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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. [ABSTRACT FROM AUTHOR]

Objective: To compare a remotely supervised weight loss and exercise intervention to lifestyle counseling for effects on cardiovascular disease risk, disease activity, and patient‐reported outcomes in older patients with rheumatoid arthritis (RA) and overweight/obesity. Methods: Twenty older (60–80 years), previously sedentary participants with seropositive RA and overweight/obesity were randomized to 16 weeks of either Supervised Weight loss and Exercise Training (SWET) or Counseling Health As Treatment (CHAT). The SWET group completed aerobic training (150 minutes/week moderate‐to‐vigorous intensity), resistance training (two days/week), and a hypocaloric diet (7% weight loss goal). The CHAT control group completed two lifestyle counseling sessions followed by monthly check‐ins. The primary outcome was a composite metabolic syndrome z‐score (MSSc) derived from fasting glucose, triglycerides, high density lipoprotein–cholesterol, minimal waist circumference, and mean arterial pressure. Secondary outcomes included RA disease activity and patient‐reported outcomes. Results: Both groups improved MSSc (absolute change −1.67 ± 0.64 in SWET; −1.34 ± 1.30 in CHAT; P < 0.01 for both groups) with no between‐group difference. Compared with CHAT, SWET significantly improved body weight, fat mass, Disease Activity Score‐28 C‐reactive protein, and patient‐reported physical health, physical function, mental health, and fatigue (P < 0.04 for all between‐group comparisons). Based on canonical correlations for fat mass, cardiorespiratory fitness, and leg strength, component‐specific effects were strongest for (1) weight loss improving MSSc, physical health, and mental health; (2) aerobic training improving physical function and fatigue; and (3) resistance training improving Disease Activity Score‐28 C‐reactive protein. Conclusion: In older patients with RA and overweight/obesity, 16 weeks of remotely supervised weight loss, aerobic training, and resistance training improve cardiometabolic health, patient‐reported outcomes, and disease activity. Less intensive lifestyle counseling similarly improves cardiovascular disease risk profiles, suggesting an important role for integrative interventions in the routine clinical care of this at‐risk RA population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Patients with rheumatoid arthritis (RA) remain at an increased risk for cardiovascular disease (CVD) and mortality. RA CVD results from a combination of traditional risk factors and RA‐related systemic inflammation. One hypothetical means of improving overall RA CVD risk is through reduction of excess body weight and increased physical activity. Together, weight loss and physical activity can improve traditional cardiometabolic health through fat mass loss, while also improving skeletal muscle health. Additionally, disease‐related CVD risk may improve as both fat mass loss and exercise reduce systemic inflammation. To explore this hypothesis, 26 older persons with RA and overweight/obesity will be randomized to 16 weeks of a usual care control arm or to a remotely Supervised Weight Loss Plus Exercise Training (SWET) program. A caloric restriction diet (targeting 7% weight loss) will occur via a dietitian‐led intervention, with weekly weigh‐ins and group support sessions. Exercise training will consist of both aerobic training (150 minutes/week moderate‐to‐vigorous exercise) and resistance training (twice weekly). The SWET remote program will be delivered via a combination of video conference, the study YouTube channel, and study mobile applications. The primary cardiometabolic outcome is the metabolic syndrome Z score, calculated from blood pressure, waist circumference, high‐density lipoprotein cholesterol, triglycerides, and glucose. RA‐specific CVD risk will be assessed with measures of systemic inflammation, disease activity, patient‐reported outcomes, and immune cell function. The SWET‐RA trial will be the first to assess whether a remotely supervised, combined lifestyle intervention improves cardiometabolic health in an at‐risk population of older individuals with RA and overweight/obesity. