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Mitochondrial Transplants

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#1 pone11

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Posted 11 January 2015 - 02:30 AM


Moderation - Posts in this topic regarding the use of 3-Bromopyruvate to fight cancer have been moved to this thread.

 

 

As I understand it, our mitochondria are basically a type of bacteria that evolution has morphed into a symbiont that lives inside our tissue cells.   Each cell has on average 1000 mitochondria.  Each mitochondria has its own DNA, its own ribosomes, and to some degree can be viewed as a self sufficient entity that lives within our cells.

 

Has anyone looked at the possibility of transplanting a young person's mitochondria into an aging adult's cells?   If they do this experiment in vitro, do the cells always reject the foreign mitochondria?   Does anyone understand the reasons for that?    Are mitochondria specific to each type of cell, so that for example mitochondria in your heart tissues would be incompatible with those in your brain?   If yes, that makes the problem many orders of magnitude tougher.

 

I guess the Plan B in this case would be to use a person's stem cells to manufacture young mitochondria, and then to try to implant those?

 

Even if this works in vitro, there would be a practical implementation issue of how do you generate enough of them, and how do you then get them into the cells?

 

Nevertheless, if the free radical theory of aging has now over time become the mitochondrial theory of aging, it is certainly interesting to observe that the mitochondria are really stand alone entities that exist on their own inside of the cell.   In theory one should be able to engineer a younger version of your mitochondria and then give those back to you, and presumably those younger mitochondria would not degrade so rapidly, in effect bringing your cellular environment back to a level of energy metabolism, antioxidant production, and free radical resistance seen when you were 10 to 30 years old.

 

The reason I find this idea so exciting is that the mitochondria is in theory an extremely primitive organism whose DNA could be easily reverse engineered, and which could - once the host acceptance issue is understood - be manufactured in a large scale.    It seems like an order of magnitude simpler to understand how to create perfect mitochondria than it would be to understand every nuance of a mammals cellular biology.


Edited by PerC, 25 January 2015 - 02:04 AM.

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#2 corb

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Posted 11 January 2015 - 08:59 AM

 

Has anyone looked at the possibility of transplanting a young person's mitochondria into an aging adult's cells?

Yes. As far as I know in vivo research is being blocked by a number of ethical committees around the world because it's de facto genetic engineering.

 

 

If they do this experiment in vitro, do the cells always reject the foreign mitochondria?

From my reading on mitochondrial transfer, which is mostly theoretical work, there IS an immune (not the correct terminology I think but you get the idea) reaction when a cell detects a foreign mitochondria so it's not a matter of supplying a healthy mitochondria but a matter of making the cell accept it. Of course if  the mitochondria is genetically identical to your own - for instance from your mother, or if you're female - from your children, there shouldn't be a problem, of course matches can be found otherwise.

 

 

and how do you then get them into the cells?

A number of methods have been discussed in the bionews section, you can search the tag mitochondria and you should find the articles.

 

As for the rest, I'm not a researcher so I'd only be able to give you an opinion that's not worth much. So I'll stop at that.


Edited by corb, 11 January 2015 - 09:00 AM.


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#3 pone11

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Posted 11 January 2015 - 10:12 AM

 

 

Has anyone looked at the possibility of transplanting a young person's mitochondria into an aging adult's cells?

Yes. As far as I know in vivo research is being blocked by a number of ethical committees around the world because it's de facto genetic engineering.

 

 

Can't they at least study this in animals?



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#4 corb

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Posted 11 January 2015 - 10:30 AM

Can't they at least study this in animals

 

 

They could, but they're mostly on the theoretical work stage right now as I already said.


Edited by corb, 11 January 2015 - 10:33 AM.


#5 Razor444

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Posted 11 January 2015 - 01:52 PM

Good read on the subject: Another Complication in Mitochondrial Dynamics is that Cells Can Transfer Mitochondria



#6 pone11

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Posted 11 January 2015 - 10:00 PM

 

I think this is an area where they should learn by empiricism rather than theory.   Why not simply do mouse studies using transplanted mitochondria and just observe what extends life and what does not?

 

I agree with SENS on this issue that science is wasting too much valuable time trying to understand theoretical bases and too little effort chasing clinical results.   This is an area where - simply by accident - they could discover an easily-repeated treatment that vastly improves health and lifespan.   That's a desirable target even if we do not understand the reasons for the result.


