In Vivo Reprogramming Reverses Vision Loss and Damage in a Mouse Model of Glaucoma
Several research groups and companies are working on in vivo applications of cellular reprogramming. Today's research materials cover recent work from David Sinclair's team showing off the use of reprogramming to produce regeneration of damaged nervous system tissue in the eye and optic nerve. Glaucoma is a condition in which rising pressure in the eyeball progressively harms the retina and optic nerve. Since nerve tissue doesn't regenerate well in mammals, loss of vision is irreversible. This is one of many conditions for which the ability to regenerate nerve tissue would be a great benefit.
Since its discovery, reprogramming has been used to produce induced pluripotent stem cells from any other type of cell. That process has been found to reverse age-related changes in epigenetic patterns and mitochondrial function characteristic of cells in old tissues. Introducing the factors capable of reprogramming cells into a living animal may produce effects akin to stem cell therapy by converting a small number of cells into induced pluripotent stem cells, followed by stem cell signaling that beneficially affects tissue health more broadly. Alternatively, many cells may have their epigenetic markers reset to a more youthful state without losing their identity to become induced pluripotent stem cells. Or both. Beyond this, there is certainly the threat of cancer or structural damage to tissue through the conversion of too many cells, and this class of therapy will require careful development to ensure safety, even as the mouse data continues to look quite interesting.
David Sinclair has been pushing an epigenetic-centric view of aging of late, with analogies to information systems and computing. The most interesting part of the the supporting work suggests that DNA repair of double strand breaks has the side-effect of driving alteration of the epigenome in characteristic ways with age. That will be an important connection between stochastic nuclear DNA damage and deterministic global effects throughout the body, should the evidence continue to hold up.
As this illustrates, however, epigenetic change is a downstream issue in aging, a reaction to events and a changing environment, not a first cause. Fixing it may or may not turn out to be particularly useful in the broader picture of aging, depending on exactly where it sits in the web of cause and consequence. As a comparable example, hypertension is a major downstream issue in aging. It is far removed from root causes such as cross-link formation and inflammation, but is also a proximate cause of many forms of further dysfunction, such as pressure damage to delicate tissues in the brain. Controlling hypertension without addressing its causes is both possible and beneficial - but the benefits are limited by the fact that those root causes are still there, chewing away at the body in a thousand other ways.
Scientists reverse age-related vision loss, glaucoma damage in mice
Scientists have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function. The team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes - Oct4, Sox2, and Klf4 - that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors. The treatment had multiple beneficial effects on the eye. First, it promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss in aging animals without glaucoma.
The team's approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.
This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction - giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue. Yet, whether DNA methylation drives age-related changes inside cells has remained unclear. In the current study, the researchers hypothesized that if DNA methylation does, indeed, control aging, then erasing some of its footprints might reverse the age of cells inside living organisms and restore them to their earlier, more youthful state.
Reprogramming to recover youthful epigenetic information and restore vision
Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, but whether older individuals retain the information needed to restore these patterns - and, if so, whether this could improve tissue function - is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4, Sox2, and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information - encoded in part by DNA methylation - that can be accessed to improve tissue function and promote regeneration in vivo.
Hi there! Just a 2 cents.
It may end up that reprogramming (as we saw in a mouse study with progeria, was halted and the mouse lived longer (but did not overcome the accelerated premature-aging disease); ..and, in a healthy control mouse, that was older...and lived a bit longer/healthier...but did not live forever neither) is may just, sadly, not be enough to stop aging process (I hope it is not the case, but, sadly, it is seemingly looking like the case; let's hope not).
Hot take/Cold take/Lukewarm take: I believe that the age of the donor/patient matters with reprogramming, as reprogramming so many cells can, as said, cause cancer/teratoma formation (if above 7 days reprogramming time window), cause erasure of cell identity (this could, potentially and also, cause neuron memories erasure/meaning you could actually lose your memories because reprogramming is 'clean slate/erasure' of cell identity and age; as such, memory content could be wiped out in the process; it's a bit like pressing 'delete' on the keyboard on all your 'digital data'...it is gone forever.. once deleted; same thing with reprogramming and brain neuron cell (that hold our entire life) memories and identity/name/persona/'who we are as a person/soul). Thus, we would have to be careful of human identity and brain memory wiping out. Reprogramming so far always avoids 'cell signature/identity' erasure...because of if it goes this far, it is in 'stem cell/germ cell' territory (Cell Dedifferentiation); basically, reverting to stem cell state with 0 identity anymore (as like stem cells are - clean slates...ready to be 'differentiated' into another 'new cell' again). I think that, even, cell reprogramming may need to be started young.
It is defeating the purpose, because reprogramming is (supposedly) 'age agnostic'...meaning you could reprogram the Oldest Oldest of Oldest...cell back to 0 'start/square 0' state....but..in reality or let's say, in a 'aged' human body/in vivo of old people...it is more complicated and may not be sufficient 'on its own' to reverse aging repeatedly to nullify it (and, thus, make LEV).
It seems, that even, reprogramming would need you to be Young - Before...so as it make it better and more effective, less need to reprogramm much..because Already Young...a person that is older...will be harder to reprogramm and overcome the entire damages (mainly DNA damage in cell nucleus and extra-cellular damages/residues) that they sustained their entire long life. The only way I see reprogramming reversing aging, even in the oldest people, is if there Complete/Total reversal of the damages; but it looks unlikely because as said, the study on mouse did not show that and that even DNA methylome reprogramming was Still limited in some way.
