Sleep Extension in Short Sleepers: An Evaluation of Feasibility and Effectiveness for Weight Management and Cardiometabolic Disease Prevention

Sleep duration has become increasingly recognized as an important influencer of health. Epidemiologic and observational studies have shown associations between short sleep duration and increased risk for chronic cardiometabolic disorders, including obesity, type 2 diabetes, and cardiovascular disease. These associations have led to investigations into the potential causal pathways through which short sleep may increase risk for these disorders. Clinical intervention studies have demonstrated that restricting sleep in normal sleepers has adverse health effects, including insulin resistance, and increased blood pressure. The totality of evidence points to negative health effects of short sleep and the recognition of sleep as a lifestyle behavior that may be targeted for disease prevention. It is well established that consistent, adequate sleep is associated with the lowest risk of obesity and cardiometabolic disorders. Yet, it is unclear whether increasing sleep in short sleepers can improve health. In today's society, it is common for individuals to deprive themselves of sleep during the work week, with the intent to sleep longer during the weekend, or have “catch-up sleep.” Studies that have examined the health effects of extended sleep, post-sleep restriction, revealed some improvements in health outcomes. However, it is uncertain whether the improvements observed with catch-up sleep are sufficient to reverse the negative health effects of constant sleep restriction. Few intervention studies have been undertaken to determine whether extending sleep, long-term, in short sleepers is feasible and whether it can reduce the disease risk burden associated with short sleep duration. The purpose of this review is to highlight these studies and evaluate information related to the impact of sleep extension on risk factors for chronic cardiometabolic disorders. We discuss limitations of current research, including variability in participant characteristics and the extent to which sleep behaviors are modified and monitored. Although the evidence-base for benefits of sleep extension is still in the early stages, studies to date indicate that prolonging sleep, in short sleepers, may improve cardiometabolic risk. Finally, our review calls attention to areas that require further study and for larger scale studies of behavior modification to establish the health effects of sleep extension in short sleepers

Body composition changes with aging: The cause or the result of alterations in metabolic rate and macronutrient oxidation?

Abstract It has been well documented that as individuals age, body composition changes, even in the absence of changes in body weight. Studies have shown that fat mass increases and muscle mass decreases with age. However, it is unclear why such changes occur. Resting metabolic rate (RMR) and substrate oxidation rates have been examined with aging. It has been proposed that reductions in RMR and fat oxidation may lead to changes in body composition. Alternatively, changes in body composition with aging may lead to reductions in RMR. The purpose of this review is to provide an overview of the literature surrounding the impact of aging on RMR and substrate oxidation. Although long-term longitudinal studies are lacking, most cross-sectional studies or short-term longitudinal studies show a reduction in RMR with aging that cannot be explained by changes in body composition including loss in fat-free mass, where the latter includes atrophy or decreases in the mass of high metabolic rate organs. There is indirect evidence suggesting that the metabolic rate of individual organs is lower in older compared with younger individuals. With aging, we conclude that reductions in the mass of individual organs/tissues and in tissue-specific organ metabolic rate contribute to a reduction in RMR that in turn promotes changes in body composition favoring increased fat mass and reduced fat-free mass

Missing Data in Randomized Clinical Trials for Weight Loss: Scope of the Problem, State of the Field, and Performance of Statistical Methods

BACKGROUND: Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed and Cochrane databases (2000-2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e(-lambdat)) where lambda was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive. CONCLUSION/SIGNIFICANCE: Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management

International audienceSHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR \textless 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended

OxPhos Defects Cause Hypermetabolism and Reduce Lifespan in Cells and in Patients With Mitochondrial Diseases

Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases