On Klotho

The Klotho gene (link to Wikipedia, a stub entry at the time of writing that I expect to see expanded) was under investigation back in 2001 and 2002 for its association with longevity:

Studying more than 2,000 anonymous samples from three ethnically distinct groups of people, the scientists found that having two copies of a less-common version of klotho is twice as prevalent in infants as in people over age 65. These results suggest that people born with the two copies die sooner than others, although the gene's exact influence on health and aging are not known, the scientists say.

...

Previously, Japanese scientists discovered klotho in mice, noticing that without klotho's protein, the mice developed atherosclerosis, osteoporosis, emphysema and other conditions common in elderly humans. Because of their interest in accelerated aging diseases, Dietz and his colleagues began studying klotho in people.

The first thing to do when you discover a mechanism that accelerates age-related degeneration in mice is to turn it around and see if can extend healthy life span - as a general rule, gerontologists are unexcited by processes that reduce life span. There are all too many of those, and most have no association with any way of extending life span - application of blunt force is one example, as a certain wag noted.

The time elapsed between the 2002 work and the present day is just about long enough to set up a decent set of life span experiments with laboratory mice and get a good sense as to how it will all turn out. In the case of the Klotho gene, this indeed came to pass. It is pleasing to see that Klotho has now been welcomed into that small, select circle of known ways to significantly extend healthy life span in mice:

In the new study, a group led by Kuro-o, now an assistant professor of pathology at the University of Texas Southwestern Medical Center at Dallas, created transgenic mice with overactive versions of the Klotho gene. Those mice proved to have life spans 20 percent or more longer than mice with the ordinary version of the gene, Kuro-o said.

"These are still animal experiments, but potentially it might be possible to use the hormone in humans," he said. "But we still don't know if the protein can be used to extend life span in humans."

A lot must still be learned about the Klotho hormone, starting with the way it works, Muro-o said. "We speculate that it blocks insulin action," he said. Specifically, it appears to block the insulin-like growth factor-1 pathway. Studies have shown that blocking that pathway extends the life span of worms, flies and mice, he said, and the same may well be true of humans.

The upper bound of life span extension in the study was 30% or so, in the same ballpark as the results of calorie restriction. The association with insulin suggests that both overexpression of Klotho and the gene expression changes caused by calorie restriction may work on an overlapping set of biochemical mechanisms - which certainly shouldn't prevent industrious researchers from trying both at once to see how that goes. I certainly would if I had the funds and a group of gene engineered Klotho mice.

I predict that this will be grist for the mill for those funded groups and companies - such as Elixir, Sirtris, etc - already working hard on metabolic science resulting from calorie restriction studies. Good news all round for those interested in near term (next five to ten years) results from currently funded longevity research.

UPDATE: I should have mentioned that Kevin Perrott has more on Klotho; I certainly agree that researchers should enter a set of Klotho mice into the Mprize for anti-aging research.

Comments

I don't understand this:

These results suggest that people born with the two copies die sooner than others, although the gene's exact influence on health and aging are not known, the scientists say.

If you have two copies of the gene, shouldn't you make more of the protein and live longer?

Posted by: David Pinto at August 26th, 2005 7:30 PM

Apparently not, at least according to that study. Effect A in mice doesn't necessarily translate to effect A in humans. If you look at the calorie restriction science of the past few years, you'll see some of the same things going on - apparently contradictory results in different species that can be explained with further examination.

Now that this has been shown to be effective at healthy life extension to some degree in mice, I'm sure we'll be finding out much more about the underlying mechanisms in the next few years as people repeat and expand on the human studies.

Posted by: Reason at August 26th, 2005 8:09 PM

I think you may be misreading the study, David.

Note that the study examined people with "two copies of a LESS-COMMON version of klotho" (my emphasis), and compared them with people having one or zero of those less common genes and presumably one or two copies of a different version of this gene.

A logical explanation might be that this less common version produces less klotho protein synthesis than do other versions of the gene. So someone with two of these underactive klotho genes would presumably have lower levels of klotho protein than someone who has at least one copy of a different version of the gene -- a version that produces more klotho protein synthesis.

Posted by: John Finlayson at August 27th, 2005 4:12 AM

Or, the less-common version is less efficient at whatever process underlies the effect.

Caloric restriction lowers available glucose. It's thought by some that glucose causes ageing-like damage through crosslinking due to its aldehyde isomer. Insulin inhibition would increase the level of blood glucose and multiply the damaging effects of glucose as seen in diabetes.

Has anyone seen any news lately regarding Cerami's AGE (advanced glycosylation endproducts) decrosslinker? After the initial reports and the patent activity, I have seen nothing new.

Posted by: William Bjornson at December 31st, 2006 10:53 AM

The study was done on people who have two copies of a recessive mutant version of Klotho. If you are heterozygous (one copy each), you have a normal phenotype, so they need to find people with 2 mutant versions. Most people have 2 normal versions of klotho - it's a highly conserved gene.

Direct injection of Klotho protein in model organisms extends lifespan. The simplest way to gain the benefits of this would be to do that t a human-scale dosage.

Purchasing recombinant human klotho, and monitoring it in the blood, and injecting the right amount on a weekly basis would costs, currently, about $5000/week or something like that (based on retail prices ($200/mg) and mg/Kg from the mouse study).

A better way to gain the benefits of klotho overexpression would be a targeted gene therapy product injected into the kidney.

Developing a vector, based on a very targeted system, like the Sangamo zinc-finger system, would probably be expensive, but would have long term effects, and require far fewer injections.

Posted by: erik at September 12th, 2010 5:22 AM

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