Michael Shannack - Fat, old flies
Kat - But first, we return to our age-old topic, at the UCL Institute of Healthy Ageing. Student Michael Shannack has been studying fruit flies carrying an altered version of a gene called glycogen synthase kinase 3, or GSK3 for short, which have longer, healthier lifespans than their normal counterparts. He's been trying to find out why.
Michael - So, the flies in this lab live normally the best part of 2 to 3 months. On average, the flies that we were working on with this manipulation of this protein were living about 10-15 % longer than the average fly.
Kat - So, have you translated that to a human that would be living an extra 10 years I guess?
Michael - Yeah, if you took a direct correlation to humans, it would be about 10 years, but of course, a fly is not human. But there are some other promising strategies as well which for example, you've got mice - we've known as maybe 100 years now - mice, if you give them about 60% of what they normally eat, they somehow live 30% longer, so that's quite nice. Obviously, we don't want humans to go starving themselves and there are some people who practice this. It's called calorie restriction. It would be nice to have a pill that does the same thing without having to actually physically starve and cut out things from your diet.
Kat - Because food is nice.
Michael - Absolutely. We love to eat, right?
Kat - Food makes me happy.
Michael - Exactly. We love to eat things that are normally not very good for us as well. So, it would be interesting to see if we could find a way of mimicking this restriction of calories in a way that doesn't actually affect the quality of life.
Kat - What exactly is the protein, the gene that you're looking at that's faulty in these flies?
Michael - So, this protein is called GSK3. It's quite central. It's got a diverse range of things. It controls survival of cells. It actually promotes the survival of cells which is great in one sense, but also, you don't want to...
Kat - You want your cells to live longer if you're going to live longer.
Michael - Exactly. So, if your cells are healthy and living longer then obviously, your organs will live longer and you will live longer. So, that's the idea. Obviously, there's a danger that you don't want to have cells living so long that they're actually replicating uncontrollably and you get into territories of cancer which is not good. On the other hand, the same protein GSK3 also controls cell death. So, it can actually promote what they call the programmed cell death. So, our body has ways of shutting off cells that aren't working very well. Actually, the interesting finding, the main finding of my study was that this is specific to different areas of the flies. So, having more of this protein in certain areas of the fly is worse off and having it in another area of the fly is better off. So, it's very tissue specific.
Kat - What have you discovered about it that makes the flies live longer?
Michael - So, one of the things we were interested in and this is something that's kind of common in ageing research is to try and stress test the things that you're working on. So, you see how do they react to different stresses. It might be in terms of starvation - how do they react to starvation - so, no nutrient at all. Actually, these flies were kind of sensitive to starvation which is interesting. Then we also gave them a different stress in terms of what we call oxidative stress. So oxidative stress is basically in the process of breathing and respiration, producing energy from food basically, you have a by-product, this thing called reactive oxygen species. These are quite nasty chemicals that go out and damage DNA and are generally not very good. We have systems in the body that actually mop these up and kind of prevent the damage.
So, we wanted to see actually, do these flies have some kind of resistance to the stress. So, when we tested it they were actually much more resistant. So, that suggests that there's something going on in the fly - maybe the defence mechanisms, the defence systems against these kind of bad chemicals are actually higher. We haven't done the tests to see whether that's right, but these are suggestive tests.
Kat - So, you know they behave differently to starvation. You know that they have some kind of weird defence against these reactive oxygen species. Obviously, that's in fruit flies. Is there any evidence that these processes might be similar in other organisms as well, or is that for the future to find out?
Michael - Well, we know the calorie restriction or what they call dietary restriction generally, has worked in everything from single-celled yeast, all the way up to the mice for sure and even some studies going on in primates. You could say that it could actually make them healthier. I saw a picture - you can see one is kind of grey and the fur is not very good and it kind of looks a bit wrinkly. The other one has been dietary restricted looks much healthier and they're both the same age. So, this is quite promising. Actually, this whole thing feeds down into what we look at here in this lab which is the way that insulin reacts with our body.
Kat - This is the chemical that helps us process sugar in the body, is it?
Michael - Exactly. So, insulin is produced basically when you eat sugary foods. It helps to take the foods that you eat and store it away for later use. So, you don't want to have too much sugar going around in your blood. We found that if you have less of this insulin going around, then actually, you tend to live longer and healthier. And this works on both worms which is worked on in this lab and also, the fruit flies.
Kat - So, in terms of the story you've been working on trying to put together what's going on in these flies with this particular mutation and why do they live longer, what's next for this particular bit of work?
Michael - Well the next thing, we've done all the - what they called phenotype studies. So, the phenotype is just looking at the behaviour. So, do they live longer? Are they able to climb better? Can they move better with age? So, you kind of study the differences in what you can see. Once you've got those differences you can say, "Okay, I'm going to start looking at this in terms of biochemical studies." So, that means testing - are they fattier than the other flies because we find that when we have mutants to do with insulin, we find they actually are generally fatter than normal flies.
Kat - How do you tell if a fly is fat?
Michael - Well, we have a test where you can test actually how much fat or lipid they have in them.
Kat - In other words, they can't just get off the ground where they're trying to fly.
Michael - Yeah, they kind of just sit there and watch the telly. There are ways - you can do tests to find out how different they are and find out different changes at a genetic level, what's changing. For example, if they have more defence, there are genes that actually protect us against the stresses that we have in our body. You can see if the expression of these genes have changed, you can see if they're higher. That will make sense if they were.
Kat - How long would you want to live for? I mean, you're a master student, you're a young guy. How long do you want to live for?
Michael - The obvious answer is forever, but the point is, you want to live as long as you enjoy the life you're in. So, you wouldn't want to live forever if forever meant living in misery. You want to be able to enjoy the things that you normally enjoy to the extent you do now. So, if I kept enjoying life as much as I do now, then the answer would be forever.
Kat - That was Michael Shannack, from the UCL Institute of Healthy Ageing.