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Plasma from Younger Mice Found to Reverse Age-Related Cognitive Declines and Muscle Damage, New Studies Suggest

Talan, Jamie

doi: 10.1097/01.NT.0000450997.02848.1f
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In three different papers, researchers found that injecting blood from younger mice to older mice resulted in a reversal of age-related cognitive decline and muscle damage. The work is preliminary, the investigators caution.

Plasma from younger people could potentially restore an aging brain that has lost its cognitive virility, suggest data from two new studies. Both studies, and a third one on the powers of younger blood on damaged skeletal muscle, were conducted on mice, but the scientists are already designing ways to test the idea in humans.

In the Nature Medicine study published ahead of print on May 4, Tony Wyss-Coray, PhD, a professor of neurology and neurological sciences at Stanford University School of Medicine, and his colleagues found that giving older mice plasma from younger mice actually gave them back a cognitive edge over their contemporaries.

If such studies hold up, Dr. Wyss-Coray said that it could lead to new ways to turn back the hands of time in patients on the road to Alzheimer's disease.

In the paper, they began to unravel the mystery of how young blood restores cognition. They observed molecular, neuroanatomical, and neurophysiological changes in the brains of the old mice following the infusion of blood from young mice when compared with blood from old mice. A number of genes turned on in the presence of young blood that led to synaptic plasticity, neurogenesis, and functional improvement on laboratory tests. In other words, older animals no longer looked the part. On many levels, they were as young (and smart) as their blood.

“Our findings suggest that stem cells in an old animal can return to a younger state when transfused with blood from a more youthful animal,” said Dr. Wyss-Coray, who is also senior research career scientist at the Veterans Affairs Palo Alto Health Care System. The irony, he said, is that this kind of study could have been done dozens of years ago when the brain was a black box. “You just give an old mouse young blood and see if the animal is smarter than before. It's just that nobody did it.”

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Dr. Wyss-Coray began working on this idea in 2008 when he collaborated with Thomas Rando, MD, PhD, a professor of neurology at Stanford and an expert in muscular dystrophy who used parabiosis models to study muscle cells. Parabiosis is the experimental technique of surgically pairing two animals so that they share a single physiological system. They showed changes in muscle cells when plasma from a young animal is mixed with plasma of an older animal.

In 2011, Dr. Wyss-Coray and his colleagues published a paper in Nature showing that the brains of old mice exposed to the blood of young mice had far more nerve cells than a group of old mice who were surgically paired with mice of the same age. In these same studies, they also found that young mice exposed to old blood lost their ability to make as many new neurons as they normally would have.

What these initial studies did not do was test whether the physiological changes led to changes in behavior. In the latest Nature Medicine study, the scientists paid special attention to changes in the hippocampus, the region particularly vulnerable to age-related changes in memory and learning. They reported that the brain changes in the older mice surgically paired with younger mice were in keeping with those of a younger brain. The hippocampal cells contained substances that are enriched in younger brains when learning takes place, said Dr. Wyss-Coray.

“It was as if these old brains were recharged by young blood,” Dr. Wyss-Coray said.

But would these changes lead to behavioral differences in the older mice that received plasma from younger mice? It would be impossible to conduct behavioral experiments on pairs of animals, so the team, building on the findings from the parabiosis studies, injected old mice intravenously with plasma from either old or young mice.

They reported that those older animals infused with young plasma performed better at orientating themselves to find a submerged platform in the classic water maze test.

They also found behavioral differences in fear responses to a new environment. Dr. Wyss-Coray said that older mice spend less time freezing in a new environment compared with younger animals. But “freezing” times for older mice with a younger store of blood increased significantly. Indeed, the older animals remembered better when they were infused with young blood, he said.

After the behavioral studies were completed, the researchers removed the hippocampus from the animals to look for differences. They conducted gene profiling and found that those with a younger circulating blood supply had a number of genes involved in the neuroplasticity network. Normally, there is very low gene expression activity in the neuroplasticity network, but they found a 20 to 50 percent increase. They also identified structural changes in the brain — a higher density of spines on the receiving end of the synapses.