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine whether novel biomarkers of cardiometabolic health improve in response to a 12‐month behavioral weight‐loss intervention and to compare benefits of diet alone with diet plus physical activity for these biomarkers. Methods: Participants (N = 374) were randomized to either diet alone (DIET), diet plus 150 min/wk of prescribed moderate‐intensity physical activity (DIET + PA150), or diet plus 250 min/wk of prescribed moderate‐intensity physical activity (DIET + PA250). Biomarker concentrations were determined using nuclear magnetic resonance spectroscopy. Mixed models assessed for a time effect, group effect, or group by time interaction. Results: All groups significantly improved body weight (time: p < 0.0001), Lipoprotein Insulin Resistance Index score (time: p < 0.0001), Diabetes Risk Index score (time: p < 0.0001), branched‐chain amino acid concentration (time: p < 0.0001), and GlycA concentration (time: p < 0.0001), with no group effect or group by time interactions. Conclusions: All intervention groups prompted a notable beneficial change among biomarkers of insulin resistance and cardiometabolic health. However, the addition of at least moderate‐intensity physical activity to a diet‐only intervention did not provide any additional benefit. These findings highlight that an average weight loss of approximately 10% profoundly impacts biomarkers of insulin resistance and cardiometabolic disease in adults with overweight or obesity. [ABSTRACT FROM AUTHOR]

Objective: To evaluate heterogeneity of treatment effects in a trial of exercise‐based interventions for knee osteoarthritis (OA). Methods: Participants (n = 350) were randomized to standard physical therapy (PT; n = 140), internet‐based exercise training (IBET; n = 142), or wait list (WL; n = 68) control. We applied qualitative interaction trees (QUINT), a sequential partitioning method, and generalized unbiased interaction detection and estimation (GUIDE), a regression tree approach, to identify subgroups with greater improvements in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 4 months. Predictors included 24 demographic, clinical, and psychosocial characteristics. We conducted internal validation to estimate optimism (bias) in the range of mean outcome differences among arms. Results: Both QUINT and GUIDE indicated that for participants with lower body mass index (BMI), IBET was better than PT (improvements of WOMAC ranged from 6.3 to 9.1 points lower), and for those with higher BMI and a longer duration of knee OA, PT was better than IBET (WOMAC improvement was 6.3 points). In GUIDE analyses comparing PT or IBET to WL, participants not employed had improvements in WOMAC ranging from 1.8 to 6.8 points lower with PT or IBT versus WL. From internal validation, there were large corrections to the mean outcome differences among arms; however, after correction, some differences remained in the clinically meaningful range. Conclusion: Results suggest there may be subgroups who experience greater improvement in symptoms from PT or IBET, and this finding could guide referrals and future trials. However, uncertainty persists for specific treatment‐effects size estimates and how they apply beyond this study sample. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease and related dementias (ADRD) are associated with changes in inflammatory and metabolic biomarkers. Here, we evaluated associations among inflammatory and metabolic biomarkers previously‐associated with age related‐morbidity and plasma p‐Tau181, Aβ‐42/Aβ‐40 ratio, neurofilament light (NfL), and glial fibrillary acid protein (GFAP) in community‐dwelling older adults. Method: We evaluated cross‐sectional associations of a panel of inflammatory and metabolic biomarkers with plasma ADRD biomarkers – quantified using the Quanterix SIMOA platform – in a subset of older adults from the Duke Performance Across the Lifespan (PALS) study (N=317; Age=75±8.6; MoCA=25±3.4). Inflammatory and metabolic biomarkers included TNF‐α, TNFR‐I, TNFR‐II, d‐dimer, IL‐6, VCAM‐1, G‐CSF, RANTES, MMP3, paraoxonase activity, adiponectin, uric acid, 11 free amino acids, and 45 acylcarnitines. We applied principal components analysis (PCA) separately to the inflammatory biomarkers, amino acids, and acylcarnitines. We used multivariate multiple regression to associate biomarker PCs with ADRD biomarkers, adjusting for age and sex. Result: Biomarkers were not normally‐distributed and were log‐transformed prior to PCA. We identified 3 inflammatory principal components (PCs), 5 acylcarnitine PCs, and 2 amino acid PCs. Of these, two inflammatory PCs, one acylcarnitine PC, and one amino acid PC were associated with plasma ADRD biomarkers (all Wilk's Λ p<0.01). On univariate analyses, one inflammatory PC loading positively