Nazif Alic - Manipulating metabolism

Kat - We return to our age-old topic, with Dr Nazif Alic at the UCL Institute of Healthy Ageing. He's figuring out if tweaking some of the genes involved in metabolic signalling could help to prolong healthy lifespan - but could it help us live forever?

Nazif -  I don't think we'd really be able to live forever, but what we might be able to do is to have a lifespan that's free of chronic and debilitating diseases that occur with age.

Kat -  So obviously, this is the big problem in our society.  We all live longer.  We don't have as many infectious diseases, but there's a long period at the end of life when it's very debilitating.

Nazif -  The final outcome of the research that we are doing or we hope the final outcome would be, to actually reduce the severity or reduce the duration of that very unhealthy period that certain people have at the end of their life.

Kat -  So, this is about health span rather than lifespan.

Nazif -  Yes, hopefully it is about health span rather than lifespan.  But lifespan does keep on increasing in our society.  So, there's a certain fear when people talk about extending lifespan, but actually, most of the medical advances that we've seen recently as well as advances in hygiene and the way the society functions have resulted in an extension of human lifespan.  It's about making that lifespan better.

Kat -  So, tell me about the work that you're doing?  How are you trying to increase health span?

Nazif -  A big part of what I'm doing, or what I have been doing recently, is trying to understand how manipulation of a single signalling pathway can extend this healthy lifespan.

Kat -  These are the messages sent inside cells that tell them to do stuff.

Nazif -  So, this is the wiring that tells you how to respond to your environment.  These signalling pathways tend to be nutrient sensing signalling pathways and the one that we are working on is the insulin/IGF signalling pathway.  So basically, the pathway exists so that your body can adapt to changing environmental conditions and in particular, to changing nutritional conditions.

Kat -  So, you eat a meal, insulin helps you use the nutrients from that meal - the sugar.

Nazif -  Insulin tells our cells what to do with that.  The sugar is present and what to do with that sugar.  Essentially, it can dictate the metabolism of the whole animal.  What the community has recently found is that if you modulate that pathway - I mean if you slightly inhibit the insulin/IGF signalling pathway, in a number of animals, you can extend their healthy lifespan.

Kat -  So, you can kind of turn it down and they'll live longer, healthier.

Nazif -  Yeah.  So you turn it down, they will live longer, they will live healthier, and also, it seems to help with a lot of diseases.  When we look at model organisms and we try to mimic human diseases in model organism, reduction insulin signalling can ameliorate those diseases as well.

Kat -  You mention model organisms - what organisms are you looking at?

Nazif -  So, I'm basically working on the fruit fly, Drosophila melanogaster.

Kat -  That's not something I'd associate with being tremendously long-lived.

Nazif -  So, they're not very long-lived which helps us do the experiment so we can finish them quite quickly.  They do live for some hundred days.  We can get them to live 200 days or even longer.

Kat -  Presumably then you can actually find flies that do live at particularly longer or healthier lives even within that timescale?

Nazif -  Yes, so what's the biggest advantage of Drosophila is that its genetics have been studied for such a long time.  There are a lot of very neat tools that we can use to alter their genetic makeup or to alter signalling within these pathways in various specific moments in time during the adulthood of the fly and in very specific tissues.  So, we can try to understand in minute detail of what kind of manipulation we need to achieve a healthy long lifespan.

Kat -  How do you tell if a fruit fly is kind of feeling old.  "My back!  I forgot where I've put my car keys."  How do you actually look at these flies and work out how they're ageing?

Nazif -  So, one of the main outputs that we've been using is really just how long they live.  So simply, we can see when a fly is dead or alive.  But more recently, we've been trying to look at more detail about their lifespan.  So, we can for example look at how well they move.  So similar to humans, as flies get older, their movement becomes slower and they find it harder to move.  

Kat -  Little flies in a Zimmer frame kind of thing.

Nazif -  Yes, little flies not walking as fast as they could 20 days before.  So, that is a very simple measure of their health and one that we've been using a lot.

Kat -  So, you can find that manipulating this pathway, this IGF pathway affects their lifespan and their health span.  What now?  Where do you want to go with this work?

Nazif -  So, the most recent work that we've done is looking at the effector of these pathways.  So, we know in modern organisms again that the beneficial effects of this pathway require a transcription factor called FOXO.  And this transcription factor essentially rewires the way the genetic information is used, remodels the way the genetic information is used so that the animal lives longer.  And we've been trying to work out exactly what genes are controlled by FOXO in which tissues and how they can result in an extended period in life and extended lifespan.

Kat -  If I was to have a child, how long would it be before I could give them some kind of FOXO manipulating thing that might make them live a much, much longer life?

Nazif -  I don't think we really know how long it's going to be.  Hopefully, it might actually be within your lifetime, that you might be able to take something that will prevent dementia or that might prevent type 2 diabetes or any chronic condition that will increase in prevalence as you age.  But we don't know.  What's quite exciting about this field is now, we've come to the point where we do have drugs that can be administered to people.  So, they're FDA approved.  They're approved for use on humans.  And those drugs in model organisms can extend a healthy lifespan. 

Kat -  So, this seems to be much closer than perhaps we might think.

Nazif -  Possibly, yes.  I think the next step will be on one hand, people like me working on model organisms, we need to refine the approaches that can be used, and the other thing that needs to happen in parallel is, for people to find means to see if those manipulations actually do work in humans.

Kat -  How long would you like to live for?

Nazif -  I think the younger you are, the less you care, but I'm starting to care more and more.  I do know that I have a very good amount of risk for cardiovascular disease and I would really like to avoid having a stroke or a very debilitating heart attack.  So for me, it may not be that much about how long I live, but just the quality of life as I get older.

Kat - That was Nazif Alic from the UCL Institute of Healthy Ageing.