1 Nov 2023

The Epigenetic Clock: DNA Methylation and Aging



Aging represents a complex and time-dependent deterioration of physiological processes that occurs in most known living organisms [1]. In the past century, there has been an extraordinary increase in the average lifespan of humans, leading to a significant rise in both the number and proportion of older individuals within the population. However, the success in prolonging life has not been accompanied by a corresponding reduction in chronic diseases [2]. Consequently, a substantial number of people experience poor health during their later years, resulting in a considerable healthcare burden.

Nevertheless, advancements in scientific research have shed light on the critical role of epigenetic mechanisms in aging and age-related diseases such as cancer [3], cardiovascular disease [4], and Alzheimer’s disease [5]. These conditions significantly impact health span, emphasizing the urgent need to comprehend the connection between epigenetic aging and our overall wellbeing.

The emerging field of epigenetic research offers promising prospects for developing novel treatments targeting age-related diseases by enhancing our understanding of the aging methylome.

Unravelling the Epigenetic Code

Epigenetics refers to heritable changes in gene activity or function that cannot be explained by changes in DNA sequence [6]. These changes include non-coding RNAs, chemical modifications, and alterations to the packaging of DNA. Among these types of epigenetic regulation, DNA methylation is particularly notable for its association with the aging process.

DNA methylation is a fundamental epigenetic mechanism that involves the addition of a tag known as a methyl group to the DNA molecule. By adding methyl groups to certain regions of the genome, cells can silence or activate specific genes, thereby influencing their functional characteristics. This process plays a critical role in the regulation of development, and cellular differentiation.

What are Epigenetic Clocks?

Epigenetic drift is a term used to describe the gradual loss and increased variability in DNA methylation patterns that occur over time. These changes accumulate as cells divide and age, resulting in a unique methylation profile associated with each person’s chronological age. As such, it became apparent that the epigenome was a dynamic landscape reflecting a variety of chronological changes.

Researchers have utilized this concept to develop epigenetic clocks, which are computational models that identify specific methylation sites consistently associated with age across individuals [7]. These epigenetic clocks have proven to accurately predict a person’s biological age [7,8]. Biological age, often referred to as the functional capacity of an individual both mentally and physically, can be a more informative measure than chronological age as it correlates more strongly with age-related diseases and mortality risks.

Epigenetic clocks have shown remarkable accuracy in estimating biological age across various tissues and cell types. This has led to the potential use of the methylome as a powerful tool for measuring health and lifespan [9,10]. Additionally, the detection of abnormal DNA methylation patterns could serve as a diagnostic tool for age-related diseases. Perhaps the most exciting feature of DNA methylation biomarkers is that epigenetic changes are reversible, raising the prospect that epigenetic age estimates might be useful for identifying or validating anti-aging interventions.

Figure 1: The epigenetic clock.

DNA methylation can be influenced by various environmental factors such as diet, hormones, stress, drugs, and exposure to chemicals, indicating that interactions with the environment could affect the pace of aging via epigenetics [11].

This was evidenced in a comprehensive epigenome-wide association study involving a cohort of 43 elderly twin pairs observed over a period of 10 years. This research revealed that 90% of the observed longitudinal changes in DNA methylation levels were solely attributable to individual unique environmental factors [12], providing a direct link between environmental factors with molecular-level epigenetic modification and the aging process.

Numerous studies are utilizing epigenetic clocks to establish a clear correlation between various lifestyle choices and the aging process [11]. One study showed compelling evidence that smoking can accelerate the epigenetic age of airway epithelial and lung tissues by approximately four to five years [13]. Additionally, a lifetime of stress was found to contribute up to 3.6 years of biological age, while every 10 units of body mass index (BMI) was shown to correspond to 1–3 years of epigenetic age across various tissues [11]. On the other hand, these investigations have also demonstrated that calorie restriction has the potential to decelerate the aging process by 2–3%, thereby potentially resulting in a remarkable 10–15% reduction in mortality rate [14].

These findings emphasize the significant role of environmental influences on the aging process, and the flexibility of DNA methylation.

Could resetting the methylome rejuvenate the body?

The accumulation of epigenetic noise has been proposed to be a primary cause of aging since it disrupts gene function and leads to the loss of cell identity and regenerative capacity [15, 16]. Therefore, if accumulative changes in DNA methylation are at the core of the aging process, is it possible to restore tissue function and vitality by reversing these changes?

In a recent study published in Nature, researchers successfully restored a youthful DNA methylation profile in retinal ganglion cells (RGCs) in the eyes of mice [17]. The treatment resulted in a significant increase in visual acuity, with half of the visual acuity lost from increased intraocular pressure being restored. The study suggests that the visual improvements were caused by changes in gene activity, as the treatment restored approximately 90% of the mRNA levels of genes affected by aging back to youthful levels [17]. This achievement represents the first successful attempt to reverse glaucoma-induced vision loss, rather than merely stem its progression.

