Epigenetics and the Programmed Aging View

The present vocal but minority view in the aging research mainstream is that aging is an evolved program with a strong epigenetic component. In this view, epigenetic changes are keyed to age, occur first, and cause the cell and tissue damage associated with aging. In the majority view of aging as a consequence of damage accumulation, the damage occurs first, and epigenetic changes are then a reaction to this damage, causing secondary and later issues. There is so much work yet to do in mapping out the detailed molecular biology of the progression of aging, and the blank spots on the map so large, that these two entirely opposing viewpoints, each with many variations, can continue to theorize and thrive.

For the damage accumulation view of aging, we fortunately don't need the full map of the molecular details of aging, an explanation of exactly how damage causes each and every age-related disease, in order to make solid progress towards the defeat of aging. All researchers need to do is to repair the root causes of aging, the forms of fundamental damage that distinguish old and young tissues, and these are well known and well cataloged. The fastest way to figure out what they are linked to in terms age-relate decline is to fix them and see what happens - which is also the fastest path to meaningful therapies. So, for example, life extension in mice has been robustly demonstrated in the case of clearing senescent cells, and clearance therapies are on their way to the clinic despite the vast amount of data yet to be gathered on how exactly aging progresses without this contribution.

The programmed aging school does need the molecular map of aging for significant progress, however. In this view, researchers should be working to list and revert epigenetic changes, and that should then either stop further damage or allow damage to be repaired by natural processes. Some such initial reversions, such as increased GDF11 levels, have been shown to produce benefits by restoring stem cell activity in old individuals - but is entirely possible for an epigenetic alteration to produce some level of benefits even if aging is caused by damage, and without addressing underlying damage, by reducing secondary issues or by forcing systems into action where they are normally in decline as a reaction to damage. Perhaps there will be consequences, such as a raised risk of cancer, but so far in the case of stem cells it is all working out better than expected. These results have boosted the confidence of the programmed aging side of the field, but I think they still overstate their case given the varying weights of evidence.

For readers who know me less well, I should introduce my perspective: I believe that aging is an evolved epigenetic program. When we are young and growing, particular genes are turned on and off with exquisite timing to determine the growth and development of bones, muscles, and organs. When we are old, the program continues, more slowly and more diffusely, but inexorably nonetheless. Genes are turned on that destroy us with inflammation and cell senescence and auto-immunity and programmed cell death, while the systems that protect us from pathogens and from free radical damage are gradually shut down. Evolution has left nothing to chance. Epigenetics is a new science in the 21st century. All the cells in one body have the same DNA (pretty much), but different genes are "expressed" (translated into proteins) in different tissues and at different times, and this is what controls the body's metabolism. In fact, only 2% of our DNA is genes, and 98% determines how the DNA is folded and spooled, opened and closed at particular times and places, and this in turn controls gene expression. We are 2% genetic and 98% epigenetic. The part of the epigenetic code on which we have the best handle at present is called "methylation of CpG islands". Long stretches of DNA have CGCGCGCG... on one strand, complemented by GCGCGCGC... on the other. Often the C's in this region get an extra methyl group, turning from cytosine to 5-methylcytosine. Then this stretch becomes a "repressor region," a signal to NOT express the adjacent gene.

DNA methylation can be persistent, turning a gene off for decades at a time. When a cell divides and its DNA is copied, the methylation pattern can be copied with it. This accounts for some of the persistence of epigenetics, and the way gene expression can be inherited across generations. DNA methylation has been appreciated for 30 years, but two recent developments make the subject attractive and accessible to research. (1) There is now a simple lab/computer technique for reading the methylation pattern from DNA. It relies on commercially available, automated machinery for PCR to sequence a full genome before and after chemical modification of the methylated C's. (2) There is now a simple lab/computer technique for changing the methylation state of any chosen target site in the DNA. It is based on CRISPR technology that is taking genetics labs by storm the last two years.

