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Aging is associated with reductions in cardiovagal baroreflex sensitivity (cBRS), which increases cardiovascular disease risk. Preclinical data indicate that low testosterone reduces cBRS. We determined whether low testosterone is associated with greater age-associated reductions in cBRS in healthy men. Twenty-six men categorized as young (

The goal of this study was to determine the bone turnover marker (BTM) response to insufficient and subsequent recovery sleep, independent of changes in posture, body weight, and physical activity.Healthy men (N = 12) who habitually slept 7-9 h/night were admitted to an inpatient sleep laboratory for a baseline 8 h/night sleep opportunity followed by six nights of insufficient sleep (5 h/night). Diet, physical activity, and posture were controlled. Serum markers of bone formation (osteocalcin, PINP) and resorption (β-CTX) were obtained over 24 h at baseline and on the last night of sleep restriction, and on fasted samples obtained daily while inpatient and five times after discharge over 3 weeks. Maximum likelihood estimates in a repeated measures model were used to assess the effect of insufficient and subsequent recovery sleep on BTM levels.There was no statistically or clinically significant change in PINP (p = 0.53), osteocalcin (p = 0.66), or β-CTX (p = 0.10) in response to six nights of insufficient sleep. There were no significant changes in BTMs from the inpatient stay through 3 weeks of recovery sleep (all p [Formula: see text] 0.63). On average, body weight was stable during the inpatient stay (Δweight = - 0.55 ± 0.91 kg, p = 0.06).No significant changes in serum BTMs were observed after six nights of insufficient or subsequent recovery sleep in young healthy men. Changes in weight and physical activity may be required to observe significant BTM change in response to sleep and circadian disruptions. Clinical Trials Registration Registered at ClinicalTrials.gov (NCT03733483) on November 7, 2018.

Context Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. Objective We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. Methods This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. Results During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = −0.41; P = 0.002), and CRP (r = −0.28; P = 0.041). Conclusion Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.

The aim of this systematic review and meta-analysis was to provide an updated analysis, including the use of more robust methods, on the effects of exercise on bone mineral density in men. Randomised Control Trials of > 24 weeks and published in English up to 01/05/20 were retrieved from 3 electronic databases, cross-referencing, and expert review. The primary outcome measures were changes in FN, LS, and lower limb BMD Standardised effect sizes were calculated from each study and pooled using the inverse heterogeneity model. A statistically significant benefit of exercise was observed on FN BMD [g = 0.21 (0.03, 0.40), Z = 2.23 p = 0.03], with no observed statistically significant benefit of exercise on LS BMD [g = 0.10 (− 0.07, 0.26), Z = 1.15 p = 0.25]. This analysis provided additional evidence to recommend ground- and/or joint-reaction force exercises for improving or maintaining FN, but not LS BMD. Additional well-designed RCTs are unlikely to alter this evidence, although interventions that include activities that directly load the lumbar spine are needed to ensure this is not a potential method of improving LS BMD.

Increased serum parathyroid hormone (PTH) during moderate-intensity exercise has been reported, suggesting that such exercise may stimulate bone resorption. This study was undertaken to observe the effects of exhausting high-intensity intermittent exercise (HIIE) on serum PTH and on blood parameters that may affect PTH secretion during exercise. Seven young trained adults exercised on 2 days after overnight fasting. On the HIIE day, they performed 6–7 exhausting bouts of 20-sec bicycle exercise (intensity, 170% VO2max) with intervening 10-sec rests. On the moderate-intensity exercise (MIE) day, the subjects biked for 60 min at 70% VO2max. The peak lactate concentration in blood after the HIIE was 15.2 ± 1.3 mmol/l. The blood lactate concentration at the end of the MIE was 2.2 ± 0.9 mmol/l. The HIIE significantly reduced the serum PTH (Pre: 30 ± 5 pg/ml, 10 min post-HIIE: 22 ± 4 pg/ml, p < 0.05), whereas the MIE significantly elevated the serum PTH. The HIIE induced a significant increase in serum ionized Ca (iCa); but MIE did not affect iCa. The serum cortisol concentration post-MIE was significantly higher than that observed pre-exercise; no changes from the pre-exercise value were noted post-HIIE. The serum phosphate concentration immediately post-HIIE increased significantly to the same level as that post-MIE. No changes in serum C-terminal telopeptide of Type I collagen (a marker of bone resorption) was observed after the HIIE or MIE. Although these results do not identify stimulator(s) for PTH secretion during HIIE and MIE, they indicate that HIIE does not induce an exercise-induced increase in PTH (which might deteriorate bone metabolism).

BACKGROUND Patients with continuous-flow left ventricular assist devices (CF-LVADs) experience limitations in functional capacity and frequently, right ventricular (RV) dysfunction. We sought to characterize RV function in the context of global cardiopulmonary performance during exercise in this population. METHODS A total of 26 patients with CF-LVAD (aged 58 ± 11 years, 23 males) completed a hemodynamic assessment with either conductance catheters (Group 1, n = 13) inserted into the right ventricle to generate RV pressure‒volume loops or traditional Swan‒Ganz catheters (Group 2, n = 13) during invasive cardiopulmonary exercise testing. Hemodynamics were collected at rest, 2 sub-maximal levels of exercise, and peak effort. Breath-by-breath gas exchange parameters were collected by indirect calorimetry. Group 1 participants also completed an invasive ramp test during supine rest to determine the impact of varying levels of CF-LVAD support on RV function. RESULTS In Group 1, pump speed modulations minimally influenced RV function. During upright exercise, there were modest increases in RV contractility during sub-maximal exercise, but there were no appreciable increases at peak effort. Ventricular‒arterial coupling was preserved throughout the exercise. In Group 2, there were large increases in pulmonary arterial, left-sided filling, and right-sided filling pressures during sub-maximal and peak exercises. Among all participants, the cardiac output‒oxygen uptake relationship was preserved at 5.8:1. Ventilatory efficiency was severely abnormal at 42.3 ± 11.6. CONCLUSIONS Patients with CF-LVAD suffer from limited RV contractile reserve; marked elevations in pulmonary, left-sided filling, and right-sided filling pressures during exercise; and severe ventilatory inefficiency. These findings explain mechanisms for persistent reductions in functional capacity in this patient population.

