Reviewing the Epigenetic Clock as a Predictor of Age-Related Mortality and Disease

Epigenetic clocks are weighted combinations of the DNA methylation status of various locations on the genome, shown to reflect chronological or biological age. DNA methylation is an epigenetic marker involved in regulating the production of proteins from their blueprint genes, and these markers constantly shift in response to circumstances, a part of the feedback loop of cellular metabolism. Definitive references to the epigenetic clock, singular, usually mean the original clock established by Steve Horvath's team and called DNA methylation age. A fair amount of work has gone into characterizing the behavior of this clock, particularly the association of higher measured ages with age-related disease: as a general rule, at a given chronological age, people who manifest age-related disease tend to have a DNA methylation age that is higher than their chronological age. This is thought to reflect a faster pace of aging.

The challenge here is that no-one has a good idea as to what exactly these characteristic DNA methylation changes actually reflect, which underlying processes of aging cause them. Since the most important goal of any reliable metric of aging is to use it to assess potential rejuvenation therapies, and thereby greatly speed up the processes of development, this lack of knowledge is a problem. Researchers cannot be assured that any specific approach to rejuvenation will actually exhibit the desired lower DNA methylation age - there is no necessary reason for any specific cause of aging to be reflected in the chosen sites for DNA methylation. They could very well turn out to reflect just a few of the full spectrum of contributing processes of damage that lie at the root of aging.

There is considerable between-person variation in the rate of ageing, and individual differences in their susceptibility to disease and death. The identification of individuals at greatest risk of age-related diseases and death would provide important opportunities for targeting prevention and intervention. There is thus great interest in molecular targets as clinical biomarkers which accurately predict the risk of age-related diseases and mortality. These biomarkers, which include cellular senescence, genomic instability, telomere attrition, and mitochondrial dysfunction, appear to capture pivotal aspects of biological age and have been associated with a number of age-related diseases and mortality.

It is well established that as individuals age, there is a raft of molecular changes that occur within the cells and tissues. Changes in DNA methylation patterns have been shown to occur with ageing, and thus may be a fundamental mechanism that drives human ageing. Epigenetic biomarkers of ageing, otherwise known as the epigenetic clock, have been developed using DNA methylation measurements. Referred to specifically as 'DNA methylation age' (DNAmAge), they provide an accurate estimate of age across a range of tissues, and at different stages of life, and are some of the most promising biomarkers of ageing. DNAmAge has also permitted the identification of individuals who show substantial deviations from their actual chronological age, and this 'accelerated biological aging' has been associated with unhealthy behaviours, frailty, cancer, diabetes, cardiovascular diseases, dementia, and mortality risk.

An increasing number of studies have investigated the association between DNAmAge, longevity, age-related disease, and mortality, with a total of 23 studies included in this systematic review and all published from 2015 onwards. Our primary finding is that there is sufficient evidence to support an association between accelerated DNAmAge and an increased risk of all-cause mortality. However, it remains unclear whether these methylation changes at specific CpGs are driving ageing or are consequences of the ageing process (cellular ageing, underlying disease processes.



Hey there! Just a 2 cents.

''However, it remains unclear whether these methylation changes at specific CpGs are driving ageing or are consequences of the ageing process (cellular ageing, underlying disease processes''

Yes, it's that old 'Causation or Correlation/uncausal 'residue' display of aging itself/visual manifestations of aging - but not Cause of it' problem...

I would say (ang guessing here), that this is not a correlation of aging - Only.

Because, it does correlate to aging but More than is Causal of it.

How so/How come? Because it happens Before...Long Before...the aging comes to that; meaning, the changes that happen on a methylation level, not only correlate, contribute, but causate the 'whole program' shifts...and thus, later, the epigenetic drifting - a self-fulfullinf proophecy/a vicious circle of more dysfunction - creating inflammation - and more damage - causing more epigenetic alteration and drifting/meaning the epigenomic signature changes towards something closer to death/dynsfunction (as in inflammatory genes are activated (TNF-a/IL-6/C-Reactive/p53/p16/p21/INF-g/Caspases/BID-BAD-BAX/TGF...etc), this in turn drives inflammation creation and inflammasome to alter the epigenetic signature towards 'dysfunction' (health threshold loss). But, later, it even changes the signature towards accelerated epigenetic aging (when the epigenome cannot bouce back anymore), so there is actually Epigenetic Advancing on The Epigenetic Clock; Irreversible Advancing of epiage. Thus, closer to stocastic-changes death that comes with regular healthy aging/time passing.

