The Aging Epigenome Booth, Lauren N.; Brunet, Anne
Molecular cell,
06/2016, Letnik:
62, Številka:
5
Journal Article
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During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs ...is unknown. Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline. These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging. We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging. Understanding age-dependent epigenomic changes will yield key insights into how aging begins and progresses and should lead to the development of new therapeutics that delay or even reverse aging and age-related diseases.
Booth and Brunet discuss how the epigenome and transcriptome change with age, and how the environment impacts epigenome aging.
Prehypertension is associated with increased risk for hypertension and cardiovascular disease. Data are limited on the temporal changes in the prevalence of prehypertension and risk factors for ...hypertension and cardiovascular disease among US adults with prehypertension. We analyzed data from 30 958 US adults ≥20 years of age who participated in the National Health and Nutrition Examination Surveys between 1999 and 2012. Using the mean of 3 blood pressure (BP) measurements from a study examination, prehypertension was defined as systolic BP of 120 to 139 mm Hg and diastolic BP <90 mm Hg or diastolic BP of 80 to 89 mm Hg and systolic BP <140 mm Hg among participants not taking antihypertensive medication. Between 1999-2000 and 2011-2012, the percentage of US adults with prehypertension decreased from 31.2% to 28.2% (
trend=0.007). During this time period, the prevalence of several risk factors for cardiovascular disease and incident hypertension increased among US adults with prehypertension, including prediabetes (9.6% to 21.6%), diabetes mellitus (6.0% to 8.5%), overweight (33.5% to 37.3%), and obesity (30.6% to 35.2%). There was a nonstatistically significant increase in no weekly leisure-time physical activity (40.0% to 43.9%). Also, the prevalence of adhering to the Dietary Approaches to Stop Hypertension eating pattern decreased (18.4% to 11.9%). In contrast, there was a nonstatistically significant decline in current smoking (25.9% to 23.2%). In conclusion, the prevalence of prehypertension has decreased modestly since 1999-2000. Population-level approaches directed at adults with prehypertension are needed to improve risk factors to prevent hypertension and cardiovascular disease.
Guidelines recommend lifestyle modification for patients with coronary heart disease (CHD). Few data demonstrate which lifestyle modifications, if sustained, reduce recurrent CHD and mortality risk ...in cardiac patients after the postacute rehabilitation phase. We determined the association between ideal lifestyle factors and recurrent CHD and all-cause mortality in REasons for Geographic and Racial Differences in Stroke study participants with CHD (n = 4,174). Ideal lifestyle factors (physical activity ≥4 times/week, nonsmoking, highest quartile of Mediterranean diet score, and waist circumference <88 cm for women and <102 cm for men) were assessed through questionnaires and an in-home study visit. There were 447 recurrent CHD events and 745 deaths over a median 4.3 and 4.5 years, respectively. After multivariable adjustment, physical activity ≥4 versus no times/week and non-smoking versus current smoking were associated with reduced hazard ratios (HRs; 95% confidence interval CI) for recurrent CHD (HR 0.69, 95% CI 0.54 to 0.89 and HR 0.50, 95% CI 0.39 to 0.64, respectively) and death (HR 0.71, 95% CI 0.59 to 0.86 and HR 0.53, 95% CI 0.44 to 0.65, respectively). The multivariable-adjusted HRs (and 95% CIs) for recurrent CHD and death comparing the highest versus lowest quartile of Mediterranean diet adherence were 0.77 (95% CI 0.55 to 1.06) and 0.84 (95% CI 0.67 to 1.07), respectively. Neither outcome was associated with waist circumference. Comparing participants with 1, 2, and 3 versus 0 ideal lifestyle factors (non-smoking, physical activity ≥4 times/week, and highest quartile of Mediterranean diet score), the HRs (and 95% CIs) were 0.60 (95% CI 0.44 to 0.81), 0.49 (95% CI 0.36 to 0.67), and 0.38 (95% CI 0.21 to 0.67), respectively, for recurrent CHD and 0.65 (95% CI 0.51 to 0.83), 0.57 (95% CI 0.43 to 0.74), and 0.41 (95% CI 0.26 to 0.64), respectively, for death. In conclusion, maintaining smoking cessation, physical activity, and Mediterranean diet adherence is important for secondary CHD prevention.