Some adipocytes are produced from bone marrow hematopoietic stem cells. In vitro studies previously indicated that these bone marrow-derived adipocytes (BMDAs) were generated from adipose tissue macrophage (ATM) that lose their hematopoietic markers and acquire mesenchymal markers prior to terminal adipogenic differentiation. Here we interrogated whether this hematopoietic-to-mesenchymal transition drives BMDA production In vitro. We generated transgenic mice in which the lysozyme gene promoter (LysM) indelibly labeled ATM with green fluorescent protein (GFP). We discovered that adipose stroma contained a population of LysM-positive myeloid cells that simultaneously expressed hematopoietic/myeloid markers (CD45 and CD11b), and mesenchymal markers (CD29, PDGFRa and Sca-1) typically found on conventional adipocyte progenitors. These cells were capable of adipogenic differentiation In vitro and In vitro, while other stromal populations deficient in PDGFRa and Sca-1 were non-adipogenic. BMDAs and conventional adipocytes expressed common fat cell markers but exhibited little or no expression of hematopoietic and mesenchymal progenitor cell markers. The data indicate that BMDAs are produced from ATM simultaneously expressing hematopoietic and mesenchymal markers rather than via a stepwise hematopoietic-to-mesenchymal transition. Because BMDA production is stimulated by high fat feeding, their production from hematopoietic progenitors may maintain adipocyte production when conventional adipocyte precursors are diminished.

Objective The purpose of this study was to determine whether suppression of ovarian function (gonadotropin-releasing hormone agonist [GnRHAG ]) for 24 weeks in premenopausal women approaching menopause causes changes in body composition and a decline in free-living physical activity energy expenditure (PAEE) and whether endurance exercise training attenuates the changes. Methods Premenopausal women who were approaching menopause (mean [SD]: age 46 [3] years, BMI 26.3 [4.8] kg/m2 ) were randomized to 24 weeks of GnRHAG (n = 14), GnRHAG + Exercise (n = 11), or placebo (n = 9). Endurance exercise was performed 4 days per week with the goal of expending 200 to 300 kcal per session. Primary outcome measurements included body composition by dual-energy x-ray absorptiometry, total daily energy expenditure (TDEE), and PAEE by doubly labeled water, and resting energy expenditure (REE) by indirect calorimetry. Results Changes in TDEE, PAEE, REE, or body composition were not different between groups. However, within the GnRHAG group, fat mass increased (mean [SE]: total 1.7 [0.4] kg, trunk 0.9 [0.2] kg, leg 0.6 [0.2] kg) and fat-free leg mass decreased (mean [SE]: -0.4 [0.2] kg) significantly. Conclusions In premenopausal women approaching menopause, ovarian hormone suppression resulted in increased adiposity without alterations in TDEE, PAEE, or REE.

Background To date, no medication has slowed the progression of Parkinson’s disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. Methods This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60–65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80–85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. Discussion SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. Trial registration ClinicalTrials.govNCT04284436. Registered on February 25, 2020.

The associations between objective measures of sleep duration and bone outcomes in older men are unknown. No consistent, significant association was identified between sleep duration and bone mineral density (BMD) in the current analysis. However, future research should determine if vitamin D status modifies this relationship. Prior studies, predominantly in women, reported that long and short self-reported sleep duration are associated with lower BMD. Associations between actigraphy-determined sleep duration and BMD or bone turnover markers (BTMs) in older men are unknown. Men in The Osteoporotic Fractures in Men (MrOS) Study with wrist actigraphy and concurrent BMD assessment but without comorbidities affecting bone health were included. Sleep duration was considered as a continuous (N = 1926) and dichotomized variable where men were classified as getting the recommended (7–8 h/night; N = 478) or short (< 6 h/night; N = 577) sleep. The cross-sectional association between BMD, BTMs, and sleep duration was examined using a t test or linear regression, where appropriate, in unadjusted and adjusted models. There were no clinically or statistically significant differences in BMD at the L-spine, total hip, or femoral neck between men getting the recommended vs. short sleep duration, using actigraphy or self-reported sleep duration (all p ≥ 0.07). When sleep duration was considered as a continuous variable, femoral neck BMD was higher in men with longer self-reported sleep duration (β = 0.006 ±0.003, p = 0.02), but this was not significant after further adjustment. In men with low 25OHD (< 20 ng/mL), longer actigraphy-determined sleep duration was associated with higher total hip BMD (β = 0.016 ± 0.008; p = 0.04). Sleep duration and BTMs were not associated. Sleep duration was not associated with hip or L-spine BMD or BTMs in older men. Future research should determine if vitamin D status or other factors modify this relationship.

Women's health and sex differences research remain understudied. In 2016, to address the topic of sex differences, the Center for Women’ s Health Research (CWHR) at the University of Colorado (cwhr@ucdenver.edu) held its inaugural National Conference, “Sex Differences Across the Lifespan: A Focus on Metabolism” and published a report summarizing the presentations. Two years later, in 2018, CWHR organized the 2nd National Conference. The research presentations and discussions from the 2018 conference also addressed sex differences across the lifespan with a focus on cardiometabolism and expanded the focus by including circadian physiology and effects of sleep on cardiometabolic health. Over 100 participants, including basic scientists, clinicians, policymakers, advocacy group leaders, and federal agency leadership participated. The meeting proceedings reveal that although exciting advances in the area of sex differences have taken place, significant questions and gaps remain about women's health and sex differences in critical areas of health. Identifying these gaps and the subsequent research that will result may lead to important breakthroughs.

Regular exercise enhances endothelial function in older men, but not consistently in estrogen-deficient postmenopausal women. Estradiol treatment improves basal endothelial function and restores improvements in endothelial function (flow-mediated dilation, FMD) to aerobic exercise training in postmenopausal women; however, estradiol treatment is controversial. Resveratrol, an estrogen receptor ligand, enhances exercise training effects on cardiovascular function and nitric oxide (NO) release in animal models, but impairs exercise training effects in men. We conducted a randomized cross-over, double-blinded, placebo-controlled pilot study to determine whether acute (single dose) resveratrol (250-mg tablet) or estradiol (0.05 mg/day transdermal patch) treatment enhances FMD at rest and after a single bout of moderate-intensity aerobic exercise in healthy estrogen-deficient postmenopausal women ( n = 15, 58.1 ± 3.2 yr). FMD was measured before and after (30, 60, and 120 min) a 40-min bout of moderate-intensity treadmill exercise (60–75% peak heart rate) under the respective conditions (separated by 1-2 wk). FMD was higher ( P < 0.05) before exercise and at all post-exercise time points in the resveratrol and estradiol conditions compared to placebo. FMD was increased from baseline by 120 min postexercise in the estradiol condition ( P < 0.001), but not resveratrol or PL conditions. Consistent with our previous findings, estradiol also enhances endothelial function in response to acute endurance exercise. Although resveratrol improved basal FMD, there was no apparent enhancement of FMD to acute exercise and, therefore, may not act as an estradiol mimetic. NEW & NOTEWORTHY The benefits of endurance exercise training on endothelial function are diminished in estrogen-deficient postmenopausal women, but estradiol treatment appears to restore improvements in endothelial function in this group. We show that basal endothelial function is enhanced with both acute estradiol and resveratrol treatments in estrogen-deficient postmenopausal women, but endothelial function is only enhanced following acute endurance exercise with estradiol treatment.

