EPIGENETICS

DNA methylation-based biomarkers and the epigenetic clock theory of ageing

Abstract

Identifying and validating molecular targets of interventions that extend the human health span and lifespan has been difficult, as most clinical biomarkers are not sufficiently representative of the fundamental mechanisms of ageing to serve as their indicators. In a recent breakthrough, biomarkers of ageing based on DNA methylation data have enabled accurate age estimates for any tissue across the entire life course. These ‘epigenetic clocks’ link developmental and maintenance processes to biological ageing, giving rise to a unified theory of life course. Epigenetic biomarkers may help to address long-standing questions in many fields, including the central question: why do we age?

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Fig. 1: Comparison of three DNA methylation-based biomarkers of ageing.
Fig. 2: Multi-tissue DNA methylation-based age and age acceleration.
Fig. 3: Tissue function versus DNA methylation-based age.

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Acknowledgements

Although the authors have made every effort to be objective, it is proper to mention that S.H. co-authored many of the articles mentioned in this Review. The authors apologize for not being able to cover all publications owing to oversight or space limitations. To ensure accuracy, the authors highlighted articles that employed large sample sizes, rigorous study designs and validated biomarkers.

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The authors contributed equally to all aspects of this article.

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Correspondence to Steve Horvath.

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The Regents of the University of California is the sole owner of several patent applications directed at the invention of measures of epigenetic age estimation for which S.H. is a named inventor. K.R. declares no competing interests.

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NIH Wednesday Afternoon Lecture Series (presentation by S. H. from 15 June 2016): https://www.youtube.com/watch?v = 0zaCKAnFogQ

Supplementary information

Glossary

Chronological age

The calendar time that has passed since birth. Zero is the time at birth. Negative numbers indicate prenatal ages, whereas positive numbers indicate postnatal ages.

Biological age

Also known as physiological age, organismal age or phenotypic age. This ambiguous concept is held to be dependent on the biological state of the individual.

Epigenetic age

The age estimate in years resulting from a mathematical algorithm based on the methylation state of specific CpGs in the genome. Negative numbers indicate prenatal ages.

CpG dinucleotides

Regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5′ to 3′ direction. Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine.

Epigenetic age estimators

Mathematical algorithms that use values assigned to the methylation state of specific CpGs in the genome to estimate the age of a person or biological sample. A multi-tissue age estimator allows one to estimate the age of any nucleated cell, tissue or organ.

Quasi-programme theories of ageing

Several variations of a theory that posits that ageing is not the intended outcome of biological processes but that some programmed processes nevertheless result in ageing. Therefore, the process of ageing can be viewed as quasi-programmed.

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Horvath, S., Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19, 371–384 (2018). https://doi.org/10.1038/s41576-018-0004-3

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