Epigenetic Clocks: Know Your Time To Death

Part 1: Hannum Clock, Horvath Clocks, GrimAge Clock, Reversing the Clock

This is Part 3 in the series Aging: the what, the why, the fix. This post is a continuation of the story on DNA Methylation from Part 2. I highly recommend reading Part 1 and Part 2 before reading this post. 

However, should you wish to skip reading the earlier parts, scroll below and start reading from the title “Basics on DNA Methylation and Epigenetic Age” and you should still be able to understand this post on Epigenetic clocks. 

All you need to know from Part 2 on DNA Methylation (explained through storytelling) is that Rosanna is King Caputi’s wife and she died from a disease called Aging. King Caputi is investigating the causes behind aging and how to measure time to death using Epigenetic clocks.

The guards bowed before King Caputi and presented a healthy looking man with a rather impatient look on his face. The man looked around him for a second, not caring in the least for the majestic statues and jewels that adorned the chandeliers. He was deep in thought, calculating a mathematical equation in his head. 

“Your Majesty, we have found Steve Horvath. He is presented before you,” said the guards deferentially.

King Caputi examined the man, making particular note of his rather plain Western attire of shirt and pants. In contrast, the King was dressed flamboyantly in a jeweled gown and a gold headgear.

“What is your name, young man?” asked the King in a stern voice.

The man was zapped out of his thoughts. “Uhh..Steve..my name is Steve Horvath.”

“Okay Steve, I have your friend DNA Methylation locked up in prison. If you want to save him, you need to help me find Aging, the murderer that killed Rosanna.”

“Uhh..sure..I don’t really know what you mean but I can try,” responded Steve.

“Good! Khalesh says that DNA Methylation killed my wife Rosanna. So we found DNA Methylation who claims that she is not the killer and in fact helps us by silencing our toxic genes. But over time she begins to change, resulting in abnormal gene expression, which summons the real killer called aging. Now, so far, does this sound right?” asked King Caputi.

“Well, yes, there are other factors that could summon aging1 but yes yes abnormal changes in DNA methylation is certainly responsible. In fact, I work on clocks that can measure your time till death based on changes in your DNA methylation profile.”

“Aha, so DNA Methylation was not lying!” Alright Steve, tell me more about these clocks you work on,” demanded King Caputi.

“Sure, I don’t have much time but..” Steve was cut short as the King’s raging voice bellowed through the halls.

“Don’t have much time? roared the King. Do you realize you are speaking with the King of Caputi? You should be glad that I haven’t already chained you for not addressing me by “Your Majesty”.

“I’m sorry but I come from the Age of Enlightenment and think scientifically. In my world of science, it is not impious to even criticize the Gods2.”

The guards hushed and immediately stepped forward to chain Steve’s hands.

The King was taken aback by the answer. In his land, it was unheard of to criticize the King, let alone the Gods. But something told him that Steve was not one to give in to showing deference. And Steve was his only solution to understanding the mysteries behind aging, so he decided to ignore Steve’s disrespect.

“It’s okay, guards. Let the man be,” the King remarked in a defeated tone.

“Look Steve, I’ll pay you whatever you ask for, explain these clocks to me and their connection to aging. I would do anything to defeat my wife’s killer,” the King begged mournfully.

Upon seeing that, Steve Horvath softened up. “Okay, before I tell you about the latest clocks, let me give you some background and history on my work surrounding these clocks. It was, in fact, by chance that I discovered that basing my clock on methylation data is quite accurate in predicting the age of the individual. 

Basics on DNA Methylation and Epigenetic Age

Steve Horvath: To refresh your memory, let me remind you that DNA Methylation is an epigenetic modification to your DNA that helps to silence your toxic genes. However, over time, and as you age, there occur changes in your DNA methylation patterns which are highly correlated with aging.

Now, since my clocks measure chronological age, epigenetic (biological) age, and time till death based on epigenetic DNA methylation patterns, they have come to be known as epigenetic clocks. 

King Caputi: Hold on, what’s the difference between chronological and epigenetic age?

Steve Horvath: Aha! Yes, so your chronological age, as you know, is simply the number of years you’ve been alive. But your epigenetic or biological age is one that’s based on your DNA methylation patterns and is often a better indicator of your true age based on health and genetics.

This implies that your epigenetic age can sometimes differ from your chronological age, and is a better indicator of your health. For example, for some people, their epigenetic age might be higher than their chronological age (age acceleration) and that can be a result of both genetics and poor lifestyle choices. Whereas, in the case of super-centenarians, their epigenetic age is often significantly lower (~8-9 years) than their chronological age (largely dictated by certain genes)3.