As if, once a methylome is 'marked/signed'...you can't just completely 'erase' everything of it (reprogramming Stops reprogramming before 7 days to avoid signature/erase signature/marks'). So I guess reprogramming will Absolutely need the other therapies in combination because it may not be enough to counter aging on its own (which is sad, because I really hoped so; but...yet, another, fail/wall...we hit); it's not a failure, it's just never Enough...aging is so hard to defeat. Thus, it is why we will have to combine so many therapies to put it down; ''unkillable'' is the word (or, in our case, with death/aging, the inverse word...100% killable (i.e. you will die, Nothing can do about it if do Nothing/no therapy/do not act on it while still young, less damage at this early point and lively enough). Our age - 'at therapy taking' - will matter strongly, reprogramming or not, as to if we live much longer or not. So the saying is: ''hurry up, don't wait'', ''before being old before being young''. If you are young, it is now that it has to happen; not later. ''Now or Never'', as ultimatum-sounding and hyperbolic-exaggeration it sounds, is quite apt/put. Aging and, especially, Death..are (an) ultimatum.
Just a 2 cents.
The fix aging at its fundamental level argument than be taken to the level of trying to stop brownian motion. If temporary expression of yamanaka factors reverses epigenetic damage then does it matter if it is downstream of stochastic DNA damage?
Hi jimofoz, just a 2 cents.
I believe it does because that is the crux here; can DNA damage be reversed/repaired by epigenetic age reprogramming therapy; or can DNA damage repair therapy, as effect, reverse the epigenetic age drifting (kind of like chicken & egg thing, which comes first), what we know so far:
DNA damage - causes - these epigenetic events/drifting/demethylation of methylome to happen and creates the 'progress/advancement' of aging 'program' (or just the mechanistic/metabolic/processive mechanisms) of aging to 'follow (their) course'... piling on more DNA damage...and destroying/loosening/uncapping the chromosomes/telomeres and depleting the methylome/histones...all this mainly in nucleus; but there is the rest too (mitos, cytosol, endoplasmic reticulum/golgi apparatus, lysosomes, proteasome, extra-cellular matrix; so many places that can be affected; with the main one (in terms of weight/to aging), being the cell nucleus.
It may end up (as we saw in old 'rejuvenated/reprogrammed' mouse) that DNA damage is still strongly consequential (if not entirely repaired) and reprogramming is not enough to completely overcome it. There are So many types of damages; it is a list long like your arm...thus, it is why reprogramming may have limited capacity to reverse aging process; now, as AdG once said (roughly) : we don't need Total/Full 100% Rejuvenation...we only need Robust-Enough rejuvenation..or enough-repair..to matter''...so that you can repeat this on and on (and thus make LEV); but, it seems, that on paper (true) but in a mouse, less so. It is why is more complicated than simple repair damages; solved. But, I am starting to think Robust repair of damages Even is not enough; it has to be (indeed) Total Repair/100%...not little bits, not enough...this % partial repair may just not be enough to 'overcome' aging and not be enough to reverse our aging process. It (seems/looks like it) has to be complete (or nearly/quasi complete repair). When you look at CR (Calorie Restriction) you realize Why it is able to extend lifespan substantially; it is because is nearly 100%/or very largely nullifies/abates damage accrual that happen with age (rising of damage accumulation is stunted/halted) and so is senescence/inflammation by CR. It means CR hits Many Many many different damages, stops them (near) totally.
Now epigenetic reprogramming, hopefully, allows the body to now dispose of residues and repair (the unrepairable before) DNA damages/double-strand breaks and other oxidative/insults peppered everywhere in our cells. We have to remember also that stochastic accrual of DNA mutations contribue (also) to epigenetic drifting/aging; it was shown that mice accumulated many more DNA mutations per cell division; this made 'huge advancement' of the DNA methyl clock/age process. Our much epigenetic reversal is able to erase these mutations is hard to say (because many of these mutations are DNA mutations;
C/T -> U (thymine to uracil) DNA purines/pyrimidines nucleotides/nucleosides changes and also Aspartic racemization (L -> D/L-amino to D-amino conversion); these swaps contribute directly to epigenetic drifting and to total mutational burden that increased/advances with age/and advances the aging process itself (faster). They also call them 'maturing' or 'differentiating' mutations (the mutations causing 'maturing' in the cell, as like a process needed 'to growing up/maturing' (in other words 'aging/growth')); in the sense that like a youthful 'spindle-like' stem cell that differentiates or 'matures' into a mature cell..they lose their undifferentiated state/get an mature identity and thus lose their 'youth'.. as 'they mature' and then age/proceed to age and later, die.
Just a 2 cents.
They have been repeating the same story for a year now. Can they make it work In vivo in humans? At least on some large animals.
@jimofoz:
"The fix aging at its fundamental level argument than be taken to the level of trying to stop brownian motion."
This is quite disingenuous. The results of "fixing aging at its fundamental level" in mice are at least as solid and much more numerous than fixing epigenetic changes ones (think for example on all the results on senolytics).
@Tony
What is your concern with the larger animal? Having cancer in 10 years after the treatment, or you think the effect cups be quite weaker, akin calorie restriction?