An Interview on the Unknowns of the Epigenetic Clock

The Life Extension Advocacy Foundation volunteers have a stack of interview materials piled up from the recent Undoing Aging conference, I'll wager. Today they published a lengthy interview with Steve Horvath, originator of one of the epigenetic clocks that assess age based on patterns of DNA methylation. I have to say that it is a pleasure to see so many researchers now willing to talk openly about therapies for aging and their hopes for the future of the field. For so very many years that just didn't happen; no researcher was willing to speak in public on the topic of treating aging as a medical condition and extending healthy life.

When I first become interested in this field, the research and funding institutions that dominated the study of aging were quite hostile towards anyone who wanted to intervene in the aging process and thereby produce longer lives in patients. Thankfully, times have certainly changed since then, and for that we can thank the hard-working community of advocates, scientists, and philanthropists who have since the turn of the century built funding and support for rejuvenation biotechnology, and for the transformation of medical science through the treatment of aging.

The Horvath epigenetic clock has a commercial implementation, myDNAage, produced by Zymo Research. The folk there claim it to be quite stable over time and circumstances in its assessment, with a margin of error of 1.7 years. As noted in the interview, it is one thing to have a metric that maps to age quite well, and shows some signs of reflecting biological age versus chronological age, but it is quite another to know what it is actually measuring. These changes in DNA methylation are some reflection of the growing damage and dysfunction of aging, but are they a very selective reflection? What if it is found that when a human undergoes a senolytic therapy to remove senescent cells, one of the root causes of aging, that before and after measures of epigenetic age are the same? That would be an interesting outcome, and we're about to find out, but what could we learn from it? This result seems unlikely given that cellular senescence appears to contribute to many aspects of age-related decline, but it isn't impossible. Researchers really don't know whether the epigenetic clock reflects one or many of the underlying aspects of aging.

Science and medicine are often a process of starting at the ends and meeting in the middle. A list of the root causes of aging exist, and measures of the state of aging exist, but there is not good map to link those two. Aging progresses in a very complex way, even though it is caused by comparatively simple and easily understood processes, because our biology is very complex. The fastest way to build rejuvenation therapies and metrics to measure the results of rejuvenation therapies is to start on both lines of research and development at the same time, and compare the results against one another. Iteration on this theme will find the path ahead, and allow unhelpful approaches to be discarded earlier rather than later.

Steve Horvath - Aging and the Epigenetic Clocks

Why is the epigenetic clock more accurate than measuring telomere length?

Yes, it is far more accurate, there is no comparison. Why is a good question. In my opinion, it shows that epigenetic changes are far more important for aging than telomere maintenance. People have studied telomeres for many years, including me, but telomere shortening alone does not explain aging. You may know that mice have perfect telomeres, but they only live three years.

It's known that cells in our body are renewed at different speeds; why does your clock measure the age of the tissue or whole organ and not the age of specific cells?

Actually, it does measure the age of specific cells. You can have liver cells, and the epigenetic clock works beautifully. It also works very well for neurons and glial cells. Even in blood, you can have sorted blood, for example T cells or B cells, and the clock works on those cells.

Does your clock represent aging?

This is a good question with two answers. One way to ask this question is to ask if methylation changes cause aging. And we honestly don't know; there is no data. The other question to ask is if the epigenetic clock is the indicator of a biochemical process that plays a role in aging. Which I think it is; it is a biomarker of a process. There is no question that this process that underlies the clock, that if you target this process, you slow aging; this, we know.

What is going to happen if we influence this methylation process?

With the methylation process, we don't know. Imagine that you have a clock; there is the clock face with the dials, and then there is the clockwork. The discussion with the epigenetic clock is whether methylation is part of the dial or is it part of the clockwork. There is no doubt that it is part of the dial, and if you interfere with the clockwork, there is no question you that rejuvenate people. But it could be that the clockwork might not be the same as methylation; we are not sure. With a clock face, you can just take the hands and move them, but it may do nothing to actual time. Behind the clock, there is the clockwork, and we don't completely understand the clockwork. A lot of people are asking about it, but we just don't know yet.

Can we slow down aging now?