Loss of total muscle force during aging has both atrophic and non-atrophic components. The former deficit is a direct consequence of reduced muscle mass while the latter has been attributed to a depression of excitation-contraction (EC) coupling. It is well established that age-onset reductions in sex hormone production regulate the atrophic component in both males and females. However, it is unknown whether the non-atrophic component is influenced by sex hormones. Since the non-atrophic component has been linked mechanistically to reduced expression of the skeletal muscle L-type Ca2+ channel (CaV1.1), we recorded L-type Ca2+ currents, gating charge movements and depolarization-induced changes in myoplasmic Ca2+ from flexor digitorum brevis (FDB) fibers of naive and gonadectomized mice of both sexes. Our first set of experiments sought to identify any basal differences in EC coupling or L-type Ca2+ flux between the sexes; no detectable differences in any of the aforementioned parameters were observed between FDB harvested from either naive males or females. In the latter segments of the study, ovariectomy (OVX) and orchiectomy (ORX) models were used to assess the possible influence of sex hormones on EC coupling and/or L-type Ca2+ flux. In these experiments, FDB fibers harvested from OVX and ORX mice both showed no differences in L-type Ca2+ current, gating charge movement or depolarization-induced changes in Ca2+ release from the sarcoplasmic reticulum. Taken together, our results indicate L-type Ca2+ channel function and EC coupling are: 1) equivalent between the sexes, and 2) not significantly regulated by sex hormones. Since recent NIH review guidelines mandate the consideration of sex differences as a criterion for review, our work indicates the suitability of either sex for the study of the fundamental mechanisms of EC coupling. Thus, our findings may accelerate the research process by conserving animals, labor and financial resources.

Purpose: The purpose of this study was to determine if the use of menopausal hormone therapy (HT) is related to the development of neovascular (NV) age-related macular degeneration (AMD), geographic atrophy (GA) and/or early/intermediate AMD.Methods: A case-control study was conducted from patients prospectively recruited from July 2014 to June 2019. Cases were females with AMD recruited into a registry and controls were females with age-related cataract and no AMD. Age-related macular degeneration was categorized into NV-AMD, GA, and early/intermediate. Hormone therapy (historic and current) was self-reported by the patient and categorized as ever/never use. Adjusted odds ratios (ORs) from multinomial logistic regressions are presented for each AMD group.Results: Female AMD case patients (n = 409) and controls (n = 132) were included in the analytic database. Almost half (45.5%) of the female AMD patients had NV-AMD, 14.9% had GA, and 39.6% had early/intermediate AMD. Among all study participants, 285 (52.7%) reported historic and/or current use of HT. Controls were significantly more likely to have any HT use (71.2%), compared to 43.0% (p ≤ 0.001) of NV-AMD patients, 47.5% (p = .002) of GA patients, and 50.6% (p ≤ 0.001) of early/intermediate AMD patients. Adjusted for potential confounders of age and Caucasian race, cases were significantly more likely to have lower HT use compared to controls: NV-AMD, OR = 0.31 (95%CI: 0.18-0.54), GA, OR = 0.40 (95%CI: 0.20-0.80), and early/intermediate AMD, OR = 0.36 (95%CI: 0.22-0.61).Conclusion: Our case-control study found that the use of HT was associated with a lower odds of all AMD stages studied: NV-AMD, GA and early/intermediate.

Simple Summary While physical activity has been associated with reduced cancer risk, it is not well understood why this is the case. One possible reason is that physical activity affects DNA methylation—a process that functions to turn certain genes “on” or “off”—which can affect cancer-related processes in the body. We tested this in an experimental study, where women aged 30–45 were randomly assigned to complete 16 weeks of exercise of varying intensity and duration. We hypothesized that higher levels of exercise would lead to changes in DNA methylation that would be associated with reduced cancer risk. Contrary to our hypotheses, we found that the total amount of exercise completed was not associated with changes in DNA methylation, though we did find that increases in VO2max, a marker of physical fitness, were associated with decreases in methylation of the BRCA1 gene, and higher levels of exercise during a follow-up period were associated with lower levels of methylation of the GALNT9 gene. This study provides preliminary evidence that increased exercise behavior or fitness may affect the methylation of some genes that are related to breast cancer. Abstract Emerging research suggests that one mechanism through which physical activity may decrease cancer risk is through its influence on the methylation of genes associated with cancer. The purpose of the current study was to prospectively test, using a rigorous experimental design, whether aerobic exercise affects DNA methylation in genes associated with breast cancer, as well as whether quantity of exercise completed affects change in DNA methylation in a dose–response manner. 276 women (M age = 37.25, SD = 4.64) were recruited from the Denver metro area for a randomized controlled trial in which participants were assigned to a supervised aerobic exercise program varying in a fully crossed design by intensity (55–65% versus 75–85% of VO2max) and duration (40 versus 20 min per session). DNA methylation was assessed via blood samples provided at baseline, after completing a 16-week supervised exercise intervention, and six months after the intervention. 137 participants completed the intervention, and 81 had viable pre-post methylation data. Contrary to our hypotheses, total exercise volume completed in kcal/kg/week was not associated with methylation from baseline to post-intervention for any of the genes of interest. An increase in VO2max over the course of the intervention, however, was associated with decreased post-intervention methylation of BRCA1, p = 0.01. Higher levels of self-reported exercise during the follow-up period were associated with lower levels of GALNT9 methylation at the six-month follow-up. This study provides hypothesis-generating evidence that increased exercise behavior and or increased fitness might affect methylation of some genes associated with breast cancer to reduce risk.

Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause—known as the menopause transition (or perimenopause)—changes in hormones and body composition increase a woman’s overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life-span are adequately represented.

