The Present Popularity of Epigenetic Reprogramming to Treat Aging

A fair number of research groups are presently working on ways to force large numbers of cells in the body to adopt more youthful epigenetic profiles. Much of this research is an outgrowth of the discovery of induced pluripotency, the ability to reprogram any cell into a pluripotent stem cell that is largely indistinguishable from an embryonic stem cell, capable of generating any of the cell types in the body. This process also happens to reset many of the epigenetic markers of age that are found in cells in old tissues, alongside restoring mitochondrial function by clearing out damaged mitochondria, and a few other interesting changes. The article here focuses on one representative project, but readers here might be more familiar with the work of Turn.bio in the same space, since it was covered recently.

The important question to be addressed here is this, since it is frequently mentioned: are epigenetic changes a cause of aging? To my eyes the answer is no, a thousand times no. They are - they must be - a downstream consequence of the true cause, which is the molecular damage that accumulates with age as a normal side-effect of the operation of cellular metabolism. However, since these epigenetic changes themselves cause further harm, one can, in principle and in animal studies, produce benefits by forcing cells to adopt a more youthful epigenetic profile for various genes of interest. But this does nothing to address the cause of aging, the underlying damage.

Without repair, the underlying causative damage of aging will continue to cause all of the problems that cannot be ameliorated by forcing a mass change in epigenetic programming and consequent cellular behavior. Consider the presence of molecular waste that the body cannot effectively clear, such as persistent cross links degrading extracellular matrix elasticity, or hardy constituents of lipofuscin making autophagy inefficient in long-lived cells, or potentially cancerous nuclear DNA damage. I predict that epigenetic reprogramming is not going to meaningfully address these line items, because youthful cells and tissues cannot meaningfully address these forms of damage if present. Reprogramming may well turn out to be as useful a tool as stem cell therapies for the purpose of regeneration of functional tissues, though with a very different focus on the type of functional improvement obtained. But be wary of those who claim that epigenetic change is the cause of aging, and that turning it back will fix all issues.

Has this scientist finally found the fountain of youth?

Izpisúa Belmonte, a shrewd and soft-spoken scientist, has access to an inconceivable power. These mice, it seems, have sipped from a fountain of youth. Izpisúa Belmonte can rejuvenate aging, dying animals. He can rewind time. But just as quickly as he blows my mind, he puts a damper on the excitement. So potent was the rejuvenating treatment used on the mice that they either died after three or four days from cell malfunction or developed tumors that killed them later.

The powerful tool that the researchers applied to the mouse is called "reprogramming." It's a way to reset the body's so-called epigenetic marks: chemical switches in a cell that determine which of its genes are turned on and which are off. Erase these marks and a cell can forget if it was ever a skin or a bone cell, and revert to a much more primitive, embryonic state. The technique is frequently used by laboratories to manufacture stem cells. But Izpisúa Belmonte is in a vanguard of scientists who want to apply reprogramming to whole animals and, if they can control it precisely, to human bodies.

Izpisúa Belmonte believes epigenetic reprogramming may prove to be an "elixir of life" that will extend human life span significantly. Life expectancy has increased more than twofold in the developed world over the past two centuries. Thanks to childhood vaccines, seat belts, and so on, more people than ever reach natural old age. But there is a limit to how long anyone lives, which Izpisúa Belmonte says is because our bodies wear down through inevitable decay and deterioration. "Aging is nothing other than molecular aberrations that occur at the cellular level." It is, he says, a war with entropy that no individual has ever won.

The treatment Izpisúa Belmonte gave his mice is based on a Nobel-winning discovery by the Japanese stem-cell scientist Shinya Yamanaka. Starting in 2006, Yamanaka demonstrated how adding just four proteins to human adult cells could reprogram them so that they look and act like those in a newly formed embryo. To many scientists, Yamanaka's discovery was promising mainly as a way to manufacture replacement tissue for use in new types of transplant treatments. Researchers at the Spanish National Cancer Research Centre took the technology in a new direction when they studied mice whose genomes harbored extra copies of the Yamanaka factors. Turning these on, they demonstrated that cell reprogramming could actually occur inside an adult animal body, not only in a laboratory dish. The experiment suggested an entirely new form of medicine. You could potentially rejuvenate a person's entire body. But it also underscored the dangers. Clear away too many of the methylation marks and other footprints of the epigenome and "your cells basically lose their identity."