on G‐CSF and RANTES associated with lesser concentrations of p‐Tau181, NfL, and GFAP (all p<0.05). An amino acid biomarker PC loading positively on hydrophobic amino acids associated with lesser concentrations of NfL and GFAP (all p<0.001). An inflammatory PC loading positively on TNF‐α, TNFR‐I, TNFR‐II and IL‐6, and d‐dimer associated with greater concentrations of p‐Tau181 and NfL (all p<0.01). An acylcarnitine PC loading positively on short‐chain acylcarnitines was associated with greater concentrations of NfL (p<0.001). None of the biomarker PCs significantly associated with the Aβ‐42/Aβ‐40 ratio. Conclusion: In community‐dwelling older adults, biomarker PCs loading on G‐CSF, RANTES, and hydrophobic amino acids were associated with lesser concentrations of some plasma ADRD biomarkers, while an inflammatory PC loading on TNF‐α, TNFR‐I, TNFR‐II, and VCAM‐1 was associated with greater concentrations. Our findings provide insight into the association of inflammatory and metabolic biomarkers with plasma biomarkers of ADRD pathology. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the independent and combined effects of high-intensity interval training (HIIT) and essential amino acids (EAA) on lean mass, muscle characteristics of the quadriceps, and 24-hr whole-body protein turnover (WBPT) in overweight and obese adults. An exploratory aim was to evaluate potential modulatory effects of sex. Sixty-six adults (50% female; Age: 36.7 ± 6.0 yrs; %BF: 36.0 ± 7.8%) were assigned to 8 wks of: (a) HIIT, 2 days/wk; (b) EAA supplementation, 3.6 g twice daily; (c) HIIT + EAA; or (d) control. At baseline, 4 wks, and 8 wks, total body, thigh LM and muscle characteristics were measured via dual-energy x-ray absorptiometry and B-mode ultrasound, respectively. In a subsample, changes in WBPT was measured using [N15]alanine. Differences between groups were assessed using linear mixed models adjusted for baseline values, followed by 95% confidence intervals on adjusted mean change scores (Δ). HIIT and HIIT + EAA improved thigh LM (Δ: +0.17 ± 0.05 kg [0.08, 0.27]; +0.22 ± 0.05 kg [0.12,0.31]) and vastus lateralis cross-sectional area (Δ: +2.73 ± 0.52 cm² [1.69,3.77]; +2.64 ± 0.53 cm² [1.58,3.70]), volume (Δ: +54.50 ± 11.69 cm³ [31.07, 77.92]; +62.39 ± 12.05 cmÁ [38.26, 86.52]), and quality (Δ: -5.46 ± 2.68a.u. [-10.84, -0.09]; -7.97 ± 2.76a.u.[-13.49, -2.45]). Protein synthesis, breakdown, and flux were greater with HIIT + EAA and EAA compared to HIIT (p < .05). Sex differences were minimal. Compared to women, men tended to respond more to HIIT, with or without EAA. For women, responses were greater with HIIT + EAA than HIIT. In overweight and obese adults, 8 weeks of HIIT, with or without EAA, improved thigh LM size and quality; EAA may enhance muscular adaptation via increases in protein turnover, supporting greater improvements in muscular size and quality. [ABSTRACT FROM AUTHOR]

Objective: In individuals with knee osteoarthritis (OA), self-reported physical function is poorer in African Americans than in whites, but whether this difference holds true for objective assessments is unclear. The purpose of this study was to examine racial differences in performance-based physical function as well as potential underlying factors contributing to these racial differences.Methods: Participants with knee OA from a randomized controlled trial completed the 2-minute step test (2MST), timed-up-and-go (TUG), and 30-second chair stand (30s-CST) at baseline. Race differences in performance-based function were assessed by logistic regression. Separate models were adjusted for sets of demographic, socioeconomic, psychological health, and physical health variables.Results: In individuals with knee OA (n = 322; 72% women, 22% African American, mean ± SD age 66 ± 11 years, mean ± SD body mass index 31 ± 8 kg/m2 ), African Americans (versus whites) had greater unadjusted odds of poorer function (30s-CST odds ratio [OR] 2.79 [95% confidence interval (95% CI) 1.65-4.72], 2MST OR 2.37 [95% CI 1.40-4.03], and TUG OR 3.71 [95% CI 2.16-6.36]). Relationships were maintained when adjusted for demographic and psychological health covariates, but they were either partially attenuated or nonsignificant when adjusted for physical health and socioeconomic covariates.Conclusion: African American adults with knee OA had poorer unadjusted performance-based function than whites. Physical health and socioeconomic characteristics diminished these differences, emphasizing the fact that these factors may be important to consider in mitigating racial disparities in function. