Younger Muscles And Minds: Protein Turns Clock Back In Mice

Nonagenarian Olga Kotelko, left, on her way to victory in her age group in the 100-meter dash at Sacramento State in July 2011. Pat Peterson, right, won a younger age group. (Ken Stone/masterstrack.com, with permission)

Nonagenarian Olga Kotelko, left, on her way to victory in her age group in the 100-meter dash at Sacramento State in July 2011. Pat Peterson, right, won a younger age group. (Ken Stone/masterstrack.com, with permission)

Just about a year ago, Harvard stem cell scientists reported promising news for elderly heart failure patients: In mice, they found, a protein called Growth Differentiation Factor 11 could undo heart damage wrought by aging.

But was it just a heart thing? Or might GDF11 apply more broadly to other ways that we get older but not better?

New research finds that the protein has similarly rejuvenating effects on brains and muscles — though again, only in mice, so it will be years before we’ll know whether humans might see similar benefits. But GDF11 does circulate in the human bloodstream as it does in the mouse, so it’s not totally outlandish to imagine that we might someday pop pills to increase our circulating GDF11 to stay stronger, smarter and generally healthier as we age. And already, researchers are discussing the need to seek potential benefits for patients with Alzheimer’s and other degenerative diseases.

Upcoming papers in the journal Science found that when given GDF11, some older mice — the equivalent of roughly 70-year-old humans — became able to run as long and smell as well as young mice.

The Harvard press release quotes Doug Melton, chair of the university’s Department of Stem Cell and Regenerative Biology, as saying he couldn’t “recall a more exciting finding to come from stem cell science and clever experiments. This should give us all hope for a healthier future. We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer:  the higher levels of the protein GDF11 we have when young. There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function.”

I spoke with Harvard stem cell biologist Amy Wagers, a leader in the GDF11 research, about what it means. Our conversation, edited:

I imagine our headline shouldn’t say ‘Fountain of Youth discovered.’ How do you prefer the effects of GDF11 to be described?

I like ‘healthy aging.’ It’s really important to say that we don’t have any idea whether GDF11 might affect lifespan at all, but it does seem to improve or enhance healthy function in multiple different tissues.

What’s our best understanding at this point of what GDF11 does biologically?

I would say our understanding is still in its infancy. What we know is that GDF11 is a protein that is produced and present in the bloodstream at high levels when you’re young and it goes away as you get older. When you add it back to older animals, there are beneficial effects on a number of different tissues.

At the organismal level, we know that it enhanced muscle repair capacity and skeletal muscle structure so that physical function is improved. We know that in the brain it increases the production of neural stem cells and functioning of the olfactory system. And we know in the heart it reverses cardiac hypertrophy.

At the cellular level, again, we’re really just starting to piece this together, but we have seen that exposure to GDF11 in muscle stem cells actually allows them to repair some damage that seems to accumulate in their genetic material, and it also then allows them to differentiate, to mature into the muscle cells that are needed for the muscle tissue to function more effectively. It also seems to improve the cell’s ability to generate energy and to improve the machinery that does quality control for proteins in the cell.

We haven’t been able yet to put in order which effects are first and which other effects might be dependent on the first, or whether they’re all independent effects of exposure to GDF11, but that’s something we’re working very hard to understand. It’s also important to understand so when we design trials [of potential drugs], we know what to look for, to say ‘This is working or not working.’

Are ‘skeletal muscles’ what we normally think of as muscles? And how much did the mice improve, in human terms?

Yes, what you normally think of as muscle, or the ones you consume when you eat a steak. In terms of the improvement, probably, the best way to describe it is that we tested them for physical functioning in two different types of experiments. One was figuring out how hard they could pull on a bar, something akin to a pull-up. The older mice that received GDF11 were the same age as controls but they could pull with about 50 percent more strength than the mice that didn’t get it.

