Program: Is it possible to stop aging?

Robyn Williams:  What about aging? Can we make it go away? Can we all be Peter Pans and Petria Pans? Meet Dr David Walker at UCLA.

David Walker:  Yeah, I've actually been studying aging for almost 30 years since I was a graduate student quite some time ago.

Robyn Williams:  What turned you onto the topic in the first place?

David Walker:   So was pretty young back then. I actually was originally intending to study cancer biology, you know, as obviously was and still remains a really important biomedical problem, but a lot, even back then, it had already been known about the basics of cancer biology in terms of over-proliferation and the inability to block the cell cycle and to avoid cell death, whereas aging was really a complete mystery and that was appealing from an academic perspective and it also was appealing from a career perspective because it really seemed like a field that was pretty wide open.

Robyn Williams:  Especially for people, but you're studying fruit flies.

David Walker:   I am, I'm studying fruit flies for a lot of reasons. I originally started studying aging in worms, but for fruit flies, they're even smaller than fruit flies, 959 cells. And so I studied aging in C. elegans for my PhD. And then when I started a postdoc at Caltech, I switched to a more complicated organism, the fruit fly.

Robyn Williams:  And they both reproduce quite quickly so you can get changes observed more easily.

David Walker:   Right, you can generate a lot of flies or worms in a relatively rapid period of time, as you say, and so you can do experiments with large sample sizes, and if you're impatient, you can test your various hypothesis over a period of weeks and months as opposed to years.

Robyn Williams: Do they have anything that approximates to be a brain or mission control?

David Walker:  Of course, they have a brain which is comprised of subsets of neurons and glial cells divided up based on which neurotransmitters are used. They have a complicated repertoire of behaviours they can learn and remember, although they don't do so quite so well as they get older. And they can do things that we can't do. We can't land on the ceiling.

Robyn Williams: When they do age, these fruit flies, do you notice anything different about their brains?

David Walker:  Yes, that's a great and timely question. you know, people have been studying changes in the aging brain, including the aging fly brain for some time. And there's a lot of overlap with what changes in fruit fly brains and mammalian brains like our own. And so there's a fairly well-established set of what are called hallmarks of aging, which are cellular markers that change with age and they include the accumulation of dysfunctional or damaged mitochondria, proteins that tend to aggregate, inflammation we've all heard of which is believed to be a strong driver of disease and all of these things occur in the aging fruit fly brain just as they do in our brains.

Robyn Williams: And do these changes affect its intellectual capacity if it has one?

David Walker:  It does have one in terms of flies can remember and you can kind of think about this as a Pavlovian-style response. So if you pair an odour with something pleasant or unpleasant, such as an electric shock, the flies will remember that odour for some time, even up to a week or more, avoid that odour because they perceive it to be associated with a negative stimulus and that declines with age. And so we and others have been studying this process and trying to figure out ways to improve cognitive function with age.

Robyn Williams: And of course if you've noticed fruit flies, especially if you've got fruit left out, crossing so quickly to find it as if they're smelling it, so the smell is an important thing.

David Walker:  Yeah, they love fermenting fruit. So you're absolutely right, that is based largely on affection or smell 

Robyn Williams:  And the accumulation of actin. Is that right?

David Walker:  Yes, so recently we've made a discovery based on something that we and others had not observed in the aging brain that was somewhat surprising and that is, as you say, related to the protein called actin, which is amongst the most abundant protein in all of our cells. And since I've been in graduate school, it's commonly thought of as what we refer to as a loading control. So often when you're looking at how do genes change in expression or protein levels change you use actin as a control with the assumption being it's stable and it doesn't really change. And we find in a somewhat serendipitous manner that in the aging brain, that's not in fact the case. And when we looked in the brains of flies of increasing ages, we started to see an accumulation of filamentous actin in a stable fashion. And we think of this as the actin levels become hyper-stabilized and actually accumulate in age neurons. And so we made that observation. And of course, we wanted to know, is this just a correlate of aging or is this actually driving the aging process?

