Epigenetic clock: a promising mirror of ageing
Authors: Zuyun Liu, Yimin Zhu
Journal: The Lancet Healthy Longevity (2021)

Ageing is one of the major risk factors for many chronic diseases. One key point that needs to be addressed to address ageing-related issues is to precisely quantify individual ageing. A panel of gerontologists has clearly stated that identifying ageing biomarkers is one of the top three priorities to further geroscience research.1Kennedy BK Berger SL Brunet A et al.Geroscience: linking aging to chronic disease.Cell. 2014; 159: 709-713Summary Full Text Full Text PDF PubMed Scopus (897) Google Scholar, 2Sierra F Kohanski R Geroscience and the trans-NIH Geroscience Interest Group, GSIG.Geroscience. 2017; 39: 1-5Crossref PubMed Scopus (64) Google Scholar DNA methylation (DNAm) has been emerging as a research focus, because some subsets of DNAm in genomic locations change predictably over the lifespan. Thus, researchers combined a set of cytosine-phosphate-guanine sites (CpGs) into composite methylation-based age predictors using mathematical algorithms.3Horvath S Raj K DNA methylation-based biomarkers and the epigenetic clock theory of ageing.Nature Rev Gen. 2018; 19: 371-384Crossref PubMed Scopus (571) Google Scholar These predictors are called epigenetic clocks or DNAm-age predictors, with the unit in years. With the advent of the first generation of epigenetic clocks by Horvath3Horvath S Raj K DNA methylation-based biomarkers and the epigenetic clock theory of ageing.Nature Rev Gen. 2018; 19: 371-384Crossref PubMed Scopus (571) Google Scholar (the pan-tissue clock) and Hannum and colleagues,4Hannum G Guinney J Zhao L et al.Genome-wide methylation profiles reveal quantitative views of human aging rates.Mol Cell. 2013; 49: 359-367Summary Full Text Full Text PDF PubMed Scopus (1311) Google Scholar many epigenetic clocks have been reported in the past 5 years. Two of these, the PhenoAge and GrimAge clock, are second-generation clocks that are commonly used. Despite differing in many aspects, a comparative analysis of 11 existing epigenetic clocks has shown that they share core signals that are relevant to the biology of ageing.5Liu Z Leung D Thrush K et al.Underlying features of epigenetic aging clocks in vivo and in vitro.Aging Cell. 2020; 19e13229Crossref PubMed Scopus (18) Google Scholar which support that epigenetic clocks serve as a promising biomarker of ageing. In the The Lancet Healthy Longevity, Felix P Chilunga and colleagues6Chilunga FP Henneman P Elliott HR et al.Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM study.Lancet Healthy Longev. 2021; (published online May 17.)https://doi.org/10.1016/S2666-7568(21)00087-8Summary Full Text Full Text PDF Scopus (3) Google Scholar used the aforementioned four epigenetic clocks to investigate the role of epigenetic ageing in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations. The main outcome of interest was epigenetic-age acceleration (EAA), calculated as residuals through regression of these epigenetic clocks on chronological age. Using data from more than 700 Ghanaians who participated in the study (365 migrants and 347 non-migrants), the authors found that migration is negatively associated with EAA, and cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Furthermore, some of the findings were replicated in two other samples of Indians and native South Africans. These findings are fascinating and interesting to researchers in many fields. In addition to the public health implications suggested by the authors—that context-based interventions for cardiometabolic diseases among transitioning populations must take into account the differing effects of biological ageing—the Article6Chilunga FP Henneman P Elliott HR et al.Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM study.Lancet Healthy Longev. 2021; (published online May 17.)https://doi.org/10.1016/S2666-7568(21)00087-8Summary Full Text Full Text PDF Scopus (3) Google Scholar contributes to the literature at least in two other aspects. First, the authors targeted unique populations from Ghana, India, and South Africa, who are known to be going through epidemiological health transitions because of rapid urbanisation and international migration. This population selection leads to some interesting observations, such as the so-called healthy-migrant effect mentioned in the Article,6Chilunga FP Henneman P Elliott HR et al.Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM study.Lancet Healthy Longev. 