As promised, today we have a look at a possible bombshell in longevity research and sirtuins. Again. This field is going to make a pretty interesting book at some point, but it's one that I'd wait a while to start writing, because the dust is hanging around pretty thickly.
Some background: in 1999, Sir2 the Guarente lab at MIT reported that Sir2 was a longevity gene in yeast. In 2001, theyextended Sir2 these results to C. elegans nematodes, lengthening their lifespan between 15 and 50% by overexpressing the gene. And in 2004, Stephen Helfand's lab at Brown reported similar results in Drosophila fruit flies. Since then, the sirtuin field has been the subject of more publications than anyone would care to count. The sirtuins are involved, it turns out, in regulating histone acetylation, which regulates gene expression, so there aren't many possible effects they might have that you can rule out. Like many longevity-associated pathways, they seem to be tied up somehow with energy homeostasis and response to nutrients, and one of the main hypotheses has been that they're somehow involved in the (by now irrefutable) life-extending effects of caloric restriction.
As an aside, you may have noticed that almost every news about something that extends life gets tied to caloric restriction somehow. There are two good reasons for that - one is, as stated, that a lot of longevity seems - reasonably enough - to be linked to metabolism, and the other one is that caloric restriction is by far the most solid of all the longevity effects that can be shown in animal models.
I'd say that the whole sirtuin story has split into two huge arguments: (1) arguments about the sirtuin genes and enzymes themselves, and (2) arguments about the compounds used to investigate them, starting with resveratrol and going through the various sirtuin activators reported by Sirtris, both before and after their (costly) acquisition by GlaxoSmithKline. That division gets a bit blurry, since it's often those compounds that have been used to try to unravel the roles of the sirtuin enzymes, but there are ways to separate the controversies.
I've followed the twists and turns of argument #2, and it has had plenty of those. It's not safe to summarize, but if I had to, I'd say that the closest thing to a current consensus is that (1) resveratrol is a completely unsuitable molecule as an example of a clean sirtuin activator, (2) the earlier literature on sirtuin activation assays is now superseded, because of some fundamental problems with the assay techniques, and (3) agreement has not been reached on what compounds are suitable sirtuin activators, and what their effects are in vivo. It's a mess, in other words.
But what about argument #1, the more fundamental one about what sirtuins are in the first place? That's what these latest results address, and boy, do they ever not clear things up. There has been persistent talk in the field that the original model-organism life extension effects were difficult to reproduce, and now two groups (those of David Gems and Linda Partridge) at University College, London (whose labs I most likely walked past last week) have re-examined these. They find, on close inspection, that they cannot reproduce them. The effects in the LG100 strain of C. elegans appear to be due to another background mutation in the dyf family, which is also known to have effects on lifespan. Another mutant strain, NL3909, shows a similar problem: its lifespan decreases on outcrossing, although the Sir2 levels remain high. A third long-lived strain, DR1786, has a duplicated section of its genome that includes Sir2, but knocking that down with RNA interference has no effect on its lifespan. Taken together, the authors say, the correlation of Sir2 with lifespan in nematodes appears to be an artifact.
How about the fruit flies? This latest paper reproduces the lifespan effects, but finds that they seem to be due to the expression system that was used to increase dSir2 levels. When the same system is used to overexpress other genes, lifespan is also increased. They then used another expression vector to crank up the fly Sir2 by over 300%, but those flies did not show an extension in lifespan, even under a range of different feeding conditions. They also went the other way, examining mutants with their sirtuin expression knocked down by a deletion in the gene. Those flies show no different response to caloric restriction, indicating that Sir2 isn't part of that effect, either - in direct contrast to the effects reported in 2004 by Helfand.
It's important to keep in mind that these aren't the first results of this kind. Others had reported problems with sirtuin effects on lifespan (or sirtuin ties to caloric restriction effects) in yeast, and as mentioned, this had been the stuff of talk in the field for some time. But now it's all out on the table, a direct challenge.
So how are the original authors taking it? Guarente, who to his credit has been right out in the spotlight throughout the whole story, has a new paper of his own, published alongside the UCL results. They partially agree, saying that there does indeed appear to be an unlinked mutation in the LG100 strain that's affecting lifespan. But they disagree that sirtuin overexpression has no effect. Instead of their earlier figure of 15 to 50%, they're claiming a 10 to 14% - not as dramatic, for sure, but the key part for the argument is that it's not zero.
And as for the fruit flies, Hefland at Brown is pointing out that in 2009, his group reported a totally different expression system to increase dSir2, which also showed longevity effects (see their Figure 2 in that link). This work, he's noting, is not cited in the new UCL paper, and from his tone in interviews, he's not too happy about that. That's leading to coverage from the "scientific feud!" angle - and it's not that I think that's inaccurate, but it's not the most important part of the story. (Another story with follow-up quotes is here).
So what are the most important parts? I'd nominate these:
1. Are sirtuins involved in lifespan extension, or not? And by that, I mean not only in model organisms, but are they subject to pharmacological intervention in the field of human aging?
2. What are the other effects of sirtuins, outside of aging? Diabetes, cancer, several other important areas touch on this whole metabolic regulation question: what are the effects of sirtuins in these?
3. What is the state of our suite of tools to answer these questions? Resveratrol may or may not do interesting things in humans or other organisms, but it's not a suitable tool compound to unravel the basic mechanisms. Do we have such compounds, from the reported Sirtris chemical matter or from other sources? And on the biology side, how useful are the reported overexpression and deletion strains of the various model organisms, and how confident are we about drawing conclusions from their behavior?
4. Getting more specific to drug discovery, are sirtuin regulator compounds drug candidates or not? Given the disarray in the basic biology, they're at the very least quite speculative. GlaxoSmithKline is the company most immediately concerned with this question, since they spent over $700 million to buy Sirtris, and have been spending money in the clinic ever since evaluating their more advanced chemical matter. And that brings up the last question. . .
5. What does GSK think of that deal now? Did they jump into an area of speculative biology too quickly? Or did they make a bold deal that put them out ahead in an important field?
I do not, of course, have answers to any of these. But the fact that we're still asking these questions ten years after the sirtuin story started tells you that this is both an important and interesting area, and a tricky one to understand.