Research Article

Obesity accelerates epigenetic aging of human liver

Steve Horvath, Wiebke Erhart, Mario Brosch, Ole Ammerpohl, Witigo von Schönfels, Markus Ahrens, Nils Heits, Jordana T. Bell, Pei-Chien Tsai, Tim D. Spector, Panos Deloukas, Reiner Siebert, Bence Sipos, Thomas Becker, Christoph Röcken, Clemens Schafmayer, and Jochen Hampe
PNAS October 28, 2014 111 (43) 15538-15543; first published October 13, 2014; https://doi.org/10.1073/pnas.1412759111

  1. Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved September 15, 2014 (received for review July 7, 2014)

Article Figures & SI

Figures

  • Fig. 1.
    Fig. 1.

    Discovery analysis. Analysis of the correlation of DNAm age to chronological age across the publicly available datasets: (A–D) This row shows the correlation of chronological age to the DNAm age in liver, adipose tissue, muscle, and blood. The red dashed line in these panels indicates the regression line. In all panels (A–H), each point corresponds to a human subject. Red circles indicate women and blue squares are used to denote male individuals. The age acceleration effect for each subject (point) corresponds to the vertical distance to the red regression line. (E–H) This row plots the relation of BMI and age acceleration in those tissues. The black horizontal line (y = 0) corresponds to an age acceleration of zero. It is evident that only liver tissue shows a significant correlation (r = 0.42, P = 6.8 × 10−4) to BMI.

  • Fig. 2.
    Fig. 2.

    Replication analysis. Independent liver (A, B, E, F), adipose tissue (C and G), and muscle (D and H) datasets were analyzed for a correlation of chronological age and DNAm age and age acceleration to BMI. The data confirm the correlation of DNAm age acceleration and BMI in liver tissue (E and F), even if the analysis is restricted to individuals without histological evidence of NAFLD (i.e., controls and healthy obese subjects) (F) and the lack of this correlation in adipose and muscle tissue (G and H).

  • Fig. 3.
    Fig. 3.

    Post hoc analyses of subgroups and histological characteristics of NASH. An adjusted measure of DNAm age is related to various measures of liver pathology. The adjusted measure of DNAm age acceleration was defined as residual from a regression model that regressed DNAm age on chronological age+BMI+sex. Note that this adjusted measure of age acceleration does not relate to (A) NAS, (B) fat percentage (steatosis), (C) inflammation, and (D) fibrosis. Each scatterplot reports the Pearson correlation coefficient and P value. Analogous results can also be found in the individual liver datasets (Figs. S3 and S4).

  • Fig. 4.
    Fig. 4.

    Effect of weight loss and exercise intervention on DNAm age. For 21 subjects, liver methylation data were available before and after bariatric surgery. As expected, BMI drops significantly within 6–9 mo following bariatric surgery (A). However, the DNAm age of the liver tissue is unaffected (B). (C) DNAm age of adipose tissue is unaffected by a 6-mo exercise intervention (20).

Tables

  • Table 1.

    Overview of the DNA methylation datasets

    Tissue sourcePlatformnData IDSourceFigurecor with BMI
    Discovery dataset
     1. LiverIllum450K62GSE48325(12)1, 3, 4r = 0.42, P = 6.8×10−4
     2. AdiposeIllum450K648E-MTAB1866(13)1r = −0.02, P = 0.68
     3. MuscleIllum450K48GSE50498(14)1r = −0.087, P = 0.56
     4. BloodIllum27K71GSE49909(15)1r = −0.066, P = 0.58
     5. BloodIllum27K92GSE37008(16)S1r = 0.26, P = 0.012
     6. BloodIllum450K111GSE53840This studyS1r = −0.18, P = 0.12
     7. AdiposeIllum450K46Reader comment(20)4r = NA, P = NA
    Replication dataset
     8. LiverIllum450K79GSE61258This study2, 3r = 0.42, P = 1.2E-4
     9. AdiposeIllum450K32GSE61257This study2r = 0.18, P = 0.32
     10. MuscleIllum450K26GSE61259This study2r = 0.085, P = 0.68
    Transcriptional data (messenger RNA)
     11. LiverHuGen1.1ST134GSE61260This studyTable 3NA

    • The rows correspond to the datasets used in this article. Columns report the tissue source, DNAm platform, number of subjects (n), access information and citation, and a reference to the use in this report. The last column reports the Pearson correlation coefficient between BMI and age acceleration, denoted as “cor,” and the corresponding P value. NA, not applicable.

  • Table 2.

    Estimation of the influence of BMI on liver DNAm age

    VariableDiscovery setReplication setCombined dataset
    Estimate (SE)PEstimate (SE)PEstimate (SE)P
    Chronological age0.77503 (0.04593)<2 ×10−160.53518 (0.06043)2.5 ×10−130.62987 (0.04472)<2 ×10−16
    BMI0.17352 (0.04616)3.9 ×10−40.23578 (0.06827)9.1 ×10−40.16789 (0.04603)3.8 ×10−4
    R20.830.510.61
    Age acceleration for 10-point increase in BMI2.2 y4.4 y2.7 y

    • In multivariate regression models of DNAm age, chronological age, and BMI remain the only significant predictors (see Table S1 for full models). BMI is a significant covariate of DNAm age in both the discovery and replication dataset. The table reports estimates of the regression coefficients and corresponding SEs, Wald test P values. The last row reports the age acceleration associated with a 10-point increase in BMI. For example, a 10-point increase in BMI is associated with an increase of 2.2 y (= 0.17352 × 10/0.77503) in DNAm age in the discovery set.

  • Table 3.

    Functional enrichment of gene transcripts associated with age acceleration

    CategoryTermnFEP Bonferroni
    279 negatively correlated genes
     Cell CompMitochondrion412.93.0 ×10−7
     KEGGOxidative phosphorylation116.53.7 ×10−4
     SP_PIRElectron transport107.81.6 ×10−3
    378 positively correlated genes
     Mol. Fnc.Nucleoside-triphosphatase regulator activity273.22.1 ×10−4
     Biol. Proc.Cell adhesion362.67.7 ×10−4
     Mol. Fnc.GTPase regulator activity263.14.8 ×10−4
     Biol. Proc.Response to wounding292.84.2 ×10−3
     SP_PIRGuanine-nucleotide releasing factor135.71.0 ×10−3
     SP_PIRAutophosphorylation99.81.2 ×10−3
     Biol. Proc.Wound healing164.21.1 ×10−2
     Mol. Fnc.GTPase binding125.37.5 ×10−3
     Biol. Pro.Cell activation193.33.1 ×10−2

    • The upper part of the table reports the results from applying DAVID EASE to 279 genes whose expression levels had a significant negative correlation with age acceleration in liver. Similarly, the lower part reports the result for the 378 positively related genes. The table reports the gene ontology (GO) enrichment categories, number of genes (n), fold-enrichment (FE), and Bonferroni-corrected P value. Biol. Proc., biological process; Mol. Fnc., molecular function; SP_PIR, spliceosome protein–protein interaction resource.

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Obesity accelerates epigenetic aging
Steve Horvath, Wiebke Erhart, Mario Brosch, Ole Ammerpohl, Witigo von Schönfels, Markus Ahrens, Nils Heits, Jordana T. Bell, Pei-Chien Tsai, Tim D. Spector, Panos Deloukas, Reiner Siebert, Bence Sipos, Thomas Becker, Christoph Röcken, Clemens Schafmayer, Jochen Hampe
Proceedings of the National Academy of Sciences Oct 2014, 111 (43) 15538-15543; DOI: 10.1073/pnas.1412759111
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