A Fountain of Youth for the Brain?

by Jim Schnabel

June 12, 2014

Reports in early May that young blood can rejuvenate old brains-at least for a while, in mice-inspired optimistic headlines around the world."Young Mouse Blood May Unlock Secret of Fountain of Youth," declared the Washington Post. "The Fountain of Youth is Flowing In Our Veins," exulted the UK Daily Mail.

However, there are reasons for a more temperate enthusiasm about these experiments and their prospects of being translated into therapies.

To begin with, though, the results from these mouse studies were indeed striking. They came from two teams of researchers, centered at Harvard and Stanford. Both used old-fashioned "parabiosis" experiments-in which two mice (genetically almost identical, to avoid immune-mismatch problems) have their circulatory systems connected with tubes for a few weeks. The goal was to determine whether blood-borne factors in young mice can bring about rejuvenating effects in the brains of older mice.

The Harvard team found that young blood reversed the normal age-related decline in the vasculature of the mouse brain, increasing the number of vessels and restoring a youthful level of blood flow throughout the brain. The increased blood flow in turn boosted the proliferation of neural stem cells, so that mice "rejuvenated" this way did markedly better on a test of odor discrimination-a function served by a stem-cell-rich region called the subventricular zone (SVZ).Other brain regions and functions were likely affected similarly by the increased blood flow.

Importantly, the researchers determined that increased levels of a blood-borne protein called GDF11, whose production normally falls with age, were responsible for at least a large part of this effect. "In our study the beneficial effect of GDF11 alone was half that parabiosis, so possibly if we were to increase the dose we'd get the full effect, or alternatively there may be other factors that normally work synergistically with GDF11," says Lida Katsimpardi, a postdoctoral researcher at Harvard who was lead author of the study.

The Stanford team's results complemented those from Harvard: Young mouse blood brought about signs of rejuvenation in the memory-related hippocampus region of older mice. These signs of rejuvenation included a greater density of dendritic spines, the processes on neurons that carry input signals; greater "synaptic plasticity," the learning-related quality that allows neuronal synapses to adapt to new stimuli; and better performance on tests of hippocampus-mediated learning ability.

More tests in mice will surely follow, but already the Harvard team-some of whom reported last year that GDF11 rejuvenates the aging mouse heart-are thinking of tests of the protein in humans, to combat aging-related diseases.

"That would be in the coming years, not right now certainly, because we still have to understand exactly how it works," says Katsimpardi.

What are GDF11's long-term effects?

Understanding exactly how GDF11 works means understanding how it works over the long term, not merely for a few weeks. Will the signs of rejuvenation persist? Will the animals live longer?

Maybe so-but maybe not. GDF11 is a member of the so-called Transforming Growth Factor beta (TGF-β) superfamily of proteins, and circulates through the blood to affect many tissues. In the endothelial cells that line blood vessel walls, and in the heart, for example, it switches on the TGF-βsignaling pathway.

That pathway has a variety of functions in adult animals, often centered on growth and repair. In the brains of adult mice, for example, TGF-β is upregulated after injury and seems to play at least a short-term role in repair and neurogenesis. Longer term, however, elevated levels of TGF-β have been reported to cause abnormal hippocampal remodeling and worsened cognition. In humans, chronic elevated TGF-β signaling occurs in the growth disorder known as Marfan syndrome, and is thought to contribute to the heart defects that typically shorten the lives of people with the disease.

For now, says researcher Caleb E. Finch from the University of Southern California, the issue of TGF-β signaling and lifespan remains "too complex," with reports suggesting "tissue- and cell-specific differences in the short- and long-term consequences of increased or decreased expression" of the protein.

But certainly there are related growth-promoting factors, such as human growth hormone and insulin growth factor 1 (IGF-1), that exhibit a clearer pattern of protecting and repairing in the short term while hastening mortality in the long term. Halving IGF-1 signaling throughout life has been reported to extend the lifespan of mice by about 26 percent on average, largely by making the mice more resistant to oxidative stress-a byproduct of normal cellular energy production. There is at least one report suggesting that lower bloodstream IGF-1 levels in people correlate with longer lifespan. People who have low IGF-1 signaling for genetic reasons also seem highly resistant to diabetes and cancer. Conversely, increased IGF-1 signaling from the genetic disease called acromegaly correlates with shortened lifespan.

An even better-known example of the tension between growth and longevity comes from research on dietary restriction. The latter inhibits growth, and yet has been shown to greatly extend rodent lifespan, and to improve resistance to age-related diseases in primates and humans.