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Defining common patterns of recovery after an acute health stressor (resiliency groups) has both clinical and research implications. We sought to identify groups of patients with similar recovery patterns across 10 outcomes following hip fracture (stressor) and to determine the most important predictors of resiliency group membership. DESIGN: Secondary analysis of three prospective cohort studies. SETTING: Participants were recruited from various hospitals in the Baltimore Hip Studies network and followed for up to 1 year in their residence (home or facility). PARTICIPANTS: Community‐dwelling adults aged 65 years or older with recent surgical repair of a hip fracture (n = 541). MEASUREMENTS: Self‐reported physical function and activity measures using validated scales were collected at baseline (within 15‐22 d of fracture), 2, 6, and 12 months. Physical performance tests were administered at all follow‐up visits. Stressor characteristics, comorbidities, and psychosocial and environmental factors were collected at baseline via participant report and chart abstraction. Latent class profile analysis was used to identify resiliency groups based on recovery trajectories across 10 outcome measures and logistic regression models to identify factors associated with those groups. RESULTS: Latent profile analysis identified three resiliency groups that had similar patterns across the 10 outcome measures and were defined as "high resilience" (n = 163 [30.1%]), "medium resilience" (n = 242 [44.7%]), and "low resilience" (n = 136 [25.2%]). Recovery trajectories for the outcome measures are presented for each resiliency group. Comparing highest with the medium‐ and low‐resilience groups, self‐reported pre‐fracture function was by far the strongest predictor of high‐resilience group membership with area under the curve (AUC) of.84. Demographic factors, comorbidities, stressor characteristics, environmental factors, and psychosocial characteristics were less predictive, but several factors remained significant in a multivariable model (AUC =.88). CONCLUSION: These three resiliency groups following hip fracture may be useful for understanding mediators of physical resilience. They may provide a more detailed description of recovery patterns in multiple outcomes for use in clinical decision making. J Am Geriatr Soc 67:2519–2527, 2019 [ABSTRACT FROM AUTHOR]

Summary: Calorie restriction (CR) without malnutrition slows aging in animal models. Oxidative stress reduction was proposed to mediate CR effects. CR effect on urinary F2‐isoprostanes, validated oxidative stress markers, was assessed in CALERIE, a two‐year randomized controlled trial. Healthy volunteers (n = 218) were randomized to prescribed 25% CR (n = 143) or ad libitum control (AL, n = 75) stratifying the randomization schedule by site, sex, and BMI. F2‐isoprostanes were quantified using LC‐MS/MS in morning, fasted urine specimens at baseline, at 12 and 24 months. The primary measure of oxidative status was creatinine‐adjusted 2,3‐dinor‐iPF(2α)‐III concentration, additional measured included iPF(2α)‐III, iPF2a‐VI, and 8,12‐iso‐iPF2a‐VI. Intention‐to‐treat analyses assessed change in 2,3‐dinor‐iPF(2α)‐III using mixed models assessing treatment, time, and treatment‐by‐time interaction effects, adjusted for blocking variables and baseline F2‐isoprostane value. Exploratory analyses examined changes in iPF(2α)‐III, iPF(2α)‐VI, and 8,12‐iso‐iPF(2α)‐VI. A factor analysis used aggregate information on F2‐isoprostane values. In CR group, 2,3‐dinor‐iPF(2α)‐III concentrations were reduced from baseline by 17% and 13% at 12 and 24 months, respectively; these changes were significantly different from AL group (p < .01). CR reduced iPF(2α)‐III concentrations by 20% and 27% at 12 and 24 months, respectively (p < .05). The effects were weaker on the VI‐species. CR caused statistically significant reduction in isoprostane factor at both time points, and mean (se) changes were −0.36 (0.06) and −0.31 (0.06). No significant changes in isoprostane factor were at either time point in AL group (p < .01 between‐group difference). We conclude that two‐year CR intervention in healthy, nonobese men and women reduced whole body oxidative stress as assessed by urinary concentrations of F2‐isoprostanes. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor focuses on the association of insulin resistance in Type 2 diabetes mellitus with patients' resistance to osteoarthritis.

