September 23, 2011
Retroransposons Suppress Aging Adult Stem Cells
Retroransposons, located areas of the genome that have not been thought to have any functional purpose, get transcribed (read from DNA into RNA) in aging stem cells. The resulting RNA fragments mess up the aging stem cells and make them less able to divide and do repair to the body. Some Buck Institute and Georgia Tech researchers have demonstrated accumulated DNA damage with age allows the retrotransposons to interfere with stem cell function.
"We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk'," said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.
Adult stem cells are not held back by shortening telomeres.
The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. They thought so because body cells are known to experience a shortening of the caps found at the ends of chromosomes, known as telomeres. But adult stem cells are known to maintain their telomeres. Much of the damage in aging is widely thought to be a result of losing telomeres. So there must be different mechanisms at play that are key to explaining how aging occurs in these adult stem cells, they thought.
The researchers looked at DNA damage at cells that had divided many times.
Researchers used adult stem cells from humans and combined experimental techniques with computational approaches to study the changes in the genome associated with aging. They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups.
They suppressed the toxic transcripts from retrotransposons and got cells more able to grow. But can this ever work in situ, i.e. in the body? I suspect the damaged cells just need to be replaced.
"We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons," said King Jordan, associate professor in the School of Biology at Georgia Tech.
"Retroransposons were previously thought to be non-functional and were even labeled as 'junk DNA', but accumulating evidence indicates these elements play an important role in genome regulation," he added.
While the young adult stem cells were able to suppress transcriptional activity of these genomic elements and deal with the damage to the DNA, older adult stem cells were not able to scavenge this transcription. New discovery suggests that this event is deleterious for the regenerative ability of stem cells and triggers a process known as cellular senescence.
"By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture," said Lunyak.
"Furthermore, by rewinding the cellular clock in this way, we were not only able to rejuvenate 'aged' human stem cells, but to our surprise we were able to reset them to an earlier developmental stage, by up-regulating the "pluripotency factors" – the proteins that are critically involved in the self-renewal of undifferentiated embryonic stem cells." she said.
So this, in a nutshell, is a major reason we grow old.
Maybe, then, cell aging can be slowed, or even reversed, by suppressing retroransposons with something like RNA-interference.
Also possibly related, is the cellular reprogramming and apparent rejuvenation reported in -
"RNA Reprograms Brain Cells Into Heart Muscle Cells"
- via 'Transcriptome Induced Phenotype Remodeling'
I thought that biologists knew by now that, when they encountered something in the human body that seemed to have no purpose (e.g., "junk genes), it merely meant that they were ignorant of the purpose, not that none existed.
Nature is efficient, with a purpose for everything (even biologists), to anthropomorphize it.
Looks like we're getting close to some effective therapies (by 'close' I mean less than ten years out). Actually, some of these look promising enough that I would expect some of the very wealthy old to start trying to speed up the process in some legally congenial location. Not looking forward to the eventual contest against nearly immortal oligarchs, but on balance it's still good.
I do not see how RNA-interference can work because it probably has to be sustained. How to deliver the interfering RNA to so many cells and every day and possibly more often than that?
DNA damage is causing the retrotransposons to exist long enough to cause problems. If we could selectively kill cells that have too much retrotransposon RNA would we need to introduce new stem cells? Or would other healthier stem cells replicate to take the place of the messed up stem cells?
What I wonder: Were the effects of damage to retrotransposon regions actually selected for in order to prevent cancer? After all, retrotransposons only cause problems if lots of DNA damage has occurred. Well, when that has happened DNA damage has likely occurred in other regions as well. If only the effects of the retrotransposon damage get blocked the net effect could be harmful for some people due to heavily damaged cells now being enabled to divide.
The supposed inertness of the supposedly non-coding regions always struck as wrong. How could so much DNA do nothing? It made no sense. I expect many more discoveries about the supposed inert regions of DNA.
If RNAi molecules could be delivered, it seems to me (non-expert opinion) that retrotransposon transcription would effectively be blocked, but I have no idea of how many types of RNAi molecules would have to delivered, nor how difficult delivery would be, nor how often, or how long treatments would last. RNAi is just a guess.
