Nature Podcast 3 May 2007

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Ben Valsler: This week, we find out what your brain is up to when you are not doing anything.

Marcus E. Raichle: Understanding these underlying dynamics of the brain is critical to understanding something like consciousness.

Ben Valsler: Azi Khatiri learns about super-heavy elements.

Heinz W. Gäggeler: Perhaps in our world we do have yet undiscovered elements. That is of course highly exciting.

Ben Valsler: And I find out why worms on a diet live a longer life.

Andrew Dillin: Because if you reduce dietary intake, it reduces the onset of cancer, neurodegenerative diseases, diabetes, and so we think that if we can trick the system, then you could actually delay the onset of those diseases.

Ben Valsler: I am Ben Valsler and this is the Nature Podcast. First this week, Chris Smith spoke to Marcus Raichle of Washington University, St. Louis, about what the brain does at rest. A study in anaesthetized monkeys showed levels of coherent activity in the brain even when the animal was profoundly unconscious. Conscious activity in the brain to control muscle movement, for example, seems to constitute only a minor part of the energy the brain consumes. Nature 447, 83–86 (03 May 2007) .

Marcus E. Raichle: The big overarching question is to understand what the brain is doing, and it comes in a context of the way in which we have tried to study the brain and that is to look at it as it responds to various tasks— and over the past several years, it has become increasingly apparent to us that that is a very small fraction of what the brain is really doing. And so the question that then comes to the fore is what is the brain doing and how is it doing it, and in my case using images of the brain obtained by magnetic resonance imaging, or MRI, to look at the brain at 'rest', if you will. When we use the term "rest", that should be put in quotation marks because your brain is never, ever at rest.

Chris Smith: Why do you want to study the brain at rest anyway? I mean surely it is more informative to look at a brain that is doing something because then you can work out how it is doing it?

Marcus E. Raichle: But if much of what it is doing is doing it at rest, then if you were ever to understand what it does when you ask it to do things, you better well understand what it is doing at rest.

Chris Smith: Fair enough, but how do you actually intend to do that? Because the problem is, is at rest for a human the same as for an experimental animal, because we do not really know whether experimental animals' brains are performing and giving them a consciousness in the same way that our brain gives us the consciousness.

Marcus E. Raichle: Well, that is a perfectly legitimate question and this paper in part addresses that. One of the things that's been most remarkable is that if you put an individual in one of these scanners and you observe what happens in the brain, first you notice that it seems quite noisy in there. These signals that we follow move up and down and if you begin to pay more close attention to it, you notice that they are organized in very remarkable patterns that appear to duplicate or reveal the very systems that become active when you ask somebody to do something. That is a little harder to explain, however, if we look at something like the areas of the brain that control the movement of your hands and so forth when you are laying there not moving your hands, and yet they appear to be beautifully organized and, as we say, coherent.

Chris Smith: So if you study someone who is not moving, what you are saying is you are just seeing areas of the brain that would coincide with the movement becoming active, even though there is no movement happening?

Marcus E. Raichle: They are active in a patterned, coherent way. It is as if you can see, well, fluctuations like the smooth oscillations of waves on a body of water or something that are coherent.

Chris Smith: So, how does that coincide with what changes when someone does want to actually make a movement then?

Marcus E. Raichle: What happens when you do make a movement is that those small changes now ride on, if you will, these waves of activity in the brain. They merely sit like white caps on a wave.

Chris Smith: How do you know that is the case, what did you actually do in this study?

Marcus E. Raichle: There are several things that needed to be addressed and so what we did in this study was to examine these activities in anaesthetized monkeys. Obviously they have a motor system like you and I and they have a visual system like you and I, and so we examined these very same systems that were quite familiar within humans.

Chris Smith: So, in other words, you can eliminate the conscious component?

