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1.
JMIR Mhealth Uhealth ; 7(9): e13238, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31573928

RESUMO

BACKGROUND: New electronic cohort (e-Cohort) study designs provide resource-effective methods for collecting participant data. It is unclear if implementing an e-Cohort study without direct, in-person participant contact can achieve successful participation rates. OBJECTIVE: The objective of this study was to compare 2 distinct enrollment methods for setting up mobile health (mHealth) devices and to assess the ongoing adherence to device use in an e-Cohort pilot study. METHODS: We coenrolled participants from the Framingham Heart Study (FHS) into the FHS-Health eHeart (HeH) pilot study, a digital cohort with infrastructure for collecting mHealth data. FHS participants who had an email address and smartphone were randomized to our FHS-HeH pilot study into 1 of 2 study arms: remote versus on-site support. We oversampled older adults (age ≥65 years), with a target of enrolling 20% of our sample as older adults. In the remote arm, participants received an email containing a link to enrollment website and, upon enrollment, were sent 4 smartphone-connectable sensor devices. Participants in the on-site arm were invited to visit an in-person FHS facility and were provided in-person support for enrollment and connecting the devices. Device data were tracked for at least 5 months. RESULTS: Compared with the individuals who declined, individuals who consented to our pilot study (on-site, n=101; remote, n=93) were more likely to be women, highly educated, and younger. In the on-site arm, the connection and initial use of devices was ≥20% higher than the remote arm (mean percent difference was 25% [95% CI 17-35] for activity monitor, 22% [95% CI 12-32] for blood pressure cuff, 20% [95% CI 10-30] for scale, and 43% [95% CI 30-55] for electrocardiogram), with device connection rates in the on-site arm of 99%, 95%, 95%, and 84%. Once connected, continued device use over the 5-month study period was similar between the study arms. CONCLUSIONS: Our pilot study demonstrated that the deployment of mobile devices among middle-aged and older adults in the context of an on-site clinic visit was associated with higher initial rates of device use as compared with offering only remote support. Once connected, the device use was similar in both groups.

2.
Epigenetics ; : 1-13, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31506003

RESUMO

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.

3.
Epigenetics ; : 1-16, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282290

RESUMO

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2 < 0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between cis-miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with cis-miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.

4.
Am J Clin Nutr ; 110(3): 742-749, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31187853

RESUMO

BACKGROUND: Genes in metabolic and nutrient signaling pathways play important roles in lifespan in model organisms and human longevity. OBJECTIVE: The aim of this study was to examine the relation of a quantitative measure of healthy diet to gene expression in a community-based cohort. METHODS: We used the 2015 Dietary Guidelines for Americans Adherence Index (DGAI) score to quantify key dietary recommendations of an overall healthy diet. Our current analyses included 2220 Offspring participants (mean age 66 ± 9 y, 55.4% women) and 2941 Third-Generation participants (mean age 46 ± 9 y, 54.5% women) from the Framingham Heart Study. Gene expression was profiled in blood through the use of the Affymetrix Human Exon 1.0 ST Array. We conducted a transcriptome-wide association study of DGAI adjusting for age, sex, smoking, cell counts, and technical covariates. We also constructed a combined gene score from genes significantly associated with DGAI. RESULTS: The DGAI was significantly associated with the expression of 19 genes (false discovery rate <0.05). The most significant gene, ARRDC3, is a member of the arrestin family of proteins, and evidence in animal models and human data suggests that this gene is a regulator of obesity and energy expenditure. The DGAI gene score was associated with body mass index (P = 1.4 × 10-50), fasting glucose concentration (P = 2.5 × 10-11), type 2 diabetes (P = 1.1 × 10-5), and metabolic syndrome (P = 1.8 × 10-32). CONCLUSIONS: Healthier diet was associated with genes involved in metabolic function. Further work is needed to replicate our findings and investigate the relation of a healthy diet to altered gene regulation.

