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Forever young, I want to be forever young / Do you really want to live forever? Forever young...

The unusual experiments of Stanford University School of Medicine neurology professor Thomas A. Rando, MD, Ph.D on laboratory rats sound like the work of a twisted madman.  But they're attracting serious scientific attention, and some believe they may hold the key to the fountain of youth.

I. Parabiosis -- the Human Centipede of the Rodent World

The basis of Professor Rando's experiment is a straightforward hypothesis that has been proposed from time to time -- could tissue transplants from a young person or hormone replacement revitalize aging tissues to resemble younger ones?

The methodology is the more controversial and unusual part of the lab leader's work.  Professor Rando has revived a technique which was pioneered by Professor Clive M. McCay at Cornell University in the 1950s.

Professor Clive M. McKay
Professor Clive M. McCay (1898-1967) was a pioneer in the field of antiaging at Cornell University.  
[Image Source: UNT Digital Library]

The procedure -- called parabiosis -- involves cutting open the skin of two rats from different groups and stitching skin together, leaving an exposed inner patch of flesh.  The approach -- which vaguely brings to mind the fictional "human centipede" of the horror movie world -- results in a conjoined double rat, as blood vessels grow between the rats.  Eventually the rats come to have essentially one circulatory system, with two beating hearts. 

Parabiotic mice
Parabiotic mice are often used to study whether endocrine or paracrine factors might be responsible for various physiological changes such as the activation of stem cells, weight gain, or other changes. [Image Source: Duyverman et al. (2012)]

An outline of the outlandish surgical procedure is found in this 1956 work by Professor McCay, published in the Bulletin of the New York Academy of Medicine.

The unusual surgery yielded one particularly interesting result -- when old rats and young rats were combined, after they were killed and dissected the tissues (particularly the cartilage) of the older rat appeared rejuventated.  At the time, medical science was unable to explain this unusual finding.

II. Rodent Fusion Enters the Modern Era

A little over a decade ago, parabiosis was relatively uncommon.  

But reviewing the over half century old work of Professor McCay, a pioneer in nutrition and anti-aging, Professor Rando was intrigued.  He hypothesized that signalling chemicals for stems cells might be responsible for the restoration of the older rats that Professor McCay had witnessed.

As mammals age, some populations of their stem cells don't die or go away, but they do fall into dormancy.  Stem cells can differentiate to replace damaged cells, restoring aged tissue.  

Embryonic stem cell
As humans age, their population of adult stem cells -- similar to embryonic stem cells -- fall dormant, robbing them of the "fountain of youth". [Image Source: Metrolic]

But in elderly mammals -- be they mice or men -- these stem cells never get the message to activate and repair the tissue.  Rather, they get that message primarily when growing during their younger years.

Comments Professor Rando:

There were plenty of stem cells there.  They just don’t get the right signals.

Thomas A. Rando
Professor Thomas A. Rando has taken up the mantle of parabiotic anti-aging research.
[Image Source: Stanford]

The medical school researcher tasked several students and collaborators with the morbid task of joining the rats and then examining their tissues after five weeks.  With the more exacting eye of modern medicine, they discovered that not only does the procedure revive the cartilage of the older rats, it also speeds up the healing of their muscle tissues to rates typically observed in young rats and grew new liver cells at a faster rate.

The team also noted something interesting.  The picture was not as pretty for the younger rats.  Their healing and their liver cell growth slowed.  It was as if the older rat had stolen part of their youthful biochemistry, artificially aging them.

Rat rejuvenation
Professor Rondo used green fluorescent protein (GFP) migration to showcase the connectivity of the rats' vascular networks -- a modern twist to the old parabiotic rat. [Image Source: Nature Letters]

The results were published as a letter to the prestigious peer-reviewed journal Nature Letters in 2005.  But until the compounds involved were identified, the research would remain a novelty.

III. Young Blood Rejuvenates the Heart and Brain

The hunt for the compounds involved has been spearheaded by a postdoctoral fellow from Professor Rando's lab: Amy Wagers, PhD.  Today Ms. Wagners is an associate professor of stem cells and regenerative biology at Harvard University.

Professor Amy Wagers
Professor Amy Wagers, Harvard University stem cell researcher [Image Source: Harvard Gazette]

Her first major followup to the 2005 work came in the form of 2010 and 2012 papers [1, 2].  The former showed that the process also rejuvenated heart tissue, while the latter showed that neural tissue was restored to youthfulness via remyelination.

Myelin sheath
The activated stem cells improve repairs of the neuronal myelin sheaths and increased vascularization, key characteristics of a healthy young brain. [Image Source: Wikimedia Commons]

Professor Wagners is also collaborating with her former graduate student, Dr. Saul Villeda.  Dr. Villeda in 2011 had shown in Nature Medicine paper the the process can be used to revitalize the hippocampus -- the area of the brain associated with memory -- in older rats.  His more recent work has showed similar effects in regions of the brain associated with smells.