Marcus E. Raichle: Absolutely, these monkeys were certifiably not conscious and yet all of this activity was still there, and then what we did was to extend this a bit further. There is a system in the brain that has been of great interest. When you engage in some kind of a task that involves, say, paying attention to the world around you, so you have to kind of forget yourself, this system tends to reduce its activity and that seems kind of mysterious to us, and it became known as a default network — that is, that to which your brain defaults to, if you will, or goes to when you are not paying attention to the world around you.

Chris Smith: Do you see the same effect in animals as well as humans?

Marcus E. Raichle: Well, that is key to this paper, because one of the important observations that we really were interested in finding out about was does the monkey have this and is it there when you are unconscious.

Chris Smith: And is it?

Marcus E. Raichle: Absolutely, it is absolutely stunning and the other thing that is really interesting about this default network is that much of the work in humans has focused on things that are thought to be uniquely human: that is, our ability to personally remember things in our past or to think about how other people think, the so-called 'theory of mind', and seeing it in it the form we see it in a monkey raises some very interesting evolutionary issues with regard to how did this system evolve. Is remembering something that a monkey can really do? Does it function exactly the same in humans? Are there differences? Those are questions that all remain to be explored.

Chris Smith: So are we probing with this and seeing a glimpse into how the brain generates consciousness, do you think?

Marcus E. Raichle: Well, it is a great question. The activity that we are monitoring, I think, is not representing the ongoing thoughts that you can talk about, but you need this very complex underlying organization to make all of those thoughts possible. Understanding these underlying dynamics of the brain, which from a brain-energy point of view are using most of the energy devoted to running the brain, is critical to understanding something like consciousness.

Ben Valsler: Marcus Raichle on how the coherent waves of resting brain activity may help us discover how the brain creates consciousness. Also, in the field of brain science, Li-Huei Tsai of the Picower Institute at MIT has been looking into a technique which may help to restore the lost memories of people with dementia. Mice with damaged brain cells were shown to have their learning and memory faculties restored by being placed in an environment rich in different stimuli. Identifying the chemical pathways involved in this could lead to new therapies for human patients. Nature advance online publication 29 April 2007.

Li-Huei Tsai: For a number of years we tried to create mouse models for human neurodegenerative diseases, especially those diseases with a very severe loss of the size of the brain and a severe reduction of the number of neurons, and these conditions are usually associated with learning impairment and memory loss. In the more severe cases, it is known as dementia. So, we created a mouse model. We think that it is a very powerful model because we have a way to induce neurodegeneration in any stage we want and also we can induce the loss of neurons in a specific brain region.

Azi Khatiri: So, what were the main findings of this study?

Li-Huei Tsai: Several observations are very exciting. First of all, we found that if we keep any mouse in an enriched environment— so this environment usually constitutes a larger cage, a number of toys of different colours, different textures, and running wheels, so the animals can exercise whenever they want, and also we usually house a few animals together, so if they want to interact socially they could, and also we change the toys daily— and we keep the animals in this environment for several weeks, we found that this can significantly improve learning impairment. So this is the first finding, and then I think what is really exciting is that we came out with a behaviour paradigm that allows us to assess the fate of a long-term memory.

Azi Khatiri: How did you study long-term memory in a mouse?

Li-Huei Tsai: In humans you can see the long-term memory is like the memories from your childhood, memory of your parents or grandparents, and in the mouse, we tried to give the mice a training trial and we leave them alone for several weeks or months, then we come back to assess whether these mice can still remember that trial. So they are normal when we give them the training trial. And then we induce neurodegenerations and we found that these animals can no longer remember. And then we found that —this is really remarkable— if we keep these mice in the enriched environment for several weeks with toys and training wheels and socialization and everything, then upon testing them again we found that somehow they can remember this trial that we gave them a long time ago, so the lost memory basically came back.

Azi Khatiri: That is very interesting.

Li-Huei Tsai: It is extremely remarkable, and that result strongly suggests to us that the so-called lost memory, it cannot be really lost. If it is really erased, then you will never be able to get it back.

Azi Khatiri: So, why do you think it is that people or even mice then lose that memory?

Li-Huei Tsai: Based on our experimental result, I would strongly suggest that the memories are really not lost, but after severe neurodegeneration, the mice just simply cannot access those memories anymore.