To others, however, the evidence for rejuvenation is plainly in its infancy. Jan Vijg, chair of the genetics department at the Albert Einstein College of Medicine in New York City, says aging consists of "hundreds of different processes" to which simple solutions are unlikely. Theoretically, he believes, science can "create processes that are so powerful they could override all of the other ones. We don't know that right now." An even broader doubt is whether the epigenetic changes that Izpisúa Belmonte is reversing in his lab are really the cause of aging or just a sign of it - the equivalent of wrinkles in aging skin. If so, Izpisúa Belmonte's treatment might be like smoothing out wrinkles, a purely cosmetic effect. "We have no way of knowing, and there is really no evidence, that says the DNA methylation is causing these cells to age," says John Greally, another professor at Einstein. The notion that "if I change those DNA methylations, I will be influencing aging has red flags all over it."

Comments

Would be interesting to see if targeting smaller areas in the bone marrow could create "young blood". This maybe less risky than targeting the whole animal and could have a knock on effect, as has been suggested with other experiments, of older animals sharing blood with younger ones.

Posted by: Peter Anderson at August 10th, 2019 3:45 AM

And you'd be wrong 1,000 times

The molecular damage that accumulates with age as a normal side-effect of the operation of cellular metabolism is predicated on those upstream epigenetic changes that occur throughout the many stages of life

The fact that you can't accept this only highlights the degree that the flawed SENS philosophy has embrued your thinking

You routinely try and sweep promising work of this nature under the rug on your posts

Your seem way to conflicted to continue to blog accurately on these matters, especially with everything real thought leaders in the area of epigenetics are publishing and learning

Posted by: Jason Zeblinsky at August 10th, 2019 7:56 AM

That epigenetic changes are a cause of aging as opposed to a result of it has not been determined as of yet. You may be correct. It is also equally likely that you are wrong. I tend to think they are a result and not cause at this point in time. "Reason" tends to look at the worse case scenario about this matter because that it the most "reasonable" approach to take at this time.

Posted by: Abelard Lindsey at August 10th, 2019 9:12 AM

@Abelard Lindsey

No it's pretty likely that he's wrong

The whole SENS mantra is based on it

Whenever they say "Messin with metabolism" or "Metabolism is too complicated", they are referring indirectly to epigenetics and the changes that ultimately alter metabolic dynamics over life course

This is why their default position for their basket of tool is "We will try and stay ahead of it"

The work of Belmonte and others, though preliminary, is highlighting that there may be more effective ways to deal with metabolism (epigenetics) that yields aging pathology deposition, than the hundreds of SENS intervention that must be developed (per Reason's post last week) to have any impact

Posted by: Jason Zeblinsky at August 10th, 2019 11:57 AM

Honest, why diss any approach - is funding really that tight? There needs to be a diversity of approaches if we hope to make progress, we can't predict apriori who'll be right, let reality sort that out

Posted by: Johannes Høher-Larsen at August 11th, 2019 11:00 AM

Gonna be honest, I completely disagree with Reason here. I think the evidence to date strongly supports that epigenetic alterations are a driver of aging, not a consequence. Some people continue to suggest that the epigenetic state are merely the hands of the clock and turning them back is the same as turning the hands of a clock back without changing the underlying aging processes. I really do not think the data supports this conclusion at all but on the plus side, I do not think we will need to wait too long now before this matter is settled once and for all given the enthusiasm for partial reprogramming.

Posted by: Steve Hill at August 11th, 2019 2:55 PM

Hey there, just a 2 cents.

'' If so, Izpisúa Belmonte's treatment might be like smoothing out wrinkles, a purely cosmetic effect. "We have no way of knowing, and there is really no evidence, that says the DNA methylation is causing these cells to age," says John Greally, another professor at Einstein. The notion that "if I change those DNA methylations, I will be influencing aging has red flags all over it."

There has been substantial demonstration (in studies) to the contrary. Whether DNA methylation causing aging or not is not really what's important; what's important is that DNA methylation is shown, through reprogramming methylome/epiclock, reversing intrisic aging processes. I don't know what more evidence you need. I am saddened by this pessimism and skepticism (I know I am quite deep in it by times) about the field. We need optimism too and, some, hope. There is even denial - people who still believe into old things when factually Proven wrong. But, It's normal, it's being realistic and just being careful to not make outlandish predictions about epireprogramming (very understandable...we've been deceived and had bad results before...so it's why 'we've been burnt'...and we're more guarded now (not gonna happen again - forgive but not forget) and pessimistic...aging is still not solved...neither cancer after trillions of dollars poured in...why would we think epiclock rejuvenation would be the holy grail we were waiting for; when everthing else before it failed..again, understandable (just being realistic, cautiously optimistic and caustiously pessimistic about it all; so, ...cautious).

When we see many Sensationalist papers/ads about aging Solved...''Imm*rtality, Rejoice! On a Silver Plater, Gratuit - Take it!'' (many would still be skeptical and say no..because Eternal life = evil/selfish/no ethics)..it's normal to want to hold back a lil to not crush people's hopes once again, with 'make belief' 'smokes & mirrors'...'vaporware' (for a long time, SENS seemed like SENSLESS vapor). Charlatanism/snake oïl selling is very frowned up now (because of internet, we are for critical of it now). AdG did an Incredible job (and Reason too) of downplaying 'hyperbole' about new stuff...to remain grounded in the real of Real/Possible/Tangible.

Just a 2c.

Posted by: CANanonymity at August 11th, 2019 3:20 PM

Also, I do not know anyone credible who thinks resetting epigenetic alterations will "fix all issues", that just isn't going to happen when we consider the Hallmarks of aging model and the other processes (most included in SENS) that are continuing alongside that single hallmark. If reprogramming did fix everything then Belmontes original mice would be alive and well but they are not, they lived significantly longer but they did not remain alive. This supports that other damage/error forms are at play independent (though some influenced by) epigenetic alterations.

End of the day, people can keep saying "meddling with metabolism" like a mantra but if it works it works and the evidence so far is promising and it is something worth pursuing!

Posted by: Steve Hill at August 11th, 2019 3:21 PM

I have a few doubts. First the test model were mice with progeria, which might bring some bias. A second thing to note is that the treated mice lived 30% longer than the controls. In fact , calorie restriction can produce better results.

So this approach alone will not bring us too far. However, it is kinda a mainstream news which will bring more attention and funding to the whole anti-aging field. On top of that biology is messy and there might be a lucky shot here that translates well for humans.

Reversing of the metilation can be beneficial the same way controlling blood pressure is. We fight with a control mechanism that is on overdrive and tune it down to stop causing more harm than good. Additionally, de-metilation or unmetilation might be the best option for the long lived cells that are not easily
replaced (neurons, for example). Also can this can solve the issue of depleted stem cells.

It seems that OISIN can use their platform to deliver Yamanka factors in vivo and compare whether it works well for older organisms and if it combines well with senolytics. In the best case scenario they might compound . In the worst slightly enhance each other. Probably not all tissues and cells will benefit from metilation reversal. Finding and proving that will take years . And even more years before demetilation is ready for humans, especially the cancerogenic versions...

