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A Look at Parabiosis Research


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#1 reason

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Posted 22 January 2015 - 12:07 PM


Parabiosis involves joining together the circulatory systems of two individuals. Joining together an old and a young mouse has proved to be very instructive now that researchers can measure quite detailed aspects of cellular biology, and in recent years it has been used to investigate age-related changes that take place in levels of various proteins in the blood. Some of those proteins can alter cellular behavior in important ways, and manipulating them in old individuals can improve degraded tissue function. This article provides a recent history of this research and hopes for the near future:

Experiments with parabiotic rodent pairs have led to breakthroughs in endocrinology, tumour biology and immunology, but most of those discoveries occurred more than 35 years ago. For reasons that are not entirely clear, the technique fell out of favour after the 1970s. In the past few years, however, a small number of labs have revived parabiosis, especially in the field of ageing research. By joining the circulatory system of an old mouse to that of a young mouse, scientists have produced some remarkable results. In the heart, brain, muscles and almost every other tissue examined, the blood of young mice seems to bring new life to ageing organs, making old mice stronger, smarter and healthier. It even makes their fur shinier. Now these labs have begun to identify the components of young blood that are responsible for these changes. And last September, a clinical trial in California became the first to start testing the benefits of young blood in older people with Alzheimer's disease.

"I think it is rejuvenation," says Tony Wyss-Coray, a neurologist at Stanford University in California who founded a company that is running the trial. "We are restarting the ageing clock." Many of his colleagues are more cautious about making such claims. "We're not de-ageing animals," says Amy Wagers, who has identified a muscle-rejuvenating factor in young mouse blood. Wagers argues that such factors are not turning old tissues into young ones, but are instead helping them to repair damage. "We're restoring function to tissues."

Six out of a planned 18 people with Alzheimer's, all aged 50 or above, have already begun to receive plasma harvested from men aged 30 or younger. In addition to monitoring disease symptoms, the researchers are looking for changes in brain scans and blood biomarkers of the disease. Wagers is eager to see the results, but she worries that a failure would be difficult to interpret and so could set the whole field back. Plasma from a 30-year-old donor may not contain factors beneficial to patients with Alzheimer's, for example. She and others would prefer to see testing for a specific blood factor or combination of known factors synthesized in the lab, for which the mechanism of action is fully understood.

There are also lingering concerns as to whether activating stem cells - which is what the young blood most often seems to do - over a long period of time would result in too much cell division. "My suspicion is that chronic treatments with anything - plasma, drugs - that rejuvenate cells in old animals is going to lead to an increase in cancer. Even if we learn how to make cells young, it's something we'll want to do judiciously."

Link: http://www.nature.co...o-blood-1.16762


View the full article at FightAging
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#2 resveratrol_guy

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Posted 22 January 2015 - 06:02 PM

Of note from the Nature article: "Plasma alone had the same effects. 'We didn't have to exchange the whole blood,' says Wyss-Coray. 'It acts like a drug'... His research, published last May, caught the attention of a company in Hong Kong owned by a family with a history of Alzheimer's disease, which is characterized by neuron loss. One family member's condition had reportedly temporarily improved after they received a plasma transfusion. So the company put forward the initial funding to translate Wyss-Coray's approach to human clinical trials. Wyss-Coray formed a start-up company, Alkahest in Menlo Park, California, and in September 2014 it began a randomized, placebo-controlled, double-blind trial at Stanford, testing the safety and efficacy of using young plasma to treat Alzheimer's disease."

 

So "temporarily improved" suggests to me that the plasma invigorated the person's stem cells to perform some repairs, which were then gradually overcome by the continuing disease process. More plasma more often given earlier in chronic disease might be a way to improve upon this anecdotal result.

 

Parabiotic plasma transfer is much safer than whole blood transfer, not the least of which because it's easy to imagine a synthetic version of plasma, which is free of problematic DNA and pathogens, and can be manufactured cheaply in bulk quantities. But in the interim, this is easily harvested from paid volunteers. My guess is that the brilliant research above will go nowhere (I mean, seriously, they've only begun plasma transfusions on 6 of an intended 18 Alzheimer's patients after months of shuffling papers?), so it will be rapidly mooted by banana republic medical tourism services. How much would you bet that within a year, you'll be able to travel to one of these places and acquire plasma for around $100 a liter? I would sell the stuff to a therapy center myself, were I young enough to produce it with sufficient quality.