Azi Khatiri: So, would you say it is more like a rewiring issue, rather than a permanent loss?

Li-Huei Tsai: Exactly so. We performed some cell-biology studies in the brain of these mice and we found that, even though environmental enrichment does not seem to really prevent neurodegeneration, but there seems to be a lot more synapses after enrichment, so there is clearly ongoing synaptogenesis and I think this is probably an important process in terms of rewiring the brain and therefore these animals after enrichment can access those memories again.

Azi Khatiri: So, how will your findings enable us to fight diseases like dementia and Alzheimer's?

Li-Huei Tsai: Another big part of our finding is that we are providing some evidence that if we can change the structure of our genetic material, the chromatin, with some small molecules, then these small molecules behave in a similar way as environmental enrichment to increase synaptogenesis in the brain and to improve learning ability or even to help recover the lost memories in our animal models. Perhaps future studies can focus on this class of molecules to see whether these molecules will be beneficial in humans as well.

Ben Valsler: Li-Huei Tsai speaking to Azi Khatiri about her work in helping to restore lost memories in mice.


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Ben Valsler: Later in the show, we will be finding out about the super-heavy element 112 and how dietary restriction can lead to an increased lifespan, but now Joshua Bandfield from Arizona State University described to Azi Khatiri how he found a large amount of water ice under the surface of Mars. Surprisingly, he was able to find patches of subsurface ice by looking for distinct warm patches. Water ice absorbs heat in the Martian summer and then this heat is radiated during the winter. An infrared camera then makes it possible to see where the ice lies. Nature 447, 64–67 (03 May 2007) .

Joshua L. Bandfield: We know about water on Mars. That seems to be discovered quite often and the purpose of the study was to see where we find water ice near the surface at high latitudes on Mars.

Azi Khatiri: And how are you trying to do this?

Joshua L. Bandfield: Specifically, I did this through looking at the temperature of the surface. Maybe the best way to explain it is let us say I have a block of ice or a mixture of dust and ice in a solid block and it was just a couple of centimetres below the surface. And during the summer, the sun has been putting energy into the surface, it is heating it up and it is kind of weird to think of it, but that ice is actually soaking up a lot of that heat and stores it through the summer and as we go into the fall season, well the sun starts to go down and the surface starts to cool off, but that heat that was stored in that block of ice will continue to pump that heat back up out to the surface, sort of elevating the temperatures a bit, and that extra warmth is what we detect and how we can say, hey, it is a little bit warmer than we think it should be here, so there has got to be some ice just underneath the surface.

Azi Khatiri: What equipment do you use to detect these temperature changes?

Joshua L. Bandfield: We operate a camera called a Thermal Emission Imaging System and it is a dual camera. It takes pictures at visible wavelengths like what you see with your eyes, but it also has an infrared camera looking at infrared wavelengths, which are much longer wavelengths than what you see with your eyes, which detects surface temperatures. This camera is on the Mars Odyssey spacecraft. It's certainly in orbit. It has been operating since 2002/2003. And it will take images of the surface and those images are temperature images and so we look at how the surface looks different and how it changes temperature between, say, late summer and early fall. In addition to that, you have to combine that with a thermal model and basically it is just a computer model that knows where the sun is in the sky and knows how much energy is being input into the surface, and it will predict what the temperature will be, and so when you combine that data set from the Mars Odyssey with the thermal model you can get something intelligent out of it and produce water-ice depth maps.

Azi Khatiri: What have you found as the result of these data sets that you have been collecting from the Mars Odyssey and also your computer models?

