The rodent fountain of youth may not be filled with water, but with blood. A trio of new studies has discovered that the blood of young mice appears to reverse some of the effects of aging when put into the circulatory systems of elderly mice.
After combining the blood circulations of two mice by conjoining them — one old, the other young — researchers found dramatic improvements in the older mouse's muscle and brain. After four weeks, stem cells in both those areas got a boost of activity and were better able to produce new neurons and muscle tissue.
They later discovered that injections of a special protein found abundantly in young blood — or even transfusions of whole young blood — gives the same advantages as sharing a blood supply.
Old mice who were injected with the protein or who received a blood transfusion navigated mazes faster and ran longer on treadmills. They easily outperformed their control peers, who were given only saline.
But for the young mice, getting old blood was a definite setback. When conjoined to an older mouse, the creation of new cells in the young mouse slowed down. Old blood effectively seemed to cause premature aging.
Two of the studies, both published online Sunday in the journal Science, came out of collaborations at the Harvard Stem Cell Institute that shared specimens of mice — one focused on muscle changes, and the other specialized in the brain. The third, published Sunday in Nature Medicine, came from a group of researchers from Stanford University and the University of California at San Francisco.
"The Stanford group has been working in this area for a while, but we weren't involved in their study," said Science study author and biologist Amy Wagers of the Harvard Stem Cell Institute. "All of the studies are very consistent — the data are complementary and support one another."
Although initial results seem promising, questions still abound. Will it work on humans? What is the proper dosing? Do you need a constant supply of young blood to maintain the effects? Are there long-term consequences?
Nature Medicine study author and neuroscientist Tony Wyss-Coray of Stanford said he hopes to dive into human studies right off the bat. His new start-up company, Alkahest, is planning the first young-blood clinical trial at Stanford this year. Patients with Alzheimer's disease will be given young blood, with researchers measuring their cognitive condition before and after.
"Right now we can't do anything for Alzheimer's patients, and this seems so easy and simple," Wyss-Coray said.
The young mice in the three studies were the human equivalent of people in their 20s, so this would probably be the age range for donors used in a clinical trial. He said treating the big-picture issue of aging could in turn alleviate the burden of many diseases.
"Most diseases that affect industrialized nations have a very strong aging component, and these are currently studied in isolation," Wyss-Coray said. "But age is the key risk factor for all these diseases."
Judith Campisi, a biochemist at the Buck Institute for Research on Aging who was not involved in the studies, agreed that fundamental aging research is necessary and can have broad-ranging benefits.
"If we understand the aging process in enough detail, we can begin to tackle the underlying mechanisms rather than treating one disease at a time," she said.
The process of aging is an area in which scientific understanding is still fuzzy at best. Organ function, cognitive ability and stem-cell activity decline over time, in both mice and men, but it isn't clear exactly why. The body becomes ever more vulnerable to disease — and even healthy elderly bodies can never be what they once were.
"Even in the best of circumstances of being completely disease-free, things just can't be maintained with age," said Ronald Kohanski, the deputy director of the National Institute on Aging, who was not involved in the research.
The studies started with a Frankenstein-like setup called parabiosis. Small flaps of skin from the sides of two genetically identical mice are cut and sewn together. As the wounds heal, their tissue begins to fuse. The mice, now conjoined, share a single blood supply. Pairing old and young mice, or heterochronic parabiosis, has become an unexpectedly insightful tool for age research.
"Heterochronic parabiosis is a gold mine in terms of what it is telling us about aging," Kohanski said.
A few recent animal studies have claimed to increase longevity. In 2009, a drug called rapamycin was shown to extend the life span of mice by roughly 10 percent. Also, a calorie-restricted diet received much attention for its proven health benefits for monkeys. However, nothing has been proven to reverse the adverse effects of aging — something that young blood appears to do.
In particular, the two studies published in Science focused on a specific protein in young blood, called growth differentiation factor 11. GDF11 circulates at high levels in the bloodstreams of youthful mice but declines with age. Last year, a study showed that injections of GDF11 appeared to rejuvenate the toughened heart muscle of elderly mice.
"[Rapamycin] and caloric restriction seemed to slow the aging process, not necessarily stop or even reverse it," Campisi said. "But GDF11 seems to reverse it."
In the new experiments, GDF11 treatment had a similar turn-back-the-clock effect on both skeletal muscle and the brain.
"It could have appeared that the GDF11 effects were limited to the heart," said Wagers, who authored both the heart and muscle studies. "These new studies extend the impact to other types of tissues."
After four to five weeks of heterochronic parabiosis, the Science study found that muscle stem cells from the older partners had less DNA damage compared with controls. Their neural stem cells got a boost of activity as well, and they had a greater amount of blood flow in their brains.
Then the researchers switched to pure GDF11 injections. When they gave a new group of aged mice four weeks of treatment, they found that the protein itself gave similar enhancements as shared circulation. There were more stem cells in their muscles to create new tissue, and they performed better on strength and endurance tests than controls given saline. GDF11 treatment also increased the amount of blood vessels in their brains.
The third paper, published online in Nature Medicine by Stanford researchers, did not distinguish a specific protein but instead injected whole, young blood. They focused on the hippocampus, a region of the brain important for memory and spatial navigation, where new neurons are created from neural stem cells. The lab's previous study found a reactivation of neural stem cells using young blood — but this time, the team wanted to see if it really meant a smarter mouse.
The researchers found that it did. The old mice treated with young blood could navigate mazes and recall fear memories better than controls.
Although none of the studies tested for longevity, the effects of GDF11 and young blood seem to last for a few weeks in mice after injection. In a small group of human subjects, Wagers has found that GDF11 levels are consistent with what she saw in mice — higher in the young and lower in the old. But she believes that scientists probably will need years of additional research before attempting any human experiments. Although humans regularly get blood transfusions, the anonymous nature of the donated blood means there has been no tracking of effects of donor age.
Kim is a freelance science journalist based in Philadelphia.