AS I have said before, a young person can die suddenly, and show a epigenetic clock much younger - still - than someone much Older, much more Advanced Clock and still very much - Healthy & Alive.

That young dead person did not 'have time' to accumulate so many alterations in the epigenome, like that old person (that old person accumulated these epimethyl changes - adaptations of 'Aging'/getting sustain function with aging; until, one time, by stocastic accumulation it becomes 'unviable' anymore for 'homeostasis' continuation (organs fail because of 'age', accumulated so much epialterations (the signature/potency is totally different and compatible with someone extremely old, - it's unviable anymore, thus natural 'healthy' death 'of old age' (I put 'healthy' in brackets because nothing 'healthy' about are still getting unhealthy..but the level of function is maintained/ you are still healthy Enough to live -but very old and could suffer in pain/be decrepit in places - not enough to kill you yet. Thus, the phase of old age with for a brief time you are getting much unhealthier and than can die suddenly in sleep or even just let go (some old people 'let go' when they lose their husband/wife of many years...very old...they let go and 'die of sadness'/heart broken when they lose their 'lover of their life'..see no point anymore continuing to live -without their lover, now gone. They Let Go. We've seen this, like the woman dies in her 80s-90s...and then the man, still alive...dies 2 weeks later or even 1 day later...just lets go. It's Not a coincidence, it is the will of the person to let go/die because too tired now and just succombs 'on purpose'/having 'lived their full life' and 'now it's time to end it')).

People can decide to die - if they are older, it is a personal/mind control, you can succomb to your age/pain and just let go when very old - all by yourself. I sometimes hear some say : ''I am very old and just wait to does not body keeps on going...why ? I don't know''.

In general, these people are more rare, it's the inverse that is more true...people can let go, much easily....if they are very old and frail..they just need to 'say it to themselves' and the mind will make the body 'stop functioning'/succomb. Placebo effect is the strongest effect/mind-control can make you survive or die; it'S the Will that keeps you living or dying.

Just a 2 cents.

Posted by: CANanonymity at April 19th, 2019 3:01 PM

"it'S the Will that keeps you living or dying"

I have witnessed this in my own family and closed friends family.

Posted by: Stephan at April 19th, 2019 6:02 PM

Hi Stephan! Thank you for that.

Thank you for sharing that...(just expounding air).

When I think about that, it makes me realize how much LEV is so so so important crucrial, imagine for a second that could live with someone you love - for nearly 'ever after' (just like in the faery counts stories : ''..and they lived happily ever after''...
we always know this is untrue; they happily (while alive) for the remainder of life until parted by death.

Not anymore, think of it like the film 'Lord of The Rings', in it there is an actress (Liv Tyler) whom plays a 'imm*rtal' elf woman whoms falls in love with a 'mortal' called Aragon (Viggo Mortesen); but she is at odds with her own self and 'super powers' of eternal life as elvewoman. Her father, whom is a an elder - but looking young like 50 years old - yet he is probably 5000 years old in chronological age...tells her, that her 'gift' given from the elv gods...should not be so easily discared for some 'random' dude that comes and she falls in love with. He values his eternal life and his daugther's too. It might soudn selfish of him to say that, but I explained before taht in the future, LEV would be a form of Altruistic Individualism (Rather than pure altruism, or, pure selfishism/egoism/individualism; thus an inbetween; where, by nature, LEV is individualistic (your sole body only) - but offered to all - thus altruistic; hence, altruistic individualism. It is better than pure narcissim/egoism just thinking LEV is for you alone and no body else - ingrate/undignified/cold/soulless (like some rich people wiht some 'prividleges' of finances greed; this in between strikes a middle ground between the unpriviledge and the priviledged. LEV is for All people, from poor, to rich ones; at the start, it will be for rich only..maybe later for poor too when we realize this is an EXISTENTIAL CRITICAL NEED to ALL humans - for Their Life. To bypass death; just like water/air...things are critical/essential/mandatory to your subsistence and existence (continued existence); LEV will become that (and I fear will be fougth against tooth & nails by the ethics lynch mobs that will basically call this a 'teenager fake dream for socionarcisstics & self-absorbed self-patting megaloman(iac)s' - thus make tyrants/prisoners/dictators becomes imm*rtal; in other words, tyranny and chaos/anarchy/government disolution/law dismantling/country sociofoundations destruction/possible outlawism on a Never before seen scale, just like what happened during the USA's Old West in mid 1800s Deep South colonizing and outlawism/criminality in the deserts of Arizona/Texas/Kansas/New Mexico border; there was no ('followed/consensus') law, only yours and you made it, to protect from absence of marshalss/policing on vast swath of rural geographic nothingness desert canyon barenland). Today, the odds of that repeating are small simply because any of this type of stuff is rapidly controled for and eliminated; so there is not 'seed' for it grow, it's 'killed in the sack/egg'..right away. Most protests are peaceful and when you look at China wtih 1 billion+ people, you realize quick that nobody wants to lose their life...if they are told : ''at 120 you cannot live any longer..because overpopulation and LEV is restrcited above that'' then you have to wonder what will the Chinese do, at their 1 billion population; the army cannot stop such a monstrous amount of people if they are hellbent of stopping gov to 'remove LEV' and 'decide' how long you live. Some people said here, that most likely this will not happen and the people would 'revolt' and laws/gov would unerected and voted in to allow LEV to be permanent for all citizens choosing to obtain it, however long they want.

