What Can be Achieved if the Epigenetic Clock is an Accurate Reflection of Aging?

The difference between having and not having an accurate, rapid, low-cost measure of biological age is night and day. If such a thing did exist, then it is immediately the case that a good few dozen interventions could be rapidly tested in humans, taking a month or two between before and after measurements. The cost is low enough that volunteer groups and philanthropy could manage it. Look at what Betterhumans is doing in trials of cheap senolytic compounds, for example, and then add a robust assessment to that in order to definitively say whether or not rejuvenation occurred. I expect that only a few of the obvious candidate interventions that people will put forward will in fact turn out to make a difference. This is still important: the absence of results for the rest should go some way towards shutting off useless work on supplements and dietary tinkering that absorbs a great deal of time and funding both within and without scientific community.

Is there such a thing as an accurate, low-cost test that measures biological age, however? The later variants of the epigenetic clock might fit the bill, though it is still impossible to say whether or not they broadly reflect the causes of aging, or are tied to just a few narrow causes of aging. Absent a way to effectively reverse one of those narrow causes on its own, the mystery will likely persist; as of today, only senolytic therapies are capable of that feat, and they are not yet widely tested in humans. That the clock is uncertain in its mechanism of action is actually all the more reason to be running these studies. Both the clock and interventions alleged to slow or reverse or compensate for the progression of degenerative aging can be validated against one another.

The posts noted here cover an outline of one possible direction for evaluation of interventions against the epigenetic clock. They are largely not the sort of thing I believe should be the primary focus of the research community. These approaches are for the most part calorie restriction mimetic and similar compounds that trigger or enhance stress responses. All such methods have been shown to scale down in the extension of healthy life span as species life span increases. Calorie restriction itself produces 40% gains in mouse life span, but is unlikely to change human lifespan by more than five years or so. That said, there is merit, I think, in being able to show, robustly, that these approaches have only small effects, and thus redirect research and development efforts elsewhere, hopefully towards the SENS damage repair approaches that can in principle produce rejuvenation rather than just a slight slowing of aging.

The Mother of All Clinical Trials, Part I

There are a great number of promising interventions that might have anti-aging benefits. There is a testing bottleneck, which means that we don't know what works. By way of contrast, there is a well-documented catalog of life extension interventions in lab worms, but for humans we're mostly in the dark. To complicate things further, lab worms are clonal populations, while every human is different, and there are growing indications that many if not most medications work for some people and not others. Horvath's methylation clock is a disruptive technology that could make human testing of longevity interventions ten times faster and 100 times cheaper than it has been in the past. No one is yet doing this kind of testing, but you and I should be advocating vigorously, and volunteering as subjects to help test whatever it is that we are already doing.

There are a great number of promising interventions that might have anti-aging benefits, singly and in combination. Some are already approved and safe for use in humans, yet we don't know what will be most effective. Because human longevity studies are prohibitively slow and expensive, none have ever been funded or conducted. (We know only accidentally that aspirin and metformin lower mortality rates in humans, because these drugs were prescribed to tens of millions of people beginning in the 1960s for cardiovascular disease and diabetes, respectively, with no premonition that they might extend lifespan.)

Testing of anti-aging interventions in humans has been so expensive and slow that we have been forced to make inferences from animal tests, supplemented by historic (human) data from drugs that happen to have a large user base going back decades. As it turns out, it is much easier to extend lifespan in worms than in mammals, and even the interventions that work in rodents don't always work in humans. Conversely, there are drugs that work in humans that don't work in mice - how are we to find them?

Just this year, a test is available that is accurate enough to measure anti-aging benefits on short time scales, without waiting for subjects to die. DNAm PhenoAge is a simple blood test developed at the lab of Steve Horvath. It determines risk of age-related mortality accurate to about 1 year of biological age. Averaging over just a hundred people pinpoints biological age with accuracy of one month. This implies that an anti-aging benefit can be detected with high reliability using a test population of just a few hundred people, followed for two years, tested at the beginning and end of this period. A study that might have required fifteen years and cost hundreds of millions of dollars can now be completed in two years at a cost of less than $1 million. When this new technology is embraced, we will have the means to separate the most effective treatment combinations from a large field of contenders.