 

Obviously there are serious ethical issues here, not the least of which being the ethical and hygenic sourcing of plasma. But to a large extent, such issues could be mitigated by colocating the donors and the recipients in order to foster communication and process knowledge.

 

I hope the third world is listening. Done right, this could benefit rich and poor, young and old, alike. In any event, let's not force the desperate to wait for science at the expense of opportunity. It will be clear enough, once a few of these gray market clinics open up, whether or not this actually works.

 


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#3 corb

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Posted 22 January 2015 - 07:13 PM

 

"My suspicion is that chronic treatments with anything - plasma, drugs - that rejuvenate cells in old animals is going to lead to an increase in cancer.

 

That's a much more interesting reason to do the experiment in itself if you ask me.
They're giving them ~30 year old blood, 30 year olds don't generate neurons in the brain, so even if it stops the AD these people won't get better. 
So that makes the whole endeavor meaningless, they could at least try to get some useful data, even if it's not related to AD.


Edited by corb, 22 January 2015 - 07:13 PM.


#4 niner

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Posted 22 January 2015 - 08:13 PM

It's not all 30 year old plasma.  The donor population is 30 and younger, so it could range down as low as 18.  Personally, I would have cut it off at 25.   I share Dr. Wagers' concern that a failure in this perhaps poorly designed trial could set the whole field back.  That would be unfortunate.  Regarding third world medical tourism, that's a possibility, but I wouldn't expect plasma at $100/liter.  I'd expect them to pay a couple bucks a liter to their impoverished donors, and charge the wealthy more like a thousand dollars a liter.

 

IMHO, Wyss-Coray is pimping this thing a little too strongly.



#5 Mind

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Posted 23 January 2015 - 12:06 PM

Yes, Wyss-Coray is overly optimistic at this point, but Dr. Wagers' is holding back progress by being overly negative. These few Alzheimer's patients have a chance...maybe miniscule...that they could be rescued from years of a terrible disease. Human trials have to occur at some point. If we wait until absolutely everything is known about such a treatment and analyze every possible short term and long term positive and negative effect, nothing will ever get done. If the patients and their families are okay with the treatment and understand the risks, hooray for them. Even if the treatment does not work, at least these people will have contributed to the knowledge of Alzheimer's and parabiosis. They are medical heroes. Hooray for the risk-takers.


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#6 Danail Bulgaria

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Posted 23 January 2015 - 03:33 PM

Sorry, misunderstood first post. :)

 

If you connect the bloodstream of two people, won't you receive immune reaction against each-other ?


Edited by seivtcho, 23 January 2015 - 03:37 PM.


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#7 ceridwen

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Posted 23 January 2015 - 06:59 PM

Why don't we set up our own system. Are there any young people out there who wouldn't mind donating?

#8 corb

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Posted 23 January 2015 - 07:47 PM

Why don't we set up our own system. Are there any young people out there who wouldn't mind donating?

 

If this works I suspect the system will get set up on it's own.

Criminally efficient.



#9 ceridwen

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Posted 23 January 2015 - 07:50 PM

Is there anything criminal about saving lives? Everyone should donate of their own free will.

#10 corb

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Posted 23 January 2015 - 10:50 PM

Is there anything criminal about saving lives? Everyone should donate of their own free will.

 

Depends on how much blood you'd need to rejuvenate a typical 60+ old "rockstar" - any rich american with all their nice little drug habits really.

I can easily see this getting way out of hand.

Even if it's one pint per person, per month, that's still a lot of blood. Especially for rare rh- blood.
And you have to consider something else. There's old people everywhere.
 

Imagine this: A family in India, the grandmother is suffering from mild age related dementia. Who will her grandchildren give the blood to? You? Or their grandmother?