The correlation between aging and epigenetic status is established beyond dispute. But what does it mean? This is the big question. Most researchers think of the body as programmed by evolution to be as strong and healthy as possible. So, when different genes are expressed in old age, they find it natural to assume that the body is protecting itself in response to damage that it has suffered over the years. We express different genes when we are older because we need different genes when we are older. The other possible interpretation is my own, and it has become common among those who are closest to the field of epigenetics. It is that epigenetic changes with age are means of self-destruction. The body is programmed to die, and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes. This idea flies in the face of traditional evolutionary theory. (How could natural selection prefer a genome that destroys itself and cuts off its own reproduction?) Nevertheless, the evidence for this hypothesis is robust. The genes that are turned on don't protect the body - quite the opposite. Genes for inflammation are dialed up. Genes for the body's defense against free radicals are dialed down. Cell turnover is dialed down. DNA repair is dialed down. The mechanisms of programmed cell death (apoptosis) are strengthened in healthy cells, at the same time that they are perversely weakened in cells that are a threat to the body, like infected cells and cancer cells.

In my opinion, the existing evidence heavily favors the hypothesis that aging is caused by epigenetic changes, rather than the other way around. When we look at the kinds of changes that occur, they seem to be pouring fuel on the fire, not putting it out. Protective genes are turned off and inflammatory genes are turned up. I also think that parabiosis experiments provide a strong clue. Three research groups have shown that injecting blood plasma from a young mouse into an old mouse makes the old mouse healthier, and relieves some problems associated with age. The blood plasma contains no cells - only signal molecules that are the product of gene expression. This is powerful evidence that youthful gene expression is supporting a strong and youthful body, and (conversely) that the kind of gene expression that characterizes old age is not doing the body any good. But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating effect.

Link: http://joshmitteldorf.scienceblog.com/2016/05/09/epigenetics-of-aging-and-prospects-for-rejuvenation/

Comments

Hey all,

''The body is programmed to die, and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes. This idea flies in the face of traditional evolutionary theory. ''

That's very true, but it still reaches evolutionary theory. Evolution selected these methylation patterns with age because they have a meaning to specie survival or not. In humans, these inflammatory gene signature of old age, are not just a preprogrammed aging progam causing dysfunction and damage; but also a consequence of aging and damage accrual - we can see it both ways - not just one or the other - but both ways paints a better picture than one or the other, it's a mix of both aging by damage and aging by inflammatory gene activation - dependent - and, also, independent of damage accumulation. Studies that show no oxidative stress showed weird things like activation of inflammation or DNA mutations. Meaning there are different types of 'stresses', some are non-oxidative; like replicative stress, reductive stress (excessively reduced state of OXPHOS) and combinational errors not dependent on damage creating them - but they themselves - creating damage as a consequence. Because the system is imperfect and flawed from the get go; and there is a normal course (pre-inscribed methylation pattern) to it. This epigenetic programmed aging creates 'opportunities' for failure (damage will 'help' this failure). Or should I say 'non'-opportunities cause this is Something like an 'opportunity' but more like a 'restriction' in a sense; but in really is a (bad) opportunity for (bad) stuff to happen. It really is a
model of complementing symbiosis between programmed aging and damage accrual - which try to balance (in/out) each other.

'' (How could natural selection prefer a genome that destroys itself and cuts off its own reproduction?)''

