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DNA Methylation and Aging
There are pronounced differences in the health status of individuals with the same chronological age, as well as in the extent to which they are affected by age-related medical conditions. The marked variability in the aging process has prompted researchers to search for biological parameters that may explain it, and for strategies to quantify not only chronological but also biological age.1 This undertaking is complicated by the fact that aging depends on the complex interplay of genetic (related to inherited characteristics passed from generation to generation) and environmental/lifestyle factors.2 However, great progress has been achieved in the identification of consistent markers of chronological and biological age. Some of the most prominent markers of aging are related to epigenetic mechanisms (mechanisms through which the environment and behavior modify the function of genes). In particular, specific modifications (methylation) of certain molecules of DNA (the carrier of genetic information in our organisms) have shown the capacity to capture factors related to chronological and biological age.
Epigenetic Clocks
Epigenetic clocks are tools that have been developed to estimate chronological and/or biological age through the epigenetic status of subsets of genes, and more specifically through their DNA methylation.3 The first DNA methylation clocks were developed as predictors of age based on DNA methylation signatures, and they successfully capture variations between an individual’s actual epigenetic age and their expected epigenetic age. The epigenetic clocks of Horvath4 and Hannum5 are two of the most widely used DNA methylation clocks that have shown extremely high correlation with chronological age.
Subsequently, DNA methylation clocks that incorporate clinical measures of observable age characteristics (phenotypic age) have also been developed. Levine et al. introduced the DNAm PhenoAge, which was created based on markers of phenotypic age and chronological age. It has shown the potential to predict several age-related outcomes, including overall mortality, health span (the part of an individual’s life during which they are in good health), the development of cancer, and physical function. Interestingly, an activation of pathways related to inflammation has been demonstrated in individuals with increased epigenetic age compared to their chronological age using DNAm PhenoAge.6 Another DNA methylation clock that aims to capture primarily biological parameters of aging is the GrimAge clock. Its creators identified DNA methylation sites that correlate closely with serum protein levels predicting mortality or with self-reported smoking history and used them to develop a novel measure of epigenetic age acceleration designated as AgeAccelGrim.7 Most DNA methylation clocks were originally developed in blood but have been shown to perform across an array of tissues. Overall, DNA methylation clocks that have been designed using age-related biochemical markers rather than only utilizing chronological age tend to correlate stronger with health outcomes related to aging, such as the lifespan and time to the development of overall comorbidities, heart disease, and cancer.7
DNA Methylation Age Acceleration and Mortality Risk
Acceleration of the DNA methylation age has consistently been associated with an increased mortality risk. Thus, a recent article systematically reviewed 156 studies on factors associated with acceleration of the epigenetic aging process. It found that mortality was associated with DNA methylation age acceleration in all four analyzed clocks (Horvath, Hannum, Levine, and GrimAge).8 This finding is consistent with the results of a large study, encompassing 13 cohorts with over 13,000 individuals, which showed that DNA methylation age acceleration determined with several different indicators was predictive of mortality. This association between DNA methylation acceleration and mortality remained significant even after an adjustment for chronological age and risk factors, and was most pronounced when accounting for blood cell composition.9 The association between DNA methylation age and mortality risk has also been analyzed in twins. For example, in an investigation that followed 413 female twin pairs over 18 years, GrimAge was a very good predictor of mortality, and smoking played an important role in the prediction of mortality by GrimAge.10
In addition to mortality risk, DNA methylation age acceleration has also been associated with an increased risk for certain medical conditions. A review of 156 previous publications found that DNA methylation age acceleration is associated with an increased risk for the development of cancer, cardiovascular disease, and diabetes across the four analyzed DNA methylation clocks.8 Moreover, an association between metabolic syndrome, body mass index (BMI; a measure of body fat), or inflammation markers and epigenetic age acceleration has been observed using some but not all approaches.8,10 For example, a study found an association of one measure of epigenetic age acceleration with the number of metabolic syndrome symptoms. This could partially be explained by an increase in an inflammatory blood marker (C-reactive protein).
A number of other medical conditions have also been associated with epigenetic age acceleration, but the results vary based on the epigenetic clock or the characteristics of the participants included in each study.8,11 These fluctuations can be expected due to the fact that different DNA methylation clocks vary in the parameters they measure. For example, some clocks include clinical characteristics of phenotypic age, whereas others do not. Moreover, some reflect properties of the aging process that are intrinsic to cells and preserved across cell types, whereas others account both for intrinsic epigenetic changes related to age and changes in blood cell composition.11
Lifestyle Factors and Interventions Aiming to Slow Down DNA Methylation Aging
In light of the association between epigenetic age and mortality risk, there is great interest to search for lifestyle or pharmacological interventions that may slow down epigenetic aging.
