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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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September 19, 2005

Klotho: Sooner Than You Think?

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Posted by Derek

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?

Comments (6) + TrackBacks (0) | Category: Aging and Lifespan


1. Reason on September 20, 2005 12:46 PM writes...

One of the scientically minded calorie restriction folks has suggested that this klotho study wasn't all that, since it didn't control adequately for calorie restriction, amongst other reasons. He makes a good case - see:

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2. Charlie (Colorado) on September 20, 2005 1:56 PM writes...

I just wrote Jane a translation; you might look and see if I mucked anything up, as it's been 20 years since medical school and I'm a computer geek not a doctor anyway.

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3. jsinger on September 20, 2005 2:46 PM writes...

One of the scientically minded calorie restriction folks has suggested that this klotho study wasn't all that, since it didn't control adequately for calorie restriction...

I don't have access to the Science article yet, but following the links back to what I assume you're referring to -- his objection is that the study was done in a relatively short-lived strain of mouse, and that the transgene only extended lifespan to what's typically average for mice.

It's a somewhat valid point, I guess, if not the killer objection the poster seems to think it is. I'd note that you can only make transgenic mice in certain strains, but I'm surprised they didn't use C57. Maybe it was because, as Derek noted, mouse aging studies take a long time (Pity the post-doc who got stuck with this! My Science paper wasn't worth the years of my life -- I hope his was!) and they wanted to use a short-lived control to move things along faster.

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4. Dick Thompson on September 20, 2005 5:36 PM writes...

I just wonder if I might have inherited an extra-strength allele of klotho. I have a mild case of type-2 diabetes, as did my maternal-paternal great grandfather, and that whole family were notably long-lived; my mother died two years ago at 99. I am currently 72 and it bothers me to see people my age suffering physical and mental depredations of aging while I am fortunate to be extremely healthy and active and mentally competent.

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5. RKN on September 20, 2005 7:52 PM writes...

Maybe it was because, as Derek noted, mouse aging studies take a long time (Pity the post-doc who got stuck with this! My Science paper wasn't worth the years of my life -- I hope his was!) and they wanted to use a short-lived control to move things along faster.

Maybe C. Elegans? The hemaphrodites are fecund as hell and turnover about once a week.

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6. Derek Lowe on September 21, 2005 7:25 AM writes...

RKN, there have indeed been a number of longevity-gene candidates found though C. elegans studies. Klotho was originally found in a mutant mouse strain showing premature aging, though, so the real test was always going to be reversing that in gain-of-function mice.

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