In high order species that are complex/with complex-organs bound for failure if one fails...like humans, it makes sense, they are vowed for destruction with a preprogrammed inflammatory-activation genome for they are fertile possible tumor/cancer grounds by their dramatically increased 'odds' of cancer in them.
Evolution's natural selection selects that for elimination with senescence and apoptosis, because it is not compatible for specie survival and reproduction either.
It would never allow reproduction to continue knowing cancerous gene transfer during reproduction to offspring - which would compromise specie integrity and survival; the specie would eliminate itself by cancer transfer. Inflammation is in part the driver and creator of the damage - which help/act as a 'response' mechanism to prevent cancer (for it drives cancer formation but is a feedback mechanism 'response' to 'act' on it by preventing it) - by killing the cell and thus eliminating the organism's chance to developp that cancer in the first place. And, thus, terminating the animal specie. These systems where selected to make sure things are 'kept' in check and cancer doesn't spread/compromise the specie('s integrity/survival). So yes, there is a 'programmed' element to it, it was selected and is written in us at birth, specifically (written/selected and tailored) for our precise specie. No single specie has the same one, we all have a programm that was selected 'fit' for us and our species survival needs/strat├ęgies (aka no 'one size fits all').

''But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating effect''

Definitely, there will be 'some' rejuvenation to a certain point. But, not entirely 'True' rejuvenation - true reversal of all types of damages - No.
We discussed this before and it showed that certain damages - are irreversible, Final, and Permanent - the genetic programm cannot reverse them, not even telomerase for all its intent/worth (such as extra cellular matrix irreversible transformations and depots), as in make them disappear; it has to deal with this problem somehow.

Induced pluripotent stem cell reprogramming and other reprogramming type studies have yet to show this in 'entire' body and entire types of cells, mitotic, non-mitotic, somatic, stem cell, etc...It's that complicated.

It's also why genetic studies in mice have never been capable of dramatically reversing aging in them (in a repetitive fashion) but only extend their average life modestly (like TgTERT mice, genetic stem cell boosting or adipose stem cell injection). And other genetic studies mimicking calorie restriction gene signature - gave the same effect as calorie restriction; which is to say a mild lifespan extension, nothing more and certainly not True biorejuvenation in the truest sense of reversal of All types of damages and waste residues - and continuously to keep the body biologically Young (reverted) and thus increase chronological lifespan exponentially.
Damage avoidance is far more powerful than any genetic research because we can see it is major driver of aging's mechanisms; besides pre-programmed (epi)genetic aging 'regular program' inscribed at birth which also works in tandem with damage accrual. Both are intercausal and intercorrelative, both are interdependent and inter-independent at the same time; it's far more complex than we think as such we can infer they are both important and both complementary of each other. The gene tinkering side of it is mostly more poor results until we harness that complexity and mapp the genome. The damage tinkering side of it is far more 'attainable' and 'we can do something about it because we mapped all of them'; SENS is on to that.

Posted by: CANanonymity at May 10th, 2016 8:25 AM

Evolution is the biggest weakness of the programmed aging theory. There is no reason whatsoever why animals should evolve to suicide themselves. And there are good evolutionary reasons why damage should increase with age: evolutionary pressure is weaker when you are past puberty.

Posted by: Antonio at May 10th, 2016 11:46 AM

An "evolved" death program doesn't pass the smell test. Why would animals that face a higher degree of predation need to evolve a "program" that killed them faster? They are already getting killed fast enough. But they are shorter lived, whether they are killed through predation or bred in the lab. The inverse relationship between predation and lifespan is a strong association. Evolved death programs don't make sense in the face of this fact.

Aging might be "programmed" in some regards, but it is not "evolved". It's simply a consequence of the evolved life plan of the organism. See the following very enlightening paper:
http://www.impactaging.com/papers/v8/n4/full/100931.html

Posted by: niner at May 10th, 2016 3:48 PM

@Antonio

Hi Antonio !

''There is no reason whatsoever why animals should evolve to suicide themselves.''

In every specie, the ultimate goal is to survive and thrive, as a specie that has a 'right' to live and be (on this earth). Evolution is all about 'bargaining' and making trade-offs with what its got (in that specie, genes, energy, complexity, resources, etc). Simply by seeing that certain uncomplex animals obtain immortality and no cancer; while tons of complex animals obtain mortality and cancer explains all there is to be understood about evolution's natural selection 'at work' deciding genetically on specie life survival, health survival, specie 'suicide/death' or specie cancer obtention.

