.8 kg/m2. Over a median follow-up of 27.0 months, all-cause mortality occurred in 11,454 patients (23%), and 11,360 participants (22%) experienced the composite endpoint. Genetically predicted BMI was associated with an increased rate of both all-cause mortality (HR per SD [4.8 BMI units] 1.21; 95% CI: 1.13-1.29; P = 9 × 10-8) and the composite outcome (HR 1.29; 95% CI: 1.20-1.38; P = 8 × 10-13). Associations were consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. Conclusions Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.

Wearable devices offer the ability to objectively characterize free-living physical activity; however, raw step-count data generated by commercial devices require systematic processing before they can support rigorous inference. We describe a transparent, reproducible standard operating procedure (SOP) for transforming epoch-level step-count data from commercial Garmin devices into participant-level analytic variables and demonstrate its application in the STRRIDE-PD Reunion study: a long-term follow-up of older adults originally enrolled in a supervised exercise intervention trial. This data pipeline standardizes timestamps, reconstructs daily epoch grids, infers wear time from observed step patterns, and applies a prespecified valid-day threshold (≥10 hours inferred wear time) to generate participant-level summaries. Among 67 participants (mean age 71.4 years, 65.7% women), the median valid-day count was 10 days, median average daily steps were 5,794, and participant-level estimates were identical across ≥10-hour and ≥6-hour valid-day thresholds. Wearable-derived step counts were significantly associated with 9 of 16 cardiometabolic and fitness outcomes, including cardiorespiratory fitness, body composition, and lipid profiles. By contrast, self-reported exercise - assessed via a frequency-by-duration composite ranked into deciles - was not significantly associated with any outcome. A regression calibration framework applied to the full sample quantified the attenuation underlying this discrepancy: the naive self-report model systematically underestimated associations relative to both the observed Garmin model and calibration-corrected estimates. These findings demonstrate that measurement approach is a determinant of scientific conclusions in physical activity research, and that reproducible wearable data pipelines are essential infrastructure for aging epidemiology.

Exercise training confers broad health benefits, yet molecular regulators of skeletal muscle adaptation, particularly sex-specific mechanisms, remain incompletely understood. Integrating new and previously published multi-omics data from the molecular transducers of physical activity consortium (MoTrPAC), we characterized metabolomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) responses to 1-8 weeks of endurance exercise training in male and female rat gastrocnemius. While transcriptomic and proteomic responses were largely sex-concordant, there were distinct sex-specific training-induced PTM signatures, particularly in the redox proteome. Females exhibited decreased mitochondrial protein cysteine oxidation alongside increased oxidation of glycolytic proteins relative to males, suggesting sex-biased subcellular reactive oxygen species (ROS) dynamics. Multi-omic factor analysis (MOFA) identified coordinated sex-concordant molecular programs and further supported female-specific mechanisms of redox buffering with training. Together, these findings indicate that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and identify future avenues for precision exercise health and medicine.

OBJECTIVE:Weight loss is often pursued to improve cardiometabolic health and quality of life. However, weight loss can lead to reductions in lean soft tissue mass and strength, compromising body composition and functional ability. Thus, identifying molecular predictors of muscular strength preservation during weight loss is critical to mitigating these effects. METHODS:We conducted a secondary analysis of the CALERIE trial, a 2-year randomized controlled study of caloric restriction or ad libitum intake in healthy adults without obesity. Changes in whole-body mass and knee extensor strength were assessed over the first 12 months of the study. Transcriptomic profiling was conducted in a subset who provided skeletal muscle samples. The relationship between strength change and gene expression change was modeled, controlling for whole-body mass change. RESULTS:Transcriptomics analysis on a subset of 42 individuals revealed 151 genes significantly associated with change in strength after accounting for change in whole-body mass, including HSP90AA1 and EIF3A. Pathway analyses revealed significant involvement of pathways related to cellular proliferation, immune regulation, and protein secretion. CONCLUSIONS:These findings highlight molecular pathways and genes supporting strength retention during caloric restriction-induced weight loss. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00427194 www. CLINICALTRIALS:gov.