Joshua L. Bandfield: At high latitudes on Mars, we know that there is water ice near the surface. We have known that for a couple of years now. What this study is showing is that we gained a factor of roughly a thousand in terms of our spatial resolution. So, it is much, much more detailed here, and it is showing how the water ice near the surface is highly variable and it seems to be affected by the nature of the surface materials. So if I have, say, a rockier surface that tends to have actually a deeper water-ice table, whereas a dusty surface tends to have a shallower water-ice table. And so when you look at where that water ice is, it sort of fits with where people have predicted that water ice is stable in the current Martian climate, and that is actually a pretty interesting thing because Mars goes through climate cycles just like Earth does. So, that goes through ice ages and relatively warm periods, and the fact that we see water ice present exactly where it should based on the current climate conditions, sort of implies that the water ice is following the climate.

Azi Khatiri: Have you had any indications as to how much of the surface of Mars is actually covered in water?

Joshua L. Bandfield: That is a good question. It looks as if apparently we see water ice within a metre or two of the surface at latitudes as low as about maybe 45 degrees. So, basically there is a permafrost layer of ice down to about 45 degrees north and south, and as far as the concentrations of that, some of these concentrations are actually quite high, but it varies anywhere from roughly 10 weight per cent, which is about roughly 20% by volume of ice, up to very close to 100%. So, there is a lot of ice locked up in the near-surface at high latitudes. As far as the total volumes, I actually do not have a good idea of what that number is — other than a lot.

Azi Khatiri: Why is it important for us to study planets like Mars?

Joshua L. Bandfield: There is times when you can look back on something and say, hey that was the golden era of something, and I feel like this is one of those eras in Mars research. We have just learnt so much in the past decade alone and we are getting a much, much clearer picture about just how the planet works, and in some ways the parallels for understanding of how the Earth works as well. This is sort of a giant science experiment set up in outer space for us to go study just to find out how things work in general.

Ben Valsler: Joshua Bandfield describing his technique for finding water ice under the surface of Mars. Staying underground now, but returning to a more familiar planet, Greg Beroza spoke to Azi Khatiri about slow earthquakes. Nature 447, 76–79 (03 May 2007) .

Gregory C. Beroza: These earthquakes range in size from the very small, from magnitude 1, to very large, magnitude 7.5, and they occur in a wide range of geologic environments everywhere from Japan to Mexico to California. They appear to have the same mechanism as the ordinary earthquakes that we are familiar with — that is, they are caused by slip on faults, but they have this interesting characteristic, and that is they take a really long time to happen relative to ordinary earthquakes. So, we describe these with the adjective 'slow'.

Azi Khatiri: When you say "slow", what exactly do you mean by slow?

Gregory C. Beroza: The speed at which regular earthquakes grow at, that is the speed at which the disturbance propagates across the fault is on the same order as the velocity that seismic waves propagate — that is, two or three kilometres per second. It is really fast. Now, how quickly the slow earthquakes spread out depends on how big they are. The ones that are equivalent to magnitude-6 earthquakes take days to happen and the slow earthquakes that are larger still, on the order the magnitude 7, they can take weeks, even months, to happen.

Azi Khatiri: Why are these earthquakes particularly slow?

Gregory C. Beroza: That is the key question. For ordinary earthquakes, the size grows explosively once the earthquake gets started. So, if an earthquake lasts twice as long, it is eight times as big in terms of the energy it releases. Now, these slow earthquakes are very different. Whether they are large or small, these slow earthquakes grow with a constant rate. They sort of creep along and grow in size in simple proportion to their duration, and your fundamental question is why does this happen and, you know, another way to put that is —what is that slows these earthquakes down? And in this paper, we offer two explanations, one idea is that if the offset that occurs across the fault is about the same, regardless of how extensive they are, that is how wide a fault area they cover, then the area faulting has to grow at a constant rate in order to get this constant rate of growth, and that means that as the earthquake gets bigger, the rupture has to slow down, and it slows down in a particular way that is characteristic of diffusive phenomena. So, that leads to the question of what is it that is diffusing, and the obvious possibility is fluids. We have evidence that, at least in some of the places where these slow earthquakes are happening, that fluids are present. Now, that is sort of a fly in the ointment, in that the rate of diffusion is way, way too fast for these to work at these great depths. We just do not think there is enough connectivity in the poor space underground for fluids to move around at speeds of tens of kilometres per hour. So, it maybe something else that is diffusing, like stress. Another possibility is that these slow earthquakes are like extremely weak ordinary earthquakes, and so their slip maybe is not constant, but if this were to be true how quickly the disturbance spreads across the fault has to decrease even more rapidly with increasing size than in the diffusive model. So, either of these models can explain the observed behaviour, but really both of them leave very much open the question of what it is that is applying the speed limit.