We examine how different transcriptional network structures can evolve from an ancestral network. By characterizing how the ancestral mode of gene regulation for genes specific to a-type cells in ...yeast species evolved from an activating paradigm to a repressing one, we show that regulatory protein modularity, conversion of one cis-regulatory sequence to another, distribution of binding energy among protein-protein and protein-DNA interactions, and exploitation of ancestral network features all contribute to the evolution of a novel regulatory mode. The formation of this derived mode of regulation did not disrupt the ancestral mode and thereby created a hybrid regulatory state where both means of transcription regulation (ancestral and derived) contribute to the conserved expression pattern of the network. Finally, we show how this hybrid regulatory state has resolved in different ways in different lineages to generate the diversity of regulatory network structures observed in modern species.
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► Protein modularity and ancestral feature exploitation bypass evolutionary constraint ► Gain of new regulator-regulator interaction transformed a transcription network ► This gain resulted in a hybrid state with ancestral and derived regulatory features ► Partial redundancy of the hybrid state enables regulatory network diversification
A comprehensive molecular dissection of transcription factors and cis-regulatory elements of yeast species with diverging transcriptional paradigms for enforcing cell-type specificity establishes a framework of stepwise changes and design principles that allow for the diversification of transcriptional networks.
The Daily Mile is a physical activity programme made popular by a school in Stirling, Scotland. It is promoted by the Scottish Government and is growing in popularity nationally and internationally. ...The aim is that each day, during class time, pupils run or walk outside for 15 min (~1 mile) at a self-selected pace. It is anecdotally reported to have a number of physiological benefits including increased physical activity, reduced sedentary behaviour, increased fitness and improved body composition. This study aimed to investigate these reports.
We conducted a quasi-experimental repeated measures pilot study in two primary schools in the Stirling Council area: one school with, and one without, intention to introduce the Daily Mile. Pupils at the control school followed their usual curriculum. Of the 504 children attending the schools, 391 children in primary classes 1-7 (age 4-12 years) at the baseline assessment took part. The follow-up assessment was in the same academic year. Outcomes were accelerometer-assessed average daily moderate to vigorous intensity physical activity (MVPA) and average daily sedentary behaviour, 20-m shuttle run fitness test performance and adiposity assessed by the sum of skinfolds at four sites. Valid data at both time points were collected for 118, 118, 357 and 327 children, respectively, for each outcome.
After correction for age and gender, significant improvements were observed in the intervention school relative to the control school for MVPA, sedentary time, fitness and body composition. For MVPA, a relative increase of 9.1 min per day (95% confidence interval or 95%CI 5.1-13.2 min, standardised mean difference SMD = 0.407, p = 0.027) was observed. For sedentary time, there was a relative decrease of 18.2 min per day (10.7-25.7 min, SMD = 0.437, p = 0.017). For the shuttle run, there was a relative increase of 39.1 m (21.9-56.3, SMD = 0.236, p = 0.037). For the skinfolds, there was a relative decrease of 1.4 mm (0.8-2.0 mm, SMD = 0.246, p = 0.036). Similar results were obtained when a correction for socioeconomic groupings was included.
The findings show that in primary school children, the Daily Mile intervention is effective at increasing levels of MVPA, reducing sedentary time, increasing physical fitness and improving body composition. These findings have relevance for teachers, policymakers, public health practitioners, and health researchers.
Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group ...trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT.
Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for
status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored.
Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (
< .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients.
The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
•One in five daily caffeine consumers exceed the recommended 400 mg daily limit.•85% of respondents report at least one caffeine-related harm in the past year.•20% of respondents met DSM-5 criteria ...for CUD, and 30% for caffeine withdrawal.•Medium and high (vs low) caffeine use tripled the odds of CUD.•Women and smokers may be more prone to CUD and withdrawal than men and non-smokers.
Caffeine Use Disorder (CUD) is not yet formally recognized in the DSM-5, but emerging evidence suggests CUD could impact up to one in five people. The primary aim of this study was to estimate levels of caffeine consumption and its associations with CUD and withdrawal, taking socio-demographic characteristics (age, gender, ethnicity, income) into account. Secondary aims were to measure caffeine-related harm and treatment preferences.
We administered an online cross-sectional survey via Facebook to a convenience sample of 2379 adults in New Zealand. Caffeine consumption was assessed across six products: coffee, tea, energy drinks, cola, alcohol mixed with caffeine, and other products (e.g., caffeine pills, sports supplements).
20% of participants met proposed criteria for CUD, with 30% meeting DSM-5 criteria for caffeine withdrawal. Moderate (200–400 mg per day) and high consumption (>400 mg per day) was associated with a three-fold increase in the odds of CUD and a two-fold increase in the odds of withdrawal. Women and current smokers were at higher risk of CUD and withdrawal even at moderate consumption levels. Nearly 85% of respondents experienced at least one caffeine-related harm in the past 12-months. The number of harms increased with level of caffeine consumption. Nearly 50% indicated a self-help treatment for caffeine reduction would be of interest.