Objective To evaluate joint tissue remodeling using the urinary collagen biomarkers urinary α-C-telopeptide of type I collagen (α-CTX) and urinary C-telopeptide of type II collagen (CTX-II) and to determine the association of these biomarkers with osteoarthritis (OA) severity, progression, and localized knee bone turnover. Methods Participants (n = 149) with symptomatic and radiographic knee OA underwent fixed-flexion knee radiography at baseline and 3 years, and late-phase bone scintigraphy of both knees at baseline, which were scored semiquantitatively for osteophyte and joint space narrowing (JSN) severity and uptake intensity, with scores summed across knees. Urinary concentrations of α-CTX and CTX-II were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis of human OA knees was performed to localize the joint tissue origin of the biomarker epitopes. Results Urinary α-CTX concentrations correlated strongly with the intensity of bone scintigraphic uptake and with JSN progression (risk ratio 13.2) and osteophyte progression (risk ratio 3). Urinary CTX-II concentrations were strongly associated with intensity of bone scintigraphic uptake, with JSN and osteophyte severity, and with OA progression based on osteophyte score. Urinary α-CTX localized primarily to high bone turnover areas in subchondral bone. CTX-II localized to the bone-cartilage interface, the tidemark, and damaged articular cartilage. Conclusion Baseline urinary α-CTX, which was localized to high turnover areas of subchondral bone, was associated with dynamic bone turnover of knees, as signified by scintigraphy, and progression of both osteophytes and JSN. Urinary CTX-II correlated with JSN and osteophyte severity and progression of osteophytes. To our knowledge, this represents the first report of serologic markers reflecting subchondral bone turnover. These collagen markers may be useful for noninvasive detection and quantification of active subchondral bone turnover and joint remodeling in knee OA. [ABSTRACT FROM AUTHOR]

Objectives To determine whether a home-based multicomponent physical activity counseling ( PAC) intervention is effective in reducing glycemic measures in older outpatients with prediabetes mellitus. Design Controlled clinical trial. Setting Primary care clinics of the Durham Veterans Affairs ( VA) Medical Center between September 29, 2008, and March 25, 2010. Participants Three hundred two overweight (body mass index 25-45 kg/m2), older (60-89) outpatients with impaired glucose tolerance (fasting blood glucose 100-125 mg/ dL, glycosylated hemoglobin (HbA1c) <7%) randomly assigned to a PAC intervention group (n = 180) or a usual care control group (n = 122). Intervention A 12-month, home-based multicomponent PAC program including one in-person baseline counseling session, regular telephone counseling, physician endorsement in clinic with monthly automated encouragement, and customized mailed materials. All study participants, including controls, received a consultation in a VA weight management program. Measurements The primary outcome was a homeostasis model assessment of insulin resistance ( HOMA- IR), calculated from fasting insulin and glucose levels at baseline and 3 and 12 months. HbA1c was the secondary indicator of glycemic control. Other secondary outcomes were anthropometric measures and self-reported physical activity, health-related quality of life, and physical function. Results There were no significant differences between the PAC and control groups over time for any of the glycemic indicators. Both groups had small declines over time of approximately 6% in fasting blood glucose ( P < .001), and other glycemic indicators remained stable. The declines in glucose were not sufficient to affect the change in HOMA- IR scores due to fluctuations in insulin over time. Endurance physical activity increased significantly in the PAC group ( P < .001) and not in the usual care group. Conclusion Home-based telephone counseling increased physical activity levels but was insufficient to improve glycemic indicators in older outpatients with prediabetes mellitus. [ABSTRACT FROM AUTHOR]