Azi Khatiri: So, what processes happen below the surface to cause these earthquakes?

Gregory C. Beroza: That is an excellent question. I can give you a partial answer. A common characteristic of these slow earthquakes is that they happen on the deep extension of faults that have damage in ordinary earthquakes. So, it is likely that those parts of the fault behave more stably and that is why we are able to have these weak and slow earthquakes. Where we are able to see it, there is evidence that there may be fluids present at these depths, so we think it is quite possible that fluids are involved in this somehow.

Azi Khatiri: What was your experimental set-up for getting this particular result?

Gregory C. Beroza: There are earthquake-monitoring networks recording the waves, and part of the reason they are so sensitive is that they are deployed not on the Earth's surface but in bore holes 100 metres deep, and a lot of these slow earthquakes were discovered in Japan because they have this very sensitive network. The largest slow earthquakes in the Pacific northwest of the US, they were discovered using global positioning satellite technology. So when one of these slow earthquakes happens, the Earth's surface moves, so you are not really sensing a wave so much as the change in the shape of the Earth's surface. So, it has been a range of different instrumentation that has been used to find this guise.

Azi Khatiri: So, how is this study going to help us deal with the general problem of earthquakes in the future?

Gregory C. Beroza: Well, they are clearly related to earthquakes that are happening on faults. They are due to slip across these faults, just like ordinary earthquakes. They are occurring immediately deeper and adjacent to the parts of the fault that host ordinary earthquakes. So the hope is that by understanding these, we will increase our understanding of ordinary earthquakes as well.

Ben Valsler: Greg Beroza of Stanford University describing how a series of recently reported earthquake phenomena all belong to a new earthquake category, a diverse class of slow seismic events, and so it can be thought of as different manifestations of the same thing. Understanding these slow earthquakes could lead to a better understanding of the larger, more energetic earthquakes.


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Ben Valsler: Next, I spoke to Bettina Engelbrecht, who studied the drought tolerance of many tree species to find out how an ecosystem responds to water availability. She found that the amount of water available to plants was a major factor in species distribution over local and regional scales. This means that the changes in water availability in response to climate change are very likely to alter the distributions of tree species and so reduce biodiversity. Nature 447, 80–82 (03 May 2007) .

Bettina M. J. Engelbrecht: We examined the role of drought for distribution of tropical rain forest shrubs and trees. Normally, if we think about tropical forests we do not associate them with drought, but then actually most tropical forests are exposed to one or even two dry seasons, and during these dry periods plants can strongly suffer from the lack of water and they grow less and they wilt or even die. And so what we examined is to what extent the tolerance of plants to drought on one hand, and that combined with a variation of the availability of water at different scales, both local and regional, is important for distribution of plant species in humid forest, or it may be other factors —such as light or nutrients — might be more important.

Ben Valsler: Have people not looked before at what different species of plants can cope with, with regards water availability?

Bettina M. J. Engelbrecht: They have done some studies, but these are usually focused on one or two, or at least very few, species and so the novelty of our study is that we were able to quantitatively link experimental and observational results and then use that to examine if drought tolerance really is the mechanism that is determining the distribution of species. We worked it with 48 species, so that we can actually say something, or begin to say something, about the community — that is what is really new in our paper.

Ben Valsler: And how did you go about doing this experimentally?

Bettina M. J. Engelbrecht: We quantified the drought tolerance of the seedlings the under study in a tropical forest in Panama, and there we transplanted seedlings out and we kept half of these seedlings dry and watered the other half of the seedlings in the dry season, and then we compared the survival in dry and wet conditions and used that as an index for the drought tolerance. This is actually one of the most comprehensive experimental studies to date for the comparative reaction of the many tropical plant species to any environmental factor.

