scholarly journals Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Daniel W Belsky ◽  
Avshalom Caspi ◽  
Louise Arseneault ◽  
Andrea Baccarelli ◽  
David L Corcoran ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Biological Aging ◽  
Surrogate Endpoints ◽  
Progressive Decline ◽  
Rates Of Change ◽  
System Integrity ◽  
Point Measure ◽  
Single Time Point ◽  
Time Point

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972–1973. Rates of change in each biomarker over ages 26–38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging.

scholarly journals Quantification of the pace of biological aging in humans through a blood test: The DunedinPoAm DNA methylation algorithm

2020 ◽  
Author(s):  
DW Belsky ◽  
A Caspi ◽  
L Arseneault ◽  
A Baccarelli ◽  
D Corcoran ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Functional Decline ◽  
Longitudinal Change ◽  
Biological Aging ◽  
Early Life Adversity ◽  
Progressive Decline ◽  
System Integrity ◽  
Aging Study ◽  
Point Measure

ABSTRACTBiological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed to serve as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood DNA-methylation measure that is sensitive to variation in the pace of biological aging among individuals born the same year. We first modeled longitudinal change in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in the Dunedin birth cohort. Rates of change in each biomarker were composited to form a measure of aging-related decline, termed Pace of Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace of Aging, called DunedinPoAm for Dunedin (P)ace (o)f (A)ging (m)ethylation. Validation analyses showed DunedinPoAm was associated with functional decline in the Dunedin Study and more advanced biological age in the Understanding Society Study, predicted chronic disease and mortality in the Normative Aging Study, was accelerated by early-life adversity in the E-risk Study, and DunedinPoAm prediction was disrupted by caloric restriction in the CALERIE trial. DunedinPoAm generally outperformed epigenetic clocks. Findings provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging.

scholarly journals DunedinPACE, a DNA methylation biomarker of the pace of aging

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Daniel W Belsky ◽  
Avshalom Caspi ◽  
David L Corcoran ◽  
Karen Sugden ◽  
Richie Poulton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Blood Test ◽  
Childhood Adversity ◽  
Effect Sizes ◽  
Biological Aging ◽  
Retest Reliability ◽  
Blood Biomarker ◽  
System Integrity ◽  
Test Retest Reliability ◽  
Single Time Point

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).Methods: We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

scholarly journals Quantification of the pace of biological aging in humans through a blood test: the DunedinPACE DNA methylation algorithm

2021 ◽  
Author(s):  
Daniel W Belsky ◽  
Avshalom Caspi ◽  
David L Corcoran ◽  
Karen Sugden ◽  
Richie Poulton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Blood Test ◽  
Functional Decline ◽  
Childhood Adversity ◽  
Original Method ◽  
Effect Sizes ◽  
Biological Aging ◽  
Retest Reliability ◽  
System Integrity ◽  
Test Retest Reliability

Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Here, we report an advance on our original method (Belsky et al. 2020). We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 organ-system integrity indicators across four timepoints spanning two decades to model Pace of Aging. We distilled two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and DNA-methylation data restricted to exclude probes with low test-retest reliability. The resulting measure, DunedinPACE, showed high test-retest reliability, was associated with functional decline, morbidity, and mortality, and indicated accelerated Pace of Aging in young adults with childhood adversity across five datasets. DunedinPACE effect-sizes were similar to GrimAge-clock effect-sizes and larger than those for other benchmark DNA-methylation-clocks. DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience

scholarly journals Social mobility and biological aging among older adults in the United States

2021 ◽  
Author(s):  
Gloria Huei-Jong Graf ◽  
Yalu Zhang ◽  
Benjamin W Domingue ◽  
Kathleen Mullan Harris ◽  
Meeraj Kothari ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Social Mobility ◽  
Healthy Aging ◽  
Upward Mobility ◽  
Blood Chemistry ◽  
The United States ◽  
Effect Sizes ◽  
Biological Aging ◽  
Educational Mobility ◽  
System Integrity