Glycans attached to immunoglobulin G (IgG) directly affect this antibody effector functions and regulate inflammation at several levels. The composition of IgG glycome changes significantly with age. In women, the most notable change coincides with the perimenopausal period. Aiming to investigate the effect of estrogen on IgG glycosylation, we analysed IgG and total serum glycomes in 36 healthy premenopausal women enrolled in a randomized controlled trial of the gonadotropin-releasing hormone analogue (GnRHAG) leuprolide acetate to lower gonadal steroids to postmenopausal levels and then randomized to transdermal placebo or estradiol (E2) patch. The suppression of gonadal hormones induced significant changes in the IgG glycome, while E2 supplementation was sufficient to prevent changes. The observed glycan changes suggest that depletion of E2 primarily affects B cell glycosylation, while liver glycosylation stays mostly unchanged. To determine whether previously identified IgG GWAS hits RUNX1, RUNX3, SPINK4, and ELL2 are involved in downstream signaling mechanisms, linking E2 with IgG glycosylation, we used the FreeStyle 293-F transient system expressing IgG antibodies with stably integrated CRISPR/dCas9 expression cassettes for gene up- and downregulation. RUNX3 and SPINK4 upregulation using dCas9-VPR resulted in a decreased IgG galactosylation and, in the case of RUNX3, a concomitant increase in IgG agalactosylation.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. The ~ 3-week protocol included two segments: “baseline,” ≥ 10-h sleep opportunity/day × 5 days; “forced desynchrony” (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20–59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (β) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. Plasma P1NP levels declined significantly within the first 10 days of FD ($$ \hat{\beta} $$ = − 1.33 μg/L per 24 h, p

The doubly labeled water (DLW) method is the gold standard methodology for determination of free-living, total daily energy expenditure (TEE). However, there is no single accepted approach for either the sampling protocols (daily vs. two-point, in which samples are collected after dosing and at the end of the measurement period) or the calculations used in the determination of the rate of carbon dioxide production (rCO2) and TEE. Moreover, fluctuations in natural background abundances introduce error in the calculation of rCO2 and TEE. The advent of new technologies makes feasible the possibility of including additional isotope measures (17O) to account for background variation, which may improve accuracy. Sixteen subjects were studied for 7 consecutive days in a whole-room indirect calorimeter (IC) with concurrent measurement of TEE by DLW. Daily urine samples were obtained and isotope ratios were determined using off-axis integrated cavity output spectroscopy (OA-ICOS). We determined the best combination of approaches for estimating dilution spaces and elimination rates and calculated average daily volume of carbon dioxide production (VCO2) using six different published equations. Using this best combination, multi-point fitting of isotope elimination rates using the daily urine samples substantially improved the average precision (4.5% vs. 6.0%) and accuracy (−0.5% vs. −3.0%) compared with the two-point method. This improvement may partly reflect the less variable day-to-day chamber measurements of energy expenditure. Utilizing 17O measurements to correct for errors due to background isotope fluctuations provided additional but minor improvements in precision (4.2% vs. 4.5%) and accuracy (0.2% vs. 0.5%). This work shows that optimizing sampling and calculation protocols can improve the accuracy and precision of DLW measurements.

Hyperhomocysteinemia is associated with endothelial dysfunction and increased cardiovascular disease (CVD). We determined whether elevated homocysteine (Hcy) and markers of Hcy metabolism were associated with the previously reported endothelial dysfunction across stages of the menopause transition. Brachial artery flow-mediated dilation (FMD) and plasma concentrations of Hcy, cysteine, and methionine were measured in healthy women ( n = 128) 22–70 yr of age categorized as premenopausal ( n = 35), perimenopausal (early: n = 16; late: n = 21), and postmenopausal (early: n = 21; late: n = 35). Dietary intake of micronutrients involved in Hcy metabolism (e.g., vitamins B6, B12, folate) was assessed in a subpopulation of women. Hcy and cysteine concentrations were progressively higher, and methionine was progressively lower across menopausal stages (all P < 0.005). The higher Hcy and cysteine concentrations correlated with lower circulating estradiol levels ( r = −0.49 and −0.50, respectively, both P < 0.001). FMD was inversely correlated with Hcy ( r = −0.25, P = 0.004) and cysteine ( r = −0.39, P < 0.001) and positively correlated with methionine concentrations ( r = 0.25, P = 0.005). Dietary intake of vitamins B6 and B12 (both P < 0.05) were lower in postmenopausal women. Vitamin B12 intake correlated with FMD ( r = 0.22, P = 0.006). These data suggest that declines in estradiol across stages of the menopause transition may lead to elevations in Hcy and cysteine that may contribute to endothelial dysfunction in postmenopausal women. Future studies should examine whether targeting Hcy metabolism during the perimenopausal to early postmenopausal period with interventions, including diet, attenuates or reverses the decline in endothelial function in women.NEW & NOTEWORTHY Declines in circulating estradiol across the stages of the menopausal transition may lead to elevations in Hcy and cysteine concentrations that may contribute to endothelial dysfunction. Abnormalities in the Hcy metabolic pathways, possibly related to dietary deficiencies of vitamins B12 and B6 and folate, may contribute to elevations in Hcy and cysteine concentrations. Findings also suggest that higher cysteine levels may be more damaging to the vascular endothelium than Hcy.

Women with type 1 diabetes (T1D) are at increased risk for fracture. We studied the association of T1D and young age at T1D onset (T1D onset before 20 years) on bone structural quality. 24 postmenopausal women with T1D (mean age 60.9 years, mean T1D duration 41.7 years) and 22 age, sex- and body mass index (BMI)-matched controls underwent dual X-ray absorptiometry (DXA) measured areal bone mineral density (aBMD) at the lumbar spine, hip and distal radius. Bone mass, geometry and estimated bone strength were assessed at distal and shaft of non-dominant radius and tibia using peripheral quantitative computed tomography (pQCT). Postmenopausal women with T1D had lower trabecular volumetric bone mineral density (vBMD) (LSM ± SEM; 166.1 ± 8.2 vs 195.9 ± 8.3 mg/cm3, p = 0.02) and compressive bone strength (24.6 ± 1.8 vs 30.1 ± 1.9 mg2/mm4, p = 0.04) at the distal radius compared to controls adjusting for age, BMI and radius length. At the distal radius, patients with young onset T1D had lower total vBMD (258.7 ± 19.7 vs 350.8 ± 26.1 mg/cm3, p = 0.02) and trabecular vBMD (141.4 ± 11.6 vs 213.6 ± 15.4 mg/cm3, p = 0.003) compared to adult onset T1D patients adjusting for age, BMI and the radius length. At the tibial shaft, young onset T1D patients had larger endosteal circumference (39.1 ± 1.2 vs 32.1 ± 1.6 mm, p = 0.005) with similar periosteal circumference (67.1 ± 0.9 vs 65.1 ± 1.2 mm, p = 0.2) resulting in reduced cortical thickness (4.4 ± 0.1 vs 5.2 ± 0.1 mm, p = 0.004) compared to adult onset T1D patients adjusting for age, BMI and the tibia length. There was no difference in the lumbar spine, femoral neck, total hip and distal radius DXA-measured aBMD between subjects with T1D and controls. T1D is associated with lower trabecular vBMD at the distal radius. T1D onset before age 20 is associated with cortical bone size deficits at the tibial shaft.