Professor Saul Villeda
Dr. Saul Villeda, UCSF [Image Source: Vimeo]

Currently a faculty fellow at University of California, San Francisco, Dr. Villeda's important 2011 work began to trace the mechanism of the mental rejuvenation, showing that these brain gains were the result of increased blood vessel growth in the brain.  A handful of protein factors -- c-Fos, Egr1, and pCreb -- were inferred to be responsible for the revitalization, a finding made possible by a piece of advanced genomics software called Ingenuity Pathway Analysis (IPA).
IPA genomics
Genes involved w/ the rejuvenation were identified via genomics. [Image Source: Nature Medicine]

Perhaps in an attempt to move things out of the creepy zone, Dr. Villeda showed that similar effects could be accomplished using plasma from the young rats.  Older rats treated with plasma injections from their younger colleagues performed substantially better in cognitive tests (the cognitive test used was so-called "fear conditioning").

Rat rejuvenation
It turns out you can get the same sorts of results from taking plasma from the young rats and injecting it into the old rats. [Image Source: Nature Medicine]

Who says you can't teach an old rat new tricks?

IV. Taking Anti-Aging Studies Off the Island of Dr. Moreau

Meanwhile Professor Wagner, Dr. Villeda's old advisor, published a similar work in Cell that used genomics to narrow the factor responsible for heart regeneration to a protein called GDF11 (growth differentiation factor 11).  

Heterochronic rats
Parabiotic pairs of a young rat and old rat are reffered to as "heterochronic" where as parabiotic control groups of the same age are known as "isochronic". [Image Source: Nature Medicine]

The study also showed that other possible causes induced by the unnatural procedure -- e.g. changes in blood pressure or changes in the conjoined rodents' behavior -- were not to blame and the effect appeared to be primarily biochemically induced.

Now Professor Wagner has an in-depth followup that's awaiting publication in Science -- another top peer-reviewed journal.  The followup work shows that GDF11 is responsible not only for much of the stem cell activation in the heart, but also some of the brain rejuvenation, as well.



She and her co-authors write in the summary abstract:

We show that factors found in young blood induce vascular remodeling, culminating in increased neurogenesis and improved olfactory discrimination in aging mice. Further, we show that GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. The identification of factors that slow the age-dependent deterioration of the neurogenic niche in mice may constitute the basis for new methods of treating age-related neurodegenerative and neurovascular diseases.

So one more time, why are scientists playing Dr. Moreau and surgically attaching rats to each other?

The long term goal of all of these studies is to identify the factors that triggered the rejuventation first observed in the 1950s.  While much of the work still remains stuck in the conjoined rat phase, some of the studies have shown similar success using plasma or other extracts.  That shows that the anti-aging effects don't require two creatures to be sewed together, they just need key factors to enter the bloodstream, factors that are only present in the blood of younger mammals.

GDF 11
GDF11 can trigger stem cells to heal hearts in parabiotic rats.  Researchers are hoping human analogues could have similar effects. [Image Source: Cell; Science]

It may strike many as odd that researchers at Harvard University, Stanford University, and other top institutions would resort to such bizarre techniques to try to derive anti-aging medication.  But you can't argue with results; few techniques have showed the remarkable effects that young blood infusions via parabiosis have.  

These studies -- horrifying as they may seem -- are casting key insight into the way stem cells activate, and then fall into dormancy over the mammalian life cycle.  And most crucially they show that you can cheat the system and restart your stem cells, if you feed them the right rejuvenatory protein factors.

Eventually, if human analogues of these factors -- like GDF11 -- are shown to have similar actions and the genes are isolated, researchers could splice them into bacteria and produce gene therapies that could literally role back the clock on a number of  human tissues.  It would be a brave new world of modern medicine if they can pull it off.

And until that era is reached, they'll likely be back at it in the lab, slicing rats open and sewing them together -- in the name of science.

Sources: YouTube, The New York Times



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Scary
By p05esto on 5/7/2014 1:48:54 PM , Rating: 4
Scary stuff. Very soon we'll have rich people having kids kidnapped to infuse them with young blood and to heal their old bodies. The kids will then be killed and buried and the process will continue. In 3rd world countries this will start and eventually hit the US. The fight to live forever is worth every penny in the world. If you can add 1 day to your life isn't that worth a billion dollars?.... if you die what good is that billion? Better to spend the billion and get an extra day of life. Now imagine if something like this adds years to your life or improves your health for longer? Scary scary scary!




