In the last decade or so we have begun to uncover the molecular mechanisms that influence how long we live and how well we age. Central to this emerging field is the study of epigenetic clocks, tools that estimate biological age by examining patterns of DNA methylation.
Research into epigenetic clocks has revealed that biological age can be decoupled from chronological age, highlighting the plasticity of ageing. Unlike chronological age, which is measured by the passage of time, biological age reflects the wear and tear on our bodies and is more closely linked to healthspan - the period of life free from disease.
Epigenetic clocks represent a powerful tool for predicting disease risk, assessing the impact of anti-ageing therapies and ultimately guiding us toward a longer, healthier life.
What is DNA Methylation? How do Epigenetic Clocks Work?
DNA methylation is a natural process where small chemical tags attach to DNA. These tags don’t change the genetic code but influence how genes are turned on or off. Lifestyle factors influence DNA methylation by altering the enzymes and molecular pathways responsible for adding or removing these tags. Over time, DNA methylation patterns shift and can reflect cellular health and exposure to lifestyle health factors.
Specific risk factors that accelerate epigenetic aging include:
Chronic Inflammation
Impaired Glucose Metabolism
Overweight and Obesity
High Systolic Blood Pressure
Being male (sex)
Smoking
Neurodegenerative Diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease)
Chronic Infections (e.g., HIV, cytomegalovirus, SARS-CoV-2)
Childhood Trauma
Post-Traumatic Stress Disorder
Major Depressive Disorder
Sleep Disturbances (e.g., insomnia, shift work, sleep deprivation)
High Cortisol Levels
Low Resilience to Stress
Financial Stress
High Body Mass Index
Studying and measuring methylation patterns at specific spots on the genome creates a personalised epigenetic 'clock' that measures one's biological age. These clocks can sometimes predict health outcomes, including disease risk and lifespan.
DNA Methylation and Diet
A poor diet high in processed foods, sugars and unhealthy fats increases oxidative stress by producing excess reactive oxygen species (ROS), which damage DNA and disrupt normal methylation patterns. For example, this can lead to hypermethylation of tumor suppressor genes (turning them off), increasing cancer risk, or hypomethylation of inflammatory genes (turning them on), driving chronic inflammation and disease.
Dietary anti-oxidant polyphenols, such as epigallocatechin gallate from green tea or curcumin from turmeric, counteract these effects by scavenging ROS, reducing oxidative damage and protecting the enzymes responsible for DNA methylation. Polyphenols can also restore healthy methylation patterns; for instance, rosmarinic acid, the primary polyphenol in the herb rosemary, has been shown to modulate methylation processes, thereby reducing inflammation and lowering chronic disease risk. (Learn more about herbs and their polyphenols here)
Diets rich in polyphenols, such as the Mediterranean diet (or any whole food, plant based diet - for example, the Singapore healthy diet), support balanced gene expression and healthier aging. This highlights the critical role of nutrition in mitigating oxidative stress and promoting healthspan and longevity.
A Timeline of Research and Progress
Each epigenetic clock differs in how they estimate biological age and their focus on health outcomes. Below is a summary of some the the key epigenetic clocks developed since 2013.
The HannumAge clock (2013) tracks biological aging across various tissues, offering insights into differences between healthy and diseased states. While it highlights the impact of gender and genetics on aging, it is less effective at predicting health outcomes compared to newer models.
HorvathAge (2015) is a versatile clock applicable to nearly all human tissues and even other species, but its ability to predict healthspan related outcomes is limited.
DNAm PhenoAge (2018) incorporates health markers like inflammation and organ function, making it a strong predictor of lifespan, healthspan and age-related diseases, though it benefits from additional clinical context.
GrimAge (2019) combines DNA methylation with lifestyle and protein data, excelling at predicting mortality and disease risks but is primarily validated in older populations.
DunedinPoAm (2020) provides a single-time-point measure of the pace of aging, offering an efficient tool for testing anti-aging interventions but it requires broader validation in diverse populations.
DunedinPACE (2022) focuses on the current rate of aging, making it highly precise and practical for clinical trials, though it is still relatively new and needs further validation across varied populations.
The Epigenetic Clocks in Detail
The following section describes each of the above clocks in detail, and links to the research papers themselves.
