Intervention doubles worm lifespan, even given in old age

As Benjamin Franklin is often quoted as saying, "nothing certain except death and taxes." But before the death bit usually comes ageing first, and that's something of a scientific mystery: why does it happen, how does it happen and can we do anything to slow down the process? Our knowledge of how we age is growing, but most of the studies that have looked into this topic have tweaked aspects of biochemistry in younger individuals and shown they live a bit longer. But, when it comes to humans, what about if we've lived fast and loose most of our lives and might now be coming to the healthy living party a bit late in the day? Can interventions at that stage still bear fruit and reverse the arrow of time? That's what Collin Ewald, at ETH Zurich, wanted to know. As he explained to Chris Smith, would worms in which an ageing-linked gene is deactivated later in life still benefit?

Collin - If you think about aging, you want to do interventions that work very late in life. So you think about when you are 60, 65 and age-dependent diseases start to hit, you want to do an intervention that could either postpone or prevent those diseases. Most interventions that have been tested in animal models are done usually when you are pretty young, maybe midlife, but not when you are really, really getting really old. So what we were wondering is, is it possible to extend the lifespan of an organism close to death, or when most of the population already died?

Chris - So if you're a member of the Rolling Stones, and you've got a well-lived-in body, it's not too late for you would be where you're going with this!

Collin - I think this is the natural hope everybody has, to rejuvenate at old age, but there's no evidence that this is even possible in any organism.

Chris - And of course, it's also frustrated by the fact that how long it takes to study aging in an long-lived species. So can we look at something that short lived and ask some of these questions there to try and get answers sooner?

Collin - This approach we took. So we chose this little roundworm called C.elegans. It's a great model organism for ageing research because it lives for three weeks. Just a single mutation in a single gene was able to double the C.elegans lifespan. So we thought, "this is a great system," so we could really measure those effects and quantify this.

Chris - What was the intervention that you did with the C.elegans?

Collin - So one of the best studied interventions, besides caloric restriction, is reducing insulin IGF-1 receptor. In C.elegans, the insulin-like growth factor one receptor is called daf-2, which stands for dauer abnormal formation and usually drives the animal in a dauer-like stage where they can endure for a long time. So we thought like, you know, daf-2 two would be the right place to start. One way to do this is to use RNA interference, which people have done. And you also able to double the lifespan with RNAi. But the promise with RNAi, it works great when the animal's younger, but then the RNAi efficacy just declines and doesn't work. So nobody knows whether interfering with IGF-1 receptor would work post reproduction, or even later in life.

Chris - I see what you're saying. So we know that animals that have changes in this particular gene do live longer. But what we don't know is whether intervening and manipulating that gene starting later in life would have the same benefit as if you target it at a younger age?

Collin - That's correct.

Chris - Is there a way around that?

Collin - When we were looking for ways around it, we stumbled across a system that has been used in plants and then optimized C.elegans. It's called the auxin-degron system. So auxin is a plant hormone that binds a sequence of a protein called degron. And then, wherever the sequence is attached to, that protein is then marked for degradation by the proteasome within half an hour.

Chris - In other words, you've got a switch on switch off system for whatever you want, whenever you want, in the worm's life cycle. I'm gonna guess then that you've, you've got a population of worms that have got this wired into them and you leave it inactive until they're old, and then you turn it on. So you can rob them of that particular gene. And you can then ask, "what happens to the ageing of those worms when our intervention comes, when they're already elderly?"

Collin - That is correct. So that was the original idea.

Chris - Okay. And what happened then when you did that, do the animals live longer once you switch this on when they're old?

Collin - So we aged out C.elegans until day 21 of adulthood. And that's a time point when about 75% of the population has died. So you only have 25% of the population still remaining. So if you don't treat any of those animals, then they die within four days. However, when we applied to half of that population auxin, that was sufficient to increase the lifespan. And it was not only sufficient to increase the lifespan by a couple more days, it was sufficient to increase the lifespan up to 26 days.

Chris - That's double! That's twice as much, isn't it. That's like me living to 200!

Collin - That's correct. And that was extremely surprising and fascinating at the same time, because, as you said, we were able, even at this very old age, to get the same effect as even the animals would be young.

Chris - The thing is that, in medicine, we dwell less on lifespan and we focus more on "health span", reasoning that actually there's no point in living forever if you're not able to make the most of it. Now, are these worms just going on forever and failing to die, but they're pretty clapped out, or are they healthy and doubling their lifespan?

Collin - I personally went into the lab to repeat that experiment because it seems so exciting. So when I was doing it and applying the auxin and see how the non-treated generation just deceased, right, I mean, at that age, the animals are just like couch materials, they just lay there basically! So when I did the intervention, what I noticed that the ones that got the auxin, right, they were still moving around. So to me, this suggests the health-span is also increased, but we need to quantify this.