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 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 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 Association of Leukocyte Telomere Length With Perceived Physical Fatigability

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 207-208
Author(s):  
Joseph Zmuda ◽  
Joseph Lee ◽  
Lawrence Honig ◽  
Kaare Christensen ◽  
Mary Feitosa ◽  
...  
Keyword(s):  
Telomere Length ◽  
Family Study ◽  
Functional Decline ◽  
Prognostic Indicator ◽  
Health Conditions ◽  
Biological Aging ◽  
Leukocyte Telomere Length ◽  
Potential Marker ◽  
Two Generations

Abstract Leukocyte telomere length (LTL) is a potential marker of biological aging, but its relationship to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability. Two generations of participants (N=1,997; 309 probands, 1,688 offspring) were from the Long Life Family Study (age=73.7±10.4, range 60-108, 54.4% women). LTL was assayed at baseline and 8.0±1.1 years later perceived physical fatigability was measured using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0-50, higher scores=greater fatigability). Prevalence of greater physical fatigability (PFS scores≥15) was 41.9%. Using multivariate linear regression, one kilobase pair shorter LTL predicted higher PFS Physical scores (β=0.9, p=0.025), adjusted for family relatedness, generation (indicator for age), field center, follow-up time, sex, and follow-up body mass index, physical activity, health conditions. LTL, a promising marker of future fatigability, may allow for early identification of those at-risk for deleterious aging.

scholarly journals Associations of Plasma Folate and Vitamin B6 With Blood DNA Methylation Age: An Analysis of One-Carbon Metabolites in the VA Normative Aging Study

2020 ◽  
Author(s):  
Jamaji C Nwanaji-Enwerem ◽  
Elena Colicino ◽  
Xu Gao ◽  
Cuicui Wang ◽  
Pantel Vokonas ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vitamin B6 ◽  
Regression Models ◽  
Biological Aging ◽  
Kernel Machine ◽  
Normative Aging Study ◽  
Kernel Machine Regression ◽  
Aging Study ◽  
Dna Methylation Age ◽  
Normative Aging

Abstract One-carbon metabolism is an important contributor to aging-related diseases; nevertheless, relationships of one-carbon metabolites with novel DNA methylation-based measures of biological aging remain poorly characterized. We examined relationships of one-carbon metabolites with 3 DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. We measured plasma levels of 4 common one-carbon metabolites (vitamin B6, vitamin B12, folate, and homocysteine) in 715 VA Normative Aging Study participants with at least 1 visit between 1999 and 2008 (observations = 1153). DNA methylation age metrics were calculated using the HumanMethylation450 BeadChip. We utilized Bayesian Kernel Machine Regression models adjusted for chronological age, lifestyle factors, age-related diseases, and study visits to determine metabolites important to the aging outcomes. Bayesian Kernel Machine Regression models allowed for the estimation of the relationships of single metabolites and the cumulative metabolite mixture with methylation age. Log vitamin B6 was selected as important to PhenoAge (β = −1.62 years, 95% CI: −2.28, −0.96). Log folate was selected as important to GrimAge (β = 0.75 years, 95% CI: 0.41, 1.09) and PhenoAge (β = 1.62 years, 95% CI: 0.95, 2.29). Compared to a model where each metabolite in the mixture is set to its 50th percentile, the log cumulative mixture with each metabolite at its 30th (β = −0.13 years, 95% CI: −0.26, −0.005) and 40th percentile (β = −0.06 years, 95% CI: −0.11, −0.005) was associated with decreased GrimAge. Our results provide novel characterizations of the relationships between one-carbon metabolites and DNA methylation age in a human population study. Further research is required to confirm these findings and establish their generalizability.

scholarly journals INTEREST GROUP SESSION—EPIDEMIOLOGY OF AGING: BIOSOCIAL RESEARCH ON BRAIN AGING AND BIOLOGICAL AGING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S348-S348
Author(s):  
Daniel W Belsky
Keyword(s):  
Life Course ◽  
Cognitive Aging ◽  
Brain Aging ◽  
Functional Decline ◽  
Biological Aging ◽  
Social Psychological ◽  
Aging Research ◽  
System Integrity ◽  
Organ Systems ◽  
The Brain