Introduction Exercise can cause a decrease in serum ionized calcium (iCa) concentration, which stimulates parathyroid hormone (PTH) secretion and activates bone resorption. We postulated that dermal Ca loss during cycling exercise is the major determinant of the serum iCa, PTH, and bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) responses. Methods To investigate this, women (n = 13) and men (n = 12) age 18 to 45 yr performed the same exercise bout under cool (18°C) and warm (26°C) conditions. Exercise was 60 min of cycling at ~75% of peak aerobic power. Sweat samples were obtained during exercise using a skin patch method, and blood samples were obtained before and during exercise and during 60 min of recovery. Results Sweat volume and estimated sweat Ca loss were 50% higher for the warm condition than the cool condition. Despite this, there were no differences between thermal conditions in the changes (mean, 95% confidence interval [95% CI]) in iCa (cool, -0.07 mg·dL; 95% CI, -0.16 to 0.03); warm, -0.07 mg·dL; 95% CI, -0.20 to 0.05), PTH (cool, 34.4 pg·mL; 95% CI, 23.6-45.2; warm: 35.8 pg·mL; 95% CI, 22.4-49.1), or CTX (cool, 0.11 ng·mL; 95% CI, 0.08-0.13; warm, 0.15 ng·mL; 95% CI, 0.11-0.18). Adjusting for exercise-related shifts in plasma volume revealed a marked decline in vascular iCa content in the first 15 min of exercise (cool, -0.85 mg·dL; 95% CI, -1.01 to -0.68; warm, -0.85 mg·dL; 95% CI, -1.05 to -0.66), before substantial sweat Ca loss had occurred. Conclusions This indicates that dermal Ca loss was not the primary trigger for the increases in PTH and CTX during exercise. Further research is necessary to understand the causes and consequences of the disruption in Ca homeostasis during exercise and specifically the extravascular shift in iCa.

There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels—a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability.

Objective Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat-free mass in older women and men enrolled in four similar clinical trials. Design Pooled analyses of data from four double-blinded, randomized controlled trials. Participants Women (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months. Measurements Twelve-month changes in BMD, fat mass, fat-free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin-like growth factor-1 (IGF-1). Results Women on DHEA had increases (mean ± SD; all P Conclusions Dehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit-to-risk profile for women than oestrogen therapy.

Objective To investigate changes in nutritive blood flow as well as interstitial glucose and lactate within an active myofascial trigger point (MTrP) following massage. Design Randomized, placebo-controlled trial. Setting Subjects were recruited from the general population; procedures were conducted at a research center affiliated with a university hospital. Participants Adults (N=25) (18-49y old) with episodic or chronic tension-type headache and an active MTrP in the upper trapezius muscle. Interventions Subjects were randomized to receive a single trigger point (TrP) release massage or sham ultrasound (US) treatment at an active MTrP in the upper trapezius muscle. Microdialysis was used to continuously sample interstitial fluid from the MTrP before, during, and for 60 minutes following intervention. Main Outcome Measures The primary outcome measure was nutritive blood flow within the MTrP as measured by microdialysis ethanol clearance; secondary measures included dialysate glucose, dialysate lactate, and subject discomfort with the procedures. Pressure-pain threshold (PPT) was determined to assess treatment effectiveness. Results There was no treatment effect of TrP release massage on nutritive blood flow (P=.663) or dialysate glucose (P=.766). The interaction for lactate was significant indicating that dialysate lactate increased for TrP release massage vs sham US (P=.04); maximum lactate increase over baseline was observed at 60 minutes after TrP release massage (P=.007, 0.128 μM, 95% confidence interval 0.045-0.212). Pain evoked by probe placement into an active MTrP was low. An interaction effect on PPT was significant (P=.005). Conclusion TrP release massage of an active MTrP affected anaerobic metabolism as represented by an increase in dialysate lactate without change in nutritive blood flow or dialysate glucose. The lack of a treatment effect on blood flow is discussed.

Non-steroidal anti-inflammatory drugs (NSAIDs) taken before exercise have been shown to impair bone formation. NSAIDs also suppress inflammatory cytokines, such as interleukin-6 (IL-6), that can have pro-resorptive effects. It is unclear how taking NSAIDs timed around exercise influences inflammatory and bone biomarkers following an acute exercise bout in older adults. To determine if timing of ibuprofen use relative to a single exercise bout has acute effects on serum IL-6, bone-specific alkaline phosphatase (BAP, marker of bone formation), and c-telopeptide of type I collagen (CTX, marker of bone resorption). As part of a 36-week exercise intervention, participants aged 60 to 75 years were randomized to 3 groups: placebo before and after exercise (PP), ibuprofen before and placebo after exercise (IP), or placebo before and ibuprofen after exercise (PI). Acute responses were studied in a subset of participants (12 PP, 17 IP, 13 PI). Blood was sampled before and immediately, 30 min, and 60 min after exercise for IL-6, BAP, and CTX. The exercise-induced increase in IL-6 was blunted in response to IP when compared to PI 60-min after exercise (p

Although estradiol (E2) has been believed to be the most critical factor in the menopause-associated decrease in bone mineral density (BMD), the role of increasing follicle stimulating hormone (FSH) during menopause is relatively unclear. We determined the extent to which hip and lumbar spine BMD differ among the stages of menopause in healthy women, and whether BMD is associated with FSH and E2 levels. A cross-sectional study of 141 healthy women classified as premenopausal (Pre, 38 &plusmn, 6 yrs, mean &plusmn, SD, n = 30), early perimenopausal (EPeri, 50 &plusmn, 3yrs, n = 31), late perimenopausal (LPeri, 4yrs, n = 30), early postmenopausal (EPost, 55 &plusmn, 3yrs, n = 24), or late postmenopausal (LPost, 62 &plusmn, 4 yrs, n = 26), was conducted. Spine/hip BMD and sex hormones were measured using dual-energy X-ray absorptiometry and enzymatic/colorimetric methods, respectively. Compared to EPeri, spine BMD was lower (p &lt, 0.05) in LPeri, EPost, and LPost and hip BMD was lower (p &lt, 0.05) in EPost and LPost. BMD was inversely associated with FSH (spine: r = &minus, 0.341, hip: r = &minus, 0.271, p &lt, 0.05) and directly associated with E2 (spine: r = 0.274, hip: r = 0.256, p &lt, 0.05). The menopause-related loss of spine and hip BMD is associated not only with low E2 but also higher FSH. Future studies are essential to delineating the mechanisms by which FSH regulates bone health in aging women.