Perhaps unsurprisingly, growth-promoting factors such as IGF-1 signaling and overeating appear to raise the risks of many cancers-one obvious route by which they can shorten lifespan. Other rejuvenation strategies, such as increasing the activity of the enzyme telomerase, also have turned out to be strategies that benefit cancer cells. TGF-β's role in cancer is less clear, but there is evidence of its involvement in promoting tumor metastasis, and TGF-β inhibitors are being developed as potential anticancer drugs. GDF11 itself is suspected of promoting metastasis in colorectal cancer.

In other words, there may be no "free lunch" here, in terms of benefits from growth-promoting factors. Boosting the growth and repair capacity of tissue-seemingly rejuvenating it-may also somehow move it faster towards its demise, like the proverbial candle that burns at both ends.

Whether that is so for GDF11 remains to be seen. Years of further experimentation will be required to determine conclusively whether its long term dosing will help or hurt the brain, the heart, and other tissues.

Is "younger" cognition always better?

The idea that major growth factors can benefit some tissues in the short run, but harm them in the long run, hints that the aging process itself-by reducing the activity of such factors-works to delay an inevitable mortality, and in that sense isn't all bad.

Some researchers have even proposed that age-related changes in the brain, leading to a decline in learning ability, may be viewed as changes for the better in terms of overall function. In particular, a reduced ability to learn new things with age, and a shift towards a reliance on existing memories and skills, are conceivably efficiency features, given that people generally learn most of what they need to know by the time they reach middle age.

There are also hints in the literature that imposing a more youthful cognitive flexibility on a mature brain may end up destabilizing prior memories that a person would prefer to keep. Scientists have found recently, in mouse experiments, that the high level of new neuron production (neurogenesis) in the very young hippocampus apparently displaces existing neurons so rapidly that the ability to form longer-term memories is impaired-thus possibly explaining why humans retain almost no memories from the first few years of their lives.

"The addition of these fresh neurons gives you more capacity to store things later, but at the same time you might lose something that you've already learned," says University of Toronto researcher Sheena A. Josselyn, a senior author of the report.

Just how much of an increase in neurogenesis is required to disrupt new memories, how far back in memory the disruption can go, and how this disruption will impact behavior, are questions that Josselyn hopes to answer with further studies-now planned in humans who take cancer chemotherapies that happen to reduce neurogenesis. "We're trying to see whether disrupting neurogenesis helps preserve the learning that takes place right before the treatment," Josselyn says.

In any case, results such as those from Josselyn and her colleagues hint that "rejuvenation" stimuli might in general have unanticipated side effects on cognition in older brains-brains whose gene programs might not be ready to respond to such stimuli in entirely beneficial ways.

Are you a man or a mouse? Or a worm?

A further broad caveat about anti-aging strategies is that the ones that have been shown to workvery wellin small, simple animal models-dramatically extending the lives of those animals-have never worked nearly so well in humans.

IGF-1 inhibition or calorie restriction, for example, can boost the lifespan of simple C. elegans roundworms by 100 percent or more. In mice, a species much closer to humans, IGF-1 inhibition can extend lifespan by a much smaller amount-only about 26 percent, lumping males and females together-and not everyone agrees that IGF-1 inhibition extends lifespan in every strain of mouse. Similarly, calorie restriction can extend rodent lifespan by only about 35 percent, depending on the strain.

Macaque monkeys are even closer to humans and have typical lifespans in captivity of 20-25 years, but they showlittle or no lifespan-extension effect from calorie-restricted diets, even though they do seem to get fewer age-related diseases such as cancer.

Clearly the small animals used to demonstrate dramatic lifespan extension don't model the full complexity of primate aging. The C. elegans worm, Finch points out, is a simple organism that also leads a simplified, lab-dish life: "then you move to the fly and you have a much more socially complex, competitive environment; then you move to the mouse and you have a whole other level of complexity."

That's not to say that future, highly advanced anti-aging strategies couldn't extend human lifespan and brain-health-span indefinitely. But as Finch and colleagues have argued in a recent review paper, relatively basic medical and behavioral changes such as those that have doubled the average American lifespan over the past 130 years-antibiotics, vaccines, statins, cleaner water,declines in smoking and red-meat-eating, etc.-may not be able to push lifespan much further. The researchers point out that "[s]ince 1997, no one has exceeded Jeanne Calment's record of 122.5 years, despite an exponential increase of centenarians."

We may be "at the wall of improvement," Finch says.



life extension

James Salvate, Ph.D.

10/14/2014 9:22:20 AM

I really enjoyed this article as it puts the idea of life extension into a much better perspective than recent articles that I have read. Most articles do not mention any negative aspects of life extension. The article puts forth a balanced view proposing that future may not offer continuous improvement in all areas of the brain along with an increased lifespan. Thank you for such a balanced article.