The Epigenetic Clock Does Not Reflect Long-Term Physical Activity Differences in Twins

Epigenetic clocks are a weighted algorithmic combination of specific DNA methylation markers, those that exhibit characteristic changes with age. The various iterations of the clock have a strong association with chronological age, and appear to reflect biological age as well, in that people with more pronounced age-related disease and populations with higher mortality rates tend to have a higher epigenetic age than their healthier peers. Since the clock was reverse engineered by analysis of DNA methylation and age data, there remains the question of what exactly it is measuring. There is no comprehensive map to definitively link changes in epigenetic markers with the progression of the causes of aging.

Thus it is presently hard for researchers to make good use of the clock in speeding up the development of potential rejuvenation therapies; given a result, there will be uncertainty over what the result means. Numerous studies have been carried out on the epigenetic clock and specific medical conditions and therapies. Some of the results are troubling, such as the one here. If one can take twins who have a lifetime of very different exercise habits behind them, and find that they have roughly the same epigenetic age, that is a challenge. The epidemiological and animal data on exercise, even the modest levels of physical activity discussed here, strongly indicates that it has a robust, measurable effect on mortality rate and risk of age-related disease. If that doesn't show up in the epigenetic clock, we must come back once again to ask just what is it that the clock measures.

Advances in the fields of molecular biology have produced novel promising candidate biomarkers and their combinations that may be considered as biological aging clocks. So far, one of the most promising new aging clocks is DNA methylation (DNAm) age, also known as the "epigenetic clock". DNAm age is a multi-tissue age estimate based on DNA methylation at 353 specific age-related CpG sites. It is determined with a special algorithm, which is publicly available. The epigenetic clock appears to be associated with a wide spectrum of aging outcomes, most consistently mortality. Discrepancy between DNAm age and chronological age, i.e., higher "age acceleration" predicts all-cause mortality.

So far, it is also not clear whether the genetic component in variation of DNAm age changes over a life span. On the other hand, some environmental exposures and behaviors such as infections, diet, alcohol use, smoking, and work exposures predispose to age-related diseases and increase probability of death. Only part of individual variation to life expectancy can be accounted for using known and measured characteristics and exposure. An epigenetic clock could provide insights into the mechanisms behind why some individuals age faster than others and are more prone to age-related diseases and accelerated decline in physical function.

Physical activity is a potentially modifiable behavior that could slow down the rate of cellular and molecular damage accumulation and blunt the decline in physiological function with increasing age. The purpose of the study was to estimate the magnitude of genetic and environmental factors affecting variation in DNAm-based age acceleration in young and older monozygotic (MZ) and dizygotic (DZ) twins with a focus on leisure time physical activity.

The relative contribution of non-shared environmental factors was larger among older compared with younger twin pairs [47% versus 26%]. Correspondingly, genetic variation accounted for less of the variance in older compared with younger pairs [53% versus 74%]. We tested the hypothesis that leisure time physical activity is one of the non-shared environmental factors that affect epigenetic aging. A co-twin control analysis with older same-sex twin pairs (seven MZ and nine DZ pairs, mean age 60.4 years) who had persistent discordance in physical activity for 32 years according to reported/interviewed physical-activity data showed no differences among active and inactive co-twins, DNAm age being 60.7 vs. 61.8 years, respectively. Results from the younger cohort of twins supported findings that leisure time physical activity is not associated with DNAm age acceleration.



I am an identical twin who has exercised (and fasted occasionally) throughout my whole life (I'm 56 now)and have no age-related or degenerative diseases. My twin brother, on the other hand, who has almost never exercised now suffers from: obesity, arthritis, GERD, high blood pressure, type 2 diabetes, and now, cataracts. I wonder if we would show the same epigenetic age.

Posted by: Kurt at January 28th, 2019 10:46 AM

Hi Kurt! Just a 2 cents. [I'm a twin too (non-identical/diff gender), and have a two/too, she is my twin sis and I'm twin bro. She was/is healthier than me (though she has nerve pain everywhere which I don't have at all, like osteporosis combined with athritis/nerve damage, yet bones are perfect) and maintained better health and youth/younger looking (although, that was Already from the very beginning at birth, a woman twin can be biologically younger than her brother twin, and in this case she is a lil bit (plus, in general, women are biologically younger than men (due to telomerase/double XX chromosome more powerful/stable genome instead of Xy male compromised genome), applying even for diff gender twins. Now, if I had been a identical twin, my twin bro (like your twin bro, though whom seems to have more health issues), might have been older/younger than me. I also have identical twin nieces of 14 years old (twins run in the family) and they are nearly equal, biologically speaking; one might be slighly ahead of the other because she is entering growth/puberty faster than the other (demonstrating faster aging/faster reproduction phase entry to become adult/mature which means faster epigenetic aging/maturing)), where as me and sis, it was pretty equal and we were both 'late late' on the puberty thing (twins generally have slowed aging (not all of course), identical twins have more chances of slowed aging because, in my point of view, it's an evolution advantage (2 children birthed at same pregnancy is evolution survival advantage (2 instead of 1 is better '2 for the price of one, the bonus', the woman mother is birthing more/per pregnancy and that is double survival advantage), thus protecting them by slowing their aging is contributory to specie survival (kind of like hte 'jackpot 'gift'' when a woman has twins, this is evolutive advantage/compensation for specie survival continuity, but this is much more applicable for identical twins than non-identical; because they share extremely high DNA/genetics, being identical (or near 98-99.8% genetically identical; not a clone (which is bad word, that twins hate (including me has twin, and in your case, must be even more so, because identical) but someone extremely similar. Though, probably like you, twins do their best to differentiate themselves to not be a copy/clone of the other, but someone 'unique' that ressemble extremely to sis/bro. I'm sure you had these convo with twin bro, I had them with twin sis (of course, being a dude is nothing like 2 twin bros and 2 twin sis, vs twin bro/twin sis...I'm a guy she is a girl so the difference is large/visible/gender. But for identical twin the same gender can make it very hard to diffentiate them (for a long time I mixed up my own nieces they looked so alike (I said their names the the wrong twin, they forgave me of course (they know I'm a twin too!) ), until around 10 years old, where their faces became distinct and had 'little marks' that shaped differently showing you can now see micro morphological differences, and not 100.000% identical].