Dietary factors
The association between dietary factors and epigenetic age has been actively investigated. A large study encompassing over 4,000 individuals showed a relatively weak correlation of dietary factors with epigenetic age, but this fact may be attributed to the significant role of genetic variability.11 The authors found an association of several dietary patterns, summarized as a high-plant diet with lean meat, with lower epigenetic age.11 Another recent investigation analyzed the association of diet quality and DNA methylation age.12 The quality of the diet was accounted for by the Dietary Approaches to Stop Hypertension (DASH) score. The DASH eating plan is flexible and aims to create healthy and well-balanced eating habits. The consumption of fruit, vegetables, and whole grains is recommended. Other included products are low-fat or fat-free dairy products, nuts, beans, poultry, fish, and vegetable oils. However, the consumption of foods containing high levels of saturated fats, such as fatty meats, tropical oils, and full-fat dairy products as well as of sweets and sugar-sweetened beverages is limited.13 The authors found that a higher DASH score, indicating higher diet quality, was associated with slower epigenetic age acceleration using three different measures of epigenetic age. Moreover, in this study the DNA methylation findings partially explained the positive effect of a high-quality diet on the lifespan.12 Another recent study analyzed the association of the Mediterranean diet with DNA methylation age.14 The Mediterranean diet is also an eating pattern that is considered well-balanced and healthy. It includes primarily fruit, vegetables, beans, nuts, grains, potatoes, seeds, and olive oil, whereas dairy products, fish, eggs, and poultry are included in low to moderate amounts.15 This pilot study followed healthy elderly individuals that started eating according to Mediterranean diet over a 1-year period and found a trend toward epigenetic rejuvenation, which reached significance only in some of the subgroups.14 Overall, the data on dietary factors and DNA methylation age suggest the significance of a high-quality diet for healthy aging, even though many questions still remain to be answered.
Experimental pharmacological interventions
A recent clinical trial was originally initiated to evaluate the potential of a specific pharmacological regimen to regenerate the thymus (an immune organ that normally diminishes with age) of healthy aging men. However, the researchers also found that the selected treatment regimen unexpectedly led to epigenetic age reversal in blood.16 These findings were observed with four different epigenetic clocks, but the safety and effectiveness of the used pharmacological treatment should be confirmed in follow up studies.
Limitations of Epigenetic Clocks and Strategies to Overcome Them
Even though DNA methylation clocks have shown the potential to capture important aspects of chronological and biological aging, they have limitations.17 The extent to which certain DNA modifications accompany findings of the aging process or active participants in it, should be delineated. Moreover, most DNA methylation clocks have been developed in blood, and even though they perform across a range of tissues, tissue-specific epigenetic clocks may show superior results. In addition, the tissues that are most relevant to certain disorders may not be easily accessible (such as brain tissue in disorders of the central nervous system), and peripheral tissues may not be able to capture all relevant processes.
One of the strategies to overcome these limitations is to create DNA methylation clocks specifically for the tissue of interest. Moreover, studies conducted in model systems provide insight into the mechanisms involved in epigenetic aging and rejuvenation. Furthermore, large scale investigations that combine genetic and epigenetic data reveal the interplay of genetic and epigenetic mechanisms in aging.
Overall, a number of DNA methylation clocks have been developed that reflect aspects of chronological and/or biological aging. The acceleration of DNA methylation aging has consistently been associated with increased mortality risk and with several age-related disorders. Therefore, there is great interest to identify lifestyle and medical interventions that may slow down biological aging. Despite some promising results, their efficacy and safety need to be replicated in independent studies, and the underlying mechanisms should be elucidated.
Literature Sources:
- Jazwinski, S.M., & Kim, S. (2019). Examination of the dimensions of biological age. Frontiers in Genetics,10, https://doi.org/10.3389/fgene.2019.00263
- https://medlineplus.gov/genetics/understanding/traits/longevity/
- Horvath, S., & Raj, K. (2018). DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics,19, 371–384.
- Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology,14(10), R115. https://doi.org/10.1186/gb-2013-14-10-r115
- Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.B., Gao, Y., Deconde, R., Chen, M., Rajapakse, I., Friend, S., Ideker, T., & Zhang, K. (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Molecular Cell,49, 359–367.
- Levine, M.E., Lu, A.T., Quach, A., Chen, B.H., Assimes, T.L., Bandinelli, S., Hou, L., Baccarelli, A.A., Stewart, J.D., Li, Y., Whitsel, E.A., Wilson, J.G., Reiner, A.P., Aviv, A., Lohman, K., Liu, Y., Ferrucci, L., & Horvath, S. (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY),10, 573–591. doi: 10.18632/aging.101414.
