Could the elixir of youth be as simple as a protein found in young blood? In recent years, researchers studying mice found that giving old animals blood from young ones can reverse some signs of aging, and last year one team identified a growth factor in the blood that they think is partly responsible for the antiaging effect on a specific tissue—the heart. Now, that group has shown this same factor can also rejuvenate muscle and the brain.
"This is the first demonstration of a rejuvenation factor" that is naturally produced, declines with age, and reverses aging in multiple tissues, says Harvard University stem cell researcher Amy Wagers, who led efforts to isolate and study the protein. Independently, another team has found that simply injecting plasma from young mice into old mice can boost learning.
The results build on a wave of studies in the last decade in which investigators sewed together the skins of two mice, joining their circulation systems, and studied the effects on various tissues. “It’s still a bit creepy for many people. At meetings, people talk about vampires,” says neuroscientist Tony Wyss-Coray of Stanford University in California, who led one of the brain studies. But he, Wagers, and others think unease will give way to excitement. The new work, he says, “opens the possibility that we can try to isolate additional factors” from blood, “and they have effects on the whole body.”
Hope and hype are high in the antiaging research arena, and other researchers caution that the work is preliminary. “These are exciting papers,” but “it’s a starting point,” says neuroscientist Sally Temple of the Neural Stem Cell Institute in Rensselaer, New York. Adds Matt Kaeberlein, a biologist who studies aging at the University of Washington, Seattle, “The therapeutic implications are profound if this mechanism holds true in people.” But that “is the million-dollar question here, and that may take some time to figure out.”
The experimental technique of joining mice’s circulatory systems dates back 150 years. Around 2000, then-postdoc Wagers and other researchers in Irving Weissman’s and Thomas Rando’s labs at Stanford revived the method, known as parabiosis, to study the fate of blood stem cells and muscle cells. To their surprise, they found that when old and young mice were joined, the muscle stem cells in old mice were revitalized. Since then, Stanford researchers and others, including Wagers, have published about a half-dozen papers showing that old-young parabiosis can also improve the health of an aging mouse’s liver, spinal cord, and brain.
More recently, Wagers’s lab, together with cardiologist Richard Lee’s lab at Brigham and Women’s Hospital in Boston, isolated a specific protein from mouse blood that they think can explain some of the effects. The protein, growth differentiation factor 11 (GDF11), was known to regulate stem cell activity; it is abundant in young mice but its level drops as the animals age. Last year in Cell, Wagers’s and Lee’s labs reported that injections of GDF11 can reduce the thickening of the heart that typically comes with aging in mice. Today, in a paper in Science Express, Wagers’s lab shows that GDF11 works nearly as well as parabiosis in helping aging mice recover from a muscle injury and boosts their performance on running and grip strength tests.
In another study of mice injected with GDF11, postdoc Lida Katsimpardi and others in the lab of Harvard neuroscientist Lee Rubin found that GDF11 also encourages growth of new blood vessels and olfactory neurons in the mouse brain. As they report in a second Science Express paper today, the animals gained a keener sense of smell. In both muscle and the brain, GDF11 appears to work in part by restoring the function of stem cells.
So far only two other interventions—the drug rapamycin and caloric restriction—have been shown convincingly to slow or reverse aging in multiple tissues, Kaeberlein says. Wagers points out that GDF11 could be safer than a drug because it’s found naturally in blood. Harvard has filed for patents on GDF11, and Wagers says she and her colleagues are "in the process of talking with people" about commercializing it to treat diseases such as Alzheimer’s and heart disease. Giving GDF11 itself "would require huge amounts of protein," Wagers says, so it may be better to use a modified form or to target the GDF11 pathway with a different molecule. “These are tractable problems," Wagers says. "The most important hurdle was figuring out a pathway to go after."
Temple agrees that GDF11 has therapeutic promise, but she says she will remain cautious until more is known about GDF11’s mechanism. She also notes that some of the “old” mice in the Harvard brain studies were only middle-aged, and whether the effects would hold up in elderly people is unclear. “It’s a matter of where you can step in,” she says. Nor have any studies yet shown that the treated mice live longer.
Already, GDF11 has a potential rival treatment. In Nature Medicine today, Wyss-Coray’s lab at Stanford and Saul Villeda and co-workers at the University of California, San Francisco, report that parabiosis can rejuvenate another part of the mouse brain, the hippocampus, where memories are made and stored. Old mice that underwent parabiosis formed more new connections between nerve cells there. Although Wyss-Coray’s group has not yet isolated any rejuvenation factors from the young blood, they have found what might be an alternative. When Wyss-Coray’s team tried a simpler experiment than parabiosis—giving old mice injections of plasma from young mice—they saw similar effects on the hippocampal neurons. The old mice also performed significantly better than untreated animals on tests of learning and memory.
Plasma is given routinely to patients, so trials of this approach, unlike those testing a new protein, would not require U.S. Food and Drug Administration approval, Wyss-Coray says. His group has started a company that is planning a small clinical trial that would give Alzheimer’s patients a series of injections of plasma from young donors. In mouse models of Alzheimer’s, they have already seen positive effects, he says.
Let a new wave of hope—and hype—begin.
View our related Science in the Classroom annotated research paper on rejuvenation of the aging mouse brain.