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September 19, 2005
Klotho: Sooner Than You Think?
There's been a lot of news in the aging-research area about the Klotho gene (and its associated protein) the last few years. Now there's a recent paper in Science that is bringing it back into the spotlight.
I won't go into all the details - that link and this one will give you some good background - but the short form is that adding an extra Klotho gene extends mouse lifespan by up to 30%. (It was already known that deleting the gene shortened lifespan drastically - the paper we're seeing now is the result of an immediate effort to take the system in the opposite direction. Aging research takes a long time!)
Some of the most interesting anti-aging genes that have turned up in roundworms and flies have to do with insulin (and insulin-related growth factor, IGF) signaling. This team of researchers thought that the Klotho protein might fall into the same category, and they were right: the protein seems to lower insulin sensitivity by affecting signaling through the insulin and IGF receptors.
Here's where my drug-discovery radar started pinging. These receptors are part of a family that carries their own kinase along to phosphorylate themselves, and that's a key even in their signaling cascade. This new work noted that Klotho suppressed autophosphorylation of the receptors, and that makes sense, considering the downstream effects. It's very interesting to note that compounds that affect the IGF receptor kinase are already being developed. They're potential anticancer agents, and a number of companies seem to be working on them.
Now, I'm not aware of anything that's been developed to inhibit the insulin receptor kinase, mainly because no one has seen a market for giving people a sort of quick-acting type II diabetes. But it's certainly possible that such a compound could be discovered, if someone were to look. What would the effects be of lower doses of such kinase inhibitors in normal humans? Could one get the effect of the Klotho hormone through that route, or does it cause other things to happen through its own pathways?
I think someone's going to be tempted to find out. Intense work is doubtless in progress in this area, and there will be many more things to be discovered. But if the insulin/IGF story continues to hold up, I don't see what's going to stop people from trying this out on themselves or on others. It's probably the nearest thing in the whole field to being realized in practice. And if it doesn't happen here, it might take place somewhere else with more. . .relaxed clinical standards. Worth keeping an eye on. . .
UPDATE: ". . .I just wish I understood more than every third word." Well, that was a kind of condensed post, I have to admit. I was a bit short on time, and it's a pretty knotty subject, even for the people who work in it. But I promise that I'll come back to it and try for a from-the-bottom-up backgrounder. And I'll try to get to it before we all need life-extension drugs. What's that? You say we all need them now?
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