It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of ...lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration,
.Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.
DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in
...studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured
and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative
human cell aging assay.
Low heart rate variability (HRV) has been linked to increased total mortality in the general population; however, the relationship between low HRV and sudden cardiac death (SCD) is less ...well-characterized. The goal of this study was to evaluate the relationship between low HRV and SCD in a community-based cohort. Our cohort consisted of 12,543 participants from the Atherosclerosis Risk in Communities (ARIC) study. HRV measures were derived from 2-minute electrocardiogram recordings obtained during the baseline exam (1987-89). Time domain measurements included the standard deviation of all normal RR intervals (SDNN) and the root mean squared successive difference (r-MSSD). Frequency domain measurements included low frequency power (LF) and high frequency (HF) power. During a median follow-up of 13 years, 215 SCDs were identified from physician adjudication of all coronary heart disease deaths through 2001. In multivariable adjusted Cox proportional hazards models, each standard deviation decrement in SDNN, LF, and HF were associated with 24%, 27% and 16% increase in SCD risk, respectively. Low HRV is independently associated with increased risk of SCD in the general population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Behavioral and lifestyle factors have been shown to relate to a number of health-related outcomes, yet there is a need for studies that examine their relationship to molecular aging rates. Toward ...this end, we use recent epigenetic biomarkers of age that have previously been shown to predict all-cause mortality, chronic conditions, and age-related functional decline. We analyze cross-sectional data from 4,173 postmenopausal female participants from the Women's Health Initiative, as well as 402 male and female participants from the Italian cohort study, Invecchiare nel Chianti.Extrinsic epigenetic age acceleration (EEAA) exhibits significant associations with fish intake (p=0.02), moderate alcohol consumption (p=0.01), education (p=3x10
), BMI (p=0.01), and blood carotenoid levels (p=1x10
)-an indicator of fruit and vegetable consumption, whereas intrinsic epigenetic age acceleration (IEAA) is associated with poultry intake (p=0.03) and BMI (p=0.05). Both EEAA and IEAA were also found to relate to indicators of metabolic syndrome, which appear to mediate their associations with BMI. Metformin-the first-line medication for the treatment of type 2 diabetes-does not delay epigenetic aging in this observational study. Finally, longitudinal data suggests that an increase in BMI is associated with increase in both EEAA and IEAA.Overall, the epigenetic age analysis of blood confirms the conventional wisdom regarding the benefits of eating a high plant diet with lean meats, moderate alcohol consumption, physical activity, and education, as well as the health risks of obesity and metabolic syndrome.
Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential ...(CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.
We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.
The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (
<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 95% 1.10-1.68;
=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 95% CI, 1.10-1.79;
=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 95% CI, 1.23-2.44;
=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 95% CI, 1.30-2.80;
<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only
CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 95% CI, 1.07-1.73;
=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 95% CI, 1.13-1.94;
=0.005).
Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
The purpose of this study was to estimate the heart rate variability (HRV)–related lifetime cardiovascular disease (CVD) risk.
We followed 9744 participants without baseline CVD and used a life-table ...approach to estimate lifetime CVD risk (coronary heart disease, heart failure, and stroke) from 45 through 85 years according to several HRV measures (the SD of RR intervals SDNN, the root mean square of successive differences of successive RR intervals, the mean of all normal RR intervals meanNN, low-frequency LF and high-frequency HF power, and the LF/HF ratio).
During 192,110 person-years of follow-up, we documented 2856 CVD events. Cox regression analyses with the false discovery rate method correction showed independent associations of SDNN, meanNN, LF, and LF/HF in women with CVD. Lifetime CVD risks in the lowest compared with the highest tertile were significantly increased in men for LF/HF (51.3% 95% confidence interval, 47.3–54.7 vs. 43.9% 40.1–47.2), and in women for SDNN (39.4% 36.0–43.0 vs. 29.9% 26.3–33.0), meanNN (39.3% 35.7–42.7 vs. 28.9% 25.7–31.7), LF (39.4% 35.9–43.0 vs. 30.0% 26.2–33.2), and LF/HF (37.6% 33.9–40.9 vs. 30.0% 26.8–32.7).
