Epigenetic Clocks: How to Measure Your Biological Age
Part 2: Limitations of Epigenetic clocks, Future clocks, Find out your Biological Age
This post is Part 2 in explaining Epigenetic Clocks, a way to measure your biological age. I highly recommend reading Part 1 before this one.
Further, Epigenetic Clocks is Part 3 in my Aging: the what, the why, the fix series. You can find Part 1 here and Part 2 here.What You Will Learn in this Post:
Heritability of Epigenetic Clocks
Limitations and Challenges of Epigenetic Clocks
Causal Clocks & Catch-22 situation!
Epigenetic Clocks and Cellular Senescence + Other Biomarkers
Variability in Test Results
Future Epigenetic Clocks
Other Types of Epigenetic Clocks
How to Measure Your Biological Age
Epigenetic Clocks: Recap, Hispanic Paradox, Heritability
King Caputi: Morning, Steve! Hope you had a restful night’s sleep. I wanted to say -thank you again for explaining some of the basics of Epigenetic clocks to me yesterday. I must say, you got me intrigued now and I can’t wait to learn more on it.
Steve Horvath: I’m very glad! Perhaps we could use some of your help in funding research projects to accelerate the progress in aging research :) 1
King Caputi: Yes, if you can fight this Aging monster, I will fund your projects!
Steve Horvath: Great, thank you! Alright, let’s do a quick recap on our discussion around epigenetic clocks yesterday. As we know, these clocks are a way to measure your biological age. Note that it is possible for different tissues and organs in your body to have different biological ages. My latest clock is the GrimAge clock, which so far, is the best predictor of lifespan and can measure your time to morbidity and death. We also discussed that ~40% of the clock is known to be heritable, and it is possible to reverse the clock using anti-aging interventions, which include better lifestyle habits such as high-intensity exercise.
King Caputi: Yes, thanks for the refresher. It would be great to hear more on the heritability and reversal of these epigenetic clocks.
Steve Horvath: Absolutely, I want to touch on a few points here. Firstly, on the heritability point. As I said, our data suggests that 40% of the clock is determined by your genes2. This might also explain the Hispanic paradox, where even though Hispanics have worse health biomarkers, they still live longer than what is average for their cohort of population. It might be because of their genes.
But the remaining 60% is determined by your lifestyle. For example, the clocks show statistically significant and high correlation between mortality risk and smoking and obesity.
Here it is also important to note that a lot of lifestyle habits can have organ specific effects, which means that different lifestyle actions may impact specific organs more so. For example, obesity greatly increases the age of the liver. On the flip side, some anti-aging interventions can also have organ specific effects, which might be okay since aging is accumulation of damage in different tissues and organs, and even improving the health of specific organs can have an overall positive impact given that biology is so intertwined. Of course, a lot more studies need to be done to show the efficacy of anti-aging interventions using epigenetic clocks.
Limitations and Challenges of Epigenetic Clocks
King Caputi: Hmm, so are there anti-aging intervention studies being done using these clocks?
Steve Horvath: This is a great segue into the limitations and challenges of epigenetic clocks. Let me elaborate.
You see, there is no consensus on a theory of aging, and without an established theory, we can’t have consensus on the biomarkers of aging either3. Without established aging biomarkers, it becomes hard to know what these clocks are actually measuring. See, even though I’ve said that the clocks are a good predictor of lifespan, given that we don’t have consensus on markers for aging, how do we measure these markers and as such how do we know what the clocks are actually tracking? Perhaps, epigenetic age itself could be one of the biomarkers of aging. But there could be more too.
Causal Clocks & Catch-22 Situation
Steve Horvath: And without an established theory of aging, it becomes harder to test anti-aging interventions. We are working on Causal clocks that would be used to measure anti-aging interventions in humans. Causal clocks means that if you rejuvenate a person by 10 years, they will end up living another 10 years. The problem with causal clocks is that we run into a Catch-22 situation. Again, this is because there are no established anti-aging human interventions - to test if the clock works we first need to be able to test the test (interventions). We don’t run into this problem in mice as several anti-aging interventions including caloric restriction and rapamycin have been established.
King Caputi: Ha, I see. So there is a lot more to understanding aging..
Steve Horvath: Yes, and I’m not finished with the limitations and challenges of these epigenetic clocks.
