Vinoth Chandar In a series of papers released yesterday, researchers showed that it’s possible to reduce many of the problems with age, including declines in memory and loss of muscle strength, simply by supplying older mice with blood plasma from younger ones. The work even identified a specific protein, GDF11, that mediates many of the effects. The work suggests that some aspects of the aging brain aren’t necessarily an internal feature of the neurons that comprise it, but a product of their interactions with their environment—an environment that could potentially be changed. The work grew out of a rather unusual laboratory technique that creates what are termed “parabionts,” genetically matched animals in which patches of skin are surgically fused. Eventually, their circulatory systems mesh, allowing factors from one animal to freely move through the body of the other. Fresh blood Assuming you’re working with normal, healthy, age-matched mice, you won’t see much of a difference. But researchers started experimenting with mice of different ages.
In a paper published in 2011, researchers working with these parabionts showed that the blood of the older mice could impose some of the problems with age, including cognitive decline, when circulated through their younger peers. This effect was eventually ascribed in part to immune signaling molecules called chemokines. Now the same research group is back, once again in Nature, and it’s analyzing the other half of the partnership. The title of the group’s new paper pretty much says it all: “Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.” Aged mice don’t form memories as readily as young ones do, but spending several weeks linked to the circulatory system of a young peer reversed that effect. The team ascribed this to a restoration of what’s called “synaptic plasticity,” meaning the ability of nerves to rearrange existing connections among themselves and form new links with other nerves. Signaling through a protein called CREB, already known to be involved in memory, seems to be key for this change. The researchers also showed that the same effect could be created by a series of injections of the blood plasma of young mice, spaced across several weeks. Heat-treating the plasma destroyed its activity, which suggests that at least some of the age-reversing factors are proteins. Which brings us to the second set of papers.
About a year ago, a different group published the results of a similar set of experiments, which used parabionts to look at the weakening of the heart that comes with age. This work also showed that young blood reversed the aging process, restoring the heart to a healthier state. And its authors performed an exhaustive search for proteins that were present in young blood but missing or reduced in older animals. They eventually focused on a factor called GDF11, which could mimic the effect of young blood. That group now has two follow-up papers coming out in Science. In one of them, the authors show that GDF11 reverses the decay and loss of muscle stem cells, which contributes to the wasting of muscles that accompanies age. In the second, they tackle the decline of the nervous system. While the Nature paper focused on the ability of the nervous system to reorganize itself in order to form new memories, the Science one looks at the brain’s ability to restore itself through the growth of stem cells. In the aging brain, the circulatory system starts to decay in the area where the stem cells reside, ultimately leading to fewer new nerve cells growing out into the brain. Giving these mice GDF11 increased blood vessel volume in this area by nearly 90 percent and also increased the fine branches within the network of blood vessels there. As a result, the stem cells were healthier and increased their pace of cell division. This in turn led to more mature neurons being produced and integrated into the brain. The authors specifically detected new neurons in the olfactory bulb, which registers the sense of smell, and showed that this improved older animals’ ability to detect odorants.
The big picture Overall, the results paint a pretty consistent picture of what’s going on. Both point to a protein found in the blood of young mice, and GDF11 clearly fits the bill. While they looked at different aspects of neural function, the results can be viewed as compatible: it’s possible that the newly produced neurons from the healthier stem cells are directly contributing to the increased ability of the brain to rearrange its connections in response to new memories. It should also be clear that a variety of evidence is building in favor of GDF11 being a general factor that promotes youthful behavior in a variety of tissues. None of the findings on their own would be earth-shattering, but there’s now a large collection of incremental results that paint a pretty compelling picture. That picture is generally good news, too. GDF11 is part of a large family of signaling molecules (the TGF-ß superfamily) that is extremely well studied. (It’s so well studied that you can order a tiny batch of 98 percent pure human GDF11 that was made in bacteria for as little as $80.)
So following up on this work won’t mean starting from scratch with a mystery molecule that no one understands. If it’s so easy to make GDF11, could places offering injections be far off in the future? Probably not, but we’re a long way from the sort of evidence that would make that a safe, approved therapy for the declines of aging. It’s possible for GDF11 to have both positive and negative effects on a variety of tissues. Even the addition of new neurons to the brain may have undesirable consequences—the flexibility they induce may disrupt old memories while enabling the formation of new ones. A lot more work will be needed before we understand the full consequences of added GDF11 in mice, never mind humans. What is somewhat more promising is the fact that researchers have now identified two classes of factors: those that restore youth and those that impose aging. It’s possible, as one of the papers notes, that delicately manipulating both of these pathways could provide the sort of therapeutic effects we’re looking for without causing major health problems. But again, figuring out how to do that will take time. Nature Medicine, 2014. DOI: 10.1038/nm.3569 and Science, 2014. DOI: 10.1126/science.1251152, 10.1126/science.1251141 (About DOIs)