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#7 Avatar of Horus

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Posted 12 January 2015 - 12:52 AM

Good read on the subject: Another Complication in Mitochondrial Dynamics is that Cells Can Transfer Mitochondria

 
I think this is an area where they should learn by empiricism rather than theory.   Why not simply do mouse studies using transplanted mitochondria and just observe what extends life and what does not?

Agreed. Myself too advocating and favoring the need of experiments, instead of just theorizing.
 

I agree with SENS on this issue that science is wasting too much valuable time trying to understand theoretical bases and too little effort chasing clinical results.

Disagree, because SENS and its advocates don't say exactly this. Rather they disfavor and critique the general, bio-med research, which aims to the full understanding of the biological and metabolism (and the like) processes, and would favor instead the, which they call as, damage removing and reversal research.
 

This is an area where - simply by accident - they could discover an easily-repeated treatment that vastly improves health and lifespan.   That's a desirable target even if we do not understand the reasons for the result.

Agreed. Because we don't fully understand, we need the experiments, both for the basic research and life extension ones.

#8 resveratrol_guy

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Posted 12 January 2015 - 02:15 AM

The idea of replacing faulty mitochondria is an ingenious one, if it could be implemented in practice. I like it specifically because it allows us to ignore the quantum electrodynamics problems of various mitochrondrial failure modes in favor of outright replacement. After all, no one analyzes dead batteries; we simply replace them.

 

It seems like the shortest success path is something along the lines of hijacking stem cells to deliver rejuvenated mitochrondria (per the above linked Fight Aging article), then upregulating said cells' tendency to donate said mitochondria, then using a caloric restriction memetic (pterostilbene or others) to upregulate mitochrondrial duplication posttransplantation.

 

So if you do it this way, you reduce most of the problem to the creation of mitochondrially youthful stem cells. In turn, it seems that the crudest solution to that problem is to sample a large number of stem cells (easily done with bone marrow or GCSF approaches, or of course via saved cord blood cells), then use statistical analysis to find the ones with the least mtDNA errors, then replicate the very cleanest stem cell, then reinject its clones into general circulation or some target tissue of interest. All you need in order to assess mtDNA error rate is a way to biopsy individual mitochondria from individual cells without destroying the latter, which is in turn a MEMS problem, likely involving the creation of a nanosyringe (3D nanoprinting?). Further down the road, we might be able to use statistical analysis to suggest ways in which faulty mtDNA might be corrected using zinc finger nucleases or the like, so we could computationally rejuvenate a sample stem cell, then reproduce it by orders of magnitude, then upregulate its mitochondrial transfer behavior prior to reinjection. But start simple: find a healthy stem cell, reproduce it, and reinject.

 

Furthermore, the Fight Aging article considers it a problem that, within an individual cell, mitochondria promiscuously swap mtDNA, allowing errors to rapidly corrupt the entire mitochondrial population. To the contrary, this is most fortunate, because it means that error rates throughout a given stem cell can be more accurately estimated merely by sampling a single mitochondrion, which in principle could be done without harm to the cell.

 

But... ethical problems -- seriously? What could be more ethical than to offer trial participants the potential to rejuvenate their own mtDNA by using their own mtDNA, as compared to injecting them with experimental pharaceuticals which hopelessly target narrow pathways and are developed in silos isolated from real metabolism? I think I would volunteer for a trial myself, were the technology available. In any event, I don't see any reasonable excuse to not be doing this in appropriate animal models, if that's what is legally required in order to progress to human studies.

 

Sadly, I would bet my last dollar that all this will be ignored and never advance in this century. Hopefully some billionaire will get fed up with this and start research in a friendly banana republic.

 


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#9 pone11

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Posted 12 January 2015 - 02:50 AM

As a follow up to my original post:   I wonder if there is an argument to be made that people should try to get some of their tissues biopsied and frozen cryogenically now, before they are too old, with the idea being that maybe in 30 years someone will be able to take your frozen tissue and mass produce mitochondria from the DNA in those frozen samples.

 

Is there anyone actually offering this on a commercial basis today?

 

To me that is a much more practical application of cryogenics than freezing an entire body after death.