Background: Continuous-flow (CF) left ventricular assist devices (LVADs) improve outcomes for patients with advanced heart failure (HF). However, the lack of a physiological pulse predisposes to side-effects including uncontrolled blood pressure (BP), and there are little data regarding the impact of CF-LVADs on BP regulation. Methods: Twelve patients (10 males, 60±11 years) with advanced heart failure completed hemodynamic assessment 2.7±4.1 months before, and 4.3±1.3 months following CF-LVAD implantation. Heart rate and systolic BP via arterial catheterization were monitored during Valsalva maneuver, spontaneous breathing, and a 0.05 Hz repetitive squat-stand maneuver to characterize cardiac baroreceptor sensitivity. Plasma norepinephrine levels were assessed during head-up tilt at supine, 30 o and 60 o . Heart rate and BP were monitored during cardiopulmonary exercise testing. Results: Cardiac baroreceptor sensitivity, determined by Valsalva as well as Fourier transformation and transfer function gain of Heart rate and systolic BP during spontaneous breathing and squat-stand maneuver, was impaired before and following LVAD implantation. Norepinephrine levels were markedly elevated pre-LVAD and improved—but remained elevated post-LVAD (supine norepinephrine pre-LVAD versus post-LVAD: 654±437 versus 323±164 pg/mL). BP increased during cardiopulmonary exercise testing post-LVAD, but the magnitude of change was modest and comparable to the changes observed during the pre-LVAD cardiopulmonary exercise testing. Conclusions: Among patients with advanced heart failure with reduced ejection fraction, CF-LVAD implantation is associated with modest improvements in autonomic tone, but persistent reductions in cardiac baroreceptor sensitivity. Exercise-induced increases in BP are blunted. These findings shed new light on mechanisms for adverse events such as stroke, and persistent reductions in functional capacity, among patients supported by CF-LVADs. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03078972.

Glycan age is a recently developed biomarker based on glycans attached to immunoglobulin G (IgG). In large population cohorts, glycan age associates well with lifestyle and disease-risk biomarkers, while some studies suggested that glycan changes precede the development of several age-associated diseases. In this study, we evaluated the effects of estrogen on the glycan age. Gonadal hormones were suppressed in 36 healthy young women by gonadotropin-releasing hormone agonist therapy for 6 months. In 15 of them, estradiol was supplemented, while 21 received placebo resulting in very low estrogen levels during the intervention. IgG was isolated from plasma samples before the intervention, after 6 months of intervention, and after subsequent 4-month recovery. At each time point, we performed IgG N- glycoprofiling by hydrophilic interaction ultra- performance liquid chromatography (HILIC-UPLC) and the glycan age index was calculated. Deprivation of gonadal hormones resulted in a median increase of glycan age for 9.1 years which was completely prevented by transdermal estradiol therapy. After the recovery period, the glycan age returned to baseline values in both groups. These results suggest that IgG glycans and consequently also the glycan age are under a strong influence of gonadal hormones and that estradiol therapy can prevent the increase of glycan age that occurs in the perimenopausal period.

Background Bone is a plastic tissue that is responsive to its physical environment. As a result, exercise interventions represent a potential means to influence the bone. However, little is currently known about how various exercise and participant characteristics interact to influence bone metabolism. Acute, controlled, interventions provide an in vivo model through which the acute bone response to exercise can be investigated, typically by monitoring circulating bone biomarkers. Currently, substantial heterogeneity in factors such as study design, quality, exercise, and participant characteristics render it difficult to synthesize and evaluate the available evidence. Using a systematic review and meta-analytic approach, the aim of this investigation is to quantify the effect of an acute exercise bout on circulating bone biomarkers as well as examine the potential factors that may moderate this response, e.g., variation in participant, exercise, and sampling characteristics. Methods This protocol was designed in accordance with the PRISMA-P guidelines. Seven databases (MEDLINE, Embase, Sport Discus, Cochrane CENTRAL, PEDro, LILACS, and Ibec) will be systematically searched and supplemented by a secondary screening of the reference lists of all included articles. The PICOS (Population, Intervention, Comparator, Outcomes and Study Design) approach was used to guide the determination of the eligibility criteria. Participants of any age, sex, training, or health status will be considered for inclusion. We will select studies that have measured the bone biomarker response before and after an acute exercise session. All biomarkers considered to represent the bone metabolism will be considered for inclusion, and sensitivity analyses will be conducted using reference biomarkers for the measurement of bone resorption and formation (namely β-CTX-1 and P1NP). Multi-level, meta-regression models within a Bayesian framework will be used to explore the main effect of acute exercise on bone biomarkers as well as potential moderating factors. The risk of bias for each individual study will be evaluated using a modified version of the Downs and Black checklist while certainty in resultant outcomes will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Discussion A better understanding of the bone metabolic response to an acute bout of exercise has the potential to advance our understanding of the mechanisms through which this stimulus impacts bone metabolism, including factors that may moderate this response. Additionally, we will identify current gaps in the evidence base and provide recommendations to inform future research. Systematic review registration This protocol was prospectively registered in the Open Science Framework Registry (https://osf.io/6f8dz)

BACKGROUND People with HIV (PWH) are at an increased risk for adiposity and sarcopenia, despite effective antiretroviral therapy. Our objective was to compare the effects of prescribed exercise on body composition in older PWH and uninfected controls. SETTING Academic medical center. METHODS Sedentary PWH (n = 27) and uninfected controls (n = 28) aged 50-75 years completed 24 weeks of cardiovascular and resistance exercise. Participants completed 12 weeks of moderate-intensity exercise and then were randomized to moderate- or high-intensity exercise for 12 additional weeks. Total lean (LEAN) and fat mass (FAT), and visceral adipose tissue area (VAT) were measured using dual-energy x-ray absorptiometry at baseline and 24 weeks; baseline and intervention differences were compared by HIV serostatus using multivariable regression analyses adjusted for baseline values, age, and exercise adherence. RESULTS At baseline, PWH had significantly lower FAT (P = 0.003), but no significant differences in LEAN or VAT compared with controls (P > 0.20). Changes over 24 weeks were not significantly different by HIV serostatus, although controls tended to gain more LEAN (0.8 kg; range, 0-1.6 kg; P = 0.04] than PWH (0.6 kg; range, -0.2 to 1.4 kg; P = 0.12) and lose less FAT and VAT (controls: (-0.9 kg; range, -1.8 to 0.0 kg and -10.3 cm; range, -19.6, 1.0) cm; both P = 0.03 vs PWH: -2.0 kg; range, -2.9 to -1.1 kg and -17.7 cm; range, -27.1 to -8.2 cm; both P < 0.001). Exercise intensity differences were not apparent for LEAN, FAT, or VAT. CONCLUSIONS Exercise reduced total and visceral fat in older PWH and controls. Minimal gains in lean mass suggest that greater emphasis on resistance exercise may be needed to more effectively increase muscle in PWH.