The Buck Institute's, Dr. Lunyak, has a U.S. Provisional Patent Application Entitled: "Downregulation of SINE/ALU Retrotransposon Transcription to Induce or Restore Proliferative Capacity and/or Pluripotency to Stem Cell" - but I cannot find it online. It may give some hint about approaches.
Another press release for the same paper you cited (from the Georgia Tech authors, I assume) -
"Modifying Senescent Adult Stem Cells Reinstates their Self-Renewal Capacity"
- suggests caution because the treatment could slow apoptosis, perhaps a cancer risk:
"Apoptosis is an important tool to prevent cancer. There could be deleterious effects to restoring cellular functioning in this way. Gene therapies and RNA interference have not yet been that successful in the clinic. It is very hard to deliver these vectors to the proper areas of the body. It is difficult to know when, if ever, this R&D will ever translate to medicine in the clinic."
I wonder whether some cellular "damage" is self-inflicted to create a more differentiated state.
Maybe you wouldn't want to watch your sausages being made, nor your cells differentiating?
Thanks for the reference - I had not seen it.
All I can offer is my interested layman's opinion - maybe increasing ARTS would help cull damaged and potentially dangerous wayward cancer-prone stem cells.
I believe that even periodic unmasking of pro-apoptotic genes by phytonutrients, like sulforaphane (in cruciferous vegetables), can selectively kill early cancer cells. If I recall correctly, several phytonutrients inhibit the histone deacetylases (HDACs) which prevent anticancer pro-apoptosis gene expression. I believe several HDAC inhibitors are in clinical trials.
I'll repeat something I've said many times before: Cures for cancer will enable many types of rejuvenation therapy which are otherwise too risky today.
Any efforts to up-regulate cellular division (e.g. the report above) in older cells run the risk of more cancer. Once we gain the ability to kill cancer cells, senescent cells and other heavily damaged cells then we can get them out of the way and up-regulate the remaining cells with much lower risk.
Aside: What I find interesting about senescent cells is that they don't just die. Is there a benefit to the body from keeping around heavily aged cells? I can see why that would be the case in some structural positions and in post-mitotic tissue. But just killing sick cells ought to make room for relatively less damaged cells to replicate and fill in for the lost cells.
It's not so much that the body benefits from keeping these cells around, as that we simply haven't been routinely living long enough for these problems to crop up, for evolution to have dealt with them. It's that long evolutionary history of almost everybody dying in their 20s and 30s that's responsible for this stuff falling apart. There just wasn't any evolutionary "drive" to evolve mechanisms to keep a body running for a couple hundred years, when accidents or disease assured you'd likely die in 2-3 decades.
There *are* some species of animals that live that long, though, such as the giant tortoise. Might be some fruitful research to be done into how they cope with these problems.
The older cells become, the more aberrant their gene expression becomes --
(The Spatial Association of Gene Expression Evolves from Synchrony to Asynchrony and Stochasticity with Age
-- so maybe slowing cell growth is a way of stopping the stochastic differentiation program from going too far astray?
Are cells "damaged" or just directed by an noisy program only optimized for survival into early adulthood (as Brett suggests)?
Too bad only a small percentage of people want to fund that research.
I've been thinking about this general topic lately, and here are my thoughts:
1. The biggest problem with senescent cells seems to be an energy deficit due to non-functional mitochondria. Shuts done repair mechanisms to conserve energy.
2. If you could restore the mitochondria, the cells might bounce back to normal, but some fraction would bounce back to being normal cancer cells. Not good.
3. So we really need a way to restore mitochondria, which also makes cancer treatment easy.
4. Mitochondria are halfway between organelles and independent symbionts: They have their own genes, but also rely on nuclear genes.
5. They degrade over time in the cell because their own genes are subject to oxidative damage due to their energy metabolism.
6. SENS proposes to transfer the last few mitochondrial genes to the nucleus, protecting them from that damage, so that they don't degrade. But how to accomplish this in already aged cells in vivo? And even if it's accomplished, the cancer issue remains.
Perhaps SENS is going in the wrong direction?
Suggestion: Restore mitochondria to being fully independent symbionts. They could be inserted into existing cells in vivo, without disturbing nuclear DNA, and make up the energy deficit. Intracellular parasites such as Toxoplasma have the capability to travel through an organism, inserting themselves into existing cells, and reproducing within them.