''And there are good evolutionary reasons why damage should increase with age: evolutionary pressure is weaker when you are past puberty.''

Yes, that's true, but even puberty has its meaning; its the 'sexual maturation' phase to be able to procreate and continue the specie. And you are right, once this phase and reproduction is complete; the individual is disposable, thus damage should increase to dispose of it - as its purpose (specie continuation) is fulfilled. But, even evolution saw Something, that you could find a middle-ground (for humans at least) that would not impact specie survival Too much and would allow humans longer lifespan. It's one of the biggest discoveries, they call it 'grand-mothering' or basically 'late parenting'. Grand-mothers passed on their longevity genes which allowed humans to increase their lifespan - this was due to a longer period of mothering the child and 'being a parent' (back in the ice age, Neanderthals practiced parenting where as some other apes don't (not all though, chimpanzees, orangutans and gorillas are like us and parent#nurture), they leave their kids to 'fend off' in the savage predatorial wild...they abadon them like orphans from birth basically; this is an effect of creating animals who are 'wild-proved' and 'hardy' but live shorter lives. Their sexual maturation is, ironically (but not) also much quicker. Life and specie survival in the wild, with no help and protection from parents, is shorter and sexual reproduction happens sooner - because time is critical (they die earlier, thus reproduce faster in their smaller time alloted)).

We see that with domestication and 'lab'raised mice vs caught mice in 'their live wild habitat'. Many species is the same, when raised in the lab - they outlive their 'in-the-wild' counterparts.

I am the opinion that damage should Not increase after puberty onset, no matter how evolution wants it. It can be 'maintained' at a adequate level but should not increase dysfunction thus there should be a balance - between damage accrual vs damage repair - a perfect balance that is Nill. Zero. (that obviously tips towards accrual with age and overcomes our capacity to rebalance towards 'a equalized balance').

Posted by: CANanonymity at May 10th, 2016 4:51 PM

@niner

Hi niner!

'' Why would animals that face a higher degree of predation need to evolve a "program" that killed them faster?''

Because predation, it seems, is not enough of a reason to alter genetics. If the specie is 'surviving enough' despite being heavily predated; I am guessing, it becomes a matter of (safety in) 'numbers'. Where predation won't even stop genetic transfer of highly mutational cancers and transformations. We have to understand that short-lived and predated animals are Highly promiscuous - for the obvious reason that they are trying to offset individuals loss to predation and - to obvious short life - predation or not; their biological aging is faster as such they Doubly limited in time; whether it be a predator ending them, getting cancer in no time or dying some other disease ultra-fast; their death is soon and there are many ways they go. Lab growing of species show that, they much more oftenly reach their full potential then when living in the wild full of predation (which increases stress/accelerate aging than a non-predatorial stress-free with their peers lab environment). Thus, even short-lived animals need a tailored evolved program for their very specie's needs and survival.

Posted by: CANanonymity at May 10th, 2016 5:14 PM

There are a number of references to papers on predation and evolution back in the archives:

https://encrypted.google.com/search?q=site%3Afightaging.org+predation

The consensus view involves antagonistic pleiotropy, in which heavy predation means creatures can load up on attributes that help them reproduce early, at the cost of falling apart later. Also since long-term maintenance is not selected for strongly, the mechanisms of maintenance are lost over evolutionary time.

Salmon are a really interesting case to confound every theory, because you also have to couple all of that with their very rapid decline into senescence following mating. Even that seems to be at least partly explicable by the behavior of the local predators, however.

Posted by: Reason at May 10th, 2016 5:36 PM

It looks like there's still a lot of contention surrounding the issue of anti-aging and reverse aging. One side thinks it's due to epigenetics; the other side thinks it's due to wear and tear. Who's right? How can we test it? How soon will we determine which is the case? And whatever the case may be, how soon can we expect viable treatments for human beings? There's so much disagreement on all of these questions. Some people think we're nowhere close, while others think we can expect the first real treatments in the 2020s. Who's right?