Background: Subfertility in obese women is associated with chronic pituitary suppression, reduced sensitivity to GnRH and decreased sex steroid production. We have found evidence for a combined effect of hyperinsulinemia and high circulating fatty acids to acutely (4h infusion) suppress pituitary gonadotropin secretion and are currently investigating the effects of one-month exposure to a eucaloric high-fat diet (HFD) on gonadotropin levels in lean women. The aim of this study is to examine the effect of the one-month HFD on physical activity and body composition. Methods: 12 normal weight (BMI < 25 kg/m2), normally cycling female participants of reproductive age were given a one-month eucaloric HFD, from the onset of menses in one cycle through the next, with 48% calories from fat. A Fitbit was provided to monitor changes in daily activity and sleep throughout the study. Measurement of gonadotropin pulsatility and reproductive hormones were done using frequent blood sampling and daily urine excretion, respectively. These measurements were obtained for a total of 4 menstrual cycles: 1 pre-diet cycle, the HFD cycle, and 2 post-diet cycles. DEXA body composition was measured at baseline and at the end of the 2nd post diet cycle. Pre and post diet comparisons were done using linear mixed model testing and reported as estimated means ± standard error. Results: Mean number of daily steps were (9,226 ± 1,140) pre diet, (9,132 ± 1,140) during the diet and (7,533 ± 1,140) post diet. Daily active calories were (1,982 ± 99) pre diet, (1,975 ± 99) during the diet and (1,856 ± 99) post diet. Means in the HFD cycle did not differ from the pre-diet cycle. Daily sleeping minutes pre diet were (443 ± 19), (451 ± 20) during the diet and (412 ± 19) post diet, with no statistical difference between the 3 time points. BMI did not differ between pre-diet (21.84 ± 0.52) and post-diet (21.77 ± 0.52). DEXA body composition measurements indicated a statistically significant decrease in total fat percentage, (32.26 ± 1.53) pre diet and (31.31 ± 1.53) post diet, which does not appear clinically significant as the difference of less than 1% falls within the anticipated measurement error of the method. Visceral fat volume (cm3) did not differ between pre diet (299.51 ± 27.76) and post diet (295.53 ± 27.76). Conclusions: The complete cohort has not yet been fully recruited and analyzed. These preliminary findings indicate that women consuming a one-month, HFD maintain their usual level of physical activity and sleep patterns, and do not appear to sustain change in visceral fat. Further accrual of participants should clarify the small decrease in total body fat observed without a change in BMI. Supported by HD087314 ROI to NS UL1TR002535 to the Colorado Clinical and Translational Sciences Institute.

Non-steroidal anti-inflammatory drugs (NSAIDs) taken before exercise have been shown to impair bone formation. NSAIDs also suppress inflammatory cytokines, such as interleukin-6 (IL-6), that can have pro-resorptive effects. It is unclear how taking NSAIDs timed around exercise influences inflammatory and bone biomarkers following an acute exercise bout in older adults.To determine if timing of ibuprofen use relative to a single exercise bout has acute effects on serum IL-6, bone-specific alkaline phosphatase (BAP, marker of bone formation), and c-telopeptide of type I collagen (CTX, marker of bone resorption).As part of a 36-week exercise intervention, participants aged 60 to 75 years were randomized to 3 groups: placebo before and after exercise (PP), ibuprofen before and placebo after exercise (IP), or placebo before and ibuprofen after exercise (PI). Acute responses were studied in a subset of participants (12 PP, 17 IP, 13 PI). Blood was sampled before and immediately, 30 min, and 60 min after exercise for IL-6, BAP, and CTX.The exercise-induced increase in IL-6 was blunted in response to IP when compared to PI 60-min after exercise (p 0.001). There were no significant differences in the change in BAP or CTX between groups at any time points CONCLUSION: Ibuprofen taken before exercise dampened the inflammatory response to exercise but had no effects on bone biomarkers in older adults. It may be necessary to monitor changes for a longer time interval after an acute exercise bout to determine whether bone turnover is altered by ibuprofen or other NSAIDs.ClinicalTrials.gov: NCT00462722; Posted 04/19/2007.

Introduction: Exercise is a cost-effective, widely available intervention that has been reported to help maintain optimal bone mineral density (BMD) in men, however, consideration of exercise modality is needed if the aim is to promote skeletal health. A previous meta-analysis of randomised controlled trials observed a moderate benefit on femoral neck (FN) but no benefit on lumbar spine (LS) BMD. However, since that analysis more randomised controlled trials (RCTs) have been published and updated methods of meta-analysis have been developed and therefore an updated systematic review and meta-analysis is required. Methods and analysis: RCTs of >24 weeks and published in English up to 01/05/20 will be retrieved by searching 3 electronic databases, cross referencing and expert review. The primary outcome measures will be changes in FN and LS BMD and lower limb BMD. Risk of bias for each study will be assessed using the Cochrane Risk of Bias instrument for RCTs, while the strength of evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument. Standardised effect sizes will be calculated from each study and pooled using the inverse heterogeneity (IVhet) model. Trial Registration number: CRD42020180441.

Endothelial function declines progressively across stages of the menopause transition; however, the mechanisms contributing to this decline are unknown. We hypothesized that differences in endothelial function among pre-, peri, and postmenopausal women are related to differences in estradiol and oxidative stress. Brachial artery flow-mediated dilation (FMD) was measured in 87 healthy women categorized by menopause stage (24 premenopausal, 17 early and 21 late perimenopausal, and 25 postmenopausal) before and after 3 days of ovarian hormone suppression (gonadotropin releasing hormone antagonist [GnRH(ant)]) alone, and an additional 3 days of GnRH(ant) with concurrent transdermal estradiol or placebo add-back treatment. In 82 women, FMD during acute vitamin C (antioxidant) infusion was measured before and after GnRH(ant) + add-back. Before GnRH(ant), FMD was different among groups (p < 0.005; reduced across stages of menopause). Vitamin C increased FMD in late peri- and post- (p < 0.005) but not pre- or early perimenopausal women (p > 0.54). After GnRH(ant) alone, FMD decreased in pre- and peri- (p < 0.01), but not postmenopausal women, and was restored to premenopausal levels by estradiol add-back in the pre- and perimenopausal groups. Vitamin C improved FMD in pre-, peri-, and postmenopausal women on GnRH(ant) + placebo. There was no effect of vitamin C on FMD in women on GnRH(ant) + estradiol. These observations support the concept that the decline in endothelial function across the menopause transition is related to the loss of ovarian estradiol. The decline in estradiol may alter redox balance, thereby increasing oxidative stress and impairing endothelial function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00236-7) contains supplementary material, which is available to authorized users.