2013, HannumAge
Using data from over 450,000 sites across the genome and blood samples from individuals aged 19 to 101, researchers created a model that tracks how the methylome - our DNA’s methylation profile - changes over time. This "aging clock" is influenced by factors like gender and genetics and can even highlight differences in aging rates between healthy tissues and tumour tissues.
The study showed that faster biological aging rates could explain "epigenetic drift," the gradual changes in DNA methylation as we age. These rates also correspond to changes in gene activity, suggesting they capture key aspects of the aging process. Interestingly, the model works across different tissues, hinting at a universal molecular clock regulating aging at the cellular level.
This research has practical applications in areas like health monitoring, disease prevention, and forensic science. For example, it could help identify how lifestyle factors such as diet, smoking or alcohol affect aging rates. Regular checks of a person’s biological aging rate could guide interventions to slow aging and prevent diseases like macular degeneration. Read the paper in full:
Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I, Friend S, Ideker T, Zhang K. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013 Jan 24;49(2):359-367. doi: 10.1016/j.molcel.2012.10.016. Epub 2012 Nov 21. PMID: 23177740; PMCID: PMC3780611.
2015, HorvathAge
The team developed an epigenetic clock working across a wide range of tissues and cell types, including healthy and cancerous samples, and can even be applied to chimpanzee tissues. By analysing 8,000 samples from multiple studies, researchers found that this clock is highly accurate and provides insights into how cells age over time.
The study revealed some fascinating findings. For example, the DNA methylation age of embryonic and stem cells is nearly zero, reflecting their "youthful" state. In cancer cells, however, the biological age is often accelerated, sometimes by decades. This age acceleration varies by cancer type and can be linked to specific mutations, such as those in breast cancer. Additionally, the researchers identified 353 specific DNA sites that make up this biological clock, providing a foundation for further study.
The results suggested that DNA methylation age reflects the overall health of an "epigenetic maintenance system" which helps keep our DNA functioning properly. Read the paper in full:
Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. doi: 10.1186/gb-2013-14-10-r115. Erratum in: Genome Biol. 2015 May 13;16:96. doi: 10.1186/s13059-015-0649-6. PMID: 24138928; PMCID: PMC4015143.
2018, PhenoAge
Unlike earlier methods that focused on chronological age, henoAge incorporates health-related markers, such as inflammation and organ system function, to assess the body's true biological state. This approach allows for better predictions of lifespan, healthspan and risks for age-related conditions, including heart disease, cancer, and Alzheimer’s.
DNAm PhenoAge was developed by analysing specific DNA sites that reflect multi-system aging processes rather than simply tracking age. These patterns are linked to pro-inflammatory pathways, reduced DNA repair, and declining cellular health - all hallmarks of aging. The tool also reveals how biological aging is influenced by genetics, lifestyle factors like smoking and individual resilience to stress. For instance, smokers tend to show faster biological aging, as measured by PhenoAge, compared to non-smokers.
PhenoAge has proven to be a reliable predictor of morbidity and mortality across diverse populations. It can be used in research to study how aging varies between individuals and to test the effectiveness of anti-aging interventions. While it complements traditional health measures, such as blood pressure or glucose levels, it provides unique insights into early, "pre-clinical" aging, making it especially useful for younger or healthier individuals.
Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, Hou L, Baccarelli AA, Stewart JD, Li Y, Whitsel EA, Wilson JG, Reiner AP, Aviv A, Lohman K, Liu Y, Ferrucci L, Horvath S. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY). 2018 Apr 18;10(4):573-591. doi: 10.18632/aging.101414. PMID: 29676998; PMCID: PMC5940111.
2019, GrimAge
This method combines information from specific DNA methylation patterns linked to plasma proteins and lifestyle factors like smoking history. By analysing over 650 individuals' blood samples, researchers found that GrimAge is more accurate than previous aging models in predicting the risk of age-related conditions like heart disease, cancer and type 2 diabetes.
This model measures whether a person’s biological age is advancing faster or slower than expected for their chronological age. Faster biological aging is linked to poorer health outcomes, including increased inflammation, metabolic issues, and a higher risk of early death. For example, one component, DNAm PAI-1, is strongly associated with conditions like type 2 diabetes, high triglycerides and fatty liver.
Interestingly, the tool also identifies links between DNA methylation and shorter telomeres (a marker of cellular aging) as well as changes in immune system composition, further highlighting its relevance in understanding the aging process.