High rates of CUD and caffeine withdrawal amongst moderate caffeine users, women and smokers suggests caffeine consumption guidelines may need refinement. Caffeine-related harm that is not clinically meaningful may still be of concern to individuals and warrants further investigation.
Recent studies have suggested that prediabetes is associated with an increased risk for cardiovascular disease (CVD) only among individuals with concomitant hypertension.
We analyzed the association ...between prediabetes and CVD by hypertension status among 3,313 black adults in the Jackson Heart Study (JHS) without diabetes or a history of CVD at baseline (2000-2004). Prediabetes was defined as fasting plasma glucose between 100 and 125 mg/dL or hemoglobin A
between 5.7 and 6.4% (39 and 46 mmol/mol). Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg and/or self-reported antihypertensive medication use. Participants were followed for incident CVD events and all-cause mortality through 31 December 2014.
Overall, 35% of JHS participants did not have prediabetes or hypertension, 18% had prediabetes alone, 22% had hypertension alone, and 25% had both prediabetes and hypertension. Compared with participants without either condition, the multivariable-adjusted hazard ratios for CVD events among participants with prediabetes alone, hypertension alone, and both prediabetes and hypertension were 0.86 (95% CI 0.51, 1.45), 2.09 (1.39, 3.14), and 1.93 (1.28, 2.90), respectively. Among participants with and without hypertension, there was no association between prediabetes and an increased risk for CVD (0.78 0.46, 1.34 and 0.94 0.70, 1.26, respectively). No association was present between prediabetes and all-cause mortality among participants with or without hypertension.
Regardless of hypertension status, prediabetes was not associated with an increased risk for CVD or all-cause mortality in this cohort of black adults.
Despite the known benefits of a physically active lifestyle, there are few examples of interventions that have been successfully implemented at a population level over a long period of time. One such ...example is The Daily Mile, a school based physical activity initiative, where a teacher takes their class out daily during class time for a short bout of ambulatory activity. At one school, this activity appears has been sustained over a long period (6 years), has the whole school participating and is now incorporated into its daily routine. The aim of this paper was to understand how The Daily Mile was implemented in primary schools and to assess factors associated with its successful implementation.
Semi-structured interviews with school staff who had a significant role in implementing The Daily Mile were conducted at four primary schools in central Scotland. Interviews were digitally recorded and transcribed verbatim. Data were analysed using thematic analysis and descriptive analysis and interpretation of data undertaken. Details regarding the school grounds and facilities were also noted during the interviews.
Having simple core intervention components, flexible delivery that supports teacher autonomy and being adaptable to suit the specific primary school context appear to be key aspects of The Daily Mile that are related to its implementation success. Other factors relating to how The Daily Mile was developed, trialled and rolled out might also have contributed towards its successful implementation.
The Daily Mile appears to have several factors which may relate to its implementation success. These are important considerations for others looking to implement The Daily Mile effectively in their primary school or in other contexts.
In previous observational studies, hemoglobin concentrations have been associated with an increased risk of stroke. However, these studies were limited by a relatively low number of stroke events, ...making it difficult to determine whether the association of hemoglobin and stroke differed by demographic or clinical factors.
Using Cox proportional hazards analysis and Kaplan-Meier plots, we examined the association of baseline hemoglobin concentrations with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults aged ≥45 years.
A total of 518 participants developed stroke over a mean 7±2 years of follow-up. There was a statistically significant interaction between hemoglobin and sex (P=0.05) on the risk of incident stroke. In Cox regression models adjusted for demographic and clinical variables, there was no association of baseline hemoglobin concentration with incident stroke in men, whereas in women, the lowest (<12.4 g/dL) and highest (>14.0 g/dL) quartiles of hemoglobin were associated with higher risk of stroke when compared with the second quartile (12.4-13.2 g/dL; quartile 1: hazard ratio, 1.59; 95% confidence interval, 1.09-2.31; quartile 2: referent; quartile 3: hazard ratio, 0.91; 95% confidence interval, 0.59-1.38; quartile 4: hazard ratio, 1.59; 95% confidence interval, 1.08-2.35). Similar results were observed in models stratified by hemoglobin and sex and when hemoglobin was modeled as a continuous variable using restricted quadratic spline regression.
Lower and higher hemoglobin concentrations were associated with a higher risk of incident stroke in women. No such associations were found in men.
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