To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs-687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs)-in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the Duke-EPESE study. Our predictive model incorporating smRNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated AUCs of 0.92 for 2-year survival in Discovery and 0.87 in external Validation. Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.

We investigated effects of three aerobic exercise interventions, varying in amount and intensity with durations of 8-9-months on small RNA (smRNA) expression and regulatory pathways in skeletal muscle and plasma from 120 participants. Using untargeted smRNA sequencing focused on miRNAs and piRNAs, adjusting for demographics and bodyweight, we identified 124 muscle smRNAs altered by exercise amount and 15 by intensity, and 47 plasma smRNAs altered by intensity and one by amount. These smRNAs were enriched in metabolic, transcriptional, translational, and cell cycle pathways. Exercise-induced changes in several smRNAs-six from muscle and five from plasma-and exercise-induced reduction in body weight, aligned with improvement in insulin sensitivity (p<0.05). These findings demonstrate tissue-specific regulation of smRNAs by exercise and identify potential candidates for exercise mimetics to modulate muscle insulin sensitivity.

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of autophagy, angiogenesis and metabolism. Further, early RE-specific phosphoproteome signatures counteracted epigenetic modifications and downregulated transcripts involved in protein turnover. Additional findings include suppression of HIPK2/3 kinase signatures linked to the acute exercise regulation of sarcomeric proteins TTN, NEB, ANKRD2 and LMOD2. Our data demonstrate distinct temporal regulation across the multi-omic landscape of human skeletal muscle, with EE and RE eliciting common and unique molecular signatures.

The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs robustly improved several physiological parameters (i.e., VO2peak, muscular strength). Temporal biospecimen (blood, muscle, and adipose) collections and processing coupled to the acute exercise bouts were highly successful. In most cases, over 90% success was achieved for blood, muscle, and adipose samples. Endurance and resistance exercise induced distinct acute and chronic physiological responses, which provide a framework to interrogate the molecular basis for health adaptations to these two popular exercise modalities.

Physical Activity Guidelines for Americans recommend at least 150 min/week of moderate (MPA) to vigorous (VPA) physical activity to maintain health, regardless of cardiovascular disease (CVD) risk. This study assessed whether physical activity (PA) intensity distinguishes between low and high CVD risk in 196 lean and obese Hispanic men aged 18-40 from the Study of Male Reproductive Epigenomics. PA was measured for 7 days using triaxial accelerometry. The 30-year "full" Framingham Risk Score (FRS) was calculated. Diet quality was assessed using the Healthy Eating Index (HEI-2020). Mean age was 30 ± 5 years with a median FRS of 14% (range: 3% to 85%). The high-risk group (n = 89) had a mean full FRS of 20.3% ± 11.1%, compared to 7.0% ± 3.6% in the low-risk group (n = 107; p <0.001). Both groups met guideline-recommended PA levels. However, the low-risk group performed more VPA (25 ± 20 vs 12 ± 12 min/day; p <0.001). Logistic regressions showed that each additional 1 min/day of VPA reduced the odds of high CVD risk by 4.4% (p = 0.007), adjusted for smoking, diet, age and Body Mass Index (BMI), while MPA did not significantly predict CVD risk (p = 0.823). Stepwise regressions showed that smoking status, BMI, VPA, and diet explained 47.8% of FRS variance (p <0.001), while MPA was excluded. In conclusion, VPA, but not MPA, significantly distinguished low from high CVD risk in young Hispanic men, highlighting the potential role of higher-intensity exercise to reduce CVD risk in this population.

