GDF11

[The Madame X]

Young Blood May Hold Key to Reversing Aging
By CARL ZIMMERMAY 4, 2014
full article at: http://www.nytimes.com/2014/05/05/scien ... .html?_r=0

Two teams of scientists published studies on Sunday showing that blood from young mice reverses aging in old mice, rejuvenating their muscles and brains. As ghoulish as the research may sound, experts said that it could lead to treatments for disorders like Alzheimer’s disease and heart disease.

“I am extremely excited,” said Rudolph Tanzi, a professor of neurology at Harvard Medical School, who was not involved in the research. “These findings could be a game changer.”

The research builds on centuries of speculation that the blood of young people contains substances that might rejuvenate older adults.

In the 1950s, Clive M. McCay of Cornell University and his colleagues tested the notion by delivering the blood of young rats into old ones. To do so, they joined rats in pairs by stitching together the skin on their flanks. After this procedure, called parabiosis, blood vessels grew and joined the rats’ circulatory systems. The blood from the young rat flowed into the old one, and vice versa.

Later, Dr. McCay and his colleagues performed necropsies and found that the cartilage of the old rats looked more youthful than it would have otherwise. But the scientists could not say how the transformations happened. There was not enough known at the time about how the body rejuvenates itself.

It later became clear that stem cells are essential for keeping tissues vital. When tissues are damaged, stem cells move in and produce new cells to replace the dying ones. As people get older, their stem cells gradually falter.

In the early 2000s, scientists realized that stem cells were not dying off in aging tissues.

“There were plenty of stem cells there,” recalled Thomas A. Rando, a professor of neurology at Stanford University School of Medicine. “They just don’t get the right signals.”

Dr. Rando and his colleagues wondered what signals the old stem cells would receive if they were bathed in young blood. To find out, they revived Dr. McCay’s experiments.

The scientists joined old and young mice for five weeks and then examined them. The muscles of the old mice had healed about as quickly as those of the young mice, the scientists reported in 2005. In addition, the old mice had grown new liver cells at a youthful rate.

The young mice, on the other hand, had effectively grown prematurely old. Their muscles had healed more slowly, and their stem cells had not turned into new cells as quickly as they had before the procedure.

The experiment indicated that there were compounds in the blood of the young mice that could awaken old stem cells and rejuvenate aging tissue. Likewise, the blood of the old mice had compounds that dampened the resilience of the young mice.

Amy J. Wagers, a member of Dr. Rando’s team, continued to study the blood of young mice after she moved in 2004 to Harvard, where she is an associate professor. Last year, she and her colleagues demonstrated that it could rejuvenate the hearts of old mice.

To pinpoint the molecules responsible for the change, Dr. Wagers and her colleagues screened the animals’ blood and found that a protein called GDF11 was abundant in young mice and scarce in old ones. To see if GDF11 was crucial to the parabiosis effect, the scientists produced a supply of the protein and injected it into old mice. Even on its own, GDF11 rejuvenated their hearts.
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Dr. Wagers and her colleagues wondered whether GDF11 was responsible for the rejuvenation of other tissues. In the current issue of the journal Science, they report an experiment on skeletal muscle in mice. They found that GDF11 revived stem cells in old muscles, making old mice stronger and increasing their endurance.

At Stanford, researchers were investigating whether the blood of young mice altered the brains of old mice. In 2011, Saul Villeda, then a graduate student, and his colleagues reported that it did. When old mice received young blood, they had a burst of new neurons in the hippocampus, a region of the brain that is crucial for forming memories.

In a study published Sunday in the journal Nature Medicine, Dr. Villeda, now a faculty fellow at the University of California, San Francisco, and his colleagues unveiled more details of what young blood does to the brains of old mice.

After parabiosis, Dr. Villeda and his colleagues found that the neurons in the hippocampus of the old mice sprouted new connections. They then moved beyond parabiosis by removing the cells and platelets from the blood of young mice and injecting the plasma that remained into old mice. That injection caused the old mice to perform far better on memory tests.

Dr. Wagers’s team has been investigating a specific region of the brain involved in perceiving smells.

