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)

Significance

Because obese people are at an increased risk of many age-related diseases, it is a plausible hypothesis that obesity increases the biological age of some tissues and cell types. However, it has been difficult to detect such an accelerated aging effect because it is unclear how to measure tissue age. Here we use a recently developed biomarker of aging (known as “epigenetic clock”) to study the relationship between epigenetic age and obesity in several human tissues. We report an unexpectedly strong correlation between high body mass index and the epigenetic age of liver tissue. This finding may explain why obese people suffer from the early onset of many age-related pathologies, including liver cancer.

Abstract

Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an “epigenetic clock”) to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10−4 in dataset 1 and r = 0.42, P = 1.2 × 10−4 in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10−9) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: shorvath{at}mednet.ucla.edu.

  • ↵2C.S. and J.H. contributed equally to this work.

  • Author contributions: S.H. and J.H. designed research; S.H. performed research; S.H., W.E., M.B., O.A., W.v.S., M.A., N.H., J.T.B., P.-C.T., T.D.S., P.D., R.S., B.S., T.B., C.R., C.S., and J.H. contributed new reagents/analytic tools; S.H. and P.-C.T. analyzed data; and S.H. and J.H. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE61256).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1412759111/-/DCSupplemental.

Freely available online through the PNAS open access option.

  1. Steve Horvatha,b,1,
  2. Wiebke Erhartc,
  3. Mario Broschd,
  4. Ole Ammerpohle,
  5. Witigo von Schönfelsf,
  6. Markus Ahrensf,
  7. Nils Heitsf,
  8. Jordana T. Bellg,
  9. Pei-Chien Tsaig,
  10. Tim D. Spectorg,
  11. Panos Deloukash,i,j,
  12. Reiner Sieberte,
  13. Bence Siposk,
  14. Thomas Beckerf,
  15. Christoph Röckenl,
  16. Clemens Schafmayerf,2, and
  17. Jochen Hamped,2
  1. Departments of aHuman Genetics, David Geffen School of Medicine,
  2. and bBiostatistics, School of Public Health, University of California Los Angeles, CA 90095;
  3. cDepartment of Internal Medicine I,
  4. fDepartment of Visceral and Thoracic Surgery,
  5. eInstitute of Human Genetics, Christian-Albrechts-University Kiel, and
  6. lInstitute of Pathology, University Hospital Schleswig-Holstein, 24015 Kiel, Germany;
  7. dMedical Department 1, University Hospital Dresden, Technical University Dresden, 01307 Dresden, Germany;
  8. gDepartment of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, United Kingdom;
  9. hWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, United Kingdom;
  10. iWellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
  11. jPrincess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia; and
  12. kInstitute of Pathology, University Hospital Tübingen, 72074 Tübingen, Germany

  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)

Significance

Because obese people are at an increased risk of many age-related diseases, it is a plausible hypothesis that obesity increases the biological age of some tissues and cell types. However, it has been difficult to detect such an accelerated aging effect because it is unclear how to measure tissue age. Here we use a recently developed biomarker of aging (known as “epigenetic clock”) to study the relationship between epigenetic age and obesity in several human tissues. We report an unexpectedly strong correlation between high body mass index and the epigenetic age of liver tissue. This finding may explain why obese people suffer from the early onset of many age-related pathologies, including liver cancer.

Abstract

Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an “epigenetic clock”) to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10−4 in dataset 1 and r = 0.42, P = 1.2 × 10−4 in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10−9) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

  • obesity
  • epigenetics
  • aging
  • biological age
  • DNA methylation

Footnotes

  • ↵1To whom correspondence should be addressed. Email: shorvath{at}mednet.ucla.edu.

  • ↵2C.S. and J.H. contributed equally to this work.

  • Author contributions: S.H. and J.H. designed research; S.H. performed research; S.H., W.E., M.B., O.A., W.v.S., M.A., N.H., J.T.B., P.-C.T., T.D.S., P.D., R.S., B.S., T.B., C.R., C.S., and J.H. contributed new reagents/analytic tools; S.H. and P.-C.T. analyzed data; and S.H. and J.H. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE61256).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1412759111/-/DCSupplemental.

Freely available online through the PNAS open access option.

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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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