28 replies to this topic

[Myme]

hot topic
http://wires.univisi...rom-centenarian

[Mind]

More and more growth factors are being discovered for this type of rejuvenation. See this thread as well.

The highlights from this stem cell regeneration study:

Lemaitre and colleagues decided to alter the standard genetic starter kit used to generate adult stemcells by adding two new ingredients -- known as transcription factors -- called NANOG and LIN28.

Experiments with human subjects ranging in age from 74 to 101 showed that the new cocktail worked.

Several critical markers of ageing in cells were "reset", including the size of telomeres, the tiny protective caps found on the ends of chromosomes that wear down with age, the researchers reported.

Telomeres and telomerase, the enzyme that control them, are a key agent in longevity.

Every time a cell divides, the telomeres get worn down a little bit. The enzyme's job is to partially rebuild them. Eventually, when the telomeres are worn beyond repair, a cell dies.

Gene expression profiles, levels of oxidative stress, and the metabolism of the cell's energy-generating mitochondria were all likewise rejuvenated, according to the study.

"The age markers in the cell has been erased," said Lemaitre. "The iPSC stemcells we got can produce functional cells of all types with a capacity to proliferate and enhance longevity."

By reversing the age-altered physiology of the cells, he added, the new reprogramming technique "may constitute an optimal strategy for developing cell-based therapies for aged patients."

A large gap remains between this "proof-of-concept" study and therapeutic applications, the researchers cautioned.

And recent experiments with mice suggests that generating adult stemcells may yet face unexpected barriers.

Certain kinds of iPSC may be rejected by the immune system even if they are derived from the same organism, the experiments showed.

I think they mean the "length of telomeres" increased. Otherwise I am not sure what the scientific meaning of "size" would be.

Anyone care to speculate as to why the immune system would reject iPSC derived cells. Is the immune system so closely linked with the aged organism that new iPSC cells are essentially identified as a foreign cell type?

[niner]

Anyone care to speculate as to why the immune system would reject iPSC derived cells. Is the immune system so closely linked with the aged organism that new iPSC cells are essentially identified as a foreign cell type?

My guess would be that the iPSCs are expressing something unusual on their surface. In the long run it should be possible either to inhibit this or to train the immune system to ignore it.

[VidX]

"Gene expression profiles, levels of oxidative stress, and the metabolism of the cell's energy-generating mitochondria were all likewise rejuvenated, according to the study." - more and more it's becoming clear that it's NOT a damage or anything, it's "merely" a shift in the gene expression (most likely - due to the pressure of a natural selection, depending on a specie). We "reprogram" the epigenetic data - we get a youth phenotype expressed once again. A direct proof is an experiment like that above...

[okok]

"Gene expression profiles, levels of oxidative stress, and the metabolism of the cell's energy-generating mitochondria were all likewise rejuvenated, according to the study." - more and more it's becoming clear that it's NOT a damage or anything, it's "merely" a shift in the gene expression (most likely - due to the pressure of a natural selection, depending on a specie). We "reprogram" the epigenetic data - we get a youth phenotype expressed once again. A direct proof is an experiment like that above...

Haven't read the papers yet, but wow if that is true. That would leave cancers as direct DNA damage hurdle.

[corb]

Anyone care to speculate as to why the immune system would reject iPSC derived cells.

The way I understand it - they used transcription factors to tamper with DNA to RNA communication and fooled the cells into dividing into "younger" cells, the interference however is not perfect and a "correct" blueprint of what cells you are supposed to be making is broadcast to the immune system. The "young" cells do not fit the description and the immune system sees them as mutations.

Of course I could be way off. Someone more knowledgeable about genetics and gene therapy might be able to give a more definitive answer.

[ChooseAName]

Is the actual paper online?

[JonesGuy]

I'm really skeptical of the decrease in oxidative stressors. I mean, I believe that there's a refreshing of the total oxidative damage in the cells, so they're rejuvenated, but I just can't think of a mechanism by which the mitochondria would refresh their DNA after all the oxidative injury mtDNA experiences.

