Assessing the Utility of Six of the Better Known Epigenetic Clocks in a Large Study Population

Epigenetic clocks to measure age emerged from the ability to cost-effectively obtain the moment to moment epigenome of an individual, the distribution of epigenetic marks on nuclear DNA that control gene expression. Cells react to their environment, and some of those reactions are characteristic of the ways in which the cellular environment changes with age. Given this data and ample computational power, it is possible to find weighted combinations of, for example, DNA methylation status at specific CpG sites that fairly accurately correlate with age. More interestingly, this appears to be a measure of biological age rather than chronological age, in that people with a higher epigenetic age than chronological age tend to have a higher incidence and later risk of age-related disease and dysfunction - and vice versa.

It remains unclear is what exactly it is that is being measured by an epigenetic clock. Which processes of aging, the accumulation of damage and downstream change, actually cause these characteristic epigenetic changes across all individuals? Is it all of them? Or only some of them? Researchers have produced clocks based on patterns of transcription and protein levels in addition to epigenetic marks, and some of these later clocks use only a handful of transcripts, proteins, or marks. It seems unlikely that the more abbreviated clocks measure more than a fraction of the causative processes of aging. Since these processes interact, and all of the facets of aging proceed at much the same pace in most people, then a clock that measures, say, only chronic inflammation, might be just as good today as a clock that is affected by all mechanisms of aging.

This is true, at least, until we start being able to repair specific forms of underlying cell and tissue damage, such as the presence of senescent cells. Some clocks will stop working usefully, and we don't really know which ones are vulnerable to the deployment of any given approach to rejuvenation. Which is a challenge, because assessing the results of therapies that repair specific forms of underlying cell and tissue damage is exactly how we'd like to use these clocks. As things stand, no clock, epigenetic or otherwise, can be trusted for such a task until it is fairly well calibrated against a class of rejuvenation therapy via multiple life span studies.

Epigenetic measures of ageing predict the prevalence and incidence of leading causes of death and disease burden

Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm.

In this study, we examined associations between six major epigenetic measures of ageing and the prevalence and incidence of the leading causes of mortality and disease burden in high-income countries. DNAm GrimAge, a predictor of mortality, associated with the prevalence of COPD and incidence of various disease states, including COPD, type 2 diabetes, and cardiovascular disease. It was associated with death due to all-cause mortality and outperformed competitor epigenetic measures of ageing in capturing variability across clinically associated continuous traits. Higher values for DunedinPoAm, which captures faster rates of biological ageing, associated with the incidence of COPD and lung cancer. Higher-than-expected DNAm PhenoAge predicted the incidence of type 2 diabetes in the present study. Age-adjusted measures of DNAm Telomere Length associated with the incidence of ischemic heart disease. Our results replicate previous cross-sectional findings between DNAm PhenoAge and body mass index, diabetes, and socioeconomic position (in a basic model). We also replicated associations between DNAm GrimAge and heart disease.

In conclusion, using a large cohort with rich health and DNA methylation data, we provide the first comparison of six major epigenetic measures of biological ageing with respect to their associations with leading causes of mortality and disease burden. DNAm GrimAge outperformed the other measures in its associations with disease data and associated clinical traits. This may suggest that predicting mortality, rather than age or homeostatic characteristics, may be more informative for common disease prediction. Thus, proteomic-based methods (as utilised by DNAm GrimAge) using large, physiologically diverse protein sets for predicting ageing and health may be of particular interest in future studies. Our results may help to refine the future use and development of biological age estimators, particularly in studies which aim to comprehensively examine their ability to predict stringent clinically defined outcomes. Our analyses suggest that epigenetic measures of ageing can predict the incidence of common disease states, even after accounting for major confounding risk factors. This may have significant implications for their potential utility in clinical settings to complement gold-standard methods of clinical disease assessment and management.

Comments

"Which processes of aging, the accumulation of damage and downstream change, actually cause these characteristic epigenetic changes across all individuals? Is it all of them?"
This statement falsely implies that such epigenetic changes are only the result of aging, and play no causative role. While this is the dominant belief, it is too early to state it as established fact. Many preeminent scientists have deduced that at least some epigenetic changes cause symptoms of aging.

Posted by: Walter H Crompton at September 6th, 2020 5:51 PM

In my recent presentation at EARDS 2020, I argued that most methylation changes are upstream of aging, they are DRIVERS of aging. But some of them are downstream, RESPONSES to damage.

I argued that the way a clock is derived can favor DRIVERS or RESPONSES, so that the CpG sites in the clock are more likely to be one or the other.

Crucially: We should only be using DRIVERS of aging to evaluate the usefulness of anti-aging interventions. This is independent of how well the particular clock predicts morbidity and mortality (which is also important).

This is a new idea to most people, and I refer you to a video of the EARDS presentation to hear a full explanation, and decide if you agree:
https://mega.nz/file/XnJ2SSKK#KkaFOZS2F59d5iWwLSsVvEGJjdVYe3TSYVl87JO6_K8

Posted by: Josh Mitteldorf at September 6th, 2020 6:44 PM

But there's no lab that will do DNAm GrimAge for you, right?

Or no way to purchase it online.

Posted by: Laur at September 7th, 2020 5:13 AM

Hi there! Just a 2 cents.

