Is DNA methylation destiny? Diving into new epigenetic clock research

I’ve been thinking more about the steady stream of epigenetic clock research out there.  How convincing is the research on such clocks? Do they tightly relate to human biological age?  The related notion of turning back such hypothetical clocks to reverse aging is exciting but controversial.

It doesn’t help that some are hyping all of this and already selling stuff.

I often find myself going back and forth in terms of how I think about this space. For most of the summer I was viewing it fairly skeptically. However, this week after reading these new papers I got more into the ideas they present even if I still have many questions.

Today I’ll go over this area, in particular related to two new papers. The research is largely based on DNA methylation studies.

Let’s dig into it.

What is an epigenetic clock?

The core idea here is that our cells have clock-like mechanisms. For instance, cells change in predictable ways as they (and we) get older. Such changes can be viewed as akin to the movement of clocks as time passes.

This hypothesis started in part based on the observation that DNA methylation generally decreases with age. However, the research is getting more specific and interesting than that. DNA methylation seems to have other predictable clock-like elements such as where it is present in the genome over time, how that changes, and what genes are nearby.

Data including from the new research papers show that these DNA methylation patterns and time-related changes happen both in people and diverse other animal species.

As a result, there’s this idea that cellular DNA methylation could be like a near-universal aging clock for animals. In turn, assays of such clock features could reveal animals’ biological ages. This includes people.

There are more layers here too. One can come up with new epigenetic clock models. The clock types in part depend on the way the researchers approach the modeling, the data used, and questions of aging. In addition, other possible biological or molecular clocks exist as well including telomere length but are less well-defined.

I would imagine that DNA methylation is not a stand-alone clock, but some view it that way. Still, I bet it connects with histone-related epigenetic mechanisms and cellular metabolism. There’s probably already research on these additional potential elements feeding into clocks.

The new epigenetic clock papers from Steve Horvath, et al.

Both new papers have Steve Horvath of Altos Labs, a leader in this research area, as senior author.

One paper was in Nature Aging. Its title is “Universal DNA methylation age across mammalian tissues.” This paper argues that epigenetic clocks are widely present in mammals and can be used to tell us the ages of many organisms. Other more specific elements of the paper, such as the potential role of PRC2, are also interesting.

The other paper, in Science, had almost 200 authors. Its title is “DNA methylation networks underlying mammalian traits.” Some of the arguments in this paper are pretty remarkable such as, “Both the epigenome-wide association analysis (EWAS) and eigengene-based analysis identified methylation signatures of maximum life span, and most of these were independent of aging, presumably set at birth, and could be stable predictors of life span at any point in life.” Note that some of the firms selling age reversal ideas may not like the maximum life span idea.

The evolutionary aspects of this study are intriguing too. They conclude “The phyloepigenetic trees indicate that divergence of DNA methylation profiles closely parallels that of genetics through evolution.”

The work also points to specific regulators. Some of these are kind of our old friends from the pluripotent stem cell field:

“The upstream regulator analysis of the EWAS of life span identified the pluripotency transcription factors OCT4, SOX2, and NANOG. Other factors, such as POLII, CTCF, RAD21, YY1, and TAF1, showed the strongest enrichment for negatively life span–related CpGs.”

This relates to the goal of Altos Labs to help people through cellular rejuvenation. One major focus there is on different kinds of cellular reprogramming.

Developmental vs. adult states

During development, cells and tissues differentiate with precise timing. For that reason, researchers have explored clock mechanisms in that context too. To me, developmental clocks make great sense because near-perfect timing is needed to generate something as complex as organisms in a defined time frame.

However, why would adults, particularly after sexual maturity, have these clocks? Such clocks seem operative even in aging people well past reproductive age.

Could these clocks in older people not necessarily have a purpose but just be present as a vestigial mechanism? Machines left ticking away from earlier times of life when biological clocks had specific mechanisms?

Or maybe any living cell will have clock-like elements? How consistent are clocks outside of mammals?

Epigenetic clock test and hype on biological aging

There’s a lot that is unknown. I’m sure Steve Horvath has answers to some of this, but the field is still in its early days.

Even so, some companies now sell biological age or epigenetic clock test products. Certain assays are less rigorous than DNA methylation tests in terms of assessing aging. For instance, I’m skeptical of telomere length assays as a reliable measure of biological age.

Despite all the old and now new papers on this, I’m still not even sure if DNA methylation assays can widely be used to accurately gauge our ages across diverse human populations. The new papers do build more of a case.

Some researchers and entrepreneurs have gotten way ahead of the data. They have hyped things up. Certain anti-aging and longevity firms have seized on these tests both to make money and as a means to sell expensive, unproven products like supplements. Certain high-profile scientists are out there broadcasting highly questionable things.

This hype often happens on Twitter (X). A typical statement or tweet might be akin to, “I took an epigenetic clock (or biological age) test and I am now a much younger than my chronological age.” Such statements also make their way into news articles.

The supposed rejuvenation is then claimed to be the result of specific lifestyle regimens or supplements.

Carl Zimmer at the NYT has a nice overview of the two new epigenetic clock studies and why some scientists are still skeptical. Some share my concerns about the hype and snake oil out there:

“There’s a lot of shenanigans and snake-oil sellers who tried to make money off this, and the epigenetic clock field is certainly rampant with it,” said Tony Wyss-Coray, an aging expert at Stanford University.

This commercial stuff reminds me sometimes of the stem cell clinic space.

I did Twitter (or shall I say “X”) polls on people’s views of telomere length testing and DNA methylation assays as tools to assess biological aging. Such polls are not scientific, but many people are highly skeptical of these assays. Yet the assays are regularly touted by high-profile individuals and even some institutions in the anti-aging space. Note that these polls ran before the new papers came out.

Tidy DNA methylation?

Finally, I’ve got to say that I love this line in the abstract of the Science paper:

“Species with longer maximum life spans have developed tidier methylation patterns within the genome”

I never thought of “tidier” as a hard science kind of word, but I get what they mean.

But now do we all have to worry that our DNA methylation patterns might be messy? Or getting messier with age?

Can fast food (or other lifestyle elements) lead to fast epigenetic clocks and hence quicker aging?

Conversely, can we tidy up our DNA methylation? People trying to sell you the test and supplements will probably tell you “yes!”

I can imagine in the near future that some of those folks who tweet or write about supposedly reversing their biological ages will jump on this. They may now start saying that their DNA methylation is tidier now too. Maybe tidier than the average person too.

And as a result they’ll live decades longer? To 130 or 150?

I don’t know about that.

From Zimmer’s NYT piece there’s this sobering point from Horvath getting back to maximum life span:

“But Dr. Horvath cautioned that his research on the epigenetic clock made him doubt that people would ever live past the maximum human life span of about 120 years.

“It’s set in stone during development,” he said.”

So do we have a maximum lifespan?

Can interventions shift clocks to at least get more people closer to the maximum lifespan?