I want to tell you that I am very optimistic and that we will have treatments against aging in a few years. I could be wrong, and I want to be cautious, but I want to tell you that I am very optimistic because we already have encouraging results. We already have treatments that have a huge effect, like the Yamanaka factors in mice, but also in human cells. If you use Yamanaka factors on human cells, it completely reverses their age. The problem is how to make them safe.

My hope is that maybe even our generation will benefit from it; certainly, my daughter should benefit from it. I would be absolutely shocked if the next generation does not live twenty years longer. On that level, I am very optimistic. If you ask me right now what you should do, I can only tell you boring things; immediately stop smoking, avoid obesity, avoid diabetes; if you are a diabetic, manage it; avoid high blood pressure, and if you have it, take action. It is boring, but all my studies show that this is the best thing we can do now.

What are the main challenges in your research in aging?

Scientific challenges, honestly I don't have them. Because there is so much work to do and I have a good plan, it is not a problem. Financially, there is a challenge; research is expensive, especially human trials. I have a very exciting collaboration with a company which has an anti-aging treatment, and to test it will cost three million dollars. So, as you can imagine, money is the challenge.

Comments

Great article, just a 2 cent.

''These changes in DNA methylation are some reflection of the growing damage and dysfunction of aging, but are they a very selective reflection? What if it is found that when a human undergoes a senolytic therapy to remove senescent cells, one of the root causes of aging, that before and after measures of epigenetic age are the same? That would be an interesting outcome, and we're about to find out, but what could we learn from it? This result seems unlikely given that cellular senescence appears to contribute to many aspects of age-related decline, but it isn't impossible. Researchers really don't know whether the epigenetic clock reflects one or many of the underlying aspects of aging. ''

There will be slight improvement in DNA methylation after senescent cell clearance but nothing to
write home about. The reason being that senescent cell are responsable for SASP and thus inflammation, which is tied to health; and DNA epignetic clock is a 'global' representation aging, it touches Both health And aging, such as one study showed that frailty was associated with DNA methyl clock.

Acquisition of aberrant DNA methylation is associated with frailty in the very old: findings from the Newcastle 85+ Study.
1. https://www.ncbi.nlm.nih.gov/pubmed/24770842

With that said, it is more difficult to say with epigenetic aging, because it touches aging and health, it'S entwined, but also independent; there are shades of grey in between. Having higher levels of methylation (global methylation) will allow to keep genes silenced (inflammatory ones) in the CpG rich islands while keeping the ones in CpG poor islands active (anti-inflammatory ones). This aberrant hypermethylation of inflammatory genes is the problem that happens has global demethylation continues and there is hypomethylation in anti-inflammatory ones.

Senescent cells, contributing to inflammation, removal would surely impact the epigenetic clock somewhat, though I wager not that much. It will mostly rearrange the DNA methyl decorum toward gene silencing of hypermethylated regions; but it will Not stop global demthylation and that is the main point - aging will continue (5-methylcytosine levels will empty which means gradual global demethylation of methylome), but the health will be improved for there will be less hypermethylation of these genes by senescent cell removal. Inflammation will be reduced since SASP will be gone (since these p16 senescent cells will be removed; the inflammatory causal element of the cells will be removed; but that will not stop the aging global demethylation process which correlates to epigenetic age).

Just a 2 cent.

Posted by: CANanonymity at March 30th, 2018 6:49 PM

PS: When we use the example of senolytics Quercetin and Dasatinib which have the same result or nearly (though they may be weaker than the p16 senescent cell removal therapy), they improve health and the p16 senescent cell removal makes the mice ahve a longer lifespan (like 20% or so). This demonstrates that there is an improvement an health - and frailty in these mice by reduction of inflammation (from p16 cells being gone), the DNA methylation clock in these mice would be changed somewhat towards reduced hypermethylastyion of aberrant 'inflammatory' genes (obviously - p16....p53, TNF, IL6 etc..). These mice still died below mouse MLSP, showing that global DNA methylome still emptied like normal and that removal of senescent cells does not stop DNA epigenetic aging, it rather rearranges it to make a 'healthier aging' (I despise this term that is what it is....'healthy aging/healthily aging', such as centenarians being healthy and living this long - but still die anyways (DNA methylome emptied))). Which means in simple terms, living to the fullest of your lifespan in best health. And then you die on clock 122 max - On' DNA epigenetic 'Clock that is.