RE: Scary
By kattanna on 5/7/2014 2:24:14 PM , Rating: 3
this nightmare scenario would come about if the compound could not be artificially created, and cheaply enough.

and if it cannot be..

then i could easily see a future where babies are breed, matrix style, as a "source" of this new medicine

lets just hope our manufacturing tech is up to the job


RE: Scary
By Azuroth on 5/7/2014 3:06:51 PM , Rating: 3
It's about 80$ for 5µg of >98% purity bacterially grown GDF11 delivered for US customers.

http://www.peprotech.com/en-US/Pages/Product/Recom...


RE: Scary
By MrBlastman on 5/7/2014 3:31:38 PM , Rating: 2
We're humans and most drugs/hormones/whatever that are administered to us are measured in milligrams. A single milligram of that stuff made by e-coli costs $3,900.00.

Can you imagine a 500 milligram treatment of it?

That's two million bucks!

Africa might be full of disease, famine and war--but those conditions are ripe for an old man with deep pockets to recruit new "employees;" with the promise of food and a roof over their head, of course.

Why, the assignment would seem benign enough. It could be disguised as a internship or something. They'll be so hungry they'll jump at the opportunity. Barring a medical exam, of course. And in that exam, through discovery, harrowing news of some obscure medical "condition" would be disclosed to the young prospect.

Fortunately for them, though, there is treatment available! The old codger generously offers to pay for it all--a series of blood refinements. Nothing serious. They lie in a easy chair for eight hours at a time as their blood is filtered through a machine.

... Little do they know they are being sapped of their human GDF11 and whatever other oddities needed for the proper cocktail. They're "milked" for some time until their numbers decrease--and they are declared "cured." Given food and money, they are sent on their way, thankful for the chance opportunity they found. Little do they know, they've already gone hollow--and return to their loved ones, aged, now a shallow, older form of their once desperate self.

And the cycle continues. New youth are selected, "cured," spent and sent, on and on.

After all, when you have enough money, why settle for a clone? You want the real stuff. The deal maker. The pure, one hundred percent primo. Anything else is chump juice.


RE: Scary
By Azuroth on 5/7/2014 3:58:10 PM , Rating: 2
Sure, that's a plausible scenario, one that I'd love to read fleshed out as a full novel even.

The way I see it though, we don't know how much of the stuff is actually needed for a full treatment (or if it even works in humans of course, but let's assume that for this sci-fi ramble). It may be much like a catalyst, or a very powerful signalling hormone, where tiny doses have huge impacts.

But let's assume that you need 500mg, and even worse, you need it weekly! Today, this relatively unknown protein costs 2,000,000 for our 500mg dose, but how much of it could they possibly be producing right now? Peprotech could be sitting on a gold mine when they figure out how to stop measuring in micrograms and start measuring in litres.

Why, for the price of a 50lbs. bag of sugar, a warm spot in the sun, and some large steel tanks, they can grow the waters of life. Forget Florida and sketchy fountains in the swamp, these tepid steel bins produce enough anti-aging proteins to supply every man, woman, and child for the rest of their now extended life at the low cost of fifty cents a day! Of course, they charge fifty dollars per dose, more if insurance is covering it, but still, they are literally growing money!

Why get involved in sketchy quasi-vampiric worker farms? After all, you can't know the true age of the people you are harvesting from. They could have some genetic anomaly that causes their precious GDF11 to be folded wrong! Buy from the only genetically guaranteed pure source! Peprotech, your gateway to eternal life!


RE: Scary
By kwrzesien on 5/7/2014 4:38:13 PM , Rating: 3
And here I was picturing a young rat being sowed on to every person!


RE: Scary
By M'n'M on 5/7/2014 9:58:49 PM , Rating: 2
I'm pretty sure the Bar assoc might say something re: that. Then again, 1 rat ... err lawyer, suckling the blood out of every person ... just might be the Bar's dream come true.


RE: Scary
By MrBlastman on 5/7/2014 4:46:13 PM , Rating: 2
I like it!

Come to think of it, being a writer myself, I started a draft a couple years ago dealing with a similar premise, albeit a bit more sinister. It is something unavoidable--you work on one piece of work and ideas for other ones inevitably pop up. You nibble at them here and there but they never hatch until you finish what you're first working on.

... You never know. :)

Astro/quantum/string/particle physics are my specialty but a little biology in sci-fi is never a bad thing.


RE: Scary
By s_p_kay on 5/7/2014 6:07:34 PM , Rating: 2
Not sure what the therapeutic dosage would be for regenerative therapy from neural or cardiac damage or deterioration. Also I imagine the current GDF11 amino acid sequence may be different in the lab experiments (certainly it's different for the species in the test than humans) and when dealing with specific actions of these long peptide chains I would guess there would need to be a lot of clinical testing to make sure the AA sequence is fully active in enhancing cell regeneration.