While GrimAge isn’t a replacement for clinical tests like blood glucose or blood pressure, it complements them by providing deeper insights into a person's biological aging and disease risk. Read the paper in full:
Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, Hou L, Baccarelli AA, Li Y, Stewart JD, Whitsel EA, Assimes TL, Ferrucci L, Horvath S. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY). 2019 Jan 21;11(2):303-327. doi: 10.18632/aging.101684. PMID: 30669119; PMCID: PMC6366976.
2020, DunedinPoAM
DunedinPoAm was designed to measure how quickly someone is aging biologically, helping researchers evaluate treatments aimed at slowing aging. Unlike traditional methods that track aging over decades, DunedinPoAm offers a single-time-point measure that predicts health risks, chronic disease and even early mortality.
The test was developed using data from the Dunedin Study, which followed 954 individuals born in 1972–1973, tracking changes in 18 biomarkers of organ health. Validation in other studies confirmed that faster-aging individuals identified by DunedinPoAm were at higher risk of poor physical and mental health, slower mobility and shorter lifespan. Conversely, those aging more slowly performed better in health tests and appeared younger.
DunedinPoAm has shown potential for use in testing anti-aging therapies. For example, in a trial on calorie restriction, the test suggested that reducing calorie intake may slow aging. This makes DunedinPoAm a valuable tool for quickly evaluating whether interventions, such as lifestyle changes or medications, can slow the aging process.
Its development relied on mostly white European participants, so further validation in diverse populations is needed. Additionally, larger studies are required to confirm how well it predicts changes in healthy lifespan due to interventions. Read the paper in full:
Belsky DW, Caspi A, Arseneault L, Baccarelli A, Corcoran DL, Gao X, Hannon E, Harrington HL, Rasmussen LJ, Houts R, Huffman K, Kraus WE, Kwon D, Mill J, Pieper CF, Prinz JA, Poulton R, Schwartz J, Sugden K, Vokonas P, Williams BS, Moffitt TE. Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm. Elife. 2020 May 5;9:e54870. doi: 10.7554/eLife.54870. PMID: 32367804; PMCID: PMC7282814.
2022, DunedinPACE
Unlike earlier methods that estimated overall biological age, DunedinPACE focuses on the current rate of aging, making it more useful for evaluating treatments aimed at slowing aging (geroprotective therapies). It was created by analysing 20 years of health data and organ function from the Dunedin Study participants and then transforming this into a single blood test using advanced statistical methods. The result is a test that is reliable, precise, and effective across different studies.
DunedinPACE predicts health outcomes like disability, disease, and even mortality. It has shown strong connections to signs of aging, such as physical decline, and it detects faster aging in those exposed to adversity, like poverty or victimisation in childhood. The test’s results are also less influenced by factors like smoking compared to similar tools.
While promising, DunedinPACE has limitations. It was developed using data from mostly white participants in New Zealand, so further testing is needed in more diverse populations and larger studies are also required to confirm its ability to predict specific diseases. Its code is publicly accessible, making it a valuable tool for advancing research into aging and healthspan. Read the paper in full:
Belsky DW, Caspi A, Corcoran DL, Sugden K, Poulton R, Arseneault L, Baccarelli A, Chamarti K, Gao X, Hannon E, Harrington HL, Houts R, Kothari M, Kwon D, Mill J, Schwartz J, Vokonas P, Wang C, Williams BS, Moffitt TE. DunedinPACE, a DNA methylation biomarker of the pace of aging. Elife. 2022 Jan 14;11:e73420. doi: 10.7554/eLife.73420. PMID: 35029144; PMCID: PMC8853656.
Final Thoughts
Epigenetic clocks represent an exciting frontier in understanding and influencing the aging process, offering a way to measure biological age and predict health risks with precision. For individuals focused on longevity, these clocks provide valuable information about how lifestyle factors and potential interventions may influence aging at the cellular level.
As we might expect, the majority of the above clocks associate accelerated aging with obesity and smoking. Some clocks link lower education and faster aging. Most clocks indicate accelerated aging among men. While we cannot change our sex there are many factors within our control that can be positively used to decelerate aging. This includes adopting a plant forward diet and increasing polyphenol consumption to support a healthy gut microbiome, breath work to reduce stress, caloric restriction and exercise, the list of healthy living factors goes on...