This will turn into a business, no way around. Otherwise people will just give the blood to old relatives that need it.
And let's be honest here - westerners have too much old people that need it and not nearly enough young that can supply it.

 

So in the end it's much better if the factors that activate your cells are isolated and synthesized. It will still cost you either way but at least the later won't turn into some ugly dystopian vampire pulp novel.



#11 niner

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Posted 24 January 2015 - 04:27 AM

Yes, Wyss-Coray is overly optimistic at this point, but Dr. Wagers' is holding back progress by being overly negative. These few Alzheimer's patients have a chance...maybe miniscule...that they could be rescued from years of a terrible disease. Human trials have to occur at some point. If we wait until absolutely everything is known about such a treatment and analyze every possible short term and long term positive and negative effect, nothing will ever get done. If the patients and their families are okay with the treatment and understand the risks, hooray for them. Even if the treatment does not work, at least these people will have contributed to the knowledge of Alzheimer's and parabiosis. They are medical heroes. Hooray for the risk-takers.

 

I disagree.  Wagers isn't holding back progress by wanting to see a trial that's more likely to work.  If this Wyss-Coray trial works, that's great, but if it doesn't work, that's a potential disaster, because everyone will look at that and say "this doesn't work in humans" and the funders will give their money to something they think is more likely to work.  If a poorly designed trial doesn't work, it doesn't contribute to knowledge as much as it muddies the water. 



#12 Danail Bulgaria

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Posted 24 January 2015 - 06:49 AM

How much blood transfusions are supposed to be needed in order to be restored the age related dementia?

 

I don't know if you know it, but many doctors will object against transfusing more than 300 ml of donated blood. This can be the reason such an effect to be missed from the modern medicine. On the other hand transfusing more in people may have serious consequences even if one blood type is used.


Edited by seivtcho, 24 January 2015 - 06:52 AM.


#13 ceridwen

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Posted 24 January 2015 - 06:59 AM

Better than the alternative

#14 resveratrol_guy

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Posted 24 January 2015 - 09:08 PM

Why worry about blood type when it sounds like plasma alone will deliver good benefits? I completely agree that this stuff should be synthesized in the long term. (Now, even your plasma is going to be made in China...) But it's also obvious that we barely have a clue how to do that at this point, first and foremost because we don't have much data on the human proteome yet. (It's probably going to involve vats of bacteria which have been genetically edited to produce human plasma components in some economically reduced fashion.)

So in the meantime, it's pretty much a foregone conclusion that plasma exchanges will be built, and sales will go from the young poor to the old rich. But we would do ourselves a disservice to assume that this has to happen in some sort of Mad Max context just because there's money involved. It's not much more complicated than providing additional donor age data on refrigerated blood to consenting donors and paying recipients. Isolating plasma might be wise for efficiency reasons, but we could start with whole blood and just deal with the excessive fluid issues. And why should we assume such huge pricing spreads? This is easily enough done with current technology that there should be a lot of competition. But like anything else, if you're not able to see where it comes from and how it's refined, don't buy it.

Furthermore what scientific study could possibly compete with a marketplace involving millions of participants, if even 1% of them actually tracked their health changes before and after? A thousand dirty data points is probably worth much more than 18 clean ones, in this case. Not that the Stanford study is useless, but the cat is already out of the bag, and economics will take over soon enough.
 



#15 niner

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Posted 24 January 2015 - 11:29 PM

If the Stanford study fails, the cat might crawl back into the bag and go to sleep.  The use of plasma instead of whole blood may simplify things, since the AB antigens are on the RBCs, but there are antibodies in plasma, so I'm not sure how simple this really is.   At least you can donate plasma without getting anemia.   I agree that there doesn't need to be a Mad Max scenario for this to happen, but I think that middlemen will probably suck a lot of money out of it, and third world donors will get only a tiny fraction of the final sale price.   If this works, and that's a pretty big if, then I suspect that it would not be long before we have a decent handle on what the factors are.  Actually getting a synthetic product on the market would probably take until 2030-ish.  That leaves a pretty large window for a plasma market.  At the moment, plasma donors in the US are paid anywhere from ten to sixty dollars per donation, depending on location and company.   It would undoubtedly be less in countries with a lower cost of living.  When you add in the screening required for safety, necessary overhead, and take into account the demand if it works well, the cost to the recipient is likely to be pretty high.


