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Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms.

ABSTRACT: BACKGROUND:Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages. RESULTS:Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers. This distinct pattern extends to other tissues and multiple cancer types. Finally, genes associated with aVMPs in trans whose expression is variably upregulated with age (733 genes) play a key role in DNA repair and apoptosis, whereas downregulated aVMP-associated genes (121 genes) are mapped to defined pathways in cellular metabolism. CONCLUSIONS:Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing.

SUBMITTER: Slieker RC

PROVIDER: S-EPMC5032245 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms.

Slieker Roderick C RC van Iterson Maarten M Luijk René R Beekman Marian M Zhernakova Daria V DV Moed Matthijs H MH Mei Hailiang H van Galen Michiel M Deelen Patrick P Bonder Marc Jan MJ Zhernakova Alexandra A Uitterlinden André G AG Tigchelaar Ettje F EF Stehouwer Coen D A CD Schalkwijk Casper G CG van der Kallen Carla J H CJ Hofman Albert A van Heemst Diana D de Geus Eco J EJ van Dongen Jenny J Deelen Joris J van den Berg Leonard H LH van Meurs Joyce J Jansen Rick R 't Hoen Peter A C PA Franke Lude L Wijmenga Cisca C Veldink Jan H JH Swertz Morris A MA van Greevenbroek Marleen M J MM van Duijn Cornelia M CM Boomsma Dorret I DI Slagboom P Eline PE Heijmans Bastiaan T BT

Genome biology 20160922 1

<h4>Background</h4>Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages.<h4>Results</h4>Here, we report on the large-scale identification of 6366 age-related variably methylated positio ...[more]

PMID: 27654999

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Project description:Importance:Bone health in early life is thought to influence the risk of osteoporosis in later life. Objective:To examine whether puberty timing is associated with bone mineral density accrual up to adulthood. Design, Setting, and Participants:This cohort study used data from the Avon Longitudinal Study of Parents and Children, a prospective population-based birth cohort initiated in 1991 to 1992 in southwest England. The participants were 6389 healthy British people who underwent regular follow-up, including up to 6 repeated bone density scans from ages 10 to 25 years. Data analysis was performed from June 2018 to June 2019. Exposures:Age at puberty from estimated age at peak height velocity (years). Main Outcomes and Measures:Gains per year in whole-body bone mineral density (grams per square centimeter), assessed by dual-energy x-ray absorptiometry at ages 10, 12, 14, 16, 18, and 25 years and modeled using linear splines. Results:A total of 6389 participants (3196 [50.0%] female) were included. The mean (SD) age at peak height velocity was 13.5 (0.9) years for male participants and 11.6 (0.8) years for female participants. Male participants gained bone mineral density at faster rates than did female participants, with the greatest gains in both male participants (0.139 g/cm2/y; 95% CI, 0.127-0.151 g/cm2/y) and female participants (0.106 g/cm2/y; 95% CI, 0.098-0.114 g/cm2/y) observed between the year before and 2 years after peak height velocity. When aligned by chronological age, per 1-year older age at puberty was associated with faster subsequent gains in bone mineral density; the magnitudes of faster gains were greatest between ages 14 and 16 years in both male participants (0.013 g/cm2/y; 95% CI, 0.011-0.015 g/cm2/y) and female participants (0.014 g/cm2/y; 95% CI, 0.014-0.015 g/cm2/y), were greater in male participants (0.011 g/cm2/y; 95% CI, 0.010-0.013 g/cm2/y) than in female participants (0.003 g/cm2/y; 95% CI, 0.003-0.004 g/cm2/y) between ages 16 and 18 years, and were least in both male participants (0.002 g/cm2/y; 95% CI, 0.001-0.003 g/cm2/y) and female participants (0.000 g/cm2/y; 95% CI, -0.001 to 0.000 g/cm2/y) between ages 18 and 25 years. Despite faster gains, older age at puberty was associated with persistently lower bone mineral density, changing from 0.050 g/cm2 (95% CI, -0.056 to -0.045 g/cm2) lower at age 14 years to 0.047 g/cm2 (95% CI, -0.051 to -0.043 g/cm2) lower at age 25 years in male participants and from 0.044 g/cm2 (95% CI, -0.046 to -0.041 g/cm2) to 0.034 g/cm2 (95% CI, -0.036 to -0.032 g/cm2) lower at the same ages in female participants. Conclusions and Relevance:People with older pubertal age should be advised on how to maximize bone mineral density and minimize its decrease in later life to help prevent fracture and osteoporosis.

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Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms.

Publications

Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms.

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