Engineer a synthetic intra-cellular 'parasite' capable of taking the place of mitochondria. It should have the following properties:
1. Ability to travel through the body, inserting itself into uninfected cells.
2. Provide energy to the cell like mitochondria.
3. Ability to remove natural, malfunctioning mitochondria.
4. Variable apitosis trigger.
4 is key: If you manufacture the new mitochondrial replacement with huge genetic diversity, perhaps by a process comparable to the shuffling mechanism that generates anti-bodies, you could arrange for the body to consist of tens of thousands, perhaps millions, of distinct cell lines, each with it's own distinct apitosis trigger.
Some of the revived cells turn out cancerous? Sample the cancer, identify the cell line, deliver the trigger, and the cancer abruptly dies. Along with a tiny fraction of non-cancerous cells, but hey, it's still better than what chemo does to you.
Existing mitochondria must be removed, both because they act as a particularly nasty form of self-reproducing inter-cellular garbage, and to make the host cells more vulnerable to the apitosis of their new mitochondrial substitutes.
This, frankly, sounds to me like it might be doable, inside of 20 years, given recent progress by people like Craig Venter.
IIRC, damaged mitochondria reproduce because the cell winds up with an energy deficit. Supplanting them would eliminate the trigger for reproduction. Perhaps the engineered substitute could generate factors to suppress it further.
If the natural mitochondria failed to reproduce after such treatment, cancers would probably wind up with nothing but the substitutes. The substitutes might also have a "division clock".
I think the biggest issue might be ova. They'd wind up propagating a single clone or a small set, and any division clock would kill a developing embryo early on. These would have to be kept out of the germ line cells.
Yes, that's why I'm proposing this as a treatment for the symptoms of aging in those already aged. The SENS approach of moving mitochondrial genes to the nucleus is certainly superior as a preventative measure, the only problem being that the easiest time to implement it would be during in vitro fertilization. Very difficult to implement in already existing people.
Thanks for that link. I should write a post about it.
I think the decline in synchronicity of gene expression underscores how much tissue changes as it ages not just in terms of accumulating damage but also in its control systems. Trying to fix the individual cells in place seems like a very daunting task because so many things go wrong.
I wonder how much of the asynchronous gene expression is due to retrotransposons. If one could suppress the retrotransposons would the tissue gene expression become more synchronous?
If memory serves, Aubrey de Grey theorizes that the damaged mitochondria out-reproduce normal mitochondria, making a given cell with a single damaged mitochondrion (no longer doing the Krebs or TCA Cycle) eventually into a cell where most or all mitochondria are damaged and spewing free radicals. I can't recall what mechanism he proposed for this though. Not sure his mechanism is correct in any case.
Putting the 15k of mitochondrial DNA into the nucleus (with added coding to carry their protein products into mitochondria) would make lots of sick mitochondria better but not perfect. The damaged mtDNA would still be in mitochondria and some of their transcribed proteins would do metabolic steps in ways threw off more reactive species.
We still need a cure for cancer independent of whether mitochondria are messed up. A cell could go cancerous without having damaged mitochondria.
Yes, that was part of the motivation for my suggestion: Install this variable apitosis trigger in every cell, and you can kill off cancers fairly easily, even if they're really unrelated to the mitochondria. Well, new cancers, anyway; Existing cancers would share in the genetic diversity.
On that concern you had, as mitochondria are kinda, sorta alive, I suppose they can be 'killed'. Perhaps the transferred mitochondrial genes could be altered to give immunity to some drug which would otherwise destroy mitochondria. Then you could kill off the damaged ones, while leaving new ones generated using the transferred genes to repopulate the cell.
An alternative version of my proposal to replace natural mitochondria with engineered ones, would be to have the modified symbiont simply handle the task of generating the proteins those genes in the mitochondria are responsible for. Genetically engineering small organisms is easier that human cells, and a lot easier than genetically engineering human cells in vivo. The symbionts would be good candidates for the target of any campaign of additive genetic engineering, because they can be engineered, and added to cells without disturbing existing nuclear DNA.