Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart

Aging is associated with a decline in cardiac function due to a decreased myocardial reserve. This adverse cardiac remodeling comprises of a variety of changes, including a reduction in mitochondrial function and a decline in the expression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a central regulator of mitochondrial biogenesis and metabolic adaptation in the myocardium. To study the etiological involvement of PGC-1α in cardiac aging, we used mouse models mimicking the modest down- and upregulation of this coactivator in the old and the exercised heart, respectively. Young mice with reduced cardiac expression of PGC-1α recapitulated part of the age-related impairment in mitochondrial gene expression, but otherwise did not aggravate the aging process. Inversely however, moderate overexpression of PGC-1α counteracts numerous key age-related remodeling changes, e.g., by improving blood pressure, age-associated apoptosis, and collagen accumulation, as well as in the expression of many, but not all cardiac genes involved in mitochondrial biogenesis, dynamics, metabolism, calcium handling and contractility. Thus, while the reduction of PGC-1α in the heart is insufficient to cause an aging phenotype, moderate overexpression reduces pathological remodeling of older hearts and could thereby contribute to the beneficial effects of exercise on cardiac function in aging

PGC-1α expression in murine AgRP neurons regulates food intake and energy balance

Food intake and whole-body energy homeostasis are controlled by agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus of the hypothalamus. Key energy sensors, such as the AMP-activated protein kinase (AMPK) or sirtuin 1 (SIRT1), are essential in AgRP and POMC cells to ensure proper energy balance. In peripheral tissues, the transcriptional coactivator PGC-1α closely associates with these sensors to regulate cellular metabolism. The role of PGC-1α in the ARC nucleus, however, remains unknown.; Using AgRP and POMC neurons specific knockout (KO) mouse models we studied the consequences of PGC-1α deletion on metabolic parameters during fed and fasted states and on ghrelin and leptin responses. We also took advantage of an immortalized AgRP cell line to assess the impact of PGC-1α modulation on fasting induced AgRP expression.; PGC-1α is dispensable for POMC functions in both fed and fasted states. In stark contrast, mice carrying a specific deletion of PGC-1α in AgRP neurons display increased adiposity concomitant with significantly lower body temperature and RER values during nighttime. In addition, the absence of PGC-1α in AgRP neurons reduces food intake in the fed and fasted states and alters the response to leptin. Finally, both in vivo and in an immortalized AgRP cell line, PGC-1α modulates AgRP expression induction upon fasting.; Collectively, our results highlight a role for PGC-1α in the regulation of AgRP neuronal functions in the control of food intake and peripheral metabolism

No evidence for tephra in Greenland from the historic eruption of Vesuvius in 79 CE: implications for geochronology and paleoclimatology

Volcanic fallout in polar ice sheets provide important opportunities to date and correlate ice-core records as well as to investigate the environmental impacts of eruptions. Only the geochemical characterization of volcanic ash (tephra) embedded in the ice strata can confirm the source of the eruption, however, and is a requisite if historical eruption ages are to be used as valid chronological checks on annual ice layer counting. Here we report the investigation of ash particles in a Greenland ice core that are associated with a volcanic sulfuric acid layer previously attributed to the 79 CE eruption of Vesuvius. Major and trace element composition of the particles indicates that the tephra does not derive from Vesuvius but most likely originates from an unidentified eruption in the Aleutian arc. Using ash dispersal modelling, we find that only an eruption large enough to include stratospheric injection is likely to account for the sizeable (24–85 μm) ash particles observed in the Greenland ice at this time. Despite its likely explosivity, this event does not appear to have triggered significant climate perturbations, unlike some other large extra-tropical eruptions. In light of a recent re-evaluation of the Greenland ice-core chronologies, our findings further challenge the previous assignation of this volcanic event to 79 CE. We highlight the need for the revised Common Era ice-core chronology to be formally accepted by the wider ice-core and climate modelling communities in order to ensure robust age linkages to precisely dated historical and paleoclimate proxy records

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases

Identifying Key Predictors of Cognitive Dysfunction in Older People Using Supervised Machine Learning Techniques: Observational Study

Background: Machine learning techniques, specifically classification algorithms, may be effective to help understand key health, nutritional, and environmental factors associated with cognitive function in aging populations. Objective: This study aims to use classification techniques to identify the key patient predictors that are considered most important in the classification of poorer cognitive performance, which is an early risk factor for dementia. Methods: Data were used from the Trinity-Ulster and Department of Agriculture study, which included detailed information on sociodemographic, clinical, biochemical, nutritional, and lifestyle factors in 5186 older adults recruited from the Republic of Ireland and Northern Ireland, a proportion of whom (987/5186, 19.03%) were followed up 5-7 years later for reassessment. Cognitive function at both time points was assessed using a battery of tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with a score Results: In the classification of a low RBANS score ( Conclusions: The results suggest that it may be possible for a health care professional to make an initial evaluation, with a high level of confidence, of the potential for cognitive dysfunction using only a few short, noninvasive questions, thus providing a quick, efficient, and noninvasive way to help them decide whether or not a patient requires a full cognitive evaluation. This approach has the potential benefits of making time and cost savings for health service providers and avoiding stress created through unnecessary cognitive assessments in low-risk patients