Posted by: CANanonymity at March 30th, 2018 7:05 PM

Reason is picking up on a similar trend I'm noticing. The researchers are becoming not only ore positive, but are actually, trying to push out the message that this is coming.

Aubrey isn't alone in this anymore.

Posted by: Mark Borbely at March 30th, 2018 7:49 PM

@Mark Borbely, and as Aubrey they begin to say that defeating ageing is not scientific but financial problem!

Posted by: Ariel at March 30th, 2018 7:56 PM

Thanks a lot for all the compliments! I'd like to note that the interview was taken jointly with a reporter from Komsomolskaya Pravda (KP), Anna Dobryukha, and we all should give her credit for a set of very deep questions. Her version of the interview with additions and lifestyle advice was published in KP right before ours, in two parts. The supporters from Russia can find them here:
https://www.kp.ru/daily/26810.5/3846177/
https://www.kp.ru/daily/26812.4/3848407/
Thanks to Anna's efforts, the articles contain direct links to SENS site, despite very strict rules of the edition regarding advertisement. Just so you know. ;) If possible, please mention Anna and KP when we indicate that the material was produced jointly. People should know all the heroes. :)

Posted by: Elena Milova at March 31st, 2018 1:33 AM

@CANanonymity - you make good points as usual

A good paper on the clock-face / clock-work dynamic is found in this paper by Sui Huang, from the Institute for Systems Biology (https://www.systemsbiology.org/) in Seattle

https://onlinelibrary.wiley.com/doi/full/10.1002/bies.200800189

The section entitled "The conventional molecular biology view and its limitations-'epigenetic marks'" is quite telling in relation to methylation dynamics per a systems view

"If DNA methylation and nucleosome modification can operate the switch of gene activity for any gene but cannot control which specific gene to actually switch on or off, then what system orchestrates the covalent modification machinery at tens of thousands of gene loci in the genome, such that the appropriate set of genes is (in)activated across the genome to generate the cell type-specific patterns of gene expression? Who writes the 'histone-code'?"

Posted by: Ira S. Pastor at March 31st, 2018 6:17 AM

"Reason is picking up on a similar trend I'm noticing. The researchers are becoming not only ore positive but are actually, trying to push out the message that this is coming.

Aubrey isn't alone in this anymore."

I can tell you from personal experience at Berlin that Aubrey is absolutely not alone in this. The place was packed with enthusiastic researchers who are confident aging can be cracked.

Posted by: Steve Hill at March 31st, 2018 7:13 AM

Would it not to be easier just to measure CD38 expression?

Posted by: Andey at March 31st, 2018 8:06 AM

@Reason I can tell you exactly what would happen to epigenetic age after senescent cell clearance, assuming there is a significant number of senescent cells to clear: epigenetic age would reduce.

This is because (again assuming) stem cells would then spawn replacement somatic cells, these cells would be closer to stem cells epigenetically, so on average the tissue would be 'younger'.

Incidentally this is also why people with longer telomeres have an accelerated epigenetic age - their somatic cells need replacement less often. This also shows why Horvath is wrong to dismiss telomeres, because these people would have better preserved stem cells (under less stress) even though his clock says they are older.

Posted by: Mark at March 31st, 2018 1:10 PM

If epigenetics is responsible for aging, it sounds like it can be remeliated using growth and regulatory compounds of various kinds. One candidate theory on the epigenetics is the increased production of FH and FSH in one's 50's. I read that Melatonin is supposed to down-regulate these factors. Hince, I am experimenting with Melatonin for the first time since the 1990's. I'll see if I notice any difference after 4 months, assuming that I can put up with the bad dreams I get from Melatonin (I experienced this in the mid 90's as well). Melatonin is nasty in generating bad dreams in one's sleep.