''In our study, an epigenetic predictor of telomere length predicted time-to-onset of ischemic heart disease. A shorter leukocyte telomere length has been shown to associate with heart disease in diverse populations, suggesting that the DNAm Telomere Length predictor may capture key facets of this clinical association.''

The telomere clock was the tightest, of course, not as tight as 6 clocks combined to get a bigger picture/more refined (but sometimes, more clocks, does not (necessarily) mean better; it is why, in the past, sometimes a single clock/element by itself, could be a better predictor than a combination of several ones; errors/deviations in results from data/statistical noise such as unhelping/haphazard/random factors tallied-in that muddy/dilute the correlation; SD/standard deviation can increase and correlation coefficient reduce; making a poor result study (in terms of correlation power)).

The other clocks more SD, thus can give more varying results...they are reliable though.
Leukocytes telomeres are very strong marker for longevity. While these other clocks can be more precise in terms of other diseases like lung cancer or diabetes. Thus, they can paint a better 'health' status picture...but on the Longevity (maximal in humans), the telomere clock is still one of the most reliable. It is telling that it associates with the heart, the heart is 'longevity-limiting' organ; animals that live centuries have hearts that barely beat/bradycardia/hypometabolism/ slowmometabolism and a heart that beats all this time (few beats spread over so long). While people who live barely 15 years due to the disesase (HGPS) suffer heart disease rapidly and have accelerated telomere attrition rate. Telomere shortening rate is inversely proportional to maximal longevity; so is demethylation of the DNA methylome (5-metC loss).

I think we should not put too much more energy in the 'programming vs damage' theory debate...
chicken&egg question, whether it is DNA Methylation changes causing DNA Damages; or, the inverse, DNA Damages causing DNA Methylation changes - Or Both, which comes first...is not so important anymore. What is, is finding a way, to tackle them both and if we can do it just by damages or just by methylation; then so be it/that's great. It seems that methylation changes promote damages because of activating/deactivating genes that participate in that; such as, tumor suppressors p21, p16, p53 which all of them raise ROS levels to destroy tumors. These damages, then, will incur more methylation changes. It is why we see methylation changes happening very early, long before, the disease happens. Thus, they are like the 'building steps' to the arrival of whatever disease. As the methylome changes (first)...the disease will happen.
The damages from the arriving disease will only accelerate further changes in methylome as 'response'...so activation and responding feedback loop...Both of them are causal to aging.

In any case, most of these clocks are great to detect the health/longevity and do something about it. But, as Reason says, no matter, we must repair damages and stop our methylome/epigenome from crumbling...otherwise, all this is just data - for - data (ok it's useful for 'qualifying/quantifying' the population's health (and gauge what to do) but...we still age in that time; the time of compiling data/infos-for-infos has to end now it has to be the time of action/acting on it (we know all these clocks - time to Reverse them) and making a therapy that reverses/stops/ends aging.

Just a 2 cents.

PS: Before it's too late. (I can't count the number of times I telling myself ''Why do they not act on it and like...follow up on their study results...like, building a therapy or something....''.

PPS: ''Oh right (forgot)..I know why...money (/lack there of), that's why (plus everything else (FDA, ethics,...)''. At least, at least ..At The Very Least they could say ::''Ok...someone do something about it...we give you the blueprint..now do it from your end''. They should actively seek the people who will do something/make something out of it. I think that there is at least 70% of research that pile up and nothing done on/about them. They merely are compilations ending the graveyard of medical litterature; kind of like that clock 'GrimAge'...grim (reaper) indeed (that is a pretty grim clock). Well that clock is now in GrimReaper grave of studies that sleep (forever) with others. When are we going to Deter Them from that hole and make something about it/we collect too much bones there (boneyard), a cemetery full of promises; alas, broken ones. Thankfully, AdG SENS, saw that before and did not waste time to do something about it; also kind of like Mrs. Parrish doing telomerase (and skipped everything), they are doing something about it (because they know time is amiss/life short). At this point, you must take it in your hands sort of and defeating aging will be the most collective But individual thing...everyone wants to live longer...but not eevryone can (because poor/rich people), so it becomes a ''will You live longer...You/alone/as 1 individual/with 1 body/1 life/1 You in You (because only you can Act on You, since only you, in you''. No one can save you if you can't save yourself/act on yourself to get help/to get saved. What will you do For You/Your Life? As selfish it sounds. And, collectively, for the others too. Thus, an Individualism (1st), mixed with Altruism (in 2nd). We would all like to be altruist first, but then that means that our own person is not as important/some people are like that (they would give their life for others, over theirs; pure selflessness (is rare)). Because if you don't care about your life/you, then, there is no you. How will you survive, alone, if you can't valorize your own self/you/own life. We cannot be 'carpets'/door mats 'welcome' to step on by others. My father would say: ''Don't let anyone step on you, you're not a doormat''. Thank god I understood, it's how I was ablve to defeat by disease (atherosclerosis) and Live/Survive. Valorize my survival. Otherwise I'd be dead. People are starting to connect the dots (lightbright), they need to take aging seriously and stop it with the 'we age...we die, and that's that; so get used to it; nothing can do about it, your number will come'.

Posted by: CANanonymity at September 8th, 2020 3:21 AM

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