Biological aging clocks—tools that quantify your biological age or how your body is aging on the inside—are capturing the interest of scientists and consumers alike. Epigenetic clocks are one method of quantifying biological age. Epigenetic clocks use advanced algorithms from artificial intelligence and machine learning that include data on the extent to which hundreds (or more) sites of a person’s genetic makeup (their genome) are methylated.
Dr. Gil Blander, Founder and Chief Scientific Officer at InsideTracker, believes that knowing your biological age is meant to both provide context into how your body is aging compared to your chronological age—the number of birthdays you’ve had—as well as act as a catalyst for health optimization.
InsideTracker’s biological age calculation (InnerAge 2.0) utilizes clinically validated blood biomarkers, which have been studied by scientists and clinicians alike for decades, because there’s an established relationship between optimal levels and aging that is grounded in biology. The function of these biomarkers is well established and there’s a clear link to health outcomes and the risk of age-related diseases (such as elevated levels of apolipoprotein B and cardiovascular disease risk). And when Dr. Blander evaluates other biological clocks, he scrutinizes the scientific support for the methods and the functional use of the tool by consumers.
So what about epigenetic clocks? Do they actually capture the biological age of the sample? Let’s break down the basics of epigenetics and methylation before Dr. Blander shares five factors to consider before interpreting the results of an epigenetic clock.
You're born with a preset genetic code outlined in your DNA. This genetic code acts as an instructional manual for everything inside the body. It guides how you grow, develop, and reproduce. Your DNA sequence doesn’t significantly change throughout your life. So if you get a DNA test at the age of 10, you wouldn’t need another one as an adult.
What does change throughout your life is how certain genes are expressed, and the term epigenetics refers to the study of how your environment, lifestyle, and behaviors affect this genetic expression. DNA methylation is one of the most studied biochemical regulators of gene expression and occurs when a methyl group (a structure of one carbon and three hydrogen molecules) is either added or removed from a portion of the DNA sequence.
There is an established correlation between DNA methylation and aging. [1-3] So an epigenetic clock aims to quantify aging based on DNA methylation levels. Commercially available epigenetic clocks typically evaluate DNA through a saliva sample. However, there are quite a few nuances to consider when interpreting those results. Here’s what Dr. Blander has noticed.
The method by which epigenetic clocks measure DNA methylation allows for a high degree of accuracy when predicting chronological age. [4] While the literature suggests that there are certain regions of methylation on DNA strands that are correlated with aging, is there enough evidence to suggest that epigenetic clocks only measure aging? Dr. Gil Blander notes that we might not be there quite yet.
It’s known that a large proportion of these methylated regions ultimately influences a person’s methylation profile as they age and can contribute to both accelerated and slowed aging compared to one's chronological age. To this end, scientists created indexes on the degree to which all DNA methylation throughout the body has changed. So, the interpretation of epigenetic clocks is as follows, "You have a methylation profile of the average 50-year-old." However, Dr. Blander believes that these clocks might reflect cell differentiation in a sample, rather than just the aging process.
Cell differentiation means a cell in the body is assigned a very specific function—nerve cells, red blood cells, fat cells, etc. Somatic cells—or adult stem cells—are undifferentiated cells that can differentiate into those specialized roles when needed. [5] And we know that as we age, our cells become more and more differentiated. [6]
Dr. Blander further expands on his theory of epigenetic clocks and cell differentiation with an example. “If you take human cells and allow them to replicate, they will replicate a certain number of times (depending on the cell type) and eventually stop (this process is known as cellular senescence). However, when you inject cells with factors that revert differentiated cells back to undifferentiated cells, they can continue to replicate. And research indicates that if an epigenetic clock is used to calculate the biological age of that sample, that also results in a lower epigenetic age. This might suggest that the epigenetic clock is also related to the differentiation status of the cells." [7,8]
So, this begs the question that Dr. Blander seeks to answer, “What causes epigenetic age to get older? Is it age? Or is it because you are becoming more and more differentiated?”
Key takeaway: While epigenetic clocks have a high correlation with aging, it’s unclear whether they measure aging, cellular differentiation, or both.
While the algorithms for epigenetic clocks are built on sound science, there are still many unknown factors of this tool. Dr. Blander has identified three main unknowns.
Key takeaway: While multitudes of research have been conducted on epigenetic clocks, there are many unanswered scientific questions.