#10 pone11

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Posted 12 January 2015 - 03:17 AM

The idea of replacing faulty mitochondria is an ingenious one, if it could be implemented in practice. I like it specifically because it allows us to ignore the quantum electrodynamics problems of various mitochrondrial failure modes in favor of outright replacement. After all, no one analyzes dead batteries; we simply replace them.

 

It seems like the shortest success path is something along the lines of hijacking stem cells to deliver rejuvenated mitochrondria (per the above linked Fight Aging article), then upregulating said cells' tendency to donate said mitochondria, then using a caloric restriction memetic (pterostilbene or others) to upregulate mitochrondrial duplication posttransplantation.

 

So if you do it this way, you reduce most of the problem to the creation of mitochondrially youthful stem cells. In turn, it seems that the crudest solution to that problem is to sample a large number of stem cells (easily done with bone marrow or GCSF approaches, or of course via saved cord blood cells), then use statistical analysis to find the ones with the least mtDNA errors, then replicate the very cleanest stem cell, then reinject its clones into general circulation or some target tissue of interest. All you need in order to assess mtDNA error rate is a way to biopsy individual mitochondria from individual cells without destroying the latter, which is in turn a MEMS problem, likely involving the creation of a nanosyringe (3D nanoprinting?). Further down the road, we might be able to use statistical analysis to suggest ways in which faulty mtDNA might be corrected using zinc finger nucleases or the like, so we could computationally rejuvenate a sample stem cell, then reproduce it by orders of magnitude, then upregulate its mitochondrial transfer behavior prior to reinjection. But start simple: find a healthy stem cell, reproduce it, and reinject.

 

Furthermore, the Fight Aging article considers it a problem that, within an individual cell, mitochondria promiscuously swap mtDNA, allowing errors to rapidly corrupt the entire mitochondrial population. To the contrary, this is most fortunate, because it means that error rates throughout a given stem cell can be more accurately estimated merely by sampling a single mitochondrion, which in principle could be done without harm to the cell.

 

I agree with the spirit of most of that, and I think the point to emphasize is these are just engineering problems that we have the technology to solve today.   All of the work that was done in sequencing and recombinant technology make most of this possible.

 

I am less clear on using statistical techniques to identify the least damaged mtDNA.   How do we know which sections are in error and which are advantageous changes?   Seems like it might be more efficacious to just map that genome and identify obvious defects and just change those when you make the model.

 

The other thing is I don't think I would upregulate distribution of those mitochondria.  There is too much risk in that approach that the new mitochondria - if they have defects - will end up killing you or causing a serious disease state.  I think what I might do is try to just introduce some small measured change through monthly transfusions.  For example, if you could change out 3% every month - and if you assume that the improvements represented in that 3% will be persistent statistically across the body going forward - then after five years you would have effectively changed out 84% of the mitochondria.   I think that is enough to ensure dramatic health improvements, while at the same time going very slow and observing all kinds of markers throughout the body for change.   If you find things going bad, then you just stop the transfusions and let mitochondria settle things out on their own before you start up again.

 

 

But... ethical problems -- seriously? What could be more ethical than to offer trial participants the potential to rejuvenate their own mtDNA by using their own mtDNA, as compared to injecting them with experimental pharaceuticals which hopelessly target narrow pathways and are developed in silos isolated from real metabolism? I think I would volunteer for a trial myself, were the technology available. In any event, I don't see any reasonable excuse to not be doing this in appropriate animal models, if that's what is legally required in order to progress to human studies.

 

Sadly, I would bet my last dollar that all this will be ignored and never advance in this century. Hopefully some billionaire will get fed up with this and start research in a friendly banana republic.

 

I just don't see the ethical problems at all.   Moreover, the arguments against the morality of cloning does NOT apply here because we are cloning what is effectively a BACTERIA and NOT human DNA!!

 

If I were in government in a country that wants to grow its healthcare sector - like Thailand - I would invest heavily in this as a research problem and then build out a sector to sell and administer those transfusions after the basic research is done.

 

You might be right about the end result, but it is mystifying to me.   This is low hanging fruit that could fundamentally change life for humans.