If replicated through further studies, this approach could pave the way for therapies to promote tissue repair across various organs and reverse aging and age-related diseases in humans.


As our understanding of epigenetic mechanisms deepens, we inch closer to unraveling the mysteries of aging, and finding new ways to enhance human health and extend our collective health span. The epigenetic clock, specifically the aging methylome, holds immense potential in transforming the landscape of healthcare, paving the way for personalized treatments and interventions that could revolutionize the aging process. By embracing and investing in epigenetic research, we take a significant step forward in the quest for healthy aging and a brighter future for all.

Further research in this field will require large-scale sequencing and computational tools capable of accurately analyzing and interpreting the complex and dynamic DNA methylation marks. At Eremid, we specialize in methylation sequencing and bioinformatics services, and understand its crucial role in advancing our understanding of the aging methylome and its implications for human health. How can we support you in your epigenetic clock research?


[1] Galloway, A., 1993. The evolutionary biology of aging. By Michael R. Rose. New York: Oxford University Press. 1991. ISBN 0-19-506133-0. American Journal of Physical Anthropology 91, 260–262. https://doi.org/10.1002/ajpa.1330910217

[2] Partridge, L., Deelen, J., Slagboom, P.E., 2018. Facing up to the global challenges of ageing. Nature 561, 45–56. https://doi.org/10.1038/s41586-018-0457-8

[3] Dawson, M.A., Kouzarides, T., 2012. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27. https://doi.org/10.1016/j.cell.2012.06.013

[4] Webster, A.L.H., Yan, M.S.-C., Marsden, P.A., 2013. Epigenetics and cardiovascular disease. Can J Cardiol 29, 46–57. https://doi.org/10.1016/j.cjca.2012.10.023

[5] Kramer, J.M., 2013. Epigenetic regulation of memory: implications in human cognitive disorders. BioMolecular Concepts 4, 1–12. https://doi.org/10.1515/bmc-2012-0026

[6] Bird, A., 2007. Perceptions of epigenetics. Nature 447, 396–398. https://doi.org/10.1038/nature05913

[7] Bocklandt, S., Lin, W., Sehl, M.E., Sánchez, F.J., Sinsheimer, J.S., et al., 2011. Epigenetic Predictor of Age. PLOS ONE 6, e14821. https://doi.org/10.1371/journal.pone.0014821

[8] Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., et al., 2013. Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates. Mol Cell 49, 359–367. https://doi.org/10.1016/j.molcel.2012.10.016

[9] Levine, M.E., Lu, A.T., Quach, A., Chen, B.H., Assimes, T.L., et al., 2018. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591. https://doi.org/10.18632/aging.101414

[10] Lu, A.T., Quach, A., Wilson, J.G., Reiner, A.P., Aviv, A., et al., 2019. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327. https://doi.org/10.18632/aging.101684

[11] Galkin, F., Kovalchuk, O., Koldasbayeva, D., Zhavoronkov, A., Bischof, E., 2023. Stress, diet, exercise: Common environmental factors and their impact on epigenetic age. Ageing Research Reviews 88, 101956. https://doi.org/10.1016/j.arr.2023.101956

[12] Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., Liang, H., 2019. Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical Epigenetics 11, 183. https://doi.org/10.1186/s13148-019-0777-z

[13] Tan, Q., Heijmans, B.T., Hjelmborg, J. v B., Soerensen, M., Christensen, K., Christiansen, L., 2016. Epigenetic drift in the aging genome: a ten-year follow-up in an elderly twin cohort. International Journal of Epidemiology 45, 1146–1158. https://doi.org/10.1093/ije/dyw132

[14] Waziry, R., Ryan, C.P., Corcoran, D.L., Huffman, K.M., Kobor, M.S., et al., 2023. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nat Aging 3, 248–257. https://doi.org/10.1038/s43587-022-00357-y

[15] Oberdoerffer, P., Michan, S., McVay, M., Mostoslavsky, R., Vann, J., et al., 2008. SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging. Cell 135, 907–918. https://doi.org/10.1016/j.cell.2008.10.025

[16] Yang, J.-H., Hayano, M., Griffin, P.T., Amorim, J.A., Bonkowski, M.S., et al., 2023. Loss of epigenetic information as a cause of mammalian aging. Cell 186, 305-326.e27. https://doi.org/10.1016/j.cell.2022.12.027

[17] Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer., et al., 2020. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129. https://doi.org/10.1038/s41586-020-2975-4


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