The Mother of All Clinical Trials, Part II

Methylation isn't the only means by which gene expression is controlled - there are many others. But it is far the best-studied and, given present technology, it is the only epigenetic marker that can be routinely measured, for a few hundred dollars in a small sample of blood, urine, or nanogram-scale biopsy of other tissue. The clock was developed by Steve Horvath, and first published in 2013. He scanned the entire genome for sites that changed most with age, and varied least from one tissue type to another. In this way, he identified 353 sites, and optimized a set of 353 multipliers, such that multiplying levels of methylation at each site by each multiplier and adding the products produced a number that could be mapped onto chronological age.

Five years after Horvath's original publication, there are several other clocks based on methylation. Just this spring, Horvath has developed a new clock, not yet published, which, to my knowledge, is the best standard we have. This is the Levine/Horvath clock. It is based on 513 methylation sites and it is calibrated not to chronological age, but to a tighter measure of age-based health, derived from blood lipid profiles, inflammatory markers, insulin resistance, etc, which Horvath calls "phenotypic age". Consequently, it is less well correlated with chronological age than the original, but it is better able to predict mortality than either the classic Horvath clock or chronological age itself.

The original Horvath clock was developed by a statistical process that took into account only chronological age. But Horvath age turns out to be a better predictor than chronological age for risk of all the diseases of old age. This is powerful evidence that methylation is measuring something fundamental about the aging process. If an individual's methylation age is higher or lower than his chronologial age, the difference is a powerful predictor of his disease risk and how long he will live. This can only be true if methylation is associated with a fundamental cause of age-related decline.


I am always wandering how the measured clocks correspond to the body health and damage.

To make a oversimplified analogy the aging clocks we can measure are more like cars mileage. Some of the measurements are measuring the metabolic mileage. Statistically they match the body damage as the car mileage matches the vehicle's damage. However, there could be a wide margin of error.

Let's say we find a good set of age markers. What if we reset them? Do we just invalidate the markers or do we really rejuvenate the body? Lipid count and inflammatory response seem like a good health indicator because they contribute to the deterioration....

Posted by: cuberat at April 30th, 2018 5:21 PM

I still don't see much usefulness in those aging biomarkers (not zero, but not much either) instead of simply using a more direct biomarker, like the number of senescent cells for senolytics or blood vessel elasticity for AGE breakers. I understand that people pursuing approaches like CR mimetics, telomerase therapy or epigenetic modification need general aging biomarkers, but don't see them so useful for SENS.

Posted by: Antonio at April 30th, 2018 6:14 PM

The question I have is, is there a Horvath clock for mice? And has anyone tested the results of senolytics on this clock? Or does anyone out there have the funding and intent to do this?

Posted by: Jim at April 30th, 2018 7:14 PM

@Jim: There is. Zymo Research sells the kits to scientists. I imagine someone already has tested it, and we're all just waiting on the peer review process.

Posted by: Reason at April 30th, 2018 7:40 PM

I have very basic criteria for these kind of theories/drugs
if anyone taking all these drugs still die of aging no matter if he lives 115-150 years its not anti-aging , Josh look 60 years old and he is 69-70 after taking all those interventions all you saved is 9-10 years , to me what anti aging is be 20 at both level. that's why I am huge supporter of SENS. also I have a gut feeling amyloids are root cause of problem because brain run everything in body , immune system,etc and if core of the machine does not work well whole machine would not work well , in my language of IT , if the kernel is not working well , the whole system would crush , who knows if we clear the brain and whole body rejuvenates itself . again its just my opinion and I am not a biologist

Posted by: Salman at May 1st, 2018 12:06 AM

Hi Salman,
since the longest confirmed human lifespan is less than 125 , so going to 150 for sure counts for live extension. Rejuvenation ? Probably not. Depends how you get to 150. By slowing down the aging or by partial damage reversion.

If there is a master [epi]genetic clock that could be reversed it means that the aging is more or less programmed and can be hacked. I don't think we are that lucky.