Posted by: MissKaioshin at May 10th, 2016 11:58 PM

My belief is that epigenetics is the response to damage. Switches are being flipped in order to keep you alive. But the mechanisms that are being turned on or off, are temporarily keeping you alive better. Like saving resources instead of wasting them on hair color.

We aren't intentionally programed to die, but we weren't programed to live beyond a certain extent. By the time these mechanism break down, you would have reproduced, and anything that happened to you wouldn't be known to evolution. If that's being mauled by a bear, or dying of cancer.

Posted by: Dukenukemx at May 11th, 2016 3:18 AM

@MissKaioshin: Testing it is in progress. On the one hand there is senescent cell clearance life span studies in mice, showing life extension. That is evidence for the damage side. On the other hand there is epigenetic alteration of things like GDF11 in mice, showing lesser benefits probably built on stem cell activation.

So both sides are testing their proposals. The challenge lies in the fact that we should probably expect some fraction of treatments that fail to address underlying causes to still produce enough in the way of gains to be considered worthwhile. The water is muddy. It will probably take the results of several different types of damage repair and epigenetic manipulation to be done and have solid date in multiple animal studies before you can look at the results in aggregate and make a call based entirely on that data.

However, there is plenty of evidence and data to consider outside that context of absolute proof. I am in favor of damage repair because of the weight of evidence. In particular there are forms of damage that our biochemistry cannot repair, such as persistent glucosepane crosslinks. I think that is where the programmed aging view fails badly. There is no epigenetic change that can be made to reverse that state of cross-linking and the harm it causes.

Posted by: Reason at May 11th, 2016 8:28 AM

CANanonymity wrote: "In every specie, the ultimate goal is to survive and thrive, as a specie that has a 'right' to live and be (on this earth). Evolution is all about 'bargaining' and making trade-offs with what its got (in that specie, genes, energy, complexity, resources, etc)."

Nope. Individuals are selected, not species. Individuals maximize their progeny, not species. Evolution doesn't care about species, it only acts on individuals. The features that are beneficial to the individual are preserved, not the features that are beneficial to the species.

Posted by: Antonio at May 11th, 2016 9:16 AM

@Antonio

Yes, you are right, I should have been more precise. It is indeed an individual (of that specie) and not a whole specie that is selected for survival and evolution. That single selected individual alone can evolve into another specie from its 'current' wide specie, no need for an entire specie but a single individual.

Posted by: CANanonymity at May 11th, 2016 1:39 PM

Just like most other things in life, I don't think it's a black or white thing.
Evolution sucks at optimizing. It just makes sure that surviving animals and plants are able to reproduce at an equal or hopefully at a faster pace than they're dying.
I'm thinking that aging is a wear and tear problem, the SENS reasoning ... but we could (and eventually should) optimize our programming (both genetic and epigenetic) to remove the bugs and shortcomings of the non-optimized evolution.
It's like treating a disease vs. curing it.
We need SENS like repair and cleansing therapies to treat aging and keep us going. Those treatments will probably be repetitive until we manage to optimize our programming so that our cells themselves have all the tools and know-how to cleanse and repair themselves and their surroundings better.
Finding out where the bugs and shortcomings are in our genome and epigenome will take much longer than coming up with SENS therapies. I think we should focus on developing SENS therapies as highest priority and start on (epi)genetic strategies as we get further. And to close as I began ... there's no black and white in the timing or level of effort that should be put in either strategies. They can run in parallel and build on each other. I just hope for more focus on SENS first (which does include some genetic reprogramming of its own).
And once that is done, we can start look into adding new features to our programming and extend ourselves ... but that's for another site :-)

Posted by: Jo Creyf at June 9th, 2016 5:53 PM

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