In a second study in Science, the team reported that parabiosis spurred the growth of blood vessels in the brain. The new blood supply led to the growth of neurons and gave older mice a sharper sense of smell.

After linking the GDF11 protein to the rejuvenation of skeletal muscle and the heart, Dr. Wagers and her colleagues studied whether the protein was also responsible for the changes in the brain. They injected GDF11 alone into the mice and found that it spurred the growth of blood vessels and neurons in the brain, although the change was not as large as that from parabiosis.

“There’s no conflict between the two groups, which is heartening,” said Dr. Richard M. Ransohoff, director of the Neuroinflammation Research Center at the Cleveland Clinic.

Dr. Ransohoff and others hope the experiments on mice will lead to studies on people to see if the human version of GDF11, or other molecules in the blood of young people, has a similar effect on older adults.

“We can turn back the clock instead of slowing the clock down,” said Dr. Toren Finkel, director of the Center for Molecular Medicine at the National Heart, Lung and Blood Institute. “That’s a nice thought if it pans out.”

This reversal could occur throughout the body, the new research suggests. “Instead of taking a drug for your heart and a drug for your muscles and a drug for your brain, maybe you could come up with something that affected them all,” Dr. Wagers said.

But scientists would need to take care in rejuvenating old body parts. Waking up stem cells might lead to their multiplying uncontrollably.

“It is quite possible that it will dramatically increase the incidence of cancer,” said Irina M. Conboy, a professor of bioengineering at the University of California, Berkeley. “You have to be careful about overselling it.”

[The Madame X]

’Vampire therapy’ could reverse ageing, say scientists
2014 05 05
By Sarah Knapton | The Telegraph
Full article at: http://www.telegraph.co.uk/science/scie ... -find.html


A transfusion of youthful blood may halt or even reverse the ageing process as two studies find that the chemical make-up of younger blood has surprising health benefits

It may seem the stuff of gothic horror novels, but transfusions of young blood could reverse the ageing process and even cure Alzheimer’s Disease, scientists believe.

Throughout history, cultures across the globe have extolled the properties of youthful blood, with children sacrificed and the blood of young warriors drunk by the victors.

It was even rumoured that the North Korean dictator Kim Jong-il injected himself with blood from healthy young virgins to slow the ageing process.

Now scientists have found that young blood actually ‘recharges’ the brain, forms new blood vessels and improves memory and learning.

In parallel research, scientists at Harvard University also discovered that a ‘youth protein’ which circulates in the blood is responsible for keeping the brain and muscles young and strong.

The protein, known as ‘GDF11’, is present in the bloodstream in large quantities when we are young but peters out as we age.

Although both the discoveries were made in mice, researchers are hoping to begin human trials in the next two to three years, in studies which could bring rapid improvements for human longevity and health.

“This should give us all hope for a healthier future,” said Prof Doug Melton, of Harvard’s Department of Stem Cell and Regenerative Biology.

“We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer.

“There seems to be little question that, GDF11 has an amazing capacity to restore aging muscle and brain function.”

Last year the team discovered that the protein could repair damaged hearts. But the new study showed that that raising the levels of the GDF11 protein in older mice improved the function of every organ in the body.

Harvard stem cell biologist Prof Lee Rubin added: “We do think that, at least in principal, there will be a way to reverse some of the decline of aging with a single protein.

"It isn't out of question that GDF11, or a drug developed from it, might be worthwhile in Alzheimer's Disease.”

It is likely that the protein is at least partly responsible for the parallel finding by Stanford University that young blood can reverse the signs of ageing.

In the study, the blood of three-month-old mice was repeatedly injected into 18-month-old mice near the end of their natural life span.

The "vampire therapy" improved the performance of the elderly mice in memory and learning tasks.

Structural, molecular and functional changes were also seen in their brains, the study published in the journal Science found.

If the same were seem in humans, it could lead to new therapies for recharging our aging brains and novel drugs for treating dementias such as Alzheimer’s disease.