Ben Valsler: Are not environmental factors quite complex? There is light availability, water availability, and nutrients, and so is it really that easy just to tease out the one factor— in this case, availability of water?

Bettina M. J. Engelbrecht: No, it is actually not easy at all, and that is part of why it has not been done and has not been tried. There are obviously many different factors that are affecting species distribution — for example, its well-known that species distribution do correlate with rainfall. But even it is a quite another question, to start, to begin, what is really driving, what is the other underlying causes for these patterns that we find; and then we have to tease apart light, nutrients and water effects. And the way we did that is we had our measure of drought tolerance and correlated that with plant-species distribution, but we also had previously published data on shade tolerance of species and we looked if that correlates with drought tolerance, and it does not in our system, and we also looked if water availability and nutrient availability do correlate, and again it does not, and so that means that we can exclude in our study that these patterns that we found are due to shades and nutrients, rather than to drought. Our paper is just kind of a start and is really diverse, for us to look like what are important factors at a community level influencing species distribution, and so we find that there is a very strong footprint of drought. It does not mean that light and nutrients are not important at all, but there is about 30% of the variation in species distribution that we can find is due to drought, and then other factors come in on top of that.

Ben Valsler: So, this would mean that things like climate change, which would affect the availability of water, is going to have a larger impact on biodiversity than perhaps we might have thought before?

Bettina M. J. Engelbrecht: Yes. So, studies like this that actually really look at underlying causes for plant distribution are really important to be able to tease apart what consequences of climate change will be for forests or its systems in general. So, in tropical forests, really it is more shift in rainfall patterns than changes in temperature that are predicted with climate change and so if we want to understand the consequences of that shift, we really have to understand the direct role of rainfall and drought for tropical forests, and our data shows that really dramatic shift in species distribution, community composition, also forest diversity and ecosystem functioning, have to be expected even with relatively small changes in dry season. That is the basis for modelling the consequences of future climate change, but also for making important decisions about forest conservation and forest management.

Ben Valsler: Bettina Engelbrecht, of the University of Kaiserslautern in Germany and the Smithsonian Tropical Research Institute in Panama, discussing how they linked experimental results and drought tolerance with environmental observation to show that availability of water is a defining characteristic in species distribution. Still to come, I spoke to Andrew Dillin about the link between dietary restriction and longevity, but first Azi Khatiri spoke to Heinz Gäggeler about his work in characterizing the super-heavy element 112. This element is short-lived and produced in small quantities — in fact, only two atoms of it were available to study. Nature 447, 72–75 (03 May 2007) .

Heinz W. Gäggeler: We were trying to study the chemical properties of new elements called super-heavy elements, and these super-heavy elements they have atomic numbers at about 112 to 114, and quite a number of scientists were searching for these elements for decades and they could not find those elements until very recently. The physicists from Dubna from the Flerov Laboratory of Nuclear Reactions claimed to have now discovered these elements, but they were not able at all to tell anything about chemical properties of these elements and that is where we came into game because we specialized in developing very fast chemical separation techniques. That means we are able to separate single atoms of elements, and this was just what was needed, and so we took all our setups we have available here in Switzerland to Russia to this institute in Dubna and after having installed these very fast separation techniques at the very big accelerator, we were trying now to study the chemical properties of one of those elements and the element we were focusing on had the atomic number 112. This element should be in the periodic table just below mercury, and you know that mercury is a very special element. It is the only heavy metal, which is liquid, and so a question was would element 112 also behave like volatile heavy metal, or even perhaps be more volatile than mercury?

Azi Khatiri: Could you explain for me your experimental set-up? How did you manage to do this?

Heinz W. Gäggeler: If you were to investigate mercury, you can use one very well known fact that with silver, for instance, or gold, mercury forms very, very strong compounds. So we were actually testing whether or not this element 112 also forms with this gold surface a very strong metal-metal bonding, or whether or not the bonding is very weak, which could also be the case, but then it would behave like a noble gas.