King Caputi: I see, so it’s possible that Rosanna’s epigenetic age was higher than her chronological age. Ah, I wish I could have used your clock to measure it and known earlier! Okay, please continue with your explanation on epigenetic clocks.

First Generation Epigenetic Clocks - Hannum Clock

Steve Horvath: It is worth noting that broadly speaking there are two generations of epigenetic clocks. Let me begin with talking about the first generation clocks. A scientist named Dr. Gregory Hannum designed the Hannum clock which was used to predict epigenetic age based on methylation patterns as well as factors such as BMI, gender, diabetes, status, and ethnicity. The Hannum clock also demonstrated how exposure to childhood adversity such as abuse, financial hardship, or neighborhood disadvantage could result in accelerated rates of epigenetic aging4. Although the Hannum clock was quite accurate in predicting epigenetic age and lifespan, it only worked on adults and the clock could only be used on a single tissue, which means there was no way of knowing whether that age was the same across all / multiple tissues in your body. (Note that different tissues in your body can have different ages - I’ll talk more about it below)

First Generation Epigenetic Clocks - Horvath Clock

Steve Horvath: To solve for the limitation that the Hannum clock was a single-tissue clock, I (Steve Horvath) came up with a multi-tissue clock, which means that I was trying to predict age based on methylation data taken from several different cell and tissue types. In fact, I also looked at how the age indicated by this multi-tissue clock using blood methylation data compares to the age in other organs and tissues of the body. 

(Here is an easier analogy: Think of an apple that is beginning to rot and you want to know if it’s still edible. By looking at the entire apple, you deduce that it’s say 4 days older than shelf life but probably fine to eat. You slice it into pieces. Now you notice that some of the pieces in fact look fresh and edible, while others are entirely rotten. 

The apple represents all the tissues used by the clock to give an age, whereas the slices are each of the different organs and tissues. Now you can see why the age deduced from all the tissues might not be the same as the age of each particular tissue.)

What I found was that the age indicated by the clock using blood methylation data was highly correlated with age in most organs, except the liver and the heart. (This means that the age of the liver and heart cannot be accurately determined by simply deploying the Horvath clock using blood methylation data. Similar to how 3 out of the 5 pieces of the apple also seem to be about 4 days older than shelf life, but the remaining 2 might be 10 days older than shelf life)

King Caputi: Ha, I see, okay so you’ve designed this multi-tissue clock that does a pretty good job in indicating my epigenetic age across most tissues except maybe the liver and the heart. How accurate are these clocks?

Steve Horvath: They are in fact quite accurate with an error estimation of ~3.6 years.

King Caputi: Alright, so what else is new with these clocks? You mentioned second generation clocks. What’s that?

Second Generation Clocks - PhenoAge and GrimAge Clocks

Steve Horvath: Yes, so as you know, science is constantly trying to make progress. With the 2nd generation clocks, we wanted them to be a better predictor of lifespan and epigenetic age, and they indeed are. These clocks measure your time to morbidity and death, and as such are good predictors of your risk to onset of diseases. In fact, the GrimAge5 clock is the best predictor we have so far for lifespan6. We are trying to make GrimAge a marker to test for the effectiveness of anti-aging studies. 

Another point to note is that the rate of change in GrimAge is associated with increased hazard of death. So for example, you might use the GrimAge clock to get your age tested every few months. And if the rate at which your GrimAge changes every few months or years is higher than what is normal for your category, it is associated with increased mortality risk. The GrimAge clock can in fact measure time to specific diseases such as coronary heart disease and cancer, and as such is a much better predictor of both lifespan and healthspan. It is however not yet ready to be used for clinical information and more work needs to be done.

Can Epigenetic Clocks be Reversed?

King Caputi: Very interesting. Okay, but even if I were able to detect Rosanna’s time to death using your GrimAge clock, could I have reversed that clock such that she didn’t die so soon? Or is this clock determined by God?

Steve Horvath: Okay, so the question you are really asking is whether it is in our control to reverse the epigenetic clock or is there not much we can do about it? Is the clock based on genetic factors or can it be controlled by lifestyle measures and anti-aging interventions?

Well, we are still trying to understand the exact mechanisms that determine the ticking of the clock, but so far, we know that the clock is 40% heritable whereas 60% is determined by your lifestyle. In other words, ~40% is mostly beyond your control and dictated by your genes7. However, this means that the remaining 60% is determined by how you live your life - if you smoke, are obese, and don’t exercise for example, your lifespan and healthspan is likely to be reduced significantly.