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#16 resveratrol_guy

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Posted 26 January 2015 - 04:18 AM

Wow, I didn't even know that plasma donation was already an industrialized process. (Nice data find, BTW.) In which case, what's not to like? The high cost of plasma? Versus what, having Alzheimer's disease and taking ineffective prescription medications? Maybe I'm missing your point, niner, but it sounds like the marketplace is even closer to reality than I had imagined. (I'm not worried about the Stanford results because they'll take forever to publish and the results will be too multifaceted to reach statistical significance with only 18 subjects. My crystal ball says the study will conclude with: "This needs more study. We need another grant.")

 

I do worry that this will start up in the most materialistic and least ethical countries. But that doesn't mean it can't be at least slightly regulated eventually so we don't end up getting plasma from imprisoned political dissidents and the like.

 



#17 drtom

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Posted 03 February 2015 - 11:27 AM

"My suspicion is that chronic treatments with anything - plasma, drugs - that rejuvenate cells in old animals is going to lead to an increase in cancer. Even if we learn how to make cells young, it's something we'll want to do judiciously."

 

I've heard this argument before...it's not so straightforward.

Fact: 90% of cancers are diagnosed in people over the age of 50! Therefore, a "youthful" microenvironment ahould promote less cancer development, not more.

 

Dr Tom


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#18 ceridwen

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Posted 03 February 2015 - 12:40 PM

yes resveratrol_Guy I think I agree with you that is how the trials will end up just like every other parabiosis trial of this kind that has been happening for I don't know how long. So much for them saying that it would have been in the clinics by Decemwe.
December sorry.

#19 ceridwen

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Posted 03 February 2015 - 12:43 PM

The problem with a high cost to the recipient is that this has to be repeated every 3 weeks. I hope that does not make it unaffordable to all except the very rich

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#20 Steve H

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Posted 15 June 2015 - 01:35 PM

I have received this from Josh Mittledorf about the Alkahest Plasma trial so it seems like they are having trouble finding candidates:
 

I wrote to Wyss-Coray about the status of his project and received a response.  Recruitment is the bottleneck. They hope to have results by the end of the year, and invite people interested in being subjects to contact contact Sharon Sha:

 

 

 
Thank you for your interest in our research and in the possibility of participating in clinical trials. The Stanford Center for Memory Disorders does have an active clinical trials program, including a trial of young blood plasma as a treatment for Alzheimer's disease. There are two ways to get involved:
(1) If there has already been an evaluation by a neurologist (or equivalent) who has performed testing and rendered a diagnosis of Alzheimer's disease or Mild Cognitive Impairment, then please assemble medical records, making sure to include (A) the MRI scan or other brain images on a computer CD, and (B) the neurologist's medical notes and lab reports explaining the diagnosis and the workup used to arrive at that diagnosis. Please mail those items to:
Sharon J. Sha, MD, MS
Stanford Center for Memory Disorders
Clinical Assistant Professor, Department of Neurology and Neurological Sciences
300 Pasteur Drive
Room A343, MC5235
Stanford, CA 94305-5235
tel: 650-723-6469
Your records will be reviewed by our faculty, and you will be contacted about potential trials that you may qualify for. You may contact Ms. Tania Marcal -- tmarcal@stanford.edu, the clinical trials coordinator, for questions about this process, including whether your records were received.
(2) If there has not yet been any evaluation by a memory/dementia specialist, then you are welcome to come to the Stanford Center for Memory Disorders as a patient. It is important to have an accurate medical diagnosis before enrolling in an experimental trial. Please contact our staff at 650-723-6469 for an appointment or for answers to your questions. We accept self-referrals, depending upon medical insurance, and we can generally accommodate new patients within 1-2 weeks. All of neurologists at the Stanford Center for Memory Disorders can speak with you about clinical trials that you may qualify for.

 


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