Posted by: Cuberat at August 11th, 2019 6:23 PM

Epigenetic reprogramming does not only cosmetic changes, but also restores function of organs. Here is a very nice abstract
Please check it out

"Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns don't just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal."
https://www.biorxiv.org/content/10.1101/710210v1

Posted by: Bejul at August 12th, 2019 3:58 AM

What If growth and aging are two separate processes, then aging is always present, it is just that in presence of growth factors, the body produces more cells than the rate of the aging clock and when growth subsides, the normal aging clock takes over.the epigenetic clock shows aging starts when we are born, it could be aging is the natural state of the dividing cells/body after patterning/morphogenesis, but growth is another state imposed on the organism which operates in parallel. the rate of growth is far higher than the rate of aging (20x weight gain for the human male). Both growth and aging are occurring when we are young, but as growth tapers off, the natural state of aging continues.
what this means both aging i.e lifespan and growth i.e body size are selected in the ecosystem.
when we are growing, aging does not affect us because cells with epigenetic
changes who progress to senescence are effectively eliminated by the young immune system. But as growth stops , the it becomes increasingly difficult for the immune system to clear out senescent cells, which leads to age related dysfunction

Posted by: kunal at August 12th, 2019 4:49 AM

Oisin have not published anything yet. The website looks the same for a year now. So far there is nothing but a lot of publicity in this blog. Once they publish something (not in mice), then we can look at the results.
https://www.oisinbio.com/#news

Posted by: z at August 12th, 2019 11:17 AM

Reason is going to have a hard time getting around the evidence David Sinclair presents in his new book "Lifespan - The Revolutionary science of why we age and why we don't have to" - David sent me a preprint. I read it. The book comes out September 10th via Simon & Schuster. He randomly cut the DNA of mice ay 3 times the frequency the naturally occurs. The mice aged 150% faster than their litter mates, all diseases evidenced themselves faster. When the body repairs DNA breaks, which happen constantly, that repair itself changes the epigenome. Sinclair took old mice who had lost vision and mice to which he damaged the vision (made blind). He administered 3 of the Yamanaka factors (the 4th factor seemed to be the one causing the cells to go too far back causing cancers) -
HE RESTORED VISION - reasoning that if you go far enough back in youth, nerve cells can regenerate, and they DID. This is VERY BIG NEWS.

Posted by: Robert Kane Pappas at August 12th, 2019 11:22 AM

@Robert
DNA damage accelerates aging, nothing new. How exactly did damage the vision of the mice?

Posted by: Johannes at August 12th, 2019 1:37 PM

@z
Alas there at no per reviewed news from OISIN. Nevertheless, their approach seems the most promising so far. But it is good that it is not the only one..

@Robert Kane
If he can reverse neural and retinal damage that would indeed be a big news. But why write a whole book while a deep documented study is enough?

Posted by: Cuberat at August 12th, 2019 3:10 PM

@Johannes crush damage to the optical nerves + normal aging. They reversed both injury and aging-induced loss of vision via reprogramming cells back to a youthful state. It that isn't rejuvenation then I don't know what is lol

Posted by: Steve Hill at August 13th, 2019 4:37 AM

@Johannes, @Steve Hill

Metal tissue regeneration is a big thing. There are tons of neuropathy and methylation diseases. If it can be done safely in humans that could info a lot of disabilities. I wonder why there is no major public resonance

Posted by: Cuberat at August 13th, 2019 11:30 AM

Cells are effectively immortal. You only have to realise that although a single humans lifespan is short, the species has been around for millennia, an ongoing chain of cells essentially. There are therefore mechanisms within cells to correct for damage to DNA and they are capable of indefinite repair and resetting of age on order to create germ cells. How else are germ cells created other than from other cells in your body. We've discovered many of the protiens that repair DNA for example, and they are epigenetically deregulated as you age, so molecular damage is a consequence of epigenetic changes. It's not hard to concieve that reprogramming epigenetics to more youthful states is the entirety of the aging process. You can think of cells as information processors, there's no limit to how long they can keep running and repairing themselves to ensure data integrity over millions of years. We have trees for example that are 5000 years old.

Posted by: Chris Mosely at August 16th, 2019 4:05 PM

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