Greater HRV was modestly associated with lower lifetime CVD risk.
Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for ...biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.
Evidence of the association between daily variation in air pollution and risk of stroke is inconsistent, potentially due to the heterogeneity in stroke etiology.
To estimate the associations between ...daily variation in ambient air pollution and risk of stroke and its subtypes among participants of the Women's Health Initiative, a large prospective cohort study in the United States.
We used national-scale, log-normal ordinary kriging models to estimate daily concentrations of fine particulate matter (PM2.5), respirable particulate matter (PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulphur dioxide, and ozone at participant addresses. Stroke was adjudicated by trained neurologists and classified as ischemic or hemorrhagic. Ischemic strokes were further classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We used a time-stratified case-crossover approach to estimate the odds ratio (OR) of the risk of stroke associated with an interquartile range (IQR) increase in concentrations of each air pollutant. We performed stratified analysis to examine whether associations varied across subgroups defined by age at stroke onset, US census region, smoking status, body mass index, and prior history of diabetes mellitus, hypertension, heart or circulation problems, or arterial fibrillation at enrollment.
Among 5417 confirmed strokes between 1993 and 2012, 4300 (79.4%) were classified as ischemic and 924 (17.1%) as hemorrhagic. No association was observed between day-to-day variation in any pollutant and risk of total stroke, ischemic stroke, or specific etiologies of ischemic stroke. We observed a positive association between risk of hemorrhagic stroke and NO2 and NOx in the 3 days prior to stroke with OR of 1.24 (95% CI: 1.01, 1.52) and 1.18 (95% CI: 1.03, 1.34) per IQR increase, respectively. The observed associations with hemorrhagic stroke were more pronounced among non-obese participants.
In this large cohort of post-menopausal US women, daily NO2 and NOx were associated with higher risk of hemorrhagic stroke, but ambient levels of four other air pollutants were not associated with higher risk of total stroke, ischemic stroke, or ischemic stroke subtypes.
•We examined associations between air pollution and stroke subtypes among US women.•Stroke cases were adjudicated by trained neurologists based on brain imaging.•We observed no associations between daily air pollution exposures and ischemic stroke and its subtypes.•We observed a positive association of NO2 and NO with haemorrhagic stroke.
Exposure to particulate matter (PM) <2.5
m in aerodynamic diameter (PM
) has been linked to detrimental health effects. This study aimed to describe the relationship between long-term PM
exposure and ...kidney disease, including eGFR, level of albuminuria, and incident CKD.
The study included 10,997 participants from the Atherosclerosis Risk in Communities cohort who were followed from 1996-1998 through 2016. Monthly mean PM
concentrations (
g/m
) were estimated at geocoded participant addresses using geographic information system-based, spatiotemporal generalized additive mixed models-including geospatial covariates such as land use-and then averaged over the 12-month period preceding participant examination. Covariate-adjusted, cross-sectional associations of PM
, baseline eGFR, and urinary albumin-creatinine ratio (UACR) were estimated using linear regression. PM
and incident CKD (defined as follow-up eGFR <60 ml/min per 1.73 m
with ≥25% eGFR decline relative to baseline, CKD-related hospitalization or death based on International Classification of Diseases 9/10 codes, or development of ESKD) associations were estimated using Cox proportional hazards regression. Modeling was stratified by study site, and stratum-specific estimates were combined using random-effects meta-analyses.
Baseline mean participant age was 63 (±6) years and eGFR was 86 (±16) ml/min per 1.73 m
. There was no significant PM
-eGFR association at baseline. Each 1-
g/m
higher annual average PM
was associated with higher UACR after adjusting for demographics, socioeconomic status, and clinical covariates (percentage difference, 6.6%; 95% confidence interval 95% CI, 2.6% to 10.7%). Each 1-
g/m
higher annual average PM
was associated with a significantly higher risk of incident CKD (hazard ratio, 1.05; 95% CI, 1.01 to 1.10).
Exposure to higher annual average PM
concentrations was associated with a higher level of albuminuria and higher risk for incident CKD in a community-based cohort.
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