Epigenetic Clocks and Cellular Senescence + Other Biomarkers
Steve Horvath: Another point to note is that the clocks don’t necessarily pick up some biomarkers that are associated with aging. For example, cellular senescence has been implicated as one of the hallmarks of aging, but the relationship between epigenetic clocks and cellular senescence is complicated. For example, the clocks will not pick up replicative senescence, however they will pick up senescence caused by radiation. Furthermore, even an immortalized cell (showing no cellular senescence) will have a ticking epigenetic clock. A lot more work needs to be done to understand the relationship between epigenetic clocks and cellular senescence.
Related to the above, it’s important to note that the clocks (specially the first generation clocks) are measuring lifespan and not healthspan. This means that it might be possible to have a higher lifespan but poor health which could be indicated by other biomarkers such as inflammation, glucose regulation, heart health etc. For example, you could live to be a 90, but the last few years of your life may not be in good health. Typically, you would think that if a person has poor health, they won’t live as long either, but as we know in the case of the Hispanic paradox, this is not always the case. And this goes back to the fact that the clocks are 40% heritable.
King Caputi: Ah, the details, always the details that hide the devil! But are these clocks accurate in measuring epigenetic age? Is there variability in results?
Variability in Test Results
Steve Horvath: Yes as I had mentioned, they are in fact quite accurate with an average error estimation of ~3.6 years. However, the results might sometimes be a little skewed depending on the type of sample being collected to test DNA methylation as well as time of day of collection of sample. For example, if the DNA sample is collected from blood vs. saliva, it may give different results. Also, DNA samples obtained at different times of the day may also yield different results. So, it might be better to rerun your results.
King Caputi: And I presume you are improving on it? What is the future for these clocks?
Future Epigenetic Clocks
Steve Horvath: We are always striving to improve and make the clocks better. The future is exciting - we are coming up with more advanced clocks that would be single tissue / cell clocks and can tell us the epigenetic age for each cell type. (Because remember the apple analogy from last time? Different tissues in your body have different ages)
Further, future epigenetic clocks will be able to measure aging across all mammalian tissues, and not just human tissues. So you can know your dog’s age too!
King Caputi: Amazing! And last question, are there other types of epigenetic clocks too?
Other Types of Epigenetic Clocks
Steve Horvath: Indeed there are! I’ve only covered some of the clocks that measure biological age based on DNA methylation patterns. However, there are some other clocks that measure age based on other markers such as inflammation. For example, there are clocks such as the iAge clock (Inflammation clock), Proteomics clock, and Transcriptome clock.
This field is quite extensive and detailed so there are definitely a lot of nuances that I haven’t touched upon. But you still have learned a lot about epigenetic clocks there is to know and in the future we can discuss more as new developments come through!
King Caputi: Wow, thank you! Can’t wait to learn about all the amazing work to come in the future!
How to Get Tested for Biological Age?
I got my biological age tested using the Index Test by Elysium Health (no affiliations, its just what I knew at that time). They do have Dr. Morgan Levine as one of their scientists and she has done some incredible work in this field of Epigenetic clocks.
I’ve listed other ones including Inside Tracker and Viome Health here.
The tests can be expensive and note that the limitations I mentioned above will likely also apply to these tests. If you are one of the early adopters / can afford it / on the older end, go ahead and test your biological age! If you want to wait a bit longer for better and improved versions of these tests, then hang tight, they will hopefully be out soon!
As always, please like, share, comment, subscribe, and connect with me on social media if you are enjoying my work! Please feel free to drop your questions in the comments section below. Thanks for reading - share this post and help spread the word on longevity science so we can all be younger for longer :)
One of the big challenges to making rapid progress in the aging field is the lack of funding resources for all that needs to be tested. If you want to help accelerate the progress, you can contribute to the Sinclair Lab here and the SENS foundation here. Please note that I have no affiliations with any of these labs.
As I noted last time, the aging community has discussed 9 hallmarks of aging but that doesn’t necessarily mean they are the causes of aging. The hallmarks have merely been associated with aging and serve as guidelines for studies in this field. There is no established consensus on the theory of aging aka what is causing aging. David Sinclair has proposed one which is the informational theory of aging I’ll talk about next time. But there is no final consensus so far. This means that when we don’t know what is causing aging, it’s hard to know how to measure this unknown cause. So how does one measure these aging biomarkers when they haven’t even been established? Dr. Steve Horvath suggests that perhaps the epigenetic clock should be a biomarker itself!