But, to come back, to the Lord of The Ring example/analogy...this elf woman tells her father : ''I am sad because he is mortal and I will see him 'age' and then die...but I will still be alive..because I am eternal...not him''. His father says 'roughly' to her : ''bs...find yourself another dude, an elf one, everything solved''. she loves Aragon so much, 'hes is the One' and only...she decides to remove her eternal powers..and become a mortal to 'die beside him/Aragon'. You look at that and you are like...ok this is real sad...bitter...sweet/ - at least...she got to live maybe a 1000 years..not bad by all accounts. And she is tired of 'mortals dying around her' while she outlives them/survives them and keeps on 'living forever'...thus she feels she has lost her purpose to her life because it never ends (with normal 'mortal' death). She thinks (like most ethics...): ''a mortal life is 'finite' and thus' beautiful in that's a certain profit from it and then 'it's done'...the limited/limitness of it - forces you to 'Appreciate it' more...and 'make that time count'...whatever left you have before your mortal death''. And when she says taht (and ethics too), I think to myself..yes, it's true life is short so make the best of it (I know I nearly died of disease),you can never 'see it coming' you just hope it last a Bit longer.

100 years is some people 100 yaers is Verrry long. In the grand scheme of things, it's nothing. If you compare it to how long death is. (it's eternally long/It's oblivion, forever). To me, that strikes as imbalance, unfair to the limitedness that we have in our short lifespan on Earth. If we DECIDE and CHOOSE when live/die..then, yes the balance is now tipped to 'JUST/JUSTICE' of our life (a short one), and our death (a long one). I would tell this fictive elf woman...''LOOK...I undersand you love him...but ask yourself if you value your life - your 1 life/your body in which are housed/ or your feel it is not worth continuing for you feel the Love of you have for him - is worth your life and willing to sacrifice for him...and die by his side when he dies of old age as mortal'' if she responsed yes, than I would say no more; I knew that she loved him enought to give her life for him or take a bullet for him..(even things like 'for her/for him' I have difficulty with relationship you don't (necessarily) do it 'FOR' someone but rather WITH someone, important difference/nuance. That does not mean you don't love them, again difference nuance. Now, I know it sounds a bit more selfish but humans are selfish by's like that..we Also very social beings and enjoy each other's company - TO A CERTAIN LIMIT/EXTENT).

''Humans unite to better divide themselves'' an old motto.

I think in the future we all self and socio-questioning (introspection and extrospection) about what it means to live (on) and/or die one day of 'old age'...old age should be eradicated once for all, so we postpone death (forever how long we wish in our life) that follows late/very old age. Jesus/God are eternal after all, even (supposedly) certain bacterias, hydras and

Humans must progress, and that means eradication of death itself. If we reach that, we will PROVEN to the entire universe that humans are the most SELFaccomplishing being, with all its limits imposed, to ever exist (beside Jesus/Gods..etc).

Just a 2 cents.

PS: sorry for ranting a bit there, it's the weekend and felt chatty. TL DR: it's complicated.

Posted by: CANanonymity at April 20th, 2019 4:14 PM

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