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."