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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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