#11 niner

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Posted 12 January 2015 - 03:36 AM

One consideration with mitochondrial transfer that may muddy the water a bit is that mitochondria aren't just bacteria that are hanging out in our cells working for us-- They are almost entirely integrated into our nuclear genome, with the exception of a handful of genes that live in the mitochondrial DNA.  Thus the engineering we can do (without messing with the nuclear genome) is limited to those proteins that are encoded by mtDNA.  We can't do something really interesting like giving ourselves whale mitochondria.   In addition, mitochondria don't just make ATP.  They are involved in multiple activities, like respiratory burst for immune purposes, or involvement in apoptosis.  The list of things that they are involved in that we're not yet aware of might be longer than the list of things we know about, so messing with mitochondria is likely to have unexpected consequences.



#12 pone11

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Posted 12 January 2015 - 03:45 AM

One consideration with mitochondrial transfer that may muddy the water a bit is that mitochondria aren't just bacteria that are hanging out in our cells working for us-- They are almost entirely integrated into our nuclear genome, with the exception of a handful of genes that live in the mitochondrial DNA.  Thus the engineering we can do (without messing with the nuclear genome) is limited to those proteins that are encoded by mtDNA.  We can't do something really interesting like giving ourselves whale mitochondria.   In addition, mitochondria don't just make ATP.  They are involved in multiple activities, like respiratory burst for immune purposes, or involvement in apoptosis.  The list of things that they are involved in that we're not yet aware of might be longer than the list of things we know about, so messing with mitochondria is likely to have unexpected consequences.

 

Are we sure what we can and cannot do?  One of the things they should do with mice is see if they can:

 

* Use a different species mitochondria

* Use mitochondria from a different mouse

* Improve coding of the existing mitochondria to upregulate things like endogenous SOD2 and catalase production

 

And I understand your point about being careful, but we are talking about cloning rather than synthesizing from scratch, and the point is to get many years of experience across many different research groups doing this in mice so we understand the limits and opportunities.


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#13 corb

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Posted 12 January 2015 - 07:10 AM

Are we sure what we can and cannot do?

 

http://www.ncbi.nlm....pubmed/24486322
http://www.ncbi.nlm....pubmed/24815168
http://www.ncbi.nlm....pubmed/22412925
http://www.ncbi.nlm....pubmed/12054926
http://www.ncbi.nlm....pubmed/17296332
http://www.ncbi.nlm....pubmed/11328868
http://www.ncbi.nlm....pubmed/24606795
http://www.ncbi.nlm....pubmed/24199594


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#14 Danail Bulgaria

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Posted 12 January 2015 - 09:45 AM

Very nice, but what is the purpose of mitochondrial transplants?



#15 pone11

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Posted 12 January 2015 - 10:16 AM

Very nice, but what is the purpose of mitochondrial transplants?

 

So the free radical theory of aging has become about the aging of mitochondria.   Every tissue cell in the body has about 1000 mitochondia, and these are the energy factories of the cell.   Aerobic metablism and the electron transport chain reside in those.   As you age, these mitochondria produce fewer antioxidants, increase the level of oxidative stress, and decrease the amount of energy produced from oxygen in aerobic metabolism.   In addition to getting less energy, presumably the less efficient mitochondria also fail to produce proteins and enzymes as efficiently.   All of that ends up affecting the main cell through reduced activity in the cytoplasm.

 

The idea in this thread is to give your cells the mitochondria of a young person - or engineered mitochondria that do not have the defects - and you might instantly become younger biochemically from this infusion.   Easy to say and apparently harder to do....



#16 Danail Bulgaria

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Posted 12 January 2015 - 12:26 PM

I know all that. I meant how this can make us younger. For example why not we freeze some of our cells, after years clone the mitochondria and transplant them in our own older cells. Then we will see if they will become younger. This is what I was asking for.



#17 pone11

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Posted 12 January 2015 - 12:30 PM

I know all that. I meant how this can make us younger. For example why not we freeze some of our cells, after years clone the mitochondria and transplant them in our own older cells. Then we will see if they will become younger. This is what I was asking for.

 

I would never have gotten that question from your earlier remark.   But the reason to transplant is that we can make the donor someone who is very young and has no mitochondrial damage.

 

Your solution might entail a 40 year old person waiting until they are 70 to become more like 40.   The solution we are discussing might entail a 40 year old person becoming more like a 20 year old person, and if it can be done from a blood transfusion alone then maybe sooner rather than later.



#18 Danail Bulgaria

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Posted 12 January 2015 - 12:33 PM

lol man, what is a better donor than yourself? Its like the blood doping. You take your own blood, freeze it, and import it back in need. You take your own mitochondria, freeze them, take them after 10-20 years, clone them, implant them and see if you become younger.