Posted by: cuberat at May 1st, 2018 9:13 AM

You think aging won't be conquered in our lifetime right ? I am 25

Posted by: salman at May 1st, 2018 10:12 AM

Hi Salman,

there is good chance we can reach the LEV if we can stick around for the next 30 years. So very good chances for you. 50/50 for me. However, I want to see how well the first senolitics can work in humans.

I am skeptical that resetting a bunch of methylation factors will revert the aging, though. A good marker could be the effect not the cause of aging. Like dying my hair doesn't make me younger or healthier. It is just masking or invalidating the marker.

It seems DNAm PhenoAge markers are good to measure the untreated age. Are they any good after the intervention?

Posted by: cuberat at May 1st, 2018 12:00 PM

I just saw this abstract this morning. I don't get it. Doesn't this mean the epigenetic clock will give us a false reading if used to measure whether an anti-aging treatment is working?

"Epigenetic age increases at a slower rate than chronological age across the life course, especially in the oldest population." 

Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data.

Posted by: NY2LA at May 3rd, 2018 11:20 AM

My own experience -- granted, this is anecdotal -- is that the epigenetic clock is not necessarily measuring true biological age in the way we think it does.

I am 64 years old, and was shocked (and dismayed) to find that my DNAge was measured as... 64.

I take enormous amounts (about 16-18 capsules a day) of TA-65, and every other anti-aging supplement you can think of. So I'm guessing -- hoping! -- that my telomeres have been lengthened, and that is screwing up the methylation pattern somehow?

My joints, skin, overall health... are exceptionally good. And seem to be getting better. Most people are visibly shocked when I tell them that I am 64. For the past few years, I don't seem to be aging... in my own eyes, anyway. So I have decided to trust the evidence before my eyes, rather than a test that no one seems to fully understand... maybe I'm wrong -- only time will tell.

If anyone has any comments or helpful suggestions, I'm all ears. I admit that I was depressed for a couple of days until my brain came up with this more optimistic scenario: maybe this means that my telomeres are getting longer, and that something good is happening here...? I haven't been tested for this. But my once-yearly comprehensive blood tests (I do it myself via LEF.org) show very good results all-around.

Posted by: Deborah R. Castleman at May 6th, 2018 12:56 PM

Firstly, I have an IT background rather than biological so i may not be qualified to comment, but after much reading I can see the value in having markers to measure progress (you cant manage what you cant measure).
It seems people are investigating and are interested in finding a single marker to represent a humans biological age, but what if an accurate marker is only possible by using a combination of measures?
According to SENS there are 7 types of damage that cause aging, so it seems logic to me that to create an accurate marker of aging, we need a rating for all 7 damage types. These ratings could be normalised by looking at the extremes of lifespan (new borns, and super centenarians), then after adding these 7 scores together you would obtain an individuals biological age. Damage in each of the 7 areas is obviously spread over the body so working out an average damage rating may be a challenge.
Any activity that changes one of the 7 forms of damage would also impact your biological age but we would need to address all the forms of damage to truly reverse aging.
Again, i'm not qualified and although i'm a long time reader, this is my first post, but i thought it was an interesting idea.

Posted by: Ben at May 8th, 2018 11:28 PM

@NY2LA: What you said may be so, since the meta-analysis noted a possible ceiling effect or plateau. Still, the meta-analysis is an argument for repeated testing of an individual across different ages.
Here's my curation of it and two other epigenetic clock studies:

Posted by: PRice at May 18th, 2018 4:56 AM

Deborah R. Castleman, you mentioned that you take "enormous amounts of TA-65, and every other anti-aging supplement you can think of." I also take many supplements, and I often wonder if these supplements actually work. I have found, for example, that the dosages in clinical trials are always much higher than what is on the label as a "recommended" dosage.The latter is just one concern I have about supplements. Just curious, have you had your telomere length tested? This would indicate whether the TA-65 is working. Very interesting, thanks for sharing.

Posted by: Angela Calvo at March 13th, 2019 12:05 AM

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