Vive la revolution! Dr David Gems on ageing
Philosopher of science Thomas Kuhn theorised that paradigm shifts are essential for the progress of science. Dr David Gems from University College London talks us through his group’s recent Nature paper, which sheds more doubt on the role of proteins called sirtuins in increasing lifespan – a major change in the field of ageing research.
What is your paper about?
The paper relates to attempts by scientists to develop drugs that can be used to slow the human ageing process. One of the ways that people have tried to do this is to make drugs that mimic the effects of dietary restriction, something that has been shown to extend the lifespan of laboratory animals.
Over the last 10 years, a number of groups in the USA have built up a body of work that suggested that they’d found a way to do this, based on proteins called sirtuins. They found that increasing levels of sirtuins led to an increase in lifespan and showed that they were required for the effects on lifespan of dietary restriction. They then found that drugs that activate sirtuins can increase lifespan, apparently mimicking the effects of dietary restriction. This work was in budding yeast, nematode worms and fruit flies.
What did you do to investigate these claims?
We worked with laboratories in Michigan, Seattle, Paris and Budapest to conduct some quite ordinary but careful experiments where we controlled the genetic background of worms and fruitflies, making sure that the longevity of these strains was not due to their genetic background. When we did that, essentially the longevity effects went away. Animals manipulated to overexpress the sirtuin gene have elevated levels of the protein, but there was no effect on lifespan.
Is this the first time doubts have been raised?
No, other people have showed that some of the initial claims were incorrect, that the drugs that activate sirtuins (such as resveratrol) actually don’t activate sirtuins, and that sirtuins probably don’t account for the anti-ageing effects of dietary restriction in yeast and worms. There have been a whole series of counterclaims against their work from a number of labs, but what our work now shows is that in worms and flies the sirtuins don’t slow ageing, or mediate the effects of dietary restriction in flies. I think it’s the most devastating counterclaim so far.
Why are negative findings important?
When I was a student I learnt all about Thomas Kuhn and the structure of scientific revolutions, and this looks to me like a classic scientific revolution. It’s very exciting because when you have wrong theories science doesn’t go forward, but when you take them away it, it frees people to start working down the right track. I gave a plenary talk at the British Society for Research on Ageing in the summer and argued that we’re in the middle of a revolution in the biology of ageing, and that a number of major ideas that have dominated the field that are imploding, including the role of oxidative damage in ageing.
Do we know what sirtuins do?
Sirtuins are very interesting proteins with complex effects. They modulate the activity of other proteins by removing parts called acetyl groups from them. They affect gene expression across the genome, particularly by silencing genes.
Is dietary restriction still important in ageing?
Oh yes! There are other ideas about dietary restriction, including that it may be working through another pathway – target of rapamycin or TOR. This is exciting because drugs exist that work on this pathway and have been shown to extend lifespan in rodents.
Has the wide appeal of anti-ageing treatments contributed to the overheating of the field?
I think that that has something to do with the general excitement around Sirtris, a company formed to develop drugs that activate sirtuins. We know in the lab that you can slow ageing and greatly improve health in later life, and if you could do this in human beings it would be absolutely wonderful. There’s also an enormous need and desire among the public for such therapies.
Away from sirtuins, there’s a huge industry of bogus anti-ageing therapies and treatments that exploits older people. In the hope that some of the promises made might be true, people part with a lot of money.
What can be done about this?
I try not to get too exasperated by it. The trouble is that the legislation to prevent the marketing of bogus anti-ageing products is rather weak – part of the problem is that anti-ageing treatments are not seen as medical treatments because ageing isn’t viewed as a disease. But probably the best way to deal with this problem is to develop treatments to slow ageing and improve late life health that really work, which I’m sure is possible.
- Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., Piper, M., Hoddinott, M., Sutphin, G., Leko, V., McElwee, J., Vazquez-Manrique, R., Orfila, A., Ackerman, D., Au, C., Vinti, G., Riesen, M., Howard, K., Neri, C., Bedalov, A., Kaeberlein, M., Sőti, C., Partridge, L., & Gems, D. (2011). Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila Nature, 477 (7365), 482-485 DOI: 10.1038/nature10296
Watch a video about Dr Gems’ research: