Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial ...fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.
Abstract
Context
Studies of the possible cardiovascular risk of testosterone treatment are inconclusive.
Objective
To determine the effect of testosterone treatment on cardiovascular biomarkers in ...older men with low testosterone.
Design
Double-blind, placebo-controlled trial.
Setting
Twelve academic medical centers in the United States.
Participants
In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials.
Intervention
Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.
Main Outcome Measures
Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage.
Results
Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, −6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, −2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, −2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, −1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, −0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo.
Conclusions and Relevance
Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes.
Compared with placebo, testosterone treatment of older men with low testosterone was associated with small reductions in total, HDL, and LDL cholesterol and in insulin and HOMA-IR but not glucose.
OBJECTIVES: To examine the associations between insulin resistance and changes in body composition in older men without diabetes mellitus.
DESIGN: Longitudinal cohort study of older men participating ...in the Osteoporotic Fractures in Men (MrOS) study.
SETTING: Six U.S. clinical centers.
PARTICIPANTS: Three thousand one hundred thirty‐two ambulatory men aged 65 and older at baseline.
MEASUREMENTS: Baseline insulin resistance was calculated for men without diabetes mellitus using the homeostasis model assessment of insulin resistance (HOMA‐IR). Total lean, appendicular lean, total fat, and truncal fat mass were measured using dual energy X‐ray absorptiometry scans at baseline and 4.6 ± 0.3 years later in 3,132 men with HOMA‐IR measurements.
RESULTS: There was greater loss of weight, total lean mass, and appendicular lean mass and less gain in total fat mass and truncal fat mass with increasing quartiles of HOMA‐IR (P<.001 for trend). Insulin‐resistant men in the highest quartile had higher odds of 5% or more loss of weight (odds ratio (OR)=1.88, 95% confidence interval (CI)=1.46–2.43), total lean mass (OR=2.09, 95% CI=1.60–2.73) and appendicular lean mass (OR=1.57, 95% CI=1.27–1.95) and lower odds of 5% or more gain in total fat mass (OR=0.56, 95% CI=0.45–0.68) and truncal fat mass (OR=0.52, 95% CI=0.42–0.64) than those in the lowest quartile. These findings remained significant after accounting for age, site, baseline weight, physical activity, and change in physical activity. These associations were also independent of other metabolic syndrome features and medications.
CONCLUSION: Greater lean mass loss and lower fat mass gain occurred in insulin‐resistant men without diabetes mellitus than in insulin‐sensitive men. Insulin resistance may accelerate age‐related sarcopenia.
As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture.
To determine whether testosterone treatment of older men ...with low testosterone increases volumetric BMD (vBMD) and estimated bone strength.
Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization.
Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year.
Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months.
There were 211 participants (mean SD age, 72.3 5.9 years; 86% white; mean SD body mass index, 31.2 3.4). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, -1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, -1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD.
Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.
clinicaltrials.gov Identifier: NCT00799617.
Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.
To test the hypothesis that testosterone treatment of older men with low ...testosterone slows progression of noncalcified coronary artery plaque volume.
Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.
Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.
The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).
Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.
Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.
clinicaltrials.gov Identifier: NCT00799617.
Lessons From the Testosterone Trials Snyder, Peter J; Bhasin, Shalender; Cunningham, Glenn R ...
Endocrine reviews,
2018-June, Letnik:
39, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Abstract
The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled,
double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of
increasing the ...testosterone levels of older men with low testosterone. Testosterone
treatment increased the median testosterone level from unequivocally low at baseline to
midnormal for young men after 3 months and maintained that level until month 12. In the
Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile
function. In the Physical Function Trial, testosterone did not increase the distance
walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants,
testosterone did increase the distance walked. In the Vitality Trial, testosterone did not
increase energy but slightly improved mood and depressive symptoms. In the Cognitive
Function Trial, testosterone did not improve cognitive function. In the Anemia Trial,
testosterone increased hemoglobin in both men who had anemia of a known cause and in men
with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral
density and the estimated strength of the spine and hip. In the Cardiovascular Trial,
testosterone increased the coronary artery noncalcified plaque volume as assessed using
computed tomographic angiography. Although testosterone was not associated with more
cardiovascular or prostate adverse events than placebo, a trial of a much larger number of
men for a much longer period would be necessary to determine whether testosterone
increases cardiovascular or prostate risk.
The Testosterone Trials were conducted to determine if testosterone treatment would
benefit older men with low testosterone. This report describes the Trials' development and
results and the lessons learned.
The fitness of Canadian children and youth has not been measured in more than two decades, a period during which childhood obesity and sedentary behaviours have increased. This paper provides ...up-to-date estimates of the fitness of Canadians aged 6 to 19 years.
Data are from the 2007-2009 Canadian Health Measures Survey (CHMS), the most comprehensive direct health measures survey ever conducted on a nationally representative sample of Canadians. Descriptive statistics for indicators of body composition, aerobic fitness and musculoskeletal fitness are provided by sex and age group, and comparisons are made with the 1981 Canada Fitness Survey (CFS).
Fitness levels of children and youth have declined significantly and meaningfully since 1981, regardless of age or sex. Significant sex differences exist for most fitness measures. Fitness levels change substantially between ages 6 and 19 years. Youth aged 15 to 19 years generally have better aerobic fitness and body composition indicators than 20- to 39-year-olds.
This decline in fitness may result in accelerated chronic disease development, higher health care costs, and loss of future productivity.
Effects of Testosterone Treatment in Older Men Snyder, Peter J; Bhasin, Shalender; Cunningham, Glenn R ...
New England journal of medicine/The New England journal of medicine,
2016-Feb-18, Letnik:
374, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.
We assigned 790 men 65 years of age or older with a serum ...testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants.
Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.
In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).
In one-third of older men with anemia, no recognized cause can be found.
To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained ...anemia would increase their hemoglobin concentration.
A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014.
Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months.
The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors.
The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline.
Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels.
clinicaltrials.gov Identifier: NCT00799617.
Macronutrients, Diet Quality, and Frailty in Older Men Shikany, James M; Barrett-Connor, Elizabeth; Ensrud, Kristine E ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
06/2014, Letnik:
69, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background.
Frailty, a phenotype of multisystem impairment and expanding vulnerability, is associated with higher risk of adverse health outcomes not entirely explained by advancing age. We ...investigated associations of macronutrients, dietary fiber, and overall diet quality with frailty status in older community-dwelling men.
Methods.
Participants were 5,925 men aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study at six U.S. centers. Diet was assessed at baseline with a food frequency questionnaire. We assessed frailty status (robust, intermediate, or frail) at baseline and at a second clinic visit (a mean of 4.6 years later) using a slightly modified Cardiovascular Health Study frailty index. We used multinomial logistic regression to assess associations between macronutrient intake, dietary fiber, and the Diet Quality Index Revised with frailty status at baseline and at the second clinic visit.
Results.
At baseline, 2,748 (46.4%) participants were robust, 2,681 (45.2%) were intermediate, and 496 (8.4%) were frail. Carbohydrate, fat, protein, and dietary fiber showed no consistent associations with frailty status. Overall diet quality exhibited fairly consistent associations with frailty status. The Diet Quality Index Revised was inversely associated with frail status relative to robust status at the baseline visit (odds ratio for Q5 vs Q1 = 0.44, 95% confidence interval: 0.30, 0.63; p for trend < .0001) and at the second clinic visit (odds ratio for Q5 vs Q1 = 0.18, 95% confidence interval: 0.03, 0.97; p for trend = .0180).
Conclusions.
Overall diet quality was inversely associated with prevalent and future frailty status in this cohort of older men.
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