Abstract Our aging global population presents a new set of challenges for public health. Individual-disease focused models are becoming outmoded as geriatricians recognize multimorbidity and frailty as the central challenges in preserving health for older adults. Evidence from research into the biology of aging suggests that a set of common cellular-level processes underpin decline in system integrity that induces vulnerability to disease across multiple organ systems, including the brain. In parallel, research in life-course gerontology indicates that the roots of aging-related decline in system integrity extend from early life and encompass histories of social, psychological, and biochemical exposures. The research presented in this symposium aims to integrate these emerging paradigms in aging research by mapping connections among measures of aging in the brain and body and social, psychological, and nutrition exposures. Our symposium focuses on (1) links between social-psychological determinants of health and biological aging in the brain and body; and (2) social and behavioral protective factors that may buffer emerging biological risk in aging. The overarching goal of this symposium is to introduce an approach to gerontology that integrates geroscience with life-course social and psychiatric epidemiology to advance understanding of cognitive aging and functional decline, and ultimately identify novel interventions to extend healthy lifespan.

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.

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 Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias

Neurology ◽  
2017 ◽  
Vol 88 (10) ◽  
pp. 961-969 ◽  
Author(s):  
Petra Steinacker ◽  
Elisa Semler ◽  
Sarah Anderl-Straub ◽  
Janine Diehl-Schmid ◽  
Matthias L. Schroeter ◽  
...  
Keyword(s):  
Functional Decline ◽  
Disease Status ◽  
Longitudinal Change ◽  
Blood Levels ◽  
Phosphorylated Tau ◽  
Left Frontal Lobe ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Primary Progressive

Objective:To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants.Methods:We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), β-amyloid (Aβ1-42), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy.Results:Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Aβ1-42achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA.Conclusions:Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative.Classification of evidence:This study provides Class I evidence that in patients with PPA, blood levels of NF-L can distinguish the logopenic variant from the nonfluent/agrammatic and semantic variants.

Decrease in Secondary Neck Vessels in Multiple Sclerosis: A 5-year Longitudinal Magnetic Resonance Angiography Study

2019 ◽  
Vol 16 (3) ◽  
pp. 215-223 ◽  
Author(s):  
Dejan Jakimovski ◽  
Matthew Topolski ◽  
Kana Kimura ◽  
Virja Pandya ◽  
Bianca Weinstock-Guttman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Magnetic Resonance ◽  
Magnetic Resonance Angiography ◽  
Longitudinal Change ◽  
Repeated Measure ◽  
Cross Sectional ◽  
False Discovery ◽  
The Common ◽  
Neck Vessels

Background: Studies have previously shown greater arterial and venous extracranial vascular changes in persons with multiple sclerosis (PwMS) when compared to healthy controls (HCs). Objectives: To determine the change in the number and size of secondary neck vessels in PwMS and HCs over a 5-year follow-up period. Methods: Both at baseline and follow-up, 83 PwMS and 25 HCs underwent magnetic resonance angiography (MRA) imaging and analysis. The number and cross-sectional area (CSA) of all secondary neck vessels (excluding the common/internal carotid, vertebral artery, and internal jugular vein) measured at levels from C2-T1 were determined by semi-automated edge detection/ contouring software. The longitudinal change in the number and CSA of the secondary neck vessels from the PwMS and HCs were analyzed by non-parametric Wilcoxon repeated measure. Benjamini-Hochberg procedure adjusted for false discovery rate (FDR). Results: For over 5 years, PwMS demonstrated a consistent longitudinal decrease in both the number of secondary neck vessels (Z-change between -3.3 and -5.4, q=0.001) and their CSA (Zchange between -2.9 and -5.2, q=0.004). On the contrary, the HCs did not demonstrate a significant longitudinal change in secondary neck vessels over the follow-up period. Due to the longitudinal decrease, the PwMS showed a lower number of secondary neck vessels when compared to HCs measured at follow-up (p<0.029, except for C4 with trending p=0.071). The PwMS changes were also corroborated within each MS phenotype. Conclusion: PwMS demonstrate a significant mid-term decrease in the number and the size of the secondary neck vessels. The clinical relevance of these findings and the effect on intracranial blood flow are currently unknown.

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.

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