RE: Scary
By geddarkstorm on 5/7/2014 4:46:45 PM , Rating: 2
Similar stuff has been seen if you simply join the two circulatory systems (i.e. by a tube doing a transfusion). Its definitely a matter of factors flowing in the blood, which means it can be purified without killing or hacking up people. As the article points out, young blood can stimulate the stem cells that are -still there- in the old. You don't lose your ability to be young, it simply turns off, that's what we've been finding lately as biologists. Evidence from fruit flies also supports the idea that aging is less related to "wear and tear" (hence why antioxidants have never increased life span), and seems to be more related to some sort of aging programming.

Basically, aging may well be a controlled process of development. Yes, the same development we talk about from egg to embryo to adult. It doesn't end just because you hit 50.

That being so, what can we do? Note, also, that this issue impacts stem cell therapies and limits their utility, as an old body will age them rapidly and -turn them off-, without chemical intervention into the individual. Conversely, with the right treatment, you can turn on your resident stem cells (no need for transplants of stem cells from foreign and possibly dangerous genomes like with embryonic stem cells), and activate regeneration (see: http://med.stanford.edu/ism/2014/february/blau.htm... where all it takes is blocking p38 pathway to reactive stem cells to youthful states).

Really, this shouldn't be scary in its implications, as it means we are on the cusp of discovering how to truly turn back aging. If it's controlled by our bodies, we can undo it and reverse it, and that's friggin cool.


RE: Scary
By macca007 on 5/8/2014 3:38:47 AM , Rating: 2
Anything is possible I guess, Who knows. But you could also argue the rich are also vulnerable possibly more so, Who is to say some crazies out there might kidnap or ransom the rich so that they can get their injection.

I will say this one thing though, You already can add a few extra days/weeks/years to your life, It's called exercise.
Yes yes I know the shock and horror of getting out and doing some physical activity brings a shiver to ones bones myself included(some days). ;)
I think the main thing is find something worth living for rather than just trying to live longer, If you are in a nursing home staring at 4 walls with no visitors or family do you really want to live an extra 20 years? Need to have something to look forward to waking up to each day, Doesn't really matter what that something is, Maybe a hot cyborg sex bot? lol hey if it keeps you going then why not.


Some errors in attribution
By Bruce Goldman on 5/7/2014 12:15:46 PM , Rating: 5
As a science writer in the Stanford University School of Medicine's office of communications, I appreciate the effort you made to communicate some recent discoveries made in our labs. But you have introduced some substantial errors of provenance. Dr. Saul Villeda, now at the University of California-San Francisco, was never a graduate student of Amy Wagers (NOTE: not "Wagners" or "Wagner"), He was the graduate student of Dr. Tony Wyss-Coray, in whose lab the discoveries regarding shared blood and brain improvements you describe in your blog post were made. This is made clear in the news release (http://med.stanford.edu/ism/2014/may/young-blood.h... we sent out to reporters and editors last week before the publication of the three "young blood" papers that, together, constitute a blockbuster.

It was indeed Dr. Thomas Rando of Stanford who first introduced the Wyss-Coray lab to the parabiosis technique. But Dr. Rando wasn't involved in the new study by Villeda, Wyss-Coray et al.

(Incidentally, Dr. Wagers, now at Harvard, was never a faculty member at Stanford. She was a postdoctoral fellow here, albeit a very productive one.)

Unfortunately, despite our best efforts the New York Times failed to credit Dr. Wyss-Coray appropriately. (Both Nature Medicine and Science moved their publication dates forward at the last minute, leaving everyone a bit disorganized.) So I can understand why you inferred that Villeda and Wagers were somehow collaborators on this study. But it's always a good idea to check your facts before publishing. That's what we're here for.




RE: Some errors in attribution
By Amiga500 on 5/7/2014 12:59:07 PM , Rating: 3
In the UK, you measure a university's response to enquiries using a calendar.


RE: Some errors in attribution
By kattanna on 5/7/2014 1:48:33 PM , Rating: 2
http://med.stanford.edu/ism/2014/may/young-blood.h...

there is a corrected link to your press release that works


RE: Some errors in attribution
By Creig on 5/7/2014 3:47:22 PM , Rating: 3
Requesting DailyTech writers to perform a fact check before publishing? Surely you jest.


Wow...
By Arkive on 5/7/2014 1:00:41 PM , Rating: 2

I was certain I misread the title of this article, or that it was a typo.




Fountain of Youth
By Apone on 5/7/2014 4:23:48 PM , Rating: 2
"The key to immortality is first living a life worth remembering." - Bruce Lee




I wonder if...
By hobbes7869 on 5/7/2014 8:41:04 PM , Rating: 2
Sewing a pigeon onto a rat would work...a pigeon rat.




How follow-up on this topic
By Yadav on 5/13/2014 9:38:12 AM , Rating: 2
Hi,
Please let me know how to follow-up this topic regarding further updates on this.

I'm very exited and very interesting area to know more.

Best,
yadav




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