#19 pone11

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Posted 12 January 2015 - 12:38 PM

 

Here are the studies I would like to see done:

 

Take old rats, young adult rats, and juvenile rats.

 

A:  Transfuse whole blood from young adult rats to old rats, 2%, 5%, or 10% of blood volume once every two weeks

 

B:  Transfuse whole blood from juvenile rats to old rats, 2%, 5%, or 10% of blood volume once every two weeks

 

C:  Remove red blood cells and transfuse remaining blood products from young adult rats to old rats, 2%, 5%, or 10% of blood volume once every two weeks

 

D:  Remove red blood cells and transfuse remaining blood products from juvenile rats to old rats, 2%, 5%, or 10% of blood volume once every two weeks

 

You might have to do some blood-letting to maintain critical blood parameters, after the transfusions have time to settle.

 

By the end of that experiment I would expect that we will know:

 

1) Whether small amounts of blood transfused frequently have as much effect as large amounts of blood

 

2) Whether red blood cells are required (probably not since they do not have mitochondria)

 

3) Whether using extremely young juvenile rats has a measurable effect against using young adults

 

4) Whether any of these populations develop cancer or other diseases with higher frequency

 

5) Quantify what the life extension effect would be

 

6) Measure many metabolites associated with aging, both intracellular and mitochondrial

 

If at the end of all of this the best result is 20% life extension, it would be hard to get excited about that.   If the result is a doubling of life, then basically you have a roadmap for how - technically - you could apply the same thing to humans in a very short timeframe.

 

That's the test that might make a difference for us today.   This other stuff with engineering mitochondria and figuring out how to insert them into cells sounds like it is 10 years away - if that - from getting results, and then figure another 10 years to figure out how to commercialize it in humans.


Edited by pone11, 12 January 2015 - 12:40 PM.


#20 orion602

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Posted 13 January 2015 - 12:29 AM

lol man, what is a better donor than yourself? Its like the blood doping. You take your own blood, freeze it, and import it back in need. You take your own mitochondria, freeze them, take them after 10-20 years, clone them, implant them and see if you become younger.

 

Perhaps you dont have to wait, you just need to take some younger mitochonria originating from the same source you received them for the first time. (egg cell) one just need to take mitochondria from younger siblings or female lineage descendants from the same mother for this "rejuvenation testing" :)

 

Also i guess even older women's eggs' mitochondria undergo mysterious 'rejuvenation' proccess after (or before?!) fertilization, so that could be another option how to get youngest mitochondria possible.


Edited by orion602, 13 January 2015 - 12:34 AM.


#21 resveratrol_guy

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Posted 13 January 2015 - 04:20 AM

I am less clear on using statistical techniques to identify the least damaged mtDNA.   How do we know which sections are in error and which are advantageous changes?   Seems like it might be more efficacious to just map that genome and identify obvious defects and just change those when you make the model.

 

The other thing is I don't think I would upregulate distribution of those mitochondria.  There is too much risk in that approach that the new mitochondria - if they have defects - will end up killing you or causing a serious disease state.  I think what I might do is try to just introduce some small measured change through monthly transfusions.  For example, if you could change out 3% every month - and if you assume that the improvements represented in that 3% will be persistent statistically across the body going forward - then after five years you would have effectively changed out 84% of the mitochondria.   I think that is enough to ensure dramatic health improvements, while at the same time going very slow and observing all kinds of markers throughout the body for change.   If you find things going bad, then you just stop the transfusions and let mitochondria settle things out on their own before you start up again.

 

I just don't see the ethical problems at all.   Moreover, the arguments against the morality of cloning does NOT apply here because we are cloning what is effectively a BACTERIA and NOT human DNA!!

 

If I were in government in a country that wants to grow its healthcare sector - like Thailand - I would invest heavily in this as a research problem and then build out a sector to sell and administer those transfusions after the basic research is done.

 

You might be right about the end result, but it is mystifying to me.   This is low hanging fruit that could fundamentally change life for humans.

 

 

At least initially, I would not advocate attempting to enhance mitochondrial function by injecting theoretically beneficial mutations. I would simply attempt to revert the mitochrondria to a healthy adult state. That state would be statistically implied by analyzing a diverse crop of mitochondria from all over the body. I don't know if mtDNA can get methylated to create epigenetic effects akin to the nuclear case, but if so, we would simply have to gather statistics on a per-organ basis instead of a per-person basis. Even in a severely mutated individual, there are simply so many mitochondria that the sample size would be hugely sufficient, provided that we sampled individual mitochondria from a distant set of cells.

