She who spins the thread

The gene's name is Klotho, the nicest of the three Fates. Science is reporting on a not-yet-available-to-me-at-least article about this gene, which affects longevity in mice.

Whereas lab mice can live about 2 years, mice engineered to overproduce this protein, called Klotho, have celebrated third birthdays, Makoto Kuro-o of the University of Texas Southwestern Medical Center in Dallas and his colleagues report online in this week's Science Express (www.sciencemag.org/cgi/content/abstract/1112766). The mutant rodents represent a rare case of a single gene substantially influencing life span in mammals.

Klotho also occurs in humans, so the news part of the story is the hope of developing new drugs to increase longevity in humans. That is also where the controversy is, since there are some reasons -- notably insulin resistance -- to think that it may not work easily in humans.

But I'm more interested in the evolution of the gene, and here there are some interesting hints. First, there is this:

While Klotho is produced only in the kidney and brain, a fragment of it slips into the blood and may act like a hormone.

And this:

As with lab animals coaxed to have lengthy life spans, the altered rodents had fertility problems. They produced about half the expected number of offspring.

That is pretty interesting. Could it be that an evolutionary increase in brain size had the side effect of higher expression of this hormonal fragment? Such a mechanism for this (or other) genes might explain human longevity as a side effect of brain evolution. (Also interesting to me because Gould (2002) suggested just the opposite: that brain size might be a side effect of increasing longevity).

And could it be that increased longevity comes with the inevitable cost of lower fertility? In that context, it would seem to take a very special genetic change to allow longevity to increase without incurring this cost to fertility. One strategy, of course, would be to increase survivorship of the offspring that are born, thereby reducing the risk of low fertility.

A question that the Science news piece doesn't answer: Is there variation in the human version of Klotho?

Fortunately, we have OMIM, which has a long entry on Klotho, including this:

Arking et al. (2002) identified a functional variant of klotho, a haplotype termed KL-VS, which is defined by the presence of 6 single-nucleotide polymorphisms (SNPs) in an 800-bp region spanning exon 2 and flanking sequence. Allele-specific oligonucleotide hybridization analysis showed complete linkage disequilibrium for the coding region mutations. Of the 3 mutations in exon 2, 1 is silent and 2 encode amino acid changes, phe352 to val (F352V) and cys370 to ser (C370S). The variant was associated with reduced human longevity when in homozygosity. The prevalence of the variant in the general population was estimated to be 0.157.

The study by Arking et al. (2002) also indicates another allele associated with reduced longevity, recognized by its linkage to a marker (allele 17) but without any recognized coding sequence variants. I suspect its effect is due to a difference in expression, but there is no evidence one way or another. Additionally, the KL-VS allele not only influenced survivorship to age 75, but also increased longevity slightly in heterozygotes older than 80 years of age.

Also of interest, the frequency of the KL-VS allele appears to be very similar (18.7 percent, 23.8 percent, and 25.7 percent) in the three study populations, including Bohemian, Baltimore Caucasian, and Baltimore African-American groups. That similarity may suggest that the variant is in selective balance broadly in human populations, and the authors do observe a slight heterozygote advantage in the Bohemian sample, although they did not look for an effect on net fertility.

I'd like to see a gene tree.