“We’ve shown that at least some age-related impairments in brain function are reversible. They’re not final,” said Dr Saul Villeda, of Stanford’s School of Medicine.

Ageing mice given eight infusions of young blood over three weeks improved their performance in mental tests of fear condition and locating a hidden platform in a water maze.

Evidence was seen of new connections forming in the hippocampus, a brain region vital to memory and sensitive to ageing.

Dendritic spines - finger-like extensions from the branches of neurons that are thought to play a role in memory formation - also became more dense.

Infusions of blood from other elderly mice had no effect, the study, published in the journal Nature, found.

“This could have been done 20 years ago,” said lead researcher Dr Tony Wyss-Coray of Stanford.

“You don’t need to know anything about how the brain works. You just give an old mouse young blood and see if the animal is smarter than before. It’s just that nobody did it.”

"Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

"Future studies are warranted in aged humans and potentially those suffering from age-related neurodegenerative disorders."

Dr Eric Karran, from the dementia charity Alzheimer's Research UK, said: “This technically complex study looks at the effects of exposing old mice to blood-borne factors from young mice on age-related cognitive decline.

“Although the treatments tested here rejuvenate certain aspects of learning and memory in mice, these studies are of unknown significance to humans.

“This research, while very interesting, does not investigate the type of cognitive impairment that is seen in Alzheimer's disease, which is not an inevitable consequence of ageing.”

[The Madame X]

Swapping Young Blood for Old Reverses Aging
Muscle tone, endurance, memory, and smell improve in elderly mice infused with blood from younger mice
by Jennifer Frazer
for National Geographic
Published May 4, 2014

Full article at: http://news.nationalgeographic.com/news ... ses-aging/



In what could have profound implications for understanding the process of aging, a trio of scientific papers published today show that infusing elderly mice with the blood of young mice can reverse many of the mental and physical impairments of growing old.

Expanding on earlier research, the three studies—published concurrently in Nature Medicine and Science—demonstrate rejuvenating effects in memory, muscle strength, endurance, and sense of smell. Together, they suggest that there might be factors in the young blood that can produce globally regenerating effects in older animals. In addition to reversing the normal ravages of aging, the papers suggest, young blood might help turn around declines in cognitive function associated with age-related conditions such as heart enlargement and Alzheimer's disease.

"The changes are astounding in terms of rejuvenating the mice both in the periphery of the body and in the brain," said Rudolph Tanzi, professor of neurology at Harvard and director of the Genetics and Aging Research Unit at Massachusetts General Hospital, who was not involved in any of the three research projects. "I'm kind of blown away, really, by the results."

The study in Nature Medicine, conducted by Saul Villeda at the University of California, San Francisco, Tony Wyss-Coray at Stanford, and their colleagues, builds on earlier work that showed young blood could stimulate the growth of brain stem cells and new neurons, as well as work that indicated that giving old blood to young mice can have the opposite effect, impairing their cognitive abilities.

As described in the Nature Medicine paper, Villeda and his colleagues physically connected the circulatory systems of old mice to young mice via surgery that stitched their abdominal cavities together. Over time, elderly mice tethered to young mice sprouted more new connections between nerve cells in their brains than did controls tethered to other elderly mice. Senior mice invigorated by their juniors' blood also produced proteins associated with neuroplasticity—the ability of the brain to reorganize itself in response to experience. The young mice were 3 months old; the elderly mice were 18 months old.

The UCSF and Stanford scientists also directly injected old mice with young-mouse blood plasma, the yellowish liquid base of blood in which proteins and other solids are suspended. Over the course of three weeks, the old mice received eight blood plasma injections from young mice. Afterward, the treated mice remembered how to find a hidden resting platform in a water maze better than the controls did. They also exhibited better recollection of a chamber they had been conditioned to associate with a mild foot shock.

While the ingredient in the young blood responsible for these effects is still unknown, a clue was provided when the scientists heated the plasma before injection, and no such benefits were seen. Since proteins are deactivated by heat, the results are consistent with the relevant circulating factor being a protein.

