The Latest on DNA Methylation as a Biomarker of Aging

Over the past few years, researchers have been working to construct and validate a biomarker of aging based on changes in DNA methylation patterns that occur over a lifetime. DNA methylation is constantly in flux, part of the complex system of epigenetic regulation that alters the output of proteins in response to circumstances in order to regulate cellular behavior. Some of these changes are driven by the accumulation of forms of cell and tissue damage that cause aging, and measurements of those should correlate well with biological age: how damaged you are, and thus how aged you are, and further how high your mortality risk is as a result.

A low-cost, quick, and reliable measure of the degree to which an individual is are damaged and aged will be a necessary tool for future research into aging and longevity. Currently the only way to assess whether or not a putative rejuvenation therapy works as intended to extend healthy life is to wait and see. That is very costly, even in studies that use short-lived species, and a therapy has to be tested in longer-lived mammals at some point on the road to clinical application. Given a reliable biomarker that measures biological age, it will be possible to rapidly assess many more potential therapies that treat the causes of aging, steering the community towards the most effective approaches, and reducing the time spent on dead ends or less effective research programs.

Several recent studies have made use of the age-related changes in methylation profiles to construct DNA methylation signatures, a DNA methylation age (DNAm age) or 'epigenetic clock', with impressively high correlations with chronological age, of about 0.7 or greater. Considering that methylation profiles are modifiable by lifestyle and other environmental influences, it has been proposed that DNAm age is a biomarker of aging, that is, that DNAm age provides a better estimate of biological age than chronological age and is associated with current and future health and mortality.

In this study, we estimated DNAm age using the frequently applied Horvath prediction model and confirmed it using the Hannum prediction model. The study sample consisted of 378 twins aged 30-82 years from the Danish Twin Registry. The oldest 86 twins (mean age 76.2 years at intake) were resampled in a 10-year follow-up study and had methylation age determined again at mean age 86.1 years. The mortality in this sample was subsequently followed for 8 years. The twin design enabled us to control partly for genetic and rearing environment in the mortality study.

We found that the DNAm age is highly correlated with chronological age across all age groups, but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12421/

Comments

Good to see studies on here supporting programmed aging. Too often websites that provide information or news suppress information which gives support to an alternative point of view.

Posted by: Santi at November 20th, 2015 5:06 PM

This study doesn't support programmed (or non-programmed) aging.

Posted by: Antonio at November 20th, 2015 5:11 PM

That there is an internal clock (DNA methylation/epigenetic clock) and changing it changes your rate of aging or chance of death is programmed aging theory. This article shows that DNA methylation has a very high correlation with age and death supports that. The fact you can change your DNA methylation by ways other than removing damage, which this study lends support to that changing your risk of death, supports it also.

Many people have criticized Reason for being so over the top pro damage theory that he is not open to other possibilities which has turned some people off to the website. I was just saying that it was good that he was showing them wrong and that he puts whatever studies are connected to aging on his site including ones that support an alternative point of view, unlike some other websites.

I don't care which theory is correct and neither should anyone else as we are all in this together. If we don't find a cure for aging we will all die.

Posted by: Santi at November 20th, 2015 6:07 PM

"and changing it changes your rate of aging or chance of death"

The study doesn't prove that.

Posted by: Antonio at November 20th, 2015 6:52 PM

To be clear, the study doesn't prove whether methylation changes are a cause or a effect of aging, only proves that they are correlated.

Posted by: Antonio at November 20th, 2015 6:57 PM

Steve Horvath has the most comprehensive DNAm testing system for aging biomarkers and you can get his software free too. I would say its one of the best assays we can use to test efficacy of a therapy. I would certainly like to use it in the mouse testing project I am working with.

Posted by: Steve H at November 21st, 2015 6:58 AM

Yes,it's true that DNA methylation changes might not be the cause of aging, but it can be a great long term logs for agings. Epigenetics, including DNA methylation, can the science to investigate the environment-genetics interactions. The current DNAm not only could be used as biomarkers of aging, but also let us know what happened during the long time of aging.

Posted by: Stan Chen at November 22nd, 2015 11:52 PM

From Horvath's site

(http://labs.genetics.ucla.edu/horvath/dnamage/faq.htm#_General_questions)

"The big picture: Most (but certainly not all) prior articles propose that age effects on DNA methylation levels represent noise or epigenetic drift, see for example the excellent recent article by A. Teschendorff et al (2013). Hum Mol Genet. PMID: 23918660. While epigenetic drift may explain age related changes for most CpGs, Horvath (2013) presents compelling data that the epigenetic clock relates to a purposeful biological process. Further, it proposes the epigenomic maintenance system (EMS) model of DNAm age."

What is interesting, but perhaps not too surprising (if levels of DNA methylation are a clock of sorts) is that the rate of epigenetic change is fastest during development. This appears to be the case for diverse tissues/cell types. Development itself is a program and in some circumstances a messy one at that given the fact evolution has a tendency not to have the best solutions (e.g., my old man prostate)... Post-development/reproduction, from an evolutionary perspective, it doesn't appear necessary for there to be a conserved program on the level of individual organisms.

The model Horvath uses is based on 353 CpG sites and appears to be highly accurate /predictive over a wide range of chronological ages. In his 2013 Genome Biology paper he points out that DNA methylation age (DNAm age) is correlated with cell passage number but that it does not represent mitotic age "since it tracks chronological age in non-proliferative tissue (for example, brain tissue) and assigns similar ages to both short and long lived blood cells." To me that is an important point. He goes on to assert that DNAm age is not a marker of senescence. Ultimately he proposes that "DNAm age is a measure of work done by an epigenetic maintenance system". Post-development there is a 'constant tick rate' that can be modified by the environment.

Just a couple of ignorant thoughts on this as I am not well read in general and especially not in this area of research:

As proposed by Horvath, would this DNAm age model provide a way to assess the effects of rejuvenation technologies? Reprogramming somatic cells to become IPSCs resets the methylation state. If this reset represents a (total) resetting of the epigenetic maintenance system model that Horvath proposes, then perhaps going from a DNAm age of 60 to a DNAm age of 20 is possible under the right circumstances.

With respect to DNAm age, from these initial studies it appears progeroid syndromes are not representative of normal aging.

Posted by: aaron at November 23rd, 2015 1:57 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.