Having said that, I don't see how we could implement selective mitochrondrial transplantation, except perhaps to separate the vascular system from the CNS, on account of the BBB. I really think you need to "just trust" the stem cells to act as delivery vehicles; at most, you might try to upregulate their tendency to donate. This is another reason why I think the issue of mitochondrial enhancement, as opposed to merely rejuvenation, is off the table until we master transplantation.

 

corb's documents linked above show a moderately advanced state of the art. There is actually hope that we might succeed here.

 

I think merely extending healthspan and not lifespan would be a major victory, as we have a major cost-of-aging crisis on our hands which is largely a mitochondrial crisis.

 

The experiments suggested above remind me of the Stanford parabiosis trials currently underway (and recently finished?), in which young people were giving blood to older people in order to test the rejuvenative effects thereof. While this is mostly concerned with growth factors, there might be some translation to the mitochondrial issue.

 

The Bahamas is actually ahead of Thailand with respect to biotech legislation, on account of Peter Nygaard's therapy center under development there.
 

Finally, if the stem cells can do it, then we might be able to do transplanation manually using some sort of electroporation: flood the plasma with "naked" mitochondria, then perform reversible electroporation (similar to the stereotactically guided irreversible variety performed in tumor destruction) on the target tissue, thereby inducing it to "import" mitochondria. (I find the implication that there exist lipid bilayer pores large enough to accomodate whole mitochondria, astounding. But perhaps I misunderstand the mechanism by which stem cells accomplish transplantation.) But this is a much more complicated problem which need not be addressed initially.


Edited by resveratrol_guy, 13 January 2015 - 04:33 AM.


#22 pone11

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Posted 13 January 2015 - 07:35 AM

 

I am less clear on using statistical techniques to identify the least damaged mtDNA.   How do we know which sections are in error and which are advantageous changes?   Seems like it might be more efficacious to just map that genome and identify obvious defects and just change those when you make the model.

 

The other thing is I don't think I would upregulate distribution of those mitochondria.  There is too much risk in that approach that the new mitochondria - if they have defects - will end up killing you or causing a serious disease state.  I think what I might do is try to just introduce some small measured change through monthly transfusions.  For example, if you could change out 3% every month - and if you assume that the improvements represented in that 3% will be persistent statistically across the body going forward - then after five years you would have effectively changed out 84% of the mitochondria.   I think that is enough to ensure dramatic health improvements, while at the same time going very slow and observing all kinds of markers throughout the body for change.   If you find things going bad, then you just stop the transfusions and let mitochondria settle things out on their own before you start up again.

 

I just don't see the ethical problems at all.   Moreover, the arguments against the morality of cloning does NOT apply here because we are cloning what is effectively a BACTERIA and NOT human DNA!!

 

If I were in government in a country that wants to grow its healthcare sector - like Thailand - I would invest heavily in this as a research problem and then build out a sector to sell and administer those transfusions after the basic research is done.

 

You might be right about the end result, but it is mystifying to me.   This is low hanging fruit that could fundamentally change life for humans.

 

 

At least initially, I would not advocate attempting to enhance mitochondrial function by injecting theoretically beneficial mutations. I would simply attempt to revert the mitochrondria to a healthy adult state. That state would be statistically implied by analyzing a diverse crop of mitochondria from all over the body. I don't know if mtDNA can get methylated to create epigenetic effects akin to the nuclear case, but if so, we would simply have to gather statistics on a per-organ basis instead of a per-person basis. Even in a severely mutated individual, there are simply so many mitochondria that the sample size would be hugely sufficient, provided that we sampled individual mitochondria from a distant set of cells.

Having said that, I don't see how we could implement selective mitochrondrial transplantation, except perhaps to separate the vascular system from the CNS, on account of the BBB. I really think you need to "just trust" the stem cells to act as delivery vehicles; at most, you might try to upregulate their tendency to donate. This is another reason why I think the issue of mitochondrial enhancement, as opposed to merely rejuvenation, is off the table until we master transplantation.

 

corb's documents linked above show a moderately advanced state of the art. There is actually hope that we might succeed here.