As the science evolves, newer clocks have improved in accuracy and relevance, particularly for those prioritising longevity and healthspan. However, these tools are not without limitations particularly as the populations studied have been limited both in size, age-range and ethnicity.
No single clock provides a complete picture, combining results from multiple models often yields the most reliable insights. Additionally, their accuracy depends on high-quality testing methods, and pinprick blood tests used in some online services currently lack the precision needed for dependable results. These clocks are best viewed as one piece of a larger puzzle. Integrating their use with traditional health assessments and personalised lifestyle changes can offer the most practical and impactful approach to promoting a longer, healthier life.
At present - for most people - perhaps their greatest value lies in their ability to spark deeper conversations about our health, ageing and how we choose to invest in our future.
With further research and refinement, epigenetic clocks have the potential to revolutionise how we approach aging, making longevity science more accessible and actionable.
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Related Studies and Resources
Fong S, Pabis K, Latumalea D, Dugersuren N, Unfried M, Tolwinski N, Kennedy B, Gruber J. Principal component-based clinical aging clocks identify signatures of healthy aging and targets for clinical intervention. Nat Aging. 2024 Aug;4(8):1137-1152. doi: 10.1038/s43587-024-00646-8. Epub 2024 Jun 19. PMID: 38898237; PMCID: PMC11333290.
Crimmins EM, Klopack ET, Kim JK. Generations of epigenetic clocks and their links to socioeconomic status in the Health and Retirement Study. Epigenomics. 2024;16(14):1031-1042. doi: 10.1080/17501911.2024.2373682. Epub 2024 Jul 18. PMID: 39023350; PMCID: PMC11404624.
McGreevy KM, Radak Z, Torma F, Jokai M, Lu AT, Belsky DW, Binder A, Marioni RE, Ferrucci L, Pośpiech E, Branicki W, Ossowski A, Sitek A, Spólnicka M, Raffield LM, Reiner AP, Cox S, Kobor M, Corcoran DL, Horvath S. DNAmFitAge: biological age indicator incorporating physical fitness. Aging (Albany NY). 2023 Feb 22;15(10):3904-3938. doi: 10.18632/aging.204538. Epub 2023 Feb 22. PMID: 36812475; PMCID: PMC10258016.
Hao Y, Han K, Wang T, Yu J, Ding H, Dao F. Exploring the potential of epigenetic clocks in aging research. Methods. 2024 Nov;231:37-44. doi: 10.1016/j.ymeth.2024.09.001. Epub 2024 Sep 7. PMID: 39251102.
Galow AM, Peleg S. How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span. Cells. 2022 Jan 29;11(3):468. doi: 10.3390/cells11030468. PMID: 35159278; PMCID: PMC8915189.
Lu AT, Binder AM, Zhang J, Yan Q, Reiner AP, Cox SR, Corley J, Harris SE, Kuo PL, Moore AZ, Bandinelli S, Stewart JD, Wang C, Hamlat EJ, Epel ES, Schwartz JD, Whitsel EA, Correa A, Ferrucci L, Marioni RE, Horvath S. DNA methylation GrimAge version 2. Aging (Albany NY). 2022 Dec 14;14(23):9484-9549. doi: 10.18632/aging.204434. Epub 2022 Dec 14. PMID: 36516495; PMCID: PMC9792204.
Duan R, Fu Q, Sun Y, Li Q. Epigenetic clock: A promising biomarker and practical tool in aging. Ageing Res Rev. 2022 Nov;81:101743. doi: 10.1016/j.arr.2022.101743. Epub 2022 Oct 4. PMID: 36206857.
Crimmins EM, Thyagarajan B, Levine ME, Weir DR, Faul J. Associations of Age, Sex, Race/Ethnicity, and Education With 13 Epigenetic Clocks in a Nationally Representative U.S. Sample: The Health and Retirement Study. J Gerontol A Biol Sci Med Sci. 2021 May 22;76(6):1117-1123. doi: 10.1093/gerona/glab016. PMID: 33453106; PMCID: PMC8140049.
Porter HL, Brown CA, Roopnarinesingh X, Giles CB, Georgescu C, Freeman WM, Wren JD. Many chronological aging clocks can be found throughout the epigenome: Implications for quantifying biological aging. Aging Cell. 2021 Nov;20(11):e13492. doi: 10.1111/acel.13492. Epub 2021 Oct 16. PMID: 34655509; PMCID: PMC8590098.
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