DNA methylation aging clocks: challenges and recommendations

Published on Nov 25, 2019in Genome Biology14.028
· DOI :10.1186/S13059-019-1824-Y
Christopher G. Bell23
Estimated H-index: 23
(QMUL: Queen Mary University of London),
Robert Lowe17
Estimated H-index: 17
(QMUL: Queen Mary University of London)
+ 18 AuthorsVardhman K. Rakyan34
Estimated H-index: 34
(QMUL: Queen Mary University of London)
Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
Figures & Tables
  • References (224)
  • Citations (12)
📖 Papers frequently viewed together
154 Citations
18 Authors (Morgan E. Levine, ..., Steve Horvath)
135 Citations
1,250 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Irene Hernando-Herraez (Babraham Institute)H-Index: 2
#2Brendan Evano (Pasteur Institute)H-Index: 2
Last. Wolf Reik (Babraham Institute)H-Index: 107
view all 9 authors...
Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated...
7 CitationsSource
#1Qian Zhang (UQ: University of Queensland)H-Index: 50
#2Costanza L. Vallerga (UQ: University of Queensland)H-Index: 6
Last. Peter M. Visscher (UQ: University of Queensland)H-Index: 109
view all 33 authors...
DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed ‘epigenetic clocks’. The deviation of predicted age from the actual age (‘age acceleration residual’, AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259...
2 CitationsSource
#1Ake T. LuH-Index: 18
#2Anne SeebothH-Index: 1
Last. Steve HorvathH-Index: 97
view all 27 authors...
2 CitationsSource
#1Daniel E. Martin-Herranz (EMBL-EBI: European Bioinformatics Institute)H-Index: 2
#2Erfan Aref-Eshghi (UWO: University of Western Ontario)H-Index: 8
Last. Janet M. Thornton (EMBL-EBI: European Bioinformatics Institute)H-Index: 119
view all 10 authors...
Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery. Using the Horvath epigenetic ...
5 CitationsSource
#1Özgen Deniz (QMUL: Queen Mary University of London)H-Index: 6
#2Jennifer M. Frost (QMUL: Queen Mary University of London)H-Index: 2
Last. Miguel R. Branco (QMUL: Queen Mary University of London)H-Index: 22
view all 3 authors...
The originally published article contained an error in Figure 2a: for the left side of the figure part (showing piRNA-directed DNA methylation of mouse transposable elements), DNMT3A/B should have been DNMT3C. The article has now been corrected online.
2 CitationsSource
#1Judith Campisi (Buck Institute for Research on Aging)H-Index: 89
#2Pankaj Kapahi (Buck Institute for Research on Aging)H-Index: 39
Last. Eric Verdin (Buck Institute for Research on Aging)H-Index: 96
view all 6 authors...
For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commerci...
10 CitationsSource
#1Stephanie O. M. Dyke (McGill University)H-Index: 13
#2Katie M. Saulnier (McGill University)H-Index: 5
Last. Yann Joly (McGill University)H-Index: 19
view all 11 authors...
As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies, will be of growing importance. Members of the International Human Epigenome Consortium (IHEC) Bioethics Workgroup considered the potential ethical, legal, and social issues (ELSI) involved in returning epigenetic research results and incidental findings in order to produce a set of ‘Points...
2 CitationsSource
#1Arne Vasli Lund Søraas (Oslo University Hospital)H-Index: 5
#2Mieko Matsuyama (Case Western Reserve University)H-Index: 4
Last. Shigemi Matsuyama S (Case Western Reserve University)H-Index: 32
view all 12 authors...
2 CitationsSource
#1Özgen Deniz (QMUL: Queen Mary University of London)H-Index: 6
#2Jennifer M. Frost (QMUL: Queen Mary University of London)H-Index: 2
Last. Miguel R. Branco (QMUL: Queen Mary University of London)H-Index: 22
view all 3 authors...
Maintenance of genome stability requires control over the expression of transposable elements (TEs), whose activity can have substantial deleterious effects on the host. Chemical modification of DNA is a commonly used strategy to achieve this, and it has long been argued that the emergence of 5-methylcytosine (5mC) in many species was driven by the requirement to silence TEs. Potential roles in TE regulation have also been suggested for other DNA modifications, such as N6-methyladenine and oxida...
6 CitationsSource
#1Ayelet Alpert (Technion – Israel Institute of Technology)H-Index: 3
#2Yishai Pickman (Technion – Israel Institute of Technology)H-Index: 2
Last. Shai S. Shen-Orr (Technion – Israel Institute of Technology)H-Index: 21
view all 18 authors...
Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual’s immune age. Here, we use multiple ‘omics’ technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular freque...
15 CitationsSource
Cited By12
#1Daniel W. Belsky (Columbia University)H-Index: 31
#2Avshalom Caspi (Duke University)H-Index: 150
Last. Renate Houts (Duke University)H-Index: 49
view all 22 authors...
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 ...
#1Satoshi Okazaki (Kobe University)H-Index: 5
#2Shusuke Numata (University of Tokushima)H-Index: 23
Last. Akitoyo Hishimoto (Kobe University)H-Index: 15
view all 8 authors...
There is high mortality among patients with bipolar disorder (BD). Studies have reported accelerated biological aging in patients with BD. Recently, Horvath and Hannum et al. independently developed DNA methylation (DNAm) profiles as “epigenetic clocks,” which are the most accurate biological age estimate. This led to the development of two accomplished measures of epigenetic age acceleration (EAA) using blood samples, namely, intrinsic and extrinsic EAA (IEAA and EEAA, respectively). IEAA, whic...
#1Flavia CerratoH-Index: 18
#2Angela SparagoH-Index: 16
Last. Fiorella Gurrieri (Università Campus Bio-Medico)
view all 23 authors...
DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation pattern...
#1Joshua J Levy (Dartmouth College)H-Index: 1
#2Alexander J. TitusH-Index: 5
Last. Brock C. Christensen (Dartmouth College)H-Index: 7
view all 6 authors...
BACKGROUND: DNA methylation (DNAm) is an epigenetic regulator of gene expression programs that can be altered by environmental exposures, aging, and in pathogenesis. Traditional analyses that associate DNAm alterations with phenotypes suffer from multiple hypothesis testing and multi-collinearity due to the high-dimensional, continuous, interacting and non-linear nature of the data. Deep learning analyses have shown much promise to study disease heterogeneity. DNAm deep learning approaches have ...
#1Man Kit Lei (UGA: University of Georgia)H-Index: 19
#2Frederick X. Gibbons (UConn: University of Connecticut)H-Index: 29
Last. Steven R. H. Beach (UGA: University of Georgia)H-Index: 60
view all 5 authors...
Smoking is one of the leading preventable causes of morbidity and mortality worldwide, prompting interest in its association with DNA methylation-based measures of biological aging. Considerable progress has been made in developing DNA methylation-based measures that correspond to self-reported smoking status. In addition, assessment of DNA methylation-based aging has been expanded to better capture individual differences in risk for morbidity and mortality. Untested to date, however, is whether...
#1Sarah Voisin (VU: Victoria University, Australia)H-Index: 11
#2Nicholas Harvey (Bond University)H-Index: 1
Last. Jonathan Cedernaes (Uppsala University)H-Index: 17
view all 16 authors...
BACKGROUND: Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. METHODS: To address this, we developed a more accurate, muscle-specific epigenetic clock based on the...
2 CitationsSource
#1Jan Klosa (Leibniz Association)H-Index: 1
#2Noah Simon (UW: University of Washington)H-Index: 14
Last. Dörte Wittenburg (Leibniz Association)H-Index: 7
view all 5 authors...
Statistical analyses of biological problems in life sciences often lead to high-dimensional linear models. To solve the corresponding system of equations, penalisation approaches are often the methods of choice. They are especially useful in case of multicollinearity which appears if the number of explanatory variables exceeds the number of ob-servations or for some biological reason. Then, the model goodness of fit is penalised by some suitable function of interest. Prominent examples are the l...
#1Alexey Moskalev (Syktyvkar State University)H-Index: 22
A comparison of nine different approaches over a period of 20 years reveals the most promising indicators for biological age.
#1Daniel W. Belsky (Columbia University)H-Index: 31
#2Avshalom Caspi (Duke University)H-Index: 150
Last. William E. Kraus (Duke University)H-Index: 79
view all 17 authors...
Biological aging is the gradual and progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the rate of biological aging are needed to serve as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging to extend healthspan. We report a blood DNA-methylation measure that is sensitive to variation in the pace of biological aging among individuals born in the same year. We first ...
#1Xin Li (MIT: Massachusetts Institute of Technology)H-Index: 1
#1Xin LiH-Index: 35
view all 22 authors...
Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunct...
1 CitationsSource