“These increased spines can positively impact cognitive function,” said Dr. Wyss-Coray. Former graduate student Saul A. Villeda, PhD, now a Faculty Fellow at the University of California, San Francisco, conducted most of the behavioral studies.

The researchers suspect that there are proteins in the young blood that are responsible for the changes that they are reporting. The hope is to identify the substance or substances and develop novel treatments for age-related cognitive decline, he said.

“We don't know yet if this will work in humans,” said Dr. Wyss-Coray, who co-founded a biotechnology company called Alkahest to explore the therapeutic implications of the new study's findings. He is director of Alkahest's scientific advisory board. “We've shown in animals that there is a benefit to the old brain. We are now trying to figure out how it protects the hippocampus.”

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In two different papers in the May 9 issue of Science, Lee Rubin, PhD, a professor in the department of stem cell and regenerative biology at Harvard Stem Cell Institute, and Amy Wagers, PhD, a professor in the same institute, independently identified a protein called growth differentiation factor-11 (GDF-11), a growth factor that they believe is rich in young blood that is responsible for the benefits they are seeing in old brains infused with young blood.

In the studies, the investigators injected the protein into animals and reported improvements in the animal's ability to exercise for longer periods of time. With more protein on board the animals were able to differentiate faster between competing smells, suggesting changes in the olfactory regions.

The Harvard researchers also used the parabiotic approach of joining two animals and measuring changes in older brains that share a blood supply from younger animals. Dr. Rubin's team used 3-D reconstruction and magnetic resonance imaging (MRI) and showed that the older mice with younger blood actually developed more blood vessels in the brain and had an increased population of neural stem cells.

Dr. Wagers reported restoration of muscle stem cell function and repair of age-related DNA damage that in turn led to repairs in damaged muscle.

“We are not saying that this is the only protein involved, but it does give us a foothold in understanding the network,” she said. “Targeting this pathway could have beneficial effects in human diseases like Alzheimer's.”

Dr. Rubin and his colleagues agreed. These findings “may constitute the basis for new methods of treating age-related neurodegenerative and neurovascular diseases,” they wrote in the Science paper. Dr. Wagers is a co-author on Dr. Rubin's study as well.



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Lennart Mucke, MD, director and senior investigator of the Gladstone Institute of Neurological Disease and professor of neurology and neuroscience at University of California, San Francisco, said he finds the science compelling. “Maybe young plasma replenishes factors important for cognition,” he said. “This is a nice follow-up to earlier observations from these groups that connecting young and old mice via their circulatory systems can have profound effects on brain structure and function.”

He added of these latest findings: “It's very exciting. Behavior is such an important read-out.”

Rudolph Tanzi, PhD, Joseph P. and Rose F. Kennedy professor of child neurology and mental retardation at Massachusetts General Hospital, said that he believes “young plasma is inducing considerable amount of beneficial gene activity that is likely driving many of the observed effects.”

But, he added, “we cannot be certain that what works in the mouse will work in the human. The mouse immune system is very different from the human system. So, effects of young plasma on gene expression, particularly immune-related genes, may not be readily translatable to humans. Time may tell.”

“It will be interesting to pin down all of the molecules involved in this,” he added. “I suspect that GDF-11 (identified by the Harvard group) is just the tip of the iceberg.”

“A circulating ‘Ponce de Leon’ factor for mice is a pretty wild concept, but the fact that several labs see similar things makes the whole thing more credible...for mice,” said Samuel E. Gandy, MD, PhD, a professor of neurology and psychiatry at the Icahn School of Medicine at Mount Sinai and associate director of Mount Sinai Alzheimer's Disease Research Center.

“The notion has clearly captured the imagination of scientists and laypeople alike. For me, the most efficient way to predict whether this story has legs and could make it to humans is to try to confirm the phenomenon in another least in rats, ideally in dogs. If you showed that puppy blood could improve the cognition in an elderly impaired dog, you would have a definite veterinary program and perhaps a human one as well.”

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•. Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014; E-pub 2014 May 4.
    •. Katsimpardi L, Litterman NK, Schein PA, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014;344(6184):630–634.
      •. Sinha M, Yang YC, Oh J, et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014;344(6184):649–652.
        © 2014 American Academy of Neurology