Azi Khatiri: So, how did you manage to produce this element 112?

Heinz W. Gäggeler: This element we have only for a few seconds, so they cannot exist in nature anymore. So, a target consisting of plutonium was bombarded with very high-energy beam of calcium ions, which had an energy of roughly 240 million electron volts, then in the interaction of these calcium ions, which are a highly radioactive target, complete fusion occurred and this fusion product is just element 112. So this element 112 was then collected and continuously swept to the gold surfaces, and opposite to these gold surfaces were positioned detectors which are able to analyse the products that were deposited on the surface of the gold at the level of single atoms.

Azi Khatiri: So, what did you observe as a result of your experiments?

Heinz W. Gäggeler: So, what we actually observed is that two atoms, only two atoms of element 112, were found on this gold surface at minus 10 degrees Centigrade. This is even lower than the temperature at which mercury deposits on the gold surface, and from this observation we could learn that element 112 is even more volatile than mercury, but it is not as volatile as a noble gas.

Azi Khatiri: It is very interesting that you have managed to gain access to such a rare element, to be able to analyse it and study it in such a way, but what is so special about these super-heavy elements?

Heinz W. Gäggeler: Well, two things are very special. The first thing is that perhaps in our world we do have yet-undiscovered elements, that is of course highly exciting, and the second aspect is that these very heavy elements, they have so many positively charged protons in their nucleus that this high charge in the centre of an atom strongly disturbs the electron shells and this is very interesting for theoretical chemists to test their models, which they use to predict any molecule. So it is a test field, so to say, for the computer modelling of chemistry in general.

Ben Valsler: Heinz Gäggeler of the Paul Scherrer Institute and the University of Bern, Switzerland, on their findings that element 112 is more volatile than mercury, but less so than a noble gas.


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Ben Valsler: Lastly for this week, I spoke to Andrew Dillin of the Salk Institute for Biological Sciences about his work identifying the genes causing extended lifespan in diet-restricted Caenorhabditis elegans, a nematode worm. By looking at the genes known to expand lifespan through controlling insulin signalling or mitochondrial action, Dillin and his team were able to identify gene pha-4 that was essential for dietary restriction to increase longevity. As it is known that dietary restriction increases longevity in every species studied, tricking the body into activating this gene could lead to therapies which could delay the onset of human age-related diseases. Nature advance online publication 2 May 2007.

Andrew Dillin: We have known since 1935 that dietary restriction can increase longevity of rodents. And this has been extended to almost every animal that has been tested. Reduce food intake to 60-70% normal increases longevity.

Ben Valsler: It seems quite surprising that because it is so often told that to live a long healthy life, we need to have a balanced diet, we need to take in daily amounts of calories, and so actually restricting our diet would increase longevity at all?

Andrew Dillin: Yeah, that is a very intuitive question. So, there is a sweet spot of where you actually have to reduce your diet. So, if you look at going from starvation to the Burger King Big Mac high-calorie diet, definitely starvation is going to shorten your lifespan, but also the really high-calorie diets are going to shorten our lifespan as well. But there is an intermediate level that actually increases lifespan in mammals by 30-40%. So, there is this really small window where you are on the borderline of crossing into starvation or crossing into being fat. That is the calorie-restriction window that we actually need to be on to increase longevity, and there is three genetic pathways that we know about that are conserved from worms all the way up to mammals. The first one is insulin IGF-1 signalling. So if you reduce insulin signalling it makes animals live a long time. If you reduce mitochondrial function that will also increase longevity. But these two are two different pathways, they function independent of each other. And the third is dietary restriction, which for long time is thought to depend upon one of those two other pathways, and so we were working with hypothesis that insulin signalling was part of the dietary-restriction pathway and the first real big surprise that we came across is that we were working on a gene that is absolutely essential for insulin signalling to regulate longevity. It is called smk-1 and what it does is it genetically interacts with a transcription factor called DAF-16, and when we look at DAF-16, if we completely knock it out, animals do not live a long time, and what is surprising is if you knock it out as well and dietary-restrict animals, they still live a long time. So, that suggested dietary restriction does not go through the insulin IGF-1 signalling pathway and a very surprising thing was that smk-1 is absolutely essential for the response of dietary restriction. So, it is doing something independent of DAF-16. Well, loss of smk-1 does dietary restriction and it also does the response insulin signalling for longevity. So that really made us make a hard-educated guess is that if it was not DAF-16 that was partnering with SMK-1, that there was something else that was partnering with it. So we hypothesized, well, maybe there was a different type of this transcription factor that was partnering with SMK-1 to dietary restriction. So, we went through the completed sequencing of this genome and looked at other ones that were very similar to DAF-16 and screened through all of them to see whether or not they were required for dietary restriction. We were very happy to find that only one of them was absolutely essential for the response to dietary restriction and this is called pha-4 and what was very exciting was that, unlike smk-1, pha-4 is only required for dietary restriction. So, if you knock it out animals cannot respond to dietary restriction, but they can respond to insulin disabling and live long that way.