 

I think merely extending healthspan and not lifespan would be a major victory, as we have a major cost-of-aging crisis on our hands which is largely a mitochondrial crisis.

 

The experiments suggested above remind me of the Stanford parabiosis trials currently underway (and recently finished?), in which young people were giving blood to older people in order to test the rejuvenative effects thereof. While this is mostly concerned with growth factors, there might be some translation to the mitochondrial issue.

 

The Bahamas is actually ahead of Thailand with respect to biotech legislation, on account of Peter Nygaard's therapy center under development there.
 

Finally, if the stem cells can do it, then we might be able to do transplanation manually using some sort of electroporation: flood the plasma with "naked" mitochondria, then perform reversible electroporation (similar to the stereotactically guided irreversible variety performed in tumor destruction) on the target tissue, thereby inducing it to "import" mitochondria. (I find the implication that there exist lipid bilayer pores large enough to accomodate whole mitochondria, astounding. But perhaps I misunderstand the mechanism by which stem cells accomplish transplantation.) But this is a much more complicated problem which need not be addressed initially.

 

 

Can you explain the statistical issue a bit better?   Assume that 20% of the mitochondria have beneficial mutations that enhance aspects of their function by 10% or more.  Assume 50% of mitochondria are degraded in various ways by 20%.  Assume the remaining 30% are a complete train wreck and are severely dysfunctional in multiple ways.

 

How could statistics ever help us to determine which mutations are beneficial and which are not?   At best you would see distributions of gene structures, but that can never tell you whether a given value is beneficial or not.   And once you understand the genome's function, why would you need to profile the distribution?

 

Thailand is nowhere on research, but many people do not know that Thailand has become a major player in providing critical care operations at budget prices.  They make a pitch to that patient that they can do an operation for 1/10th the cost, and you get a nice vacation thrown in for free.    Given Thailand is building out their distribution system for delivering the care, it makes sense for them to find a market where they could be one of the few players providing a service.   If no one else wants to touch blood/mitochondrial transplants from young to old, they could step in and take advantage of that to build experience and market share.



#23 Turnbuckle

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Posted 13 January 2015 - 12:41 PM

lol man, what is a better donor than yourself? Its like the blood doping. You take your own blood, freeze it, and import it back in need. You take your own mitochondria, freeze them, take them after 10-20 years, clone them, implant them and see if you become younger.

 

 

A better donor than yourself would be a world famous athlete. One who has superior mitochondria to begin with. Of course, the mtDNA contains only a small fraction of the required coding for its operation, but there are still many varieties in the gene pool, and some are no doubt better than others.



#24 Danail Bulgaria

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Posted 13 January 2015 - 12:43 PM

 

lol man, what is a better donor than yourself? Its like the blood doping. You take your own blood, freeze it, and import it back in need. You take your own mitochondria, freeze them, take them after 10-20 years, clone them, implant them and see if you become younger.

 

Perhaps you dont have to wait, you just need to take some younger mitochonria originating from the same source you received them for the first time. (egg cell) one just need to take mitochondria from younger siblings or female lineage descendants from the same mother for this "rejuvenation testing" :)

 

Also i guess even older women's eggs' mitochondria undergo mysterious 'rejuvenation' proccess after (or before?!) fertilization, so that could be another option how to get youngest mitochondria possible.

 

 

lol I am a male :) I haveno egg cells lol :) Is there a way for a mitochondira to be "cloned" ? People, who have biological and genetic background may try to clone a mitochondria.
 



#25 Danail Bulgaria

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Posted 13 January 2015 - 12:45 PM

 

lol man, what is a better donor than yourself? Its like the blood doping. You take your own blood, freeze it, and import it back in need. You take your own mitochondria, freeze them, take them after 10-20 years, clone them, implant them and see if you become younger.

 

 

A better donor than yourself would be a world famous athlete. One who has superior mitochondria to begin with. Of course, the mtDNA contains only a small fraction of the required coding for its operation, but there are still many varieties in the gene pool, and some are no doubt better than others.

 

 

Fine, but will your cells reject the better donor mitochondira? Plus the mtDNA is not yours. Isn't it better to be yours exactly mtDNA?
 