Lower socioeconomic status is associated with faster biological aging, the gradual and progressive decline in system integrity that accumulates with advancing age. Efforts to promote upward social mobility may therefore extend healthy lifespan. However, recent studies suggest that upward mobility may also have biological costs related to the stresses of crossing social boundaries. We analyzed blood-chemistry and DNA methylation (DNAm) data from n=9286 participants in the 2016 Health and Retirement Study (HRS) Venous Blood Study to test associations of life-course social mobility with biological aging. We quantified social mobility from childhood to later-life using data on childhood family characteristics, educational attainment, and wealth accumulation. We quantified biological aging using three DNA methylation "clocks" and three blood-chemistry algorithms. We observed substantial social mobility among study participants. Those who achieved upward mobility exhibited less-advanced and slower biological aging. Associations of upward mobility with less-advanced and slower aging were consistent for blood-chemistry and DNAm measures of biological aging and were similar for men and women and for Black and White Americans (Pearson-r effect-sizes ~0.2 for blood-chemistry measures and the DNAm GrimAge clock and DunedinPoAm pace-of-aging measures; effect-sizes were smaller for the DNAm PhenoAge clock). Analysis restricted to educational mobility revealed differential effects by racial identity, suggesting that mediating links between educational mobility and healthy aging may be disrupted by structural racism. In contrast, mobility producing accumulation of wealth appeared to benefit White and Black Americans equally, suggesting economic intervention to reduce wealth inequality may have potential to heal disparities in healthy aging.

Trajectories of Depressive Symptoms and Incident Diabetes: A Prospective Study

2021 ◽  
Author(s):  
Rachel J Burns ◽  
Esther Briner ◽  
Norbert Schmitz
Keyword(s):  
Depressive Symptoms ◽  
Incident Diabetes ◽  
Diabetes Incidence ◽  
Single Time ◽  
Increased Risk ◽  
Trajectory Group ◽  
Single Time Point ◽  
Over Time ◽  
Time Point

Abstract Background Elevated depressive symptoms are associated with an increased risk for diabetes. Depression is a heterogeneous and chronic condition in which symptoms may remit, emerge, lessen, or intensify over time. Purpose The purpose of this study was to determine if trajectories of depressive symptoms measured at five time points over 8 years predicted incident diabetes over an 8-year follow-up in middle-aged and older adults. A secondary aim was to determine if trajectories of depressive symptoms predict incident diabetes, above and beyond depressive symptoms measured at a single time point. Methods Data came from the Health and Retirement Study (n = 9,233). Depressive symptoms were measured biennially from 1998 to 2006. Self-reported incident diabetes was measured during an 8-year follow-up. Results Five trajectories of depressive symptoms were identified (no depressive symptoms, low depressive symptoms, low-moderate depressive symptoms, moderate depressive symptoms, elevated and increasing depressive symptoms). Compared to the no depressive symptoms trajectory group (referent), all other trajectory groups were at higher risk of developing diabetes after adjusting for covariates. In most cases, trajectory group membership was associated with incident diabetes after controlling for depressive symptoms at a single time point. Conclusions Patterns of depressive symptoms over time were associated with incident diabetes. Patterns of depressive symptoms may be more predictive of diabetes incidence than depressive symptoms measured at a single time point.

scholarly journals Does psychological distress directly increase risk of incident cardiovascular disease? Evidence from a prospective cohort study using a longer-term measure of distress

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e039628
Author(s):  
Jennifer Welsh ◽  
Emily Banks ◽  
Grace Joshy ◽  
Peter Butterworth ◽  
Lyndall Strazdins ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cohort Study ◽  
Psychological Distress ◽  
Functional Limitations ◽  
Single Time ◽  
Time Points ◽  
Health Related ◽  
Single Time Point ◽  
Time Point