- Lu, A.T., Quach, A., Wilson, J.G., Reiner, A.P., Aviv, A., Raj, K., Hou, L., Baccarelli, A.A., Li, Y., Stewart, J.D., Whitsel, E.A., Assimes, T.L., Ferrucci, L., & Horvath S. (2019) DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY),11, 303-327. doi: 10.18632/aging.101684.
- Oblak, L., van der Zaag, J., Higgins-Chen, A.T., Levine, M.E., & Boks, M.P. (2021) A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration. Ageing Research Reviews,69, 101348. doi: 10.1016/j.arr.2021.101348.
- Chen, B.H., Marioni, R.E., Colicino, E., Peters, M.J., Ward-Caviness, C.K., Tsai, P.C., Roetker, N.S., Just, A.C., Demerath, E.W., Guan, W., Bressler, J., Fornage, M., Studenski, S., Vandiver, A.R., Moore, A.Z., Tanaka, T., Kiel, D.P., Liang, L., Vokonas, P., Schwartz, J., Lunetta, K.L., Murabito, J.M., Bandinelli, S., Hernandez, D.G., Melzer, D., Nalls, M., Pilling, L.C., Price, T.R., Singleton, A.B., Gieger, C., Holle, R., Kretschmer, A., Kronenberg, F., Kunze, S., Linseisen, J., Meisinger, C., Rathmann, W., Waldenberger, M., Visscher, P.M., Shah, S., Wray, N.R., McRae, A.F., Franco, O.H., Hofman, A., Uitterlinden, A.G., Absher, D., Assimes, T., Levine, M.E., Lu, A.T., Tsao, P.S., Hou, L., Manson, J.E., Carty, C.L., LaCroix, A.Z., Reiner, A.P., Spector, T.D., Feinberg, A.P., Levy, D., Baccarelli, A., van Meurs, J., Bell, J.T., Peters, A., Deary, I.J., Pankow, J.S., Ferrucci, L., & Horvath, S. (2016) DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY),8, 1844–1865. doi: 10.18632/aging.101020.
- Föhr, T., Waller, K., Viljanen, A., Sanchez, R., Ollikainen, M., Rantanen, T., Kaprio, J., & Sillanpää, E. (2021) Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs. Clinical Epigenetics,13, 128. doi: 10.1186/s13148-021-01112-7.
- Quach, A., Levine, M.E., Tanaka, T., Lu, A.T., Chen, B.H., Ferrucci, L., Ritz, B., Bandinelli, S., Neuhouser, M.L., Beasley, J.M., Snetselaar, L., Wallace, R.B., Tsao, P.S., Absher, D., Assimes, T.L., Stewart, J.D., Li, Y., Hou, L., Baccarelli, A.A., Whitsel, E.A., & Horvath, S. (2017) Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging (Albany NY),9, 419–446. doi: 10.18632/aging.101168.
- Kim, Y., Huan, T., Joehanes, R., McKeown, N.M., Horvath, S., Levy, D., & Ma. J. (2021) Higher diet quality relates to decelerated epigenetic aging. The American Journal of Clinical Nutrition,2021 Jun 16, nqab201. doi: 10.1093/ajcn/nqab201.
- https://www.nhlbi.nih.gov/health-topics/dash-eating-plan
- Gensous, N., Garagnani, P., Santoro, A., Giuliani, C., Ostan, R., Fabbri, C., Milazzo, M., Gentilini, D., di Blasio, A.M., Pietruszka, B., Madej, D., Bialecka-Debek, A., Brzozowska, A., Franceschi, C., & Bacalini, M.G. (2020) One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project. GeroScience,42, 687–701. https://doi.org/10.1007/s11357-019-00149-0
- https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/nutrition-basics/mediterranean-diet
- Fahy, G.M., Brooke, R.T., Watson, J.P., Good, Z., Vasanawala, S.S., Maecker, H., Leipold, M.D., Lin, D.T..S, Kobor, M.S., & Horvath, S. (2019) Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell,18, e13028. doi: 10.1111/acel.13028.
- Bell, C.G., Lowe, R., Adams, P.D., Baccarelli, A.A., Beck, S., Bell, J.T., Christensen, B.C., Gladyshev, V.N., Heijmans, B.T., Horvath, S., Ideker, T., Issa, J.J., Kelsey, K.T., Marioni, R.E., Reik, W., Relton, C.L., Schalkwyk, L.C., Teschendorff, A.E., Wagner, W., Zhang, K., & Rakyan, V.K. (2019) DNA methylation aging clocks: challenges and recommendations. Genome Biolology,20, 249.