Purpose The purpose of this work is to determine whether an uncoupling of bone turnover markers (BTMs) occurs in women exposed to the combination of sleep restriction with circadian disruption (SRCD), as previously reported in men. Methods Four bone biomarkers (N-terminal propeptide of type I procollagen [P1NP] and osteocalcin = bone formation; C-telopeptide [CTX] = bone resorption; sclerostin = bone formation inhibitor) were measured in bihourly samples over 24 hours at baseline and after approximately 3 weeks of sleep restriction (~5.6 hours of sleep/24 hours) with concurrent circadian disruption (SRCD, recurring 28-hour “day” in dim light). Maximum likelihood estimation in a repeated-measures model was used to assess the effects of SRCD and age on bone biomarkers. Results Five women were young (22 ± 2.8 years) and four were older (58 ± 1.8 years). Baseline bone biomarker levels did not differ by age (all P ≥ .07). Bone formation markers were lower after SRCD (estimate ± SEE, ΔP1NP = –9.5 ± 2.8 μg/L, P = .01; Δosteocalcin = –2.3 ± 0.9 ng/mL, P = .04). The P1NP decline was greater in young women (ΔP1NP = –12.9 ± 3.7 μg/L, P = .01). After SRCD, CTX was significantly higher in young women (0.182 ± 0.069 ng/mL, P = .04) but did not change in older women. Conclusions These pilot data are similar to previous findings in men and suggest that SRCD negatively altered bone metabolism in women by decreasing markers of bone formation and, in young women, increasing a marker of bone resorption. If sustained, this pattern of BTM uncoupling may lead to bone loss and lower bone mineral density.

Age-related declines in skeletal muscle mass (i.e., sarcopenia) contribute to physical disability in older women. Although a menopause-related increase in fat mass is well documented, whether menopause influences muscle mass and sarcopenia is unclear. We determined the extent to which skeletal muscle mass differs across the stages of the menopause transition in women and whether these differences are associated with estradiol or other sex hormones. This was a cross-sectional study of 144 healthy women (aged 30–70 yr) classified as premenopausal [n = 30, 38 ± 6 yr (means ± SD)], early (n = 31, 50 ± 3 yr) and late (n = 30, 50 ± 4 yr) perimenopausal, and early (n = 26, 55 ± 3 yr) and late (n = 27, 62 ± 4 yr) postmenopausal. Appendicular lean mass (ALM) adjusted by the square of height in meters (ALM index; ALMi) was assessed by dual-energy X-ray absorptiometry. ALMi was lower (P < 0.05) in late perimenopausal and postmenopausal compared with early perimenopausal, with no significant differences between other groups (premenopausal 6.6 ± 0.6, early perimenopausal 6.8 ± 0.8, late perimenopausal 6.1 ± 0.8, early postmenopausal 6.5 ± 1.1, and late postmenopausal 6.2 ± 0.9 kg/m(2)). The prevalence of sarcopenia (ALMi ≤ 5.67 kg/m(2)) was 7%, 3%, 30%, 27%, and 32% in premenopausal, early and late perimenopausal, and early and late postmenopausal groups, respectively. ALMi measured across menopause stages was inversely correlated to follicle-stimulating hormone (FSH; r = −0.28, P = 0.003) but not to estradiol (r = 0.088, P = 0.34). The menopause transition appears to be a vulnerable period for the loss of skeletal muscle mass that may begin during the late perimenopausal transition. Future studies are necessary to investigate the potential effect of FSH on skeletal muscle. NEW & NOTEWORTHY Our data suggest that the late perimenopausal stage may be a vulnerable period for the loss of skeletal muscle, potentially related to elevations in FSH.

Key points Despite growing interest in right ventricular form and function in diseased states, there is a paucity of data regarding characteristics of right ventricular function - namely contractile and lusitropic reserve, as well as ventricular-arterial coupling, in the healthy heart during rest, as well as submaximal and peak exercise. Pressure-volume analysis of the right ventricle, during invasive cardiopulmonary exercise testing, demonstrates that that the right heart has enormous contractile reserve, with a three- or fourfold increase in all metrics of contractility, as well as myocardial energy production and utilization. The healthy right ventricle also demonstrates marked augmentation in lusitropy, indicating that diastolic filling of the right heart is not passive. Rather, the right ventricle actively contributes to venous return during exercise, along with the muscle pump. Ventricular-arterial coupling is preserved during submaximal and peak exercise in the healthy heart. Abstract Knowledge of right ventricular (RV) function has lagged behind that of the left ventricle and historically, the RV has even been referred to as a 'passive conduit' of lesser importance than its left-sided counterpart. Pressure-volume (PV) analysis is the gold standard metric of assessing ventricular performance. We recruited nine healthy sedentary individuals free of any cardiopulmonary disease (42 ± 12 years, 78 ± 11 kg), who completed invasive cardiopulmonary exercise testing during upright ergometry, while using conductance catheters inserted into the RV to generate real-time PV loops. Data were obtained at rest, two submaximal levels of exercise below ventilatory threshold, to simulate real-world scenarios/activities of daily living, and maximal effort. Breath-by-breath oxygen uptake was determined by indirect calorimetry. During submaximal and peak exercise, there were significant increases in all metrics of systolic function by three- to fourfold, including cardiac output, preload recruitable stroke work, and maximum rate of pressure change in the ventricle (dP/dtmax ), as well as energy utilization as determined by stroke work and pressure-volume area. Similarly, the RV demonstrated a significant, threefold increase in lusitropic reserve throughout exercise. Ventricular-arterial coupling, defined by the quotient of end-systolic elastance and effective arterial elastance, was preserved throughout all stages of exercise. Maximal pressures increased significantly during exercise, while end-diastolic volumes were essentially unchanged. Overall, these findings demonstrate that the healthy RV is not merely a passive conduit, but actively participates in cardiopulmonary performance during exercise by accessing an enormous amount of contractile and lusitropic reserve, ensuring that VA coupling is preserved throughout all stages of exercise.