5.
Menopause ; 26(10): 1204-1212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31188284

RESUMO

OBJECTIVE: We hypothesize that mechanisms associated with extended reproductive age may overlap with mechanisms for the selection of genetic variants that slow aging and decrease risk for age-related diseases. Therefore, the goal of this analysis is to search for genetic variants associated with delayed age of menopause (AOM) among women in a study of familial longevity. METHODS: We performed a meta-analysis of genome-wide association studies for AOM in 1,286 women in the Long Life Family Study (LLFS) and 3,151 women in the Health and Retirement Study, and then sought replication in the Framingham Heart Study (FHS). We used Cox proportional hazard regression of AOM to account for censoring, with a robust variance estimator to adjust for within familial relations. RESULTS: In the meta-analysis, a single nucleotide polymorphism (SNP) previously associated with AOM reached genome-wide significance (rs16991615; HR = 0.74, P = 6.99 × 10). A total of 35 variants reached >10 level of significance and replicated in the FHS and in a 2015 large meta-analysis (ReproGen Consortium). We also identified several novel SNPs associated with AOM including rs3094005: MICB, rs13196892: TXNDC5 | MUTED, rs72774935: SSBP2 | ATG10, rs9447453: COL12A1, rs114298934: FHL2 | NCK2, rs6467223: TNPO3, rs9666274 and rs10766593: NAV2, and rs7281846: HSPA13. CONCLUSIONS: This work indicates novel associations and replicates known associations between genetic variants and AOM. A number of these associations make sense for their roles in aging. VIDEO SUMMARY: Supplemental Digital Content 1, http://links.lww.com/MENO/A420.

6.
JAMA Netw Open ; 2(4): e192745, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31002329

RESUMO

Importance: Dementia risk may be attenuated by physical activity (PA); however, the specific activity levels optimal for dementia prevention are unclear. Moreover, most older adults are unable to meet the nationally recommended PA guidelines, set at 150 minutes of moderate to vigorous PA per week. Objective: To assess the association of total steps walked per day and total dose (intensity × duration) of PA with brain volumes on magnetic resonance imaging (MRI) among Framingham Heart Study participants. Design, Setting, and Participants: This cross-sectional, community-based cohort study of the association of accelerometry-determined PA with brain MRI measures in Framingham, Massachusetts, included the Framingham Heart Study third-generation (examination 2, 2008-2011) and offspring (examination 9, 2011-2014) cohorts. Of 4021 participants who agreed to wear an accelerometer and had valid data (≥10 hours/day for ≥3 days), 1667 participants who did not undergo brain MRI (n = 1604) or had prevalent dementia or stroke (n = 63) were excluded. Data analysis began in 2016 and was completed in February 2019. Exposures: Physical activity achieved using accelerometry-derived total activity (steps per day) and 2 intensity levels (light intensity and moderate to vigorous intensity). Main Outcomes and Measures: Differences in total brain volume and other MRI markers of brain aging. Results: The study sample of 2354 participants had a mean (SD) age of 53 (13) years, 1276 (54.2%) were women, and 1099 (46.7%) met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging (ß estimate, 0.22; SD, 0.07; P = .003). Among individuals not meeting the PA guidelines, each hour of light-intensity PA (ß estimate, 0.28; SD, 0.11; P = .01) and achieving 7500 steps or more per day (ß estimate, 0.44; SD, 0.18; P = .02) were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume. Conclusions and Relevance: Every additional hour of light-intensity PA was associated with higher brain volumes, even among individuals not meeting current PA guidelines. These data are consistent with the notion that the potential benefits of PA on brain aging may accrue at a lower, more achievable level of intensity or duration.

7.
J Med Internet Res ; 21(3): e12143, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30821691

RESUMO

BACKGROUND: New models of scalable population-based data collection that integrate digital and mobile health (mHealth) data are necessary. OBJECTIVE: The aim of this study was to describe a cardiovascular digital and mHealth electronic cohort (e-cohort) embedded in a traditional longitudinal cohort study, the Framingham Heart Study (FHS). METHODS: We invited eligible and consenting FHS Generation 3 and Omni participants to download the electronic Framingham Heart Study (eFHS) app onto their mobile phones and co-deployed a digital blood pressure (BP) cuff. Thereafter, participants were also offered a smartwatch (Apple Watch). Participants are invited to complete surveys through the eFHS app, to perform weekly BP measurements, and to wear the smartwatch daily. RESULTS: Up to July 2017, we enrolled 790 eFHS participants, representing 76% (790/1044) of potentially eligible FHS participants. eFHS participants were, on average, 53±8 years of age and 57% were women. A total of 85% (675/790) of eFHS participants completed all of the baseline survey and 59% (470/790) completed the 3-month survey. A total of 42% (241/573) and 76% (306/405) of eFHS participants adhered to weekly digital BP and heart rate (HR) uploads, respectively, over 12 weeks. CONCLUSIONS: We have designed an e-cohort focused on identifying novel cardiovascular disease risk factors using a new smartphone app, a digital BP cuff, and a smartwatch. Despite minimal training and support, preliminary findings over a 3-month follow-up period show that uptake is high and adherence to periodic app-based surveys, weekly digital BP assessments, and smartwatch HR measures is acceptable.