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#26 Turnbuckle

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Posted 13 January 2015 - 01:01 PM

 

 

lol man, what is a better donor than yourself? Its like the blood doping. You take your own blood, freeze it, and import it back in need. You take your own mitochondria, freeze them, take them after 10-20 years, clone them, implant them and see if you become younger.

 

 

A better donor than yourself would be a world famous athlete. One who has superior mitochondria to begin with. Of course, the mtDNA contains only a small fraction of the required coding for its operation, but there are still many varieties in the gene pool, and some are no doubt better than others.

 

 

Fine, but will your cells reject the better donor mitochondira? Plus the mtDNA is not yours. Isn't it better to be yours exactly mtDNA?
 

 

 

 

Every time a new human is created, they get whatever mtDNA the mother had, whether it is optimum for their genetic makeup or not. Perhaps you would be better off with some other strain. One way to get that more optimum strain is to get a transfusion of blood--preferably from a young donor athlete. As long as you have the same blood type, you should be fine. In fact, all you may need are the platelets. Platelets are 1/5 the size of red blood cells, yet have mitochondria that they sometimes shed as free mitochondria, and sometimes encapsulated in exosomes. Exosomes and their contents are known to be absorbed by somatic cells, which could thereby seed new mitochondria throughout the body.


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#27 Danail Bulgaria

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Posted 13 January 2015 - 01:18 PM

Is this a theory, or some one has tried it?



#28 Turnbuckle

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Posted 13 January 2015 - 02:25 PM

Is this a theory, or some one has tried it?

 

It's been done, at least in vitro, and for other purposes--

 

In the present work, we demonstrate the possibility of using human blood platelets as mitochondrial donors for the repopulation of mtDNA-less (rho 0) cells. The noninvasive nature of platelet isolation, combined with the prolonged viability of platelet mitochondria and the simplicity and efficiency of the mitochondria-transfer procedure, has substantially increased the applicability of the rho 0 cell transformation approach for mitochondrial genetic analysis and for the study of mtDNA-linked diseases.

 

http://www.ncbi.nlm....les/PMC1918182/

 



#29 resveratrol_guy

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Posted 13 January 2015 - 11:07 PM

As to statistics, pone11 you are right, of course: in general, we have no clue whether a given mutation is good or evil. So I would not initially aim to enhance. I would aim for the center of the distribution. Nuclear DNA sequencing can be done by shotgun sequencing, which is a well known and fast algorithm for whole genome use. While it's not as simple as saying "there's a 73% chance that base pair #208 is adenine", mainly because some mutations change the length of the genome, one can use various applications of Bayesian logic to deduce with confidence the most "native" nucleotide to write at a given location. I see no reason why this would not work even more effectively with mtDNA, which is extremely short and junk-free by comparison.

Let's look at an example. Say you have:

TCCCAGGGTCAGGTAATGC
TCCCAGTTCAGGTAATGC
TCCCAGGTTCAGGTACTGC
TCCCAGGTTAATGC

We obviously have some mutations here, some of which affecting length, but a reasonable "median" sequence would be:

TCCCAGTTCAGGTAATGC

With many more base pairs, there would surely be a large number of equally good approximations, but we would reduce our chances of fatal mutations by doing the most uninteresting thing at each point in the sequence.

 

A quick and dirty alternative process, involving much less computation, would be to simply copy the most statistically unremarkable mtDNA ring, verbatim. That way, we avoid the risk of explosively dangerous single-nucleotide mutations, at the cost of being in some way metabolically suboptimal. Thus in your example, we would just reproduce one of the "boring" 50% which are 20% degraded. It might help to look at the health of the host cell in order to select a winner, obviously.

Turnbuckle's comments just prove to me that I need to relearn stem cell theory every day. It's mindblowing that I can just import some random athelete's mitochondria, and not have the cytoplasmic equivalent of an allergic reaction. It seems scary to inject oneself with foreign mitochondria, but certainly this is worth further research, as it would potentially obviate the above risky analysis.
 



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#30 niner

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Posted 14 January 2015 - 12:26 AM

I don't see a need to worry greatly about "making a mistake" if we were to mess with mtDNA. You wouldn't put them into a human immediately, you'd put them into cell culture and see what happens to the cells. Do they exhibit improved energetics? Do they live longer? There are many bench level assays that could be employed to evaluate the health of the cells.

As an aside, I wonder how much of the effect seen in heterochronic parabiosis is due to organelle transfer?
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