And the other test was endurance — we put the mice on a treadmill to see how long they could run, up to 90 minutes, before they got exhausted and gave up. Mice love to run. Older mice usually give up much earlier than the 90-minute trial, but in the animals treated with GDF11, they varied but some of them could run as long as the control mice could.

So it’s like a 70-year-old running as far as a 30-year-old can…So what connects all these dots, between heart and brain and muscle? Is there some common thread or pathway?

I think that is one of the most exciting aspects of this. We’ve known for a relatively long time that something in young blood improves many different tissues in older animals — brain, muscle, spinal cord. It could have been a different substance that was talking to each one of these tissues. What these new papers add to the story is that in fact, it’s the same molecule that’s talking to very different tissues with different responses to aging, with different mechanisms for maintaining themselves and for repairing after injury. So it says there’s actually some coordination between them, and it helps us understand a little bit about aging and why there might be synchrony between the emergence of aging-related dysfunction in various tissues that seem quite different.

The other exciting aspect of this is that it tells us it’s actually feasible now to start thinking about therapeutic strategies that might be targeting the root causes of these age-related dysfunctions and might be beneficial for multiple tissues.

It sounds like it could be a kind of a central key to why we may get worse in some ways as we get older?

I think our experiments so far are suggestive of that but we haven’t yet fully tested whether having high levels of GDF11 is essential for staying young. We’ve added it back in older animals and seen it improve how they function but we haven’t taken it away from younger animals.

It’s not a given that it’s a youth maintenance factor as well as a restoring factor in old age. But we’ve generated the mice we’ll need to test that, and that will tell us about whether determining someone’s level of GDF11 would be informative or not.

I imagine we could do that tomorrow if we wanted, test people’s GDF11 levels.

But we need to know what it means.

What are your next steps?

We’re very interested in the therapeutic translation of this work. So there are some things we need to understand. We need to understand why GDF11 goes away with age: because the cells that make it are dying or changing? Or because the cells that make it just stop making as much? Or because there’s some sort of inhibitor that’s destroying it? That’s very important for figuring out the best way we would up-regulate this pathway in the clinical sense.

We’d also like to know whether other tissues are affected by GDF11 in age.

Which ones?

All of them. My lab’s priority is the blood system, and there are known effects of the protein in red blood cell production. We think the source of GDF11 may be in the blood system. Also, I don’t want to leave anyone with the impression that GDF11 is ‘it.’ We actually think from our ongoing experiments there are probably other factors that can have similar effects. So we want to use GDF11 to help us piece together the larger network of factors in the blood that could have effects on aging and function.

Is there a name for those factors?

I’ve used ‘rejuvenation factors.’ Though another thing we don’t know is whether the improved function that we cause with GDF11 in animals is identical to young function. Or is it a ‘pseudo-youth’ stage? One could argue that on a therapeutic level maybe it doesn’t matter, but for trying to understand the normal process of aging it does matter.

According to the press release, the research groups are talking with a venture capital group to get funding to prepare for human clinical trials.

We’re talking through how to move forward, and have been working with other people who’ve worked on similar pathways. It will take a few years.

A perhaps frivolous question: Earlier work found that blood from younger mice improved function in older mice. So I’m wondering why we older humans aren’t already vampires? That is, wouldn’t I want younger blood to help me stay more youthful?

It’s a fair question. There are, obviously, a lot of substances in blood, and everyone has slightly different level of any substance in blood. If you don’t know what the active component of blood is that’s causing these effects, there’s no way to track whether you’ve given enough or too much. The more we can stay close to regulating one or a handful of specific pathways and know exactly what they do, the less chance of side effects. My view is that I really would want to understand how this works, so that we can design the most optimal method, really monitor the dosage, monitor the effects.

But have past experiments found healthful effects of infusing old humans with younger humans’ blood?

I suppose there’s lore about this that has existed for hundreds of years, but as far as a controlled clinical trial, I’m not aware of one.

Further reading:

The New York Times: Young blood may hold key to reversing aging

USA Today: Blood of young mice boosts brains, muscles of older ones

Science: Young blood renews old mice

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