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting articular joints and skeletal muscle. To assess the role of cytokines upon muscle strength in RA, we developed an in vitro tissue-engineered human skeletal muscle model (myobundle). Myobundles were generated using primary skeletal muscle cells from the vastus lateralis muscle of RA patients and age-matched healthy controls. RA myobundles were more sensitive to 5 ng/mL IFN-γ, exhibiting reduced contractile force and altered contraction kinetics. Addition of IL-6 with or without IFN-γ led to a small but significant increase in striated fibers. Gene sets involved in the response to hypoxia, MTOR1 signaling, and the unfolded protein response were enriched in IFN-γ-treated RA myobundles, but not IFN-γ-treated controls. Tofacitinib increased contractile force, myosin heavy chain, and PIM1 protein levels in RA myobundles treated with IFN-γ. Thus, in RA muscle, low levels of IFN-γ selectively increase gene pathways that reduce contractile force.

CONTEXT:Insulin resistance (IR) contributes to the pathogenesis of type 2 diabetes mellitus and is a risk factor for cardiovascular and neurodegenerative diseases. Amino acid and lipid metabolomic biomarkers associate with future type 2 diabetes mellitus risk in several epidemiological cohorts. Whether these biomarkers can accurately monitor changes in IR status following treatment is unclear. OBJECTIVE:Herein we evaluated the performance of clinical and metabolomic biomarker models to forecast altered IR, following lifestyle-based interventions. DESIGN:We contrasted the performance of two distinct insulin assay types (high-sensitivity ELISA and immunoassay) and built IR diagnostic models using cross-sectional clinical and metabolomic data. These models were used to stratify IR status in preintervention fasting samples, from 3 independent cohorts (META-PREDICT (n = 179), STRRIDE-AT/RT (n = 116), and STRRIDE-PD (n = 149)). Linear and Bayesian projective prediction strategies were used to evaluate models for fasting insulin and homeostatic model assessment 2 for insulin resistance and change in fasting insulin with treatment. RESULTS:Both insulin assays accurately quantified international standard insulin (R2 > 0.99), yet agreement between fasting insulins was less congruent (R2 = 0.65). A mean treatment effect on fasting insulin was only detectable using the ELISA. Clinical-metabolomic models were statistically related to fasting insulin (R2 0.33-0.39) but with modest capacity to classify IR at a clinically relevant homeostatic model assessment 2 for insulin resistance threshold. Furthermore, no model predicted treatment responses in any cohort. CONCLUSION:We demonstrate that the choice of insulin assay is critical when quantifying the influence of treatment on fasting insulin, whereas none of the clinical-metabolomic biomarkers, identified in cross-sectional studies, are suitable for monitoring longitudinally changes in IR status.

Introduction The threat of heart failure with preserved ejection fraction (HFpEF) continues to increase affecting more than 4 million adults in the U.S. resulting in a 50% mortality rate within 3-5 years of diagnosis and affecting unrepresented groups disproportionately. Onset of clinical symptoms such as unexplained dyspnea and chest pressure, signaling early HFpEF, often unrecognized, occurs months, sometimes years before HFpEF diagnosis. Contemporary evidence suggests that modifiable inflammatory-metabolic mechanisms play a significant role leading to HFpEF, thus providing an underutilized window of opportunity for earlier intervention. Preliminary data suggests that echo markers of ventricular-arterial coupling (VAC) signal early onset of incident HFpEF. Methods Sample - new onset HFpEF in patients >18yrs of age identified first by ICD10 code through Duke DEDUCE then refined by chart review applying the European Society of Cardiology definition for HFpEF. VAC was measured from previously acquired echo images from up to 20 years leading to the time of incident HFpEF. Using the single beat method, validated by Chen et al, 2001. VAC was calculated. The analysis involved comparing echo VAC from the retrospective longitudinal Duke HFpEF cohort (HFpEF retro) and comparing to the prospective Duke HFpEF cohort (HFpEF pro) with primary focus of detecting changes in VAC markers leading to HFpEF and time intervals of changes before diagnosis. Student's t-tests or Wilcoxon rank sum test, was used to compare the mean physiological and echocardiographic biomarkers between groups at similar intervals of visits preceding HFpEF diagnosis. Secondary analysis included comparing echo VAC markers between cohorts, stratified by age, race and sex comparing both noninvasive and invasive markers. All analysis involved only de-identified data thus protecting private health information and human subject's privacy rights. Results and Conclusions Echo markers of VAC signaled early heart failure with preserved ejection fraction (HFpEF) up 10-20 years and as close as 3 to 6 months before incident HFpEF diagnosis. Limitations included a small sample size and unequal number of echo VAC markers obtained per patient thus limiting the generalizability. Future research opportunities include validating these findings within large prospectively obtained datasets and incorporating the use of artificial intelligence (AI). Clinical implication: validated results from this study will enable clinicians to predict those patients at-risk for developing incident HFpEF.