I suspect there's actually a natural selection effect here. A bunch of cells were dedifferentiated, and cells that retained a few 'healthy' mt genomes were able to survive the protocol and then dominate the petri dish. So, when they checked for oxidative injury in the colonies, they found low levels.

[VidX]

I think the most important thing here is that a REVERSAL of aging (even if in "just" a cell) was demonstrated full force. If that's not a begining of "leaps" in this science, then I don't know what is it... I can see quite a potential in these latest news of recent days.

[niner]

Is the actual paper online?

sorta. not in pubmed or google scholar as far as I can see, but if you go to the journal site, you can at least get the abstract. Here it is:

Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state

Laure Lapasset, Ollivier Milhavet, Alexandre Prieur, Emilie Besnard, Amelie Babled, Nafissa Aït-Hamou, Julia Leschik, Franck Pellestor, Jean-Marie Ramirez, John De Vos,Sylvain Lehmann and Jean-Marc Lemaitre

Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. These results provide new insights into iPSC technology and pave the way for regenerative medicine for aged patients.

Sorry, not much extra info here. The full paper is behind a paywall.

[Mind]

I think the most important thing here is that a REVERSAL of aging (even if in "just" a cell) was demonstrated full force. If that's not a begining of "leaps" in this science, then I don't know what is it... I can see quite a potential in these latest news of recent days.

Following the logic of JonesGuy's previous post, then there wouldn't be any true reversal of aging, only natural selection of a few "younger' cells among the population. It should be considered until we learn more.

[VidX]

I think the most important thing here is that a REVERSAL of aging (even if in "just" a cell) was demonstrated full force. If that's not a begining of "leaps" in this science, then I don't know what is it... I can see quite a potential in these latest news of recent days.

Following the logic of JonesGuy's previous post, then there wouldn't be any true reversal of aging, only natural selection of a few "younger' cells among the population. It should be considered until we learn more.

Yes, I agree, tho' this quote from abstract kind of hints that they are pretty sure these cells are "fully reset": " Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. "..
It's quite big (I'd actually say - huge, as we are talink an actual reversal of cellular aging. I'm not sure people yet fully grasp the importance of this.), I doubt they'd let something like that to slip through.

Edited by VidX, 08 November 2011 - 01:50 AM.

[niner]

I think the most important thing here is that a REVERSAL of aging (even if in "just" a cell) was demonstrated full force. If that's not a begining of "leaps" in this science, then I don't know what is it... I can see quite a potential in these latest news of recent days.

Following the logic of JonesGuy's previous post, then there wouldn't be any true reversal of aging, only natural selection of a few "younger' cells among the population. It should be considered until we learn more.

Yes, I agree, tho' this quote from abstract kind of hints that they are pretty sure these cells are "fully reset": " Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. "..
It's quite big (I'd actually say - huge, as we are talink an actual reversal of cellular aging. I'm not sure people yet fully grasp the importance of this.), I doubt they'd let something like that to slip through.

I agree that this is big, if it really works that way. I can see where they might do something that activates telomerase and extends the telomeres, but if there are mitochondrial or nuclear mutations, how would those be fixed? How would this procedure take care of lipofuscin deposits? I guess if they're growing up new cells, after a few generations the lipofuscin is no longer a problem. Still doesn't deal with mutation, though. Seems too good to be true...

Edited by niner, 08 November 2011 - 02:58 AM.

[VidX]

I agree that this is big, if it really works that way. I can see where they might do something that activates telomerase and extends the telomeres, but if there are mitochondrial or nuclear mutations, how would those be fixed? How would this procedure take care of lipofuscin deposits? I guess if they're growing up new cells, after a few generations the lipofuscin is no longer a problem. Still doesn't deal with mutation, though. Seems too good to be true...

Yeah...need to get hands on the full paper, it's very interesting.

[JonesGuy]

It's still an awesome result, especially with regards to regenerative surgeries (etc.). This means that people will be able to replace their organs with their own 'younger' tissues, buying time.

[okok]

study attached.