Now, I still need to answer your question: can you reverse your epigenetic clock? Let’s look at a person who is unhealthy, obese, and / or smokes. If this person decides to adopt a healthy lifestyle which entails quitting smoking, losing weight, eating clean and exercising, yes this person can likely reduce his / her epigenetic age and increase lifespan by 10-15 years, if not more. Not to mention that adopting a healthy lifestyle will come with improved health biomarkers too.

Now, let’s take the example of someone who is already healthy, exercises regularly, maintains a healthy weight, eats clean, and sleeps well. If such a person starts exercising even more, lowers their body fat further, and optimizes their health perfectly, will they also be able to reverse their epigenetic clock by 10-15 years? I’m not so sure. My guess is that the reversal would only be about 2-3 years8, but more studies need to be done here. However, these people will almost certainly improve their health biomarkers (lower their risk of getting age-related diseases; be healthy even in their old age) and feel more energetic on a daily basis.

King Caputi: Alright, thank you for explaining all that on clocks to me. Also, is it true that you scientists are working on anti-aging interventions beyond lifestyle factors that could increase my lifespan?

Steve Horvath: Yes, a lot of brilliant people are working in the field of rejuvenation therapeutics such as cellular reprogramming and senolytics. Much progress has been made, but lots to come.

King Caputi: Okay good. Hope you discover it before I become captive to aging. Is there more I should know about these clocks?

Steve Horvath: Well, if you’d like to, I can explain some of the challenges and limitations of these clocks, and future clocks we’re working on. 

King Caputi: Okay, how about we do that tomorrow morning? This was enough information for me for today. Besides, you said it’s important for me to get a good night’s sleep to reduce my epigenetic age.

Steve Horvath: Indeed! Catch you in the morning for Part 2 on Epigenetic clocks then!

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What’s to come in Part 2 on Epigenetic clocks:

  1. More on reversal of epigenetic clocks

  2. Limitations and Challenges with the clocks

  3. Ways to get your epigenetic age tested

  4. Future clocks being worked on

  5. Other types of epigenetic clocks

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P.S. As always, don’t forget to like, share, donate and subscribe if you learn from these posts and enjoy them! Your small action makes a big difference to me and others who can learn from my writing. This post specially took me a lot of time to research and write (the field is quite extensive - see below), so please try to support in any way you can!
P.P.S. Please note that this area of study on Epigenetic clocks is rather extensive and these posts are mostly intended to provide a basic primer plus some more. Further, there are more clocks outside of the Horvath clocks which I won’t be discussing in these posts. There is a lot of work being done in this area and I’ll probably write more on Epigenetic clocks as new developments are published.
Disclaimer: The words above are not directly from Steve Horvath. I’ve written about his research in my words. He is one of the characters in my story and does not bear responsibility for any of my writing, except for his papers and interviews that I may have cited of course.
Credit: Thank you to Jose and Dr. Morgan Levine for answering some of my questions on Epigenetic clocks.
1

The gerontology (aging science) community has identified 9 hallmarks of aging that I’ll probably write about some time. If you want to read more about them for now, this is a good starting point. Slow down or reverse any of these hallmarks of aging and you could slow down aging. However, note that there is actually no consensus in the aging community on a definition of aging or an established theory of aging. The hallmarks are not necessarily causes of aging, but they have been implicated and are associated with aging. The hallmarks merely serve as guide points on exploring different anti-aging interventions and continuing with research in the field.

2

The phrase “It is not impious to criticize gods” has been taken from one of my favorite chapters A Dream of Socrates from a great book called The Beginning of Infinity which has been highly recommended by Naval Ravikant.

3

Offsprings of super-centenarians are typically ~5 years younger according to the epigenetic age vs. their chronological age. https://www.foundmyfitness.com/topics/epigenetic-clocks

5

The GrimAge Clock was in fact named after the Grim Reaper, a mythological character that personifies death.

6

PhenoAge is another clock worked on by Dr. Morgan Levine. The clock uses methylation data and clinical chemistry measures such as kidney/liver panel, CBC, lipids, glucose, etc. to also predict time to disease and death. While, the GrimAge clock is a better predictor in blood than than the PhenoAge clock, the “difference is that the GrimAge clock seems to be specific to aging in the blood (leukocytes), whereas the PhenoAge clock also tracks age in most other tissues and is being shown to differentiate cancer versus normal tissue and is associated with Alzheimer’s disease in brain tissue and IPF in lung tissue.”

7

Super-centenarians have certain longevity genes that is likely responsible for their long lifespans.