Ben Valsler: How have you demonstrated this experimentally?

Andrew Dillin: Well, there is a couple different ways that we demonstrated this experimentally. We could look at loss of function of pha-4 through either siRNA technologies or mutation. We have also been able to overexpress PHA-4 by making transgenic nematodes, in which we inject in different amounts of the pha-4 gene and get overexpression phenotypes, but actually achieving dietary restriction within worms is not at all trivial and it seems like it should be, because, you know, with mice or with humans you just feed them a certain amount of diet and they are dietary restricted. Worms normally feed on, at least in the laboratory, they feed on E. coli bacteria and so we can actually put them in liquids that have varying amounts of E. coli, so we have a range of food concentrations and this gives us going from starvation all the way to overfeeding and then we can find the sweet spot in the middle where reduction of food actually increases longevity.

Ben Valsler: The pathway that you have spotted that seems to come into play, they all seem to be energy-based pathways, insulin and mitochondrial action, so is it an efficiency thing, is it that these genes mean that we get the best out of our diet?

Andrew Dillin: Probably what all three of these different pathways are doing is they are putting the cell or the organism into a state where they are mildly stressed. So, they are under a condition where they are not getting their full compliment of nutrients and things that they are normally used to and so they have gone down a little bit. This is a very little level of stress and I think what happens is that the cell or organism responds to this in a way that it up- regulates the stress management to protect the resources that you actually still have within your cells.

Ben Valsler: So, could this eventually lead to pharmaceutical applications to actually increase longevity by perhaps taking a specific drug or activating certain genes?

Andrew Dillin: Absolutely. This is the first gene that is absolutely essential and specific for the response of dietary restriction. It is the number one target for eliciting the dietary restriction response without having to go though that whole regimen of reducing food intake. That is why we think this will be essential for age-onset diseases. Because if you reduce dietary intake, it reduces the onset of cancer, neurodegenerative diseases, diabetes, and so we think that if we can trick the system into up-regulating PHA-4 without having to reduce your food intake, then you could actually delay the onset of those diseases. Whether or not it is going to extend human longevity, I do not think that is actually the goal. The goal is actually to reduce the onset of these age-related diseases.

Ben Valsler: Andrew Dillin explaining how knowing more about the pathways which control ageing could lead to therapies to delay the diseases of old age, leading to a healthier, if not longer, life. That's it for this week. Please join us again for next week's Nature Podcast, where we will be finding out about the latest organism to have its genome sequenced. Until then, feel free to send any comments or feedback to If you want even more science, then don't forget the Naked Scientist's Podcast — this week has been discussing population genetics in man and in moths. That is available for free from This week's podcast was produced and presented by me, Ben Valsler, Azi Khatiri and Chris Smith, with additional production by Sabina Michnowicz. So until next week, good-bye.


The Nature Podcast is sponsored by Bio-Rad, at the centre of scientific discovery for over 50 years, and on the web at

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