8.
Exp Gerontol ; 119: 203-211, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30771463

RESUMO

BACKGROUND: Older adults may have difficulty meeting the Physical Activity (PA) Guidelines. A favorable balance between PA and sedentary time (SED) is an important determinant of physical performance in older adults. Our objective was to explore associations of PA/SED with physical performance across mid-older age in adults without overt mobility disability. METHODS: Framingham Offspring Study participants free of mobility disability with accelerometry and physical performance data (gait speed, chair stand time, and handgrip strength), were studied in cross-sectional analysis (n = 1352). We regressed physical performance on PA level, measured using steps, moderate to vigorous (MV)PA and SED. We stratified by age groups, adjusted for covariates, and modelled MVPA and SED separately and together as predictors. RESULTS: Only 38% of adults 50-64 years and 15% of adults ≥75 years met the PA Guidelines (i.e., 150 min MVPA per week). Individuals achieving at least 5 min/day of MVPA had 0.062 ±â€¯0.013 m/s greater gait speed and better chair stands and handgrip strength (in women) than those with <5 min/day of MVPA (p < 0.01) across mid-older age. SED was associated with poorer performance on gait speed and chair stand tests, but results were not significant after adjusting for MVPA (p > 0.05). For adults ≥75 years, every 5000 more steps/day related to ~0.045 m/s greater gait speed (p = 0.006). CONCLUSION: Our cross-sectional study demonstrated that, across mid-older adulthood, MVPA related to better physical performance, but in adults ≥75 years, total steps walked associated with better gait speed. These data warrant future research on the impact of PA on physical performance and health outcomes in older age.

9.
J Diabetes Res ; 2019: 2718465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729134

RESUMO

Aims: Circulating insulin-like growth factor- (IGF-) 1, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) levels are often lower in individuals with diabetes mellitus (DM) and are important for repairing vascular and neuronal dysfunction. The purpose of this investigation was to determine the cross-sectional relations of physical activity to circulating concentrations of IGF-1, VEGF, and BDNF in individuals with and without DM. Methods: In 1730 participants from the Framingham Offspring Study examination cycle 7, including those with DM (n = 179, mean age 64 years, 39% women) and without DM (n = 1551, mean age 60 years, 46% women), we related self-reported physical activity variables to circulating concentrations of IGF-1, VEGF, and BDNF using linear multivariable regression models. We also tested for interactions by age. Participants with prevalent cardiovascular disease, stroke, and dementia or taking hormone replacement therapy were excluded. Results: In participants with DM, more ambulatory physical activity was associated with higher IGF-1 levels (ß ± standard error (SE) = 0.22 ± 0.08, p = 0.009), and more total physical activity was related to higher BDNF levels (ß ± SE = 0.18 ± 0.08, p = 0.035), but physical activity was not significantly related to circulating VEGF. In participants without DM, no associations were observed. Moreover, in the examination of interactions by age, the association of ambulatory physical activity with IGF-1 levels was only observed in older adults with DM (age ≥ 60 years, ß ± SE = 0.23 ± 0.11, p = 0.042) but not in middle-aged adults with DM (age < 60 years, ß ± SE = 0.06 ± 0.13, p = 0.645). Conclusion: Our results suggest that more physical activity is associated with higher circulating IGF-1 and BDNF in participants with DM. These results, dissecting interactions by both age and DM status, may also help to explain some of the inconsistent results in studies relating physical activity to growth and neurotrophic factors.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Diabetes Mellitus/sangue , Exercício/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autorrelato , Inquéritos e Questionários
10.
Artigo em Inglês | MEDLINE | ID: mdl-30010802

RESUMO

Background: Biologic age may better reflect an individual's rate of aging than chronologic age. Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at one second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array. Results: Our discovery sample included 2163 participants from the Framingham Offspring cohort (mean age 67±9 years, 55% women). A total of 481 genes were significantly associated with ∆age (P<2.8x10-6). Among them, 415 genes were validated (P<0.05/481=1.0x10-4) in 2946 participants from the Framingham Third Generation cohort (mean age 46± 9 years, 53% women). Many of significant genes were involved in the ubiquitin mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59±8, 52% women) found 104 of 415 validated genes reached nominal significance (P <0.05). Conclusion: We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults.