Attached Files

•  2248.full.pdf   1.13MB   1197 downloads

[Elus]

I just read the paper and I'll read it again. I'm completely boggled as to how and why all this repair is happening. They added two additional factors to their hESC reprogramming soup. These factors, along with the other four caused all this rejuvenation. Wtf? Must the two factors work in concert with the other four? Can those two factors be introduced into cell media and reverse the aging phenotype without necessarily having to reprogram the old cells at all?

[Elus]

There is something very unusual going on here. This is truly remarkable. I have many, many questions.

• Mitochondrial trans-membrane potential & mitochondrial protein composition in iPSCs from a freaking 90 year-old was restored to levels observed in hESC. HOW?!
• Telomeres actually got longer. This means telomerase was activated. HOW?! (Answer this one and you could figure out a drug to activate telomerase in-vivo)
• How/why were both p16 & p21 downregulated in their 70 to 90-year old iPSC model?
• Why didn't their iPSCs enter premature senescence?!
• The transcriptome (THE ENTIRE FREAKIN' PROTEIN LIBRARY) of the iPSCs was similar to hESCs. How was the DNA repaired to such a degree so as to allow similar protein levels in both young and old cells??

Guys, what the hell is going on here? I'm at a loss for words.

This goes FAR, FAR BEYOND stem cells. What we have here is a rejuvenation on an unprecedented scale, and a hidden mechanism behind that rejuvenation. Supposing we can figure out why all this is happening, you might not even need use stem cell therapy at all! You could simply deliver a drug which activates this universal repair mechanism in-vivo. Simply incredible.

I also agree with niner, though. This seems far too good to be true.

Edited by Elus, 08 November 2011 - 07:22 PM.

[okok]

Looks like everything's already set in place and we just have to turn on a switch. Don't forget the yeast study. Maybe there's a connection to the germ-line, meiotic rejuvenation.

[Elus]

Looks like everything's already set in place and we just have to turn on a switch. Don't forget the yeast study. Maybe there's a connection to the germ-line, meiotic rejuvenation.

What if we wanted to induce the repair mechanism without necessarily reverting the cell back to its stem cell state? Maybe just one of the factors will induce the repair and the rest will lead to a change in cell type.

Would it be worth testing each of those stem cell factors individually to see if they rejuvenate the cell?

Lets say I wanted to design a drug that would make my cells young again. I wouldn't want this drug to make all my existing cells stem cells, now would I? So, I would want the drug to only activate the repair part that is demonstrated in this paper. Can you think of a way this might be done?

Edited by Elus, 08 November 2011 - 08:15 PM.

[Mind]

Absorbing much information about the complicated process of human aging over the last decade, it seems it always turns out more complicated than expected. I would be surprised if there are such powerful "rejuvenation factors" that can be administered to work separately from that which reset the cells to hESCs. Most cell processes are dynamically interlinked (not sure if this is the best terminology, but tripping one significant trigger in a cell usually sends off a crap-ton of secondary effects). I won't rule out a magic bullet (or two) but I don't have my hopes up too far yet.

[okok]

I wish i were more knowledgeable, but probably there's no need to try to directly rejuvenate specialized cells as the iPSCs consequently will differentiate on their own in the target tissue?

Edited by okok, 08 November 2011 - 10:26 PM.

[niner]

It's a good bet to not get one's hopes up too high in this field. I've been thinking about this, and was wondering if I'm overestimating the effect of mutations. The mutation rate of germline cells at the population level is well known, and I'm sure someone knows what the mutation rate of somatic cells is. It probably varies a lot from tissue to tissue, too. The majority of mutations will do little or nothing. A few are lethal, so the cell line terminates. A few screw up growth control, and if enough of the firebreaks are breached, then you have a cancerous cell. For these three kinds of mutation, they either don't matter or you aren't going to select them. There must be a fourth category that are non lethal, non cancerous, but have a negative impact on function. I suppose there would have to be a fifth kind that have positive impacts on function, too. At any rate, given all this slicing and dicing, maybe, even in a 100 year old cell, the mutation level isn't really such a problem. That's just a hypothesis, one that I've not checked out at all. I suspect that part of the rejuvenation involves growing up a couple generations of new cells, so there's probably a limit to what can be done in vivo. However, regarding the mysterious 'rejuvenation factors', those parabiotic mice, where a young mouse is sutured to an old mouse, or at least has its circulatory system connected, keeps kicking around in the back of my mind. This is looking more and more like a programming problem, where the code is some collection of proteins. The parabiotic experiments give a whole new meaning to the old man in the creepy van who says "hey kid, come here... I've got candy..."