Hydrologic Conditions Describe West Nile Virus Risk in Colorado

We examine the relationship between hydrologic variability and the incidence of human disease associated with West Nile virus (WNV; family Flaviviridae, genus Flavivirus) infection (hereafter termed “human WN cases”) in Colorado from 2002 to 2007. We find that local hydrologic conditions, as simulated by the Mosaic hydrology model, are associated with differences in human WN cases. In Colorado’s eastern plains, wetter spring conditions and drier summer conditions predict human WN cases. In Colorado’s western mountains, drier spring and summer conditions weakly predict human WN cases. These findings support two working hypotheses: (1) wet spring conditions increase the abundance of Culex tarsalis vectors in the plains, and (2) dry summer conditions, and respondent irrigational practices during such droughts, favor Cx. pipiens and Cx. tarsalis abundance throughout Colorado. Both of these processes potentially increase the local vector-to-host ratio, favoring WNV amplification among competent avian hosts and bridging to humans

Assessing for interaction between APOE ε4, sex and lifestyle on cognitive abilities

Objective: To test for interactions between APOE ε4 genotype and lifestyle factors on worse cognitive abilities in UK Biobank. Methods: Using UK Biobank cohort data, we tested for interactions between APOE ε4 allele presence, lifestyle factors of alcohol intake, smoking, total physical activity and obesity, and sex, on cognitive tests of reasoning, information processing speed, and executive function (n range = 70,988–324,725 depending on the test). We statistically adjusted for potential confounders of age, sex, deprivation, cardiometabolic conditions, and educational attainment. Results: There were significant associations between APOE ε4 and worse cognitive abilities, independent of potential confounders, and between lifestyle risk factors and worse cognitive abilities; however, there were no interactions at multiple correction-adjusted p < 0.05, against our hypotheses. Conclusions: Our results do not provide support for the idea that ε4 genotype increases vulnerability to the negative effects of lifestyle risk factors on cognitive ability, but rather support a primarily outright association between APOE ε4 genotype and worse cognitive ability

Heaviness, health and happiness: a cross-sectional study of 163 066 UK Biobank participants

<b>Background</b><p></p> Obesity is known to increase the risk of many diseases and reduce overall quality of life. This study examines the relationship with self-reported health (SRH) and happiness.<p></p> <b>Methods</b> <p></p>We conducted a cross-sectional study of the 163 066 UK Biobank participants who completed the happiness rating. The association between adiposity and SRH and happiness was examined using logistic regression. SRH was defined as good (excellent, good), or poor (fair, poor). Self-reported happiness was defined as happy (extremely, very, moderately) or unhappy (moderately, very, extremely). <p></p> <b>Results</b> <p></p>Poor health was reported by 44 457 (27.3%) participants. The adjusted ORs for poor health were 3.86, 2.92, 2.60 and 6.41 for the highest, compared with lowest, deciles of Body Mass Index, waist circumference, waist to hip ratio and body fat percent, respectively. The associations were stronger in men (p<0.001). Overall, 7511 (4.6%) participants felt unhappy, and only class III obese participants were more likely to feel unhappy (adjusted OR 1.33, 95% CI 1.15 to 1.53, p<0.001) but the associations differed by sex (p<0.001). Among women, there was a significant association between unhappiness and all levels of obesity. By contrast, only class III obese men had significantly increased risk and overweight and class I obese men were less likely to be unhappy. <p></p> <b>Conclusions</b><p></p>Obesity impacts adversely on happiness as well as health, but the association with unhappiness disappeared after adjustment for self-reported health, indicating this may be mediated by health. Compared with obese men, obese women are less likely to report poor health, but more likely to feel unhappy. <p></p&gt

Peroxisome proliferator-activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging

Age-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor α-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and cell death pathway activation in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1α in muscle cells. Accordingly, mice with muscle-specific gain-of-function and loss-of-function of PGC-1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1α on muscle function and overall health span in aging

Gender differences in the association between adiposity and probable major depression: a cross-sectional study of 140,564 UK Biobank participants

<b>Background</b><p></p> Previous studies on the association between adiposity and mood disorder have produced contradictory results, and few have used measurements other than body mass index (BMI). We examined the association between probable major depression and several measurements of adiposity: BMI, waist circumference (WC), waist-hip-ratio (WHR), and body fat percentage (BF%).<p></p> <b>Methods</b><p></p> We conducted a cross-sectional study using baseline data on the sub-group of UK Biobank participants who were assessed for mood disorder. Multivariate logistic regression models were used, adjusting for potential confounders including: demographic and life-style factors, comorbidity and psychotropic medication.<p></p> <b>Results</b><p></p> Of the 140,564 eligible participants, evidence of probable major depression was reported by 30,145 (21.5%). The fully adjusted odds ratios (OR) for obese participants were 1.16 (95% confidence interval (CI) 1.12, 1.20) using BMI, 1.15 (95% CI 1.11, 1.19) using WC, 1.09 (95% CI 1.05, 1.13) using WHR and 1.18 (95% CI 1.12, 1.25) using BF% (all p <0.001). There was a significant interaction between adiposity and gender (p = 0.001). Overweight women were at increased risk of depression with a dose response relationship across the overweight (25.0-29.9 kg/m2), obese I (30.0-34.9 kg/m2), II (35.0-39.9 kg/m2) and III (≥40.0 kg/m2) categories; fully adjusted ORs 1.14, 1.20, 1.29 and 1.48, respectively (all p < 0.001). In contrast, only obese III men had significantly increased risk of depression (OR 1.29, 95% CI 1.08, 1.54, p = 0.006).<p></p> <b>Conclusion</b><p></p> Adiposity was associated with probable major depression, irrespective of the measurement used. The association was stronger in women than men. Physicians managing overweight and obese women should be alert to this increased risk