11.
Artigo em Inglês | MEDLINE | ID: mdl-29917058

RESUMO

Background: Frailty is a risk factor for cardiovascular disease. Underlying mechanisms to explain the connection between frailty and cardiovascular disease are unclear. We sought to examine the association between frailty and arterial stiffness, a precursor of hypertension and cardiovascular disease. Methods: We conducted a cross-sectional analysis of community-dwelling Framingham Heart Study Offspring and Omni participants ≥60 years of age examined in 2005-2008. Frailty was defined primarily according to the Fried physical phenotype definition, which identifies non-frail, pre-frail, and frail individuals. Arterial stiffness was assessed using carotid femoral pulse wave velocity (CFPWV). Generalized linear regression was used to examine the association between frailty level and CFPWV (modeled as -1000/CFPWV in msec/m, then transformed back to the original scale, m/s), adjusted for age, sex, cohort, mean arterial pressure, heart rate, height, and smoking. Results: Of 2,171 participants (55% women, 91% white), 45% were pre-frail and 7% frail. Mean ages were 67, 70, and 73 years and adjusted CFPWV least squares means were 10.0 (95% CI, 9.9-10.1), 10.3 (10.2-10.5), and 10.5m/s (10.1-11.0), P=0.0002 for non-frail, pre-frail and frail groups respectively. Results were similar using the Rockwood cumulative deficit model of frailty, and in a sensitivity analysis adjusting for prevalent coronary heart disease and diabetes. Conclusions: Pre-frailty and frailty were associated with higher arterial stiffness in a cohort of community-dwelling older adults. Arterial stiffness may help explain the relationship between frailty and cardiovascular disease.

12.
Front Pharmacol ; 9: 207, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29740313

RESUMO

Background: Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk. Methods: We conducted an epigenome-wide association study of sTNFR2 levels in the Framingham Heart Study Offspring cohort (examination 8; 2005-2008). sTNFR2 was quantitated by enzyme immunoassay and DNA methylation by microarray. The concentration of sTNFR2 was loge-transformed and outliers were excluded. We conducted linear mixed effects models to test the association between sTNFR2 level and methylation at over 400,000 CpGs, adjusting for age, sex, BMI, smoking, imputed cell count, technical covariates, and accounting for familial relatedness. Results: The study sample included 2468 participants (mean age: 67 ± 9 years, 52% women, mean sTNFR2 level 2661 ± 1078 pg/ml). After accounting for multiple testing, we identified 168 CpGs (P < 1.2 × 10-7) that were differentially methylated in relation to sTNFR2. A substantial proportion (27 CpGs; 16%) are in the major histocompatibility complex region and in loci overrepresented for antigen binding molecular functions (P = 1.7 × 10-4) and antigen processing and presentation biological processes (P = 1.3 × 10-8). Identified CpGs are enriched in active regulatory regions and associated with expression of 48 cis-genes (±500 kb) in whole blood (P < 1.1 × 10-5) that coincide with genes identified in GWAS of diseases of immune dysregulation (inflammatory bowel disease, type 1 diabetes, IgA nephropathy). Conclusion: Differentially methylated loci in leukocytes associated with sTNF2 levels reside in active regulatory regions, are overrepresented in antigen processes, and are linked to inflammatory diseases.

13.
Nat Commun ; 9(1): 387, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374233

RESUMO

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

14.
J Clin Endocrinol Metab ; 103(3): 991-1004, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325096

RESUMO

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective: To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures: Genetic determinants of serum E2 and E1 levels. Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.


Assuntos
Aromatase/genética , Densidade Óssea/genética , Estradiol/sangue , Densidade Óssea/fisiologia , Cromossomos Humanos X , Estudos de Coortes , Estradiol/genética , Estradiol/fisiologia , Estrona/sangue , Estrona/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Genótipo , Hormônios Esteroides Gonadais/sangue , Humanos , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Vértebras Lombares/fisiologia , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Testosterona/sangue
15.
Menopause ; 25(4): 451-457, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29112599