Building sustainable lifestyle habits such as consuming a nutrient-rich diet and getting regular exercise are well-studied ways to slow some of the effects of aging. [9] And often, knowing one’s biological age is a catalyst for wanting to build these habits: “Those who want to know their biological aging score are typically motivated to make lifestyle changes to improve how they’re aging,” says Dr. Blander.
And, “in order to tie a particular lifestyle intervention to a reversal in methylation-based age, then interventional clinical trials are required, and we haven't seen too many of those yet,” notes Blander. In addition, the age clock itself isn't as well studied in a clinical setting, so (as the previous section alludes to) we don’t yet know the function and risks of the methylation patterns as we do with clinical measurements—such as blood biomarkers.
While evidence shows that it is possible to modify your score from an epigenetic clock, measuring the impact of lifestyle modifications on epigenetic clocks is a challenge. As Dr. Blander puts it, “It takes a pretty drastic health change to see an impact on your score from an epigenetic clock, for example, if a heavy smoker stopped smoking, or if an individual with a very high BMI were to lose significant weight.” [10,11]
One small pilot study published in 2021, investigated the impact of multiple lifestyle modifications on epigenetic age in 43 healthy males, and found promising results in reversal of epigenetic age. [12] However, the sample size of this study was small, and more work is needed to truly understand the relationship between methylation status at a given location, and a given lifestyle intervention.
Key takeaway: Consumers who seek their biological age score are typically motivated to improve their score—yet the scores from epigenetic clocks are hardly modifiable.
Epigenetic clocks are just one way to measure biological age. But we know that aging is multidimensional—and its measurement tools should account for its complex nature. For example, cellular senescence is a well-known hallmark of aging, yet epigenetic clocks do not account for the impact of this process. Dr. Blander notes that simultaneously using multiple different types of clocks can deliver more accurate and specific insights into how the body is aging biologically.
And there are multiple different types of biological aging clocks that are being used or are currently being developed. For example, Dr. Blander notes that the rate of aging can differ between organs, and organ-specific clocks analyze the biological age of each. Other types of clocks are blood-based biological clocks—a tool that uses well-established biological connections—like blood glucose levels and aging—to quantify how one is aging internally. [14]
Key takeaway: Epigenetic clocks are just one method of estimating biological age. We know that aging is multidimensional, so using multiple types of clocks provides more specificity and accuracy in uncovering biological age.
Certain diseases are known to impact the rate of human aging. [15] However, the scores from epigenetic clocks do not necessarily account for that increased rate of aging. Dr. Blander references a specific disease in making this point, “In a 2020 study, investigators found that epigenetic clocks marked people with type 1 diabetes as younger than their chronological age. Further, the study found that epigenetic clocks didn’t classify patients with type 2 diabetes as older than their healthy counterparts, although biology and research suggest that people with diabetes [type 1 or 2] age more quickly than metabolically healthy individuals.” [16]
"For example, among InsideTracker users, aging is highly correlated with increasing values for HbA1c, a marker of insulin sensitivity, as well as fasting glucose," says Dr. Blander.
Key takeaway: The presence of diseases known to impact the rate of aging does not factor into epigenetic clock scores.
According to Dr. Blander, “While epigenetic clocks are very accurate for predicting chronological age—we don’t quite understand how they relate to specific, functional outcomes, like how specific diseases of aging are reflected in the methylation status of the genome at a given location. We need to uncover why DNA methylation so accurately reflects aging. Connecting epigenetic clocks back to biology, and revealing the mechanism, will provide us with tools and actions to improve how we age. And we see that other types of clocks that connect back to biology, like transcriptomes and blood-based clocks, and provide the consumer with ways to improve their health, giving the power back to people to live healthier longer.”
References
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482848/
[2] https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-015-0118-4
[3] https://www.frontiersin.org/articles/10.3389/fgene.2020.00171/full
[4] https://pubmed.ncbi.nlm.nih.gov/35141217/
[5] https://open.oregonstate.education/aandp/chapter/3-6-cellular-differentiation/
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344376/
[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351826/
[8] https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01158-7
[9] https://pubmed.ncbi.nlm.nih.gov/35128993/
[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323361/
[11] https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01038-0
[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064200/
[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361673/
[14] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.312806
[15] https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-7762-5
[16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8900303/