[Elus]

We just saw what happened when senescent cells were removed from an artificially old mouse (in the other thread). Now we have a potential mechanism for doing something very similar, but not by removing senescent cells - instead by converting those cells back into their proper functioning form.

 Screen Shot 2011-11-08 at 5.52.45 PM.png   155.63KB   7 downloads

The parabiotic experiments give a whole new meaning to the old man in the creepy van who says "hey kid, come here... I've got candy..."

I don't mean to derail the thread but....

Edited by Elus, 08 November 2011 - 10:54 PM.

[VidX]

This is looking more and more like a programming problem, where the code is some collection of proteins. The parabiotic experiments give a whole new meaning to the old man in the creepy van who says "hey kid, come here... I've got candy..."

Lol... Vampires are onto something afterall..
As for programming - it's getting more and more clear (imho) that it IS a programming issue, all the damage/etc is irrelevant or close to irreleveant as it's the effect, not the cause (once again I want to mention M.R.Rose and his experiments). ANd it may be good news if bio-it science progresses rapidly. In that case we may have a nice "cocktail" of pharmateuticals (or more likely - a coctail of various peptides/proteins we would inject regulary) designed to "reprogram" our cells.

Edited by VidX, 08 November 2011 - 11:12 PM.

[Elus]

This is looking more and more like a programming problem, where the code is some collection of proteins. The parabiotic experiments give a whole new meaning to the old man in the creepy van who says "hey kid, come here... I've got candy..."

Lol... Vampires are onto something afterall..
As for programming - it's getting more and more clear (imho) that it IS a programming issue, all the damage/etc is irrelevant or close to irreleveant as it's the effect, not the cause (once again I want to mention M.R.Rose and his experiments). ANd it may be good news if bio-it science progresses rapidly. In that case we may have a nice "cocktail" of pharmateuticals (or more likely - a coctail of various peptides/proteins we would inject regulary) designed to "reprogram" our cells.

I can't help but ask why this might be the case. I mean we've got some great evidence here for that, but shouldn't it be relatively simple for evolution to maintain those genes switched on?

The normal argument for why we aren't immortal is usually because evolution doesn't select for it because it takes too much effort to clear up all that damage, but would the same argument hold true if it was a simple matter of reprogramming?

[okok]

Interesting question. Maybe phylogenetic adaptability was more successfull than ontogenetic.

[Logic]

"... So what, if anything, is special about Lin28? Quite a lot, it turns out. Apparently Lin28 not only promotes pluripotency, but it also interacts with a very well-known type of microRNA called let-7. As we saw here, let-7 does several things that help suppress cancer. For one thing, let-7 regulates the oncogene Ras, apparently by binding to the mRNA encoding Ras, thereby inhibiting protein expression. (See here.) For another thing, and more to the point, let-7 tends to negate some of the "stemness" of stem cells, and pushes them onto a path for differentiation into more specialized cell types. (See here.) This helps inhibit cancer by reducing the ability of suspected cancer stem cells to proliferate. Let-7 has also been mentioned as an inhibitor of oncogenicity of c-Myc..."

http://scienceandrea...-and-lin28.html

[addx]

What if cells "state" is purposeful rather than accidental.

I know for a fact that for example kappa opioid receptors on serotonergic neurones serve the purpose of basically shutting them down, depending on some other factors. The shutdown is achieved through p38 map kinase or so basically stressing/degrading the cell into non-function. I do believe this mechanism facilitates what we experience as emotional/memory repression. The cell is a pathway to "stressing" memory schemas so is degraded to reduce its activity.

So, point being, side-effects of such a "healing process" being delivered body-wide(untargeted) could prove to be quite... unnerving

Not sure if its important, but kappa opioid receptors on neuronal stem cells seems to induce differentiation. And what is being discussed here is basically reversing differentiation.