"When I first heard this story from Tony Wyss-Coray, I thought it was absolutely amazing," said Tanzi. "I thought it was too good to be true." Now that two additional papers have come out in Science with similar findings, and all three papers are by well-respected labs, "now you have to believe it's real," he said.

In the first of the two papers in Science, a team from Harvard found that by either connecting the circulatory systems of young and old mice, or injecting old mice with a signaling protein isolated from young blood, they could strengthen and rejuvenate aged muscles. The improvement was measured in several ways, according to Amy Wagers, professor of stem cell and regenerative biology at Harvard and one of the paper's chief authors. The DNA of old muscle stem cells was repaired; muscle fibers and cell structures called mitochondria morphed into healthier, more youthful versions; grip strength improved; and the mice were able to run on treadmills longer than their untreated counterparts.

The protein used in the study, called GDF11, was already known to reduce age-related heart enlargement, which is characteristic of heart failure. But Wagers said the new work shows that GDF11 has a similar age-reversal effect on other tissue, in particular the skeletal muscle and brain.

"That means that this protein is really acting in somewhat of a coordinating way across tissues," she said, and that drugs could be developed to target a "single common pathway" seen in a variety of age-related dysfunctions, including muscle weakness, neurodegeneration, and heart disease.

In the second Science paper, another team from Harvard, led by research associate Lida Katsimpardi, also transferred GDF11 from young mice to old ones either by surgically linking their circulatory systems or through injections. They then looked at cells in the subventricular zone, an area in the mouse brain related to odor perception. The young blood improved circulation in this region, which in turn stimulated the production of new nerve cells. When these cells migrated to the olfactory bulb and matured, the elderly mouse's sense of smell improved, reversing the loss in sensitivity normally associated with aging.

What's most exciting about this work, said Katsimpardi, is that the bolstered blood flow was observed not only in the olfactory regions but throughout the brain. This could also help explain the improvement in memory and learning seen in the Nature Medicine paper. The three papers taken together are "like a whole story now," Katsimpardi said.

The Harvard researchers plan to continue work to see whether GDF11 is the sole factor involved in the rejuvenation, or whether it is one of several. "My bet is that there is more than one protein that is going to explain aging," Wagers said.

Bradley Wise, chief of the Neurobiology of Aging Branch at the National Institute on Aging and the administrator of the team's grant, said it's too soon to recommend wholesale transfusion of young human blood into elderly people. He said any treatments derived from this research will likely come from individual blood factors, either administered directly or via pharmaceuticals designed to mimic their effects. "The big question is: What are those factors?" he said.

Tanzi said the three papers mesh well with recent research into the importance of inflammation in conditions such as Alzheimer's disease, heart disease, diabetes, stroke, and cancer.

"The young blood is to some extent curbing inflammation in the body and brain, which is one of the main problems leading to age-dependent deterioration," he said. Taken together, Tanzi added, the new findings are "a game changer for sure."

[The Madame X]

Young blood makes old mice more youthful
By Elizabeth Landau, CNN
updated 4:58 PM EDT, Mon May 5, 2014

full article at: posting.php?mode=reply&f=5&t=4762

(CNN) -- The fountain of youth might not be made of water after all.

Three new studies describe how the blood of young mice may help rejuvenate the brains and muscle tissues of older mice. For now, it has only been tried in rodents, but this line of research might one day lead to therapies for medical conditions often found in aging humans.

"It's really exciting," said Amy Wagers of the Harvard Stem Cell Institute, senior author of one of the studies published in the journal Science. "It says there's a coordination of signals through the blood system that's affecting aging in many different organs."

Advances in this line of research raises the possibility of a single treatment for conditions such as cardiac disease, neurodegeneration and muscle wasting, Wagers said.
The fountain of youth may be in a mouse?

The three new studies are all consistent with each other, and support the idea that there are substances in the blood that could be important therapeutically, she said.

A protein boost

Two studies, both in Science, focused on a protein called GDF11, which, in its mature form, is identical in mice and humans, Wagers said.

"By boosting the levels of GDF11, we could, in mice, see a restoration of the ability of muscle to repair itself after injury," she said.