I hope your brother gets better. From this study here it is not easy coming to conclusions about epigeenetic aging, but I believe wihtout a shadow of a doubt, that aging is something else and is connected with health, but are different nonetheless (like a threshold for health 2nd layer element, that is independent of 'time passing aging' 1st element); it's why there is confusion in such studies and might see variations or contradictions. In this study the twins were 60.7 & 61.8 years by the S Horvath epiclock I presume. 4-5 years older than you (I'm youger, closing on 40s soon, my twin sis too (obviously ;), yet I suffered atherosclerosis, though my sis did have high cholesterol too but not enough to be serious, unlike me where it was; so we are not 100% of same health problems, in this study the two twins showed difference in physicaly exercice activity and health...but not much on epiclock,

This strengthnes my pov that indeed health and aging are two things and uncoupled. So on your thought of wondering if you would show same age, it's very likely yes. Now, T2D, obesity and, especially, high blood pressure can definitely accelerate epigenetic aging; that's 100% assured but nowhere to what studies have said in past; it's why you might see that your twin bro is not that older than you in epiclock (or strangely, might be younger than you, very possible). When you have these diseases it is not an assurance that aging will show (because as said, health/aging are uncoupable/dissociable, we always think they are 100% undividable and cannot be 2 things, but are 1 thing/the same thing; ....they are/can be 2 things and can 'act' independently while keeping that 'co-'/codependence - at the same time). Since he suffers from high blood pressure, t2d and has cataracts (due to H2O2/ROS/AGEs forming in eye len), then there is possibility it would show on the epiclock but not assurance. That is where we still don't know 100% sure and why would your brother not be older than you (after suffering/still all that) OR he is older...and it makes sense after all this disease...but then it would mean that there is a 'threshold' where at a certain point, poor health becomes 'accelerating of aging'. But if you keep aobve threshold, then no, aging continues its course at regular speed, and you keep healthy, until natural death (cause of time passing/aging your full human healthy possible life up to 120 years MLSP).

Just a 2 cents.

PS: yes, it's still ambiguous (DNA egigenetics).

Posted by: CANanonymity at January 28th, 2019 7:31 PM

PPS: ''The relative contribution of non-shared environmental factors was larger among older compared with younger twin pairs [47% versus 26%]. Correspondingly, genetic variation accounted for less of the variance in older compared with younger pairs [53% versus 74%].'' This is explainable as longer environmental exposure, by a longer life completed so far/because older/lived longer. The young ones had less time so far/to env exposure in their still young life. Still, don't take this study too much at face value; because they clearly Undervalue the contribution of genetics/epigenetics to Even older people; env exposure is not the 'be all end all' that they claim; and why you could see two twins, one poor health, one healthy, same age, yet exact same epiclock. This shows how much they undervalue genetics contribution and try to say environment is responsable. I mean, when you separate identical twins and make them live in different env, of course, there is more contribution in env exposure weight 'in the balance' of their development/growth/ that sense. But, still, you can see that, indeed, the epiclock is barely changed; showing aging/health are uncoupled and that they greatly undervalue the (epi)genetics contribution to aging. Why, I believe becayse they can't 'pin it' and see similarity so come to conclusion that genetics 'has no say' as you age...that's very wrong. genetics has immmense say.

Posted by: CANanonymity at January 28th, 2019 8:31 PM

Thank you CANanonymity for your in-depth point of view.

Posted by: Kurt at January 29th, 2019 10:20 AM

The results of this study is encouraging, rather than problematic, to me.

A reason for considering it problematic may be a lack of interest in youthful aesthetics. We already know from studies, for example, people in their 80s who ride bicycles have the immune systems of people in their 20s. But just look at the faces of subjects in such studies. They still look their age. Therefore, they are obviously still aging.

Epigenetic clocks may help stop people from confusing health measures with aging measures.

Posted by: NY2LA at January 31st, 2019 1:14 AM

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