Robyn Williams: As if it's a waste product that won't go away, perhaps.

David Walker:  There is a lot of evidence to suggest that the pathways within our cells that remove wastes do decline with age. There is a connection, but we actually don't think it's as simple as the one you suggested. And we don't actually believe that actin is accumulating due to a lack of turnover or waste removal. We think that actin stabilization itself is causing a major pathway within the cell, which is the major or a major cellular clearance pathway. And the accumulation or hyperstabilization of actin seems to disrupt that process. So when actin is accumulating in age neurons, the pathway of autophagy becomes impaired. And we know this is a causal relationship because using genetics and pharmacological approaches we were able to disrupt the actin in the aged brain and we were able to restore autophagy. 

And that's something that's quite remarkable and something that is very interesting because as I say, an impairment in autophagy has been reported in the aged brains of many organisms and has also been linked to various neurodegenerative diseases. So the idea that we can not only better understand what's leading to an impairment of autophagy, but find an approach to restore autophagy levels to a youthful level, and we were very excited to see.

Robyn Williams: Now if we look at the word autophagy, I eat myself in other words. Doing it for myself and eating, phagy if you like, and the cells are supposed to clear the way. In fact, when I was growing up as a teenager, well, even earlier than that, as you grow up, the brain tends to mature by cleaning out the aspects of itself that it doesn't need anymore. You know, lots of experimental pathways which you don't need, and so you slim down a little bit, but enough to make the more adult brain. Is that more or less right?

David Walker:  Yes, during development, including the skin between our fingers are known to be cleared as we develop. That we think of more as removing entire cells. What autophagy does is remove the contents within the cells. So it's related, but there's a distinction there. I think there is a time and a place where removing entire cells can be beneficial, especially during development. But if you think about an aging brain, which is comprised almost entirely of post mitotic cells, cells which can no longer divide and be replaced. If we could clean out the contents of those neurons and glial cells without actually removing the cell itself, that would be something that we'd like to aspire to.

Robyn Williams: How close are you getting?

David Walker:  In fruit flies, we can do it. So in fruit flies, one of the other amazing reasons we're excited to are not only is their entire genome sequenced and we know each and every gene, but we can manipulate each and every one of those genes and we can do so in a very targeted and precise manner. We can activate and inactivate any gene we're interested in in specific cell types. And we can also do so in a temporally controlled manner meaning we can take an old fly and switch on and off a gene within a specific cell type. And when we do that with genes that control this accumulation of actin, and we do it in a way to prevent the accumulation of hyper-stabilized actin, then we can restore autophagy and we can actually improve the cognitive function of the flies. So we can certainly do these things in fruit flies. Of course, the next question is, can we apply these approaches to mammals like ourselves?

Robyn Williams: I would not have dared to ask that question, but you asked it of yourself. When is it for us?

David Walker:  My lab is entirely based on basic scientific discovery and our hope usually is that we inspire others to study the same pathways and processes in other organisms. We'd be interested in doing so in a collaborative manner, but that is not something my lab exclusively would tackle by ourselves.

Robyn Williams: Does our brain have actin? We normally think of tangles. The proteins you mentioned before as being responsible for this sort of thing, but actin?

David Walker:  For sure, our brain cells and neurons have actin. There is reason to believe that there could be an accumulation of filamentous actin in certain neurodegenerative conditions in people. The challenge, of course, it's not possible to do interventionist studies. We can simply look and see what changes. And so we can't say yet, of course, that the accumulation of F-actin is driving brain aging in people yet.

Robyn Williams:  But soon we hope. David Walker is Professor in the Department of Physiology and Integrative Biology, UCLA. And for a summary of aging plus other future possibilities, do look at the cover story in The Economist magazine of March 28th. The rise of the superhuman, it's called. And they discount the misinformation. But look at the real possibilities scientifically.