RESUMO

OBJECTIVE: To better understand the relationship between cardiovascular disease risk and age-at-natural menopause using genetic data. METHODS: Early menopause is associated with cardiovascular disease risk. We constructed a genetic risk score comprising 56 age-at-natural menopause decreasing alleles in men and women from the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and the Rotterdam Study. If the genetic predisposition to earlier age-at-natural menopause is associated with increased cardiovascular disease risk, it is reasonable to ask whether the risk is shared by men carrying the alleles, despite not experiencing menopause. We estimated the hazard ratio for the score for time to first cardiovascular event. To investigate the possible genetic pleiotropy between age-at-natural menopause and cardiovascular disease, we performed cross-trait linkage disequilibrium score regressions between age-at-natural menopause and cardiovascular disease and risk factors using genome-wide association studies. RESULTS: Twenty-two thousand five hundred and sixty-eight cardiovascular disease-free participants at baseline were analyzed (9,808 men, 12,760 women). Each additional unit of the genetic propensity to earlier age-at-natural menopause increased the hazard of both cardiovascular disease and cardiac death in women (cardiovascular disease: hazard ratio 1.10 [1.04-1.16], P = 9.7 × 10; cardiac death: 1.12 [1.02-1.24], P = 0.03), whereas no effect was observed for either outcome in men (hazard ratio 0.99 [0.95-1.04], P = 0.71; 1.05 [0.94-1.16], P = 0.34). We found significant negative genetic correlations in women, but not men, between age-at-natural menopause and cardiovascular disease and risk factors. CONCLUSION: Genetic variants associated with earlier age-at-natural menopause are associated with increased cardiovascular disease risk in women, but not men, suggesting sex-specific genetic effects on cardiovascular disease risk.

16.
J Gerontol A Biol Sci Med Sci ; 73(6): 757-762, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28977464

RESUMO

Background: We tested the association of biologic age (BA) measures constructed from different types of biomarkers with mortality and disease in a community-based sample. Methods: In Framingham Offspring participants at Exams 7 (1998-2001, mean age 62 ± 10) and 8 (2005-2008, mean age 67 ± 9), we used the Klemera-Doubal method to estimate clinical BA and inflammatory BA and computed the difference (∆age) between BA and CA. Clinical ∆age was computed at Exam 2 (1979-1983, mean age 45 ± 10). At Exam 8, we computed measures of intrinsic and extrinsic epigenetic age. Participants were followed through 2014 for outcomes. Cox proportional hazards models tested the association of each BA estimate with each outcome adjusting for covariates. Results: Sample sizes ranged from 2532 to 3417 participants. In multivariable models, each 1-year increase in clinical ∆age at Exam 2 (hazard ratio [HR] = 1.04-1.06, p < 2 × 10-16) and clinical ∆age and inflammatory ∆age at Exam 7 significantly increased the hazards of mortality and incident cardiovascular disease (HR = 1.01-1.05, p < 2 × 10-7), whereas inflammatory ∆age increased the hazards of cancer (HR = 1.01, p < .05). At Exam 8, increased clinical ∆age, inflammatory ∆age, and extrinsic epigenetic age all significantly increased the hazard of mortality (HR = 1.03-1.05, all p < .05); clinical ∆age and inflammatory ∆age increased cardiovascular disease risk (HR = 1.04-1.05, all p < .01); and clinical ∆age increased cancer risk (HR = 1.03, p < .01) when all three BA measures were included in the model. Intrinsic epigenetic age was not significantly associated with any outcome. Conclusions: Our findings suggest BA measures may be complementary in predicting risk for mortality and age-related disease.

17.
Aging Cell ; 17(1)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29044988

RESUMO

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10-4 (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10-5 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases.

18.
Aging (Albany NY) ; 9(11): 2288-2301, 2017 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-29135455

RESUMO

Chronic low grade inflammation is a fundamental mechanism of aging. We estimated biologic age using nine biomarkers from diverse inflammatory pathways and we hypothesized that genes associated with inflammatory biological age would provide insights into human aging. In Framingham Offspring Study participants at examination 8 (2005 to 2008), we used the Klemera-Doubal method to estimate inflammatory biologic age and we computed the difference (∆Age) between biologic age and chronologic age. Gene expression in whole blood was measured using the Affymetrix Human Exon 1.0 ST Array. We used linear mixed effect models to test associations between inflammatory ∆Age and gene expression (dependent variable) adjusting for age, sex, imputed cell counts, and technical covariates. Our study sample included 2386 participants (mean age 67A±9 years, 55% women). There were 448 genes significantly were associated with inflammatory ∆Age (P<2.8x10-6), 302 genes were positively associated and 146 genes were negatively associated. Pathway analysis among the identified genes highlighted the NOD-like receptor signaling and ubiquitin mediated proteolysis pathways. In summary, we identified 448 genes that were significantly associated with inflammatory biologic age. Future functional characterization may identify molecular interventions to delay aging and prolong healthspan in older adults.


