Jennifer Tullett - Ageing & metabolism

Kat - Last month we took a look at the researchers hunting for the genes behind ageing, and now we're returning to the topic with a closer look at the links between genes, ageing and metabolism - that's how we use food to generate energy in the body, and how animals respond to changes in the environment. To start with, I spoke to Dr Jennifer Tullett, from the University of Kent, to find out more about her work in this area.

Jennifer -  I try and understand the function of individual genes that affect lifespan and healthspan.  We're very interested in that here.  I also look at how you can alter the environment of an organism.  For example, you can alter its dietary intake and extend its lifespan.  So, we're interested in that and also, how these dietary interventions for example impact on the expression of genes and the function of genes in these processes.

Kat -  So, how the things around us control whether our genes are switched on or off at different times.

Jennifer -  Yes, exactly.

Kat -  Because this might seem strange because you think, "Well, I've got my genes and they just do their thing."  Actually, the genome is changing all the time in terms of which genes are on and which genes are off.

Jennifer -  Yes, it's very important that genes are switched on and off but it's probably much more intricate than that and there's a lot of different levels of gene expression.  And it's a coordination expression of lots of different things at once.

Kat -  So, it's about the kind of the orchestra, how it plays these different genes. 

Jennifer -  Yeah, that's a very nice analogy.

Kat -  So tell me, what are you studying?  How are you trying to home in on these genes and how they interact with our environment?

Jennifer -  So, I guess my main focus is, I look at different transcription factors that are involved in ageing.  Transcription factors are proteins that are responsible for controlling the expression of a whole range of other genes.  So, they're key regulatory molecules.

Kat -  Kind of master switches I guess.

Jennifer -  Master switches, yeah.  And I'm interested in two of those specifically.  One is called DAF-16 and the other one is called SKN-1.  So, I look at the activity of these genes.  I look at these other genes that they regulate and I try and understand how they function in different scenarios and which one of their target genes that they're regulating are important for lifespan.

Kat -  So, it could be doing all sorts of things from just keeping the worms going, to actually controlling how long they're going to live for.

Jennifer -  They live for about 3 weeks normally, but if you mutate either DAF-16 or SKN-1, then you'll dramatically shorten that lifespan by about 30%.

Kat -  So, like two weeks.

Jennifer -  Two weeks, yeah.

Kat -  What kind of things are you finding so far that seem to be important that these genes do?

Jennifer -  One gene that seems to be very interesting is AMPK which is AMP - activated protein kinase.

Kat -  Sounds complicated.

Jennifer -  And that's a very important metabolic enzyme and that seems to be very important for regulating lifespan as well.

Kat -  It seems to me that there seems to be a lot about the metabolism, how our bodies use energy that is linked to ageing.  Is it something to do with like, 'the faster you burn, the shorter you live'?

Jennifer -  That's the rate of living hypothesis type idea.  That doesn't seem to be quite as fashionable any more in the ageing field because there are examples of small animals that have high metabolic rates that live for quite a long time.  So, it doesn't necessarily correlate the two things.

Kat -  What do we know about how metabolism is affecting these worms in their lifespan and how does it all seem to fit together?

Jennifer -  In C. elegans, actually, one of the most amazing lifespan extending mutations is a mutation in a gene called DAF-2.  And if you make one single point mutation in this gene then you can double and even sometimes triple the lifespan of a worm.

Kat -  That's pretty incredible.

Jennifer -  It's very incredible and it is also conserved so you get the same effect in flies, you get it in mice, and there's also a small amount of evidence that the same thing could happen in humans as well.  So, if you have this massive lifespan extension with mutation of DAF-2 - DAF-2 is the insulin receptor.  So, these worms must have altered metabolism.  In fact, if this was a human, they would be severely diabetic.

Kat -  Because insulin is how your body controls the level of sugar that goes into a cell and stuff like that.

Jennifer -  Yes, exactly.  So, this lifespan extension caused by mutation of DAF-2 is dependent on those two transcription factors that I mentioned which are DAF-16 and SKN-1.  These transcription factors are really important because they are regulating a whole variety of other genes. One of the genes that I've recently discovered that does contribute to this massive lifespan extension of DAF-2 worms is this gene called AMPK.  This is a critical metabolic enzyme and it is responsible for regulating the energy homeostasis in the cell.  So, it can sense when the body has low amounts of energy available and that switches it on.

Kat -  So, it'll kind of stop you burning so much energy, just keeps you going.

Jennifer -  Yes, keeps everything under control.  It seems that if you make mutations in this enzyme, then the worms can't live as long.

Kat -  Where do you want to see this go?  I mean obviously, this is in worms and that could be quite useful thing to do for the worm population I guess.  But where do you see the applications of this work going?

Jennifer -  Well, something that we do a lot of here is, we try and look between species.  Worms are really great to do ageing studies in because they're so short-lived.  That's why so many people do it.  Drosophila are also very good.  Their short-lived but still, it's still a lot longer than a worm.  So, what we try and do here is, if we find something in a worm, we then try and move it into a fly and then we can also try and move up to a mammalian model as well with the hope that if this research holds true in a mammal then it could also be relevant to humans.

Kat -  And it does seem to me that there's a lot of interest in the field of ageing in metabolism and tweaking metabolism, and people having very, very low calorie diets or taking all these kind of supplements and things.  Are there things that we definitely know at the moment will work in humans?  If I wanted to live longer and tweak my metabolism, is there anything I know that I should definitely be trying to do?

Jennifer -  I think in terms of an anti-ageing pill, if that's what you're asking, I don't think we're quite there yet.  We do know in lower organisms that there are certain drugs that can be given to the animals to extend their lifespan.  There are a number of those including rapamycin.  That's a very good one.  But in terms of humans, I wouldn't like to recommend that anyone takes any of these things in the very near future.  I think the best thing people can do for now is just maintain a healthy diet, healthy lifestyle...

Kat -  the boring stuff! 

Jennifer -  Basically the usual boring stuff, yes, and you're probably in with a good chance of living a healthy existence.

Kat -  How long would you want to live for?

Jennifer -  I would want to live for as long as I can be healthy and independent.  I think that's probably the same for a lot of people.  If I'm healthy and independent then I'm likely to be very happy and I can just carry on.  But that is what our research is geared towards.  We're not geared towards making people live forever in an awful decrepit state.  That's nothing.  That's not what we want at all.  What we really are interested in is increasing the healthy lifespan of an individual.

That's what we really want to achieve.  And the amazing thing to me as a researcher, the thing that's really kept me going in this field is the fact that if you have these point mutations that extend the lifespan of a worm or a fly or a mouse, not only do they live longer, but they are actually an awful lot healthier.  That's the amazing thing about them.  So, I think the fact that we study ageing and lifespan as an endpoint is one thing, but the really important thing to bear in mind is that we're really interested in health span.

Kat - That was Jennifer Tullett from the University of Kent.