Posted by: Abelard Lindsey at March 31st, 2018 4:45 PM

@Abelard, there will be no single silver bullet -- we need to get rid of all damage to get LEV or even any real rejuvenation. Higly unlikely that epigenetics is a primary cause of ageing, but as a secondary cause it influences ageing in many ways. And we need to keep our eyes on.

Posted by: Ariel at March 31st, 2018 5:15 PM

Highly unlikely that epigenetics is a primary cause of ageing.

I agree. But given how cheap Melatonin is, its still worth a try.

Posted by: Abelard Lindsey at March 31st, 2018 8:01 PM

@Abelard
Just started with Melatonin a week ago. What outcomes are you expecting?

Posted by: bardu at April 1st, 2018 12:43 AM

For scientists getting into this game now they are getting in on the ground floor. Its like being a computer programmer in 1970, who also could see some of the potential.

Posted by: aa3 at April 1st, 2018 3:23 AM

@bardu
More energy and generally better overall feeling.

Posted by: Abelard Lindsey at April 1st, 2018 10:34 AM

Do realize I actually do not subscribe to any of the programmed aging theories. So, I don't expect anything. However, at $4 for a 4 months supply, its about the cheapest self-experiment I can think of. So its worth a try.

Posted by: Abelard Lindsey at April 1st, 2018 10:36 AM

So are you folks enjoying the interviews we have coming from Undoing Aging?

Reason is right to wager we have a stack of stuff lined up from the conference and there is more incoming.

Posted by: Steve Hill at April 1st, 2018 4:15 PM

@Steve

Oh yeah! I'm eating this up! Keep it coin!

Posted by: Mark Borbely at April 1st, 2018 11:06 PM

I was wondering why Steve said he would be shocked if his daughter's generation doesn't live 20 years longer. Are his expectations only that we will be able to extend life 20 years. That's good, but with Yamanaka factors and reversing the epigenetic clock we should be able to extend life much further than that right?

Posted by: Robert Link at April 2nd, 2018 12:54 AM

@Robert Link epigenetic changes are only one part of the aging puzzle. we need to tackle all 9 hallmarks for a signifficant increase

Posted by: scott emptage at April 2nd, 2018 5:10 AM

@ Robert Link also consider that Steve might be being conservative here. I can tell you that he was very enthusiastic about the prospects of doing something about aging while trying to remain cautious as good scientists always are.

Posted by: Steve Hill at April 2nd, 2018 6:29 AM

@ Steve and Elenka : Thanks to the LEAF team and to Anna from KP for your fresh, juicy interviews ! It's always interesting to learn about what's happening in the anti-ageing laboratories and hear the thoughts of leading scientists and advocates.

Your reports that participants at Undoing Ageing were optimistic about upcoming research and treatments is great news. It's another confirmation that the field is going into the right direction.

Posted by: Spede at April 2nd, 2018 6:38 AM

@Robert Link, because he as any very specialised researcher can see only his area. SENS is a divide-and-conquer approach, and one cannot be optimistic about the overall outcome unless one is informed about all the components. To assemble first full rejuvenation panel we need more high level engineers, and people like Aubrey de Grey. That is like in aerospace engineering -- there are hundreds of engineers who design parts but we need one engineer who will design the ship!

For example, cell engineers make predictions as though there will be no progress in bionics, and bionics engineers make predictions as though the will be no progress in cell engineering. Each technology alone unlikely will be game changer but when combined their impact will be enormous!

And we do not count bionics and medical nanorobots! Where progress is very slow but steady -- just waits its own high level engineer like Aubrey de Grey.

Posted by: Ariel at April 2nd, 2018 8:44 AM

@Abelard
How much melatonin are you taking?
Have you done the myDNAge methylation test (or other brand)?

Posted by: CD at April 2nd, 2018 11:09 AM

@Ableard and Badru, melatonin may extend life by inhibiting melthlylation but it is likely to be a miserable life as methylation is necessary for DNA synthesis of red blood cells and Lymphocytes, impaired methylation will likely result in megaloblastic anemia.

Posted by: JohnD at April 2nd, 2018 11:20 AM

@JohnD thanks for the alert. Are there any supporting papers you can point to?

Posted by: bardu at April 2nd, 2018 8:28 PM

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