Among the wondrous apparent benefits of this protein: In a resting state the muscles of older mice were structurally improved, and they could generate more force when pulling on a bar, too.
An old mouse, left, may benefit from the blood of a young mouse, right.
An old mouse, left, may benefit from the blood of a young mouse, right.

Wagers and colleagues did experiments on pairs of mice, in which a 2-month-old mouse, analogous to a 20-year-old person, was surgically joined to the same circulatory system as 2-year-old mouse, which is akin to a 65- or 70-year-old human.

It also appeared that old mice didn't need to be surgically joined to young mice in order to act young again.

Thanks to daily injections of GDF11, apparently, older mice could run on a treadmill as long as younger mice -- and longer than those who did not get the treatment.

Researchers saw that injections were about as good as the surgical joining when it came to muscle repair. But in previous experiments focusing on the heart, old mice fared better when conjoined to a young mouse's blood system. That could mean that there are other substances in the blood having positive effects, or that the dosing and timing was off in the protein injection treatment.

A second Science study also focused on GDF11. Lida Katsimpardi and colleagues found the protein, when injected, improved the vasculature -- the system of blood vessels -- in key areas of the brains of old mice.

"It is possible that increased blood flow might result in increased neural activity and function, opening new therapeutic strategies for treating age-related neurodegenerative conditions," study authors wrote.

When young mice were attached to the blood supply of old mice, young blood seemed to promote the formation of new neurons related to olfactory senses in old mice, too. Researchers found that the old mice had a better sense of smell as a result.

How does this happen? It appears blood flow increased to neural stem cells as a result of GDF11, which pumps up the generation of neurons.

A plasma infusion

Unlike the Science studies, the study in the journal Nature Medicine did not single out any particular blood protein. Instead, researchers focused on plasma, the part of the blood without cells in it.

As in the Science studies, Stanford researchers also joined pairs of old and young mice to the same blood supply.

They looked for changes in the hippocampus, a seahorse-shaped structure the brain that plays an important role in memory, in old mice. One result of Alzheimer's disease in the brain is a hippocampus whose structure and function are atrophied.

The blood supply of younger mice seemed to have a positive effect on the hippocampi of older mice to whom they were surgically connected. In those pairs, the old mouse was likely to have a hippocampus more similar to that of younger mice than old mice hooked up to old mice.

"It was as if these old brains were recharged by young blood," the study's senior author Tony Wyss-Coray, neurology professor at Stanford University School of Medicine, said in a statement.

Researchers also saw benefits of injecting old mice with the plasma of young mice. These old mice performed better on a maze test -- in which they had to find a hidden platform in a container with water -- than old mice who got plasma from other old mice, or who were not injected.

In another test, researchers trained mice to freeze in place in a particular environment. This fear response lasted longer in mice who more easily recognized the environment. Older mice who received young plasma did better on this test after receiving young plasma, but not old plasma.

It is possible that GDF11 in the plasma could be responsible for these results as well, but that has yet to be investigated, Wagers said.

Trying it in humans

Wagers said she and colleagues are working on designing the optimal trial for GDF11. But they still want to understand what it is and how it works.

For instance, are people born with a finite amount of GDF11, or is there an age at which the substance peaks in the blood before declining later in life? Why does it decline with age?

No side effects were seen in Wagers' study, but it remains to be seen how humans would respond to the treatment.

Irina Conboy, principal investigator at the Berkeley Stem Cell Center, cautions that GDF11 and other proteins that promote blood vessel formation have also been associated with the growth of tumors and metastasis. A study on colorectal cancer in the International Journal of Oncology found associations with tumors and with cancer-related deaths.

Wyss-Coray co-founded a company that is going to look into the potential of using his group's idea -- young blood plasma -- for human therapies. He is the director of the company's scientific advisory board.

"Under controlled conditions in a clinical trial setting, I think this is definitely warranted," Saul Villeda, lead author of the Nature Medicine study, told CNN. "It's definitely worth pursuing in humans. I just think it should be in an appropriate context."

More investigation is necessary to see the youth we crave can be attained from substances in the blood of our younger friends.