2021; (published online May 17.)https://doi.org/10.1016/S2666-7568(21)00087-8Summary Full Text Full Text PDF Scopus (3) Google Scholar although these results require further investigation, given that we don't know enough about the socioenvironmental circumstances of these unique populations. These observations from transitioning African populations would benefit other populations who are expected to go through such transitions in the next decades. Second, this is one of the the first times that epigenetic clocks have been used to disentangle the role of biological ageing in low-income and middle-income countries.7Nwanaji-Enwerem JC Nwanaji-Enwerem U Van Der Laan L Galazka JM Redeker NS Cardenas A A longitudinal epigenetic aging and leukocyte analysis of simulated space travel: the Mars-500 mission.Cell Rep. 2020; 33108406Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar Although epigenetic clocks have not been validated outside of high-income countries, this application is a promsing first step. With the availability of epigenetic data in various populations, there are remaining issues to be considered in the future application of epigenetic clocks.8Levine ME Assessment of epigenetic clocks as biomarkers of aging in basic and population research.J Gerontol A Biol Sci Med Sci. 2020; 75: 463-465Crossref PubMed Scopus (10) Google Scholar First, although researchers mostly emphasise what these clocks have in common, including Chilunga and colleagues,6Chilunga FP Henneman P Elliott HR et al.Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM study.Lancet Healthy Longev. 2021; (published online May 17.)https://doi.org/10.1016/S2666-7568(21)00087-8Summary Full Text Full Text PDF Scopus (3) Google Scholar we should acknowledge their potential differences.3Horvath S Raj K DNA methylation-based biomarkers and the epigenetic clock theory of ageing.Nature Rev Gen. 2018; 19: 371-384Crossref PubMed Scopus (571) Google Scholar, 5Liu Z Leung D Thrush K et al.Underlying features of epigenetic aging clocks in vivo and in vitro.Aging Cell. 2020; 19e13229Crossref PubMed Scopus (18) Google Scholar Second, relevant to the first issue, what do these epigenetic clocks have in common? Given that most epigenetic clocks are trained using supervised machine-learning algorithms, statistically significant CpGs without explicit biological signals seem to have been included and combined into a composite score. As a first step, previous analysis highlights biological pathways such as metabolism, immunity, chromatin modifications, and autophagy5Liu Z Leung D Thrush K et al.Underlying features of epigenetic aging clocks in vivo and in vitro.Aging Cell. 2020; 19e13229Crossref PubMed Scopus (18) Google Scholar that need further experimental validation. Uncovering the biological signals of epigenetic clocks would facilitate our understanding of what drives or mediates the relationship between exposures (lifestyle factors in this Article)6Chilunga FP Henneman P Elliott HR et al.Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM study.Lancet Healthy Longev. 2021; (published online May 17.)https://doi.org/10.1016/S2666-7568(21)00087-8Summary Full Text Full Text PDF Scopus (3) Google Scholar and diseases. Third, the development of epigenetic clocks is still ongoing, and we are therefore not sure whether the results from analysis using new epigenetic clocks would be similar. For instance, Belsky and colleagues9Belsky DW Caspi A Arseneault L et al.Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm.eLife. 2020; (published online Feb 7.)https://doi.org/10.1101/2020.02.05.927434PubMed Google Scholar have developed a single-time-point measure of a person's pace of biological ageing, called DunedinPoAm, which works better in many aspects (eg, mortality prediction) relative to previous epigenetic clocks. The development of new clocks will challenge many previous findings, including those of the Article by Chilunga and colleagues.6Chilunga FP Henneman P Elliott HR et al.Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM study.Lancet Healthy Longev. 2021; (published online May 17.)https://doi.org/10.1016/S2666-7568(21)00087-8Summary Full Text Full Text PDF Scopus (3) Google Scholar We are witnessing rapid progress in the intersection of ageing and epigenetics. With advances in this field, we believe that epigenetic clocks could help answer the ultimate question—what is ageing and how does it contribute to disease progression across different populations? We declare no competing interests. This work was supported by the 2020 Irma and Paul Milstein Programme for Senior Health project award (Milstein Medical Asian American Partnership Foundation), the Fundamental Research Funds for the Central Universities, Alibaba Cloud, the Natural Science Foundation of Zhejiang Province ( LQ21H260003 ), and the National Key Research and Development Programme of China ( 2017YFC0907004 ). Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM substudyOur study shows that migration is negatively associated with EAA among Ghanaians. Moreover, cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Our results call for context-based interventions for cardiometabolic diseases among transitioning populations that account for the effects of biological ageing. Full-Text PDF Open Access