Understanding how exercise improves whole-body insulin sensitivity (Si) involves complex molecular signaling. This study examines skeletal muscle gene expression changes related to Si, considering sex differences, exercise amount, and intensity to identify pharmacologic targets mimicking exercise benefits. Fifty-three participants from STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) I and II completed eight months of aerobic training. Gene expression was assessed via Affymetrix and Illumina technologies, and Si was measured using intravenous glucose tolerance tests. A novel discovery protocol integrating literature-derived and data-driven modeling identified causal pathways and direct transcriptional targets. In women, exercise amount primarily influenced transcription factor targets, which were generally inhibitory, while in men, exercise intensity drove activating targets. Common transcription factors included ATF1, CEBPA, BACH2, and STAT1. Si-related transcriptional targets included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key pathways mediating Si improvements were identified: estrogen signaling and protein kinase C (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. The molecular pathways underlying Si improvements varied by sex and exercise parameters, highlighting potential skeletal muscle-specific drug targets such as EGFR to replicate the metabolic benefits of exercise.

Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.

Introduction: Attending cardiac rehabilitation (CR) improves fitness and quality of life and decreases the risk of future death from heart disease. Unfortunately, once an individual finishes a CR program, continued participation in physical activity (PA) too often reverts to previous sedentary patterns and is even more prevalent among older adults. Thus, this pilot study tested the feasibility of a health coaching intervention to improve PA and physical function after CR among older adults. Hypothesis: Compared to education alone, we hypothesized that health coaching would maintain or improve PA participation and physical function 3 months after CR completion. Methods: A total of 13 older adults who graduated from CR were randomized to either an education or health coaching group for 3 months. The education group received one 30-minute education session within the first month of randomization. The health coaching group received 6 health coaching sessions across the 3-month study duration. Both groups received a Garmin wrist-worn device and step goal ranging from 5,000-8,000 steps per day based on baseline step count. The Senior Fitness Test assessed physical function at baseline and 3 months. Paired t -tests were used to test within-group differences in mean change of outcomes and independent t -tests were used to test between-group differences in mean change of outcomes. Results: Participants were on average 70.8 + 7.0 years old, white (84.6%), and female (61.5%). Average step count adherence was 110.4% + 26.8% and 102.7% + 18.1% for the health coaching and education groups, respectively. Regardless of group, participants significantly improved their waist circumference (-3.3 + 4.4 cm; p = 0.019), chair stands (2.0 + 2.4; p = 0.015), arm curls (2.0 + 2.0; p = 0.005), and 2-minute steps (4.8 + 7.3; p = 0.043). Participants increased their average daily step count by 1194 + 1641 and 545 + 1762 in the health coaching and education groups, respectively. There were no significant between-group differences in this small sample. Conclusions: This pilot study demonstrates utilizing health coaching and education to maintain or increase PA and physical function 3 months after CR is feasible. Future studies should employ a similar approach among a larger sample size to determine the relative efficacy and effectiveness of health coaching and education on PA and physical function after CR amongst older adult populations.