ObjectiveCardiovascular disease (CVD) incidence is elevated among people with psychological distress. However, whether the relationship is causal is unclear, partly due to methodological limitations, including limited evidence relating to longer-term rather than single time-point measures of distress. We compared CVD relative risks for psychological distress using single time-point and multi-time-point assessments using data from a large-scale cohort study.DesignWe used questionnaire data, with data collection at two time-points (time 1: between 2006 and 2009; time 2: between 2010 and 2015), from CVD-free and cancer-free 45 and Up Study participants, linked to hospitalisation and death records. The follow-up period began at time 2 and ended on 30 November 2017. Psychological distress was measured at both time-points using Kessler 10 (K10), allowing assessment of single time-point (at time 2: high (K10 score: 22–50) vs low (K10 score: <12)) and multi-time-point (high distress (K10 score: 22–50) at both time-points vs low distress (K10 score: <12) at both time-points) measures of distress. Cox regression quantified the association between distress and major CVD, with and without adjustment for sociodemographic and health-related characteristics, including functional limitations.ResultsAmong 83 906 respondents, 7350 CVD events occurred over 410 719 follow-up person-years (rate: 17.9 per 1000 person-years). Age-adjusted and sex-adjusted rates of major CVD were elevated by 50%–60% among those with high versus low distress for both the multi-time-point (HR=1.63, 95% CI 1.40 to 1.90) and single time-point (HR=1.53, 95% CI 1.39 to 1.69) assessments. HRs for both measures of distress attenuated with adjustment for sociodemographic and health-related characteristics, and there was little evidence of an association when functional limitations were taken into account (multi-time-point HR=1.09, 95% CI 0.93 to 1.27; single time-point HR=1.14, 95% CI 1.02 to 1.26).ConclusionIrrespective of whether a single time-point or multi-time-point measure is used, the distress–CVD relationship is substantively explained by sociodemographic characteristics and pre-existing physical health-related factors.

scholarly journals Nonsurgical miniscrew-assisted rapid maxillary expansion results in acceptable stability in young adults

2016 ◽  
Vol 86 (5) ◽  
pp. 713-720 ◽  
Author(s):  
Sung-Hwan Choi ◽  
Kyung-Keun Shi ◽  
Jung-Yul Cha ◽  
Young-Chel Park ◽  
Kee-Joon Lee
Keyword(s):  
Young Adults ◽  
Treatment Modality ◽  
Orthodontic Treatment ◽  
Rapid Maxillary Expansion ◽  
Maxillary Expansion ◽  
Initial Examination ◽  
The Stability ◽  
Maxillary Deficiency ◽  
Time Point

ABSTRACT Objective:  To evaluate the stability of nonsurgical miniscrew-assisted rapid maxillary expansion (MARME) in young adults with a transverse maxillary deficiency. Materials and Methods:  From a total of 69 adult patients who underwent MARME followed by orthodontic treatment with a straight-wire appliance, 20 patients (mean age, 20.9 ± 2.9 years) with follow-up records (mean, 30.2 ± 13.2 months) after debonding were selected. Posteroanterior cephalometric records and dental casts were obtained at the initial examination (T0), immediately after MARME removal (T1), immediately after debonding (T2), and at posttreatment follow-up (T3). Results:  Suture separation was observed in 86.96% of subjects (60/69). An increase in the maxillary width (J-J; 1.92 mm) accounted for 43.34% of the total expansion with regard to the intermolar width (IMW) increase (4.43 mm; P &lt; .001) at T2. The amounts of J-J and IMW posttreatment changes were −0.07 mm (P &gt; .05) and −0.42 mm (P  =  .01), respectively, during retention. The postexpansion change in middle alveolus width increased with age (P &lt; .05). The postexpansion change of interpremolar width (IPMW) was positively correlated with the amount of IPMW expansion (P &lt; .05) but not with IMW. The changes of the clinical crown heights in the maxillary canines, first premolars, and first molars were not significant at each time point. Conclusions:  Nonsurgical MARME can be a clinically acceptable and stable treatment modality for young adults with a transverse maxillary deficiency.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

scholarly journals High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

2021 ◽  
Author(s):  
Katja Bender ◽  
Eilís Perez ◽  
Mihaela Chirica ◽  
Julia Onken ◽  
Johannes Kahn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Central Nervous System ◽  
Nervous System ◽  
World Health ◽  
Central Nervous System Tumor ◽  
High Grade ◽  
Thoracic Spinal Cord ◽  
High Grade Astrocytoma ◽  
Tumor Entity

Abstract Purpose High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

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