Assuntos
Envelhecimento/genética , Inflamação/genética , Transcriptoma , Fatores Etários , Idoso , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Modelos Lineares , Masculino , Massachusetts , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Mapas de Interação de Proteínas , Transdução de Sinais
19.
JAMA Intern Med ; 177(11): 1586-1593, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973115

RESUMO

Importance: Gamification, the application of game design elements such as points and levels in nongame contexts, is often used in digital health interventions, but evidence on its effectiveness is limited. Objective: To test the effectiveness of a gamification intervention designed using insights from behavioral economics to enhance social incentives within families to increase physical activity. Design, Setting, and Participants: The Behavioral Economics Framingham Incentive Trial (BE FIT) was a randomized clinical trial with a 12-week intervention period and a 12-week follow-up period. The investigation was a community-based study between December 7, 2015, and August 14, 2016. Participants in the modified intent-to-treat analysis were adults enrolled in the Framingham Heart Study, a long-standing cohort of families. Interventions: All participants tracked daily step counts using a wearable device or a smartphone, established a baseline, selected a step goal increase, and received daily individual feedback on goal performance by text message or email for 24 weeks. Families in the gamification arm could earn points and progress through levels based on physical activity goal achievement during the 12-week intervention. The game design was meant to enhance collaboration, accountability, and peer support. Main Outcomes and Measures: The primary outcome was the proportion of participant-days that step goals were achieved during the intervention period. Secondary outcomes included the proportion of participant-days that step goals were achieved during the follow-up period and the change in the mean daily steps during the intervention and follow-up periods. Results: Among 200 adults comprising 94 families, the mean age was 55.4 years, and 56.0% (n = 112) were female. During the intervention period, participants in the gamification arm achieved step goals on a significantly greater proportion of participant-days (0.53 vs 0.32; adjusted difference, 0.27; 95% CI, 0.20-0.33; P < .001) and had a significantly greater increase in the mean daily steps compared with baseline (1661 vs 636; adjusted difference, 953; 95% CI, 505-1401; P < .001) than the control arm. During the follow-up period, physical activity in the gamification arm declined but remained significantly greater than that in the control arm for the proportion of participant-days achieving step goals (0.44 vs 0.33; adjusted difference, 0.12; 95% CI, 0.05-0.19; P < .001) and the mean daily steps compared with baseline (1385 vs 798; adjusted difference, 494; 95% CI, 170-818; P < .01). Conclusions and Relevance: Gamification designed to leverage insights from behavioral economics to enhance social incentives significantly increased physical activity among families in the community. Trial Registration: clinicaltrials.gov Identifier: NCT02531763.


Assuntos
Exercício , Saúde da Família , Jogos Experimentais , Motivação , Caminhada/fisiologia , Feminino , Metas , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial
20.
J Am Geriatr Soc ; 65(10): 2257-2264, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28832926

RESUMO

OBJECTIVE: To evaluate the association between thoracic kyphosis and physical function. DESIGN: Prospective cohort. SETTING: Framingham, Massachusetts. PARTICIPANTS: Framingham Heart Study Offspring and Third Generation cohort members who had computed tomography (CT) performed between 2002 and 2005 and physical function assessed a mean 3.4 years later (N = 1,100; mean age 61 ± 8, range 50-85). MEASUREMENTS: Thoracic kyphosis (Cobb angle, T4-T12) was measured in degrees using supine CT scout images. Participants were categorized according to Cobb angle to compare those in the highest quartile (Q4, most-severe kyphosis) with those in the lowest quartiles (Q1-Q3). Quick walking speed (m/s), chair-stand time (seconds), grip strength (kg), and self-reported impairments were assessed using standardized procedures. Analyses were adjusted for age, height, weight, smoking, follow-up time, vertebral fractures, and prevalent spinal degeneration. RESULTS: Thoracic kyphosis was not associated with physical function in women or men, and these results were consistent in those younger than 65 and those aged 65 and older. For example, walking speed was similar in adults younger than 65 with and without severe kyphosis (women, Q4: 1.38 m/s, Q1-Q3: 1.40 m/s, P = .69; men, Q4: 1.65 m/s, Q1-Q3: 1.60 m/s; P = .39). CONCLUSION: In healthy relatively high-functioning women and men, kyphosis severity was not associated with subsequent physical function. Individuals at risk of functional decline cannot be targeted based on supine CT thoracic curvature measures alone.


Assuntos
Avaliação da Deficiência , Exercício/fisiologia , Cifose/fisiopatologia , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Avaliação Geriátrica/métodos , Humanos , Cifose/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Decúbito Dorsal , Velocidade de Caminhada
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