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Sunday, December 27, 2009

The Genetics of Living To 100

Is there a gene for long life?

Boston-based group Sebastiani et al say they've found not one but two, in RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans.

They took 4 groups of "oldest old" people: from New England, Italy, and Japan, and American Ashkenazi Jews. All were aged 90 or more, and many of them were 100, centenarians. As control groups, they used random healthy people who weren't especially old. The total sample size was an impressive 2105 old vs. 3044 controls.

On the basis of a pilot study, they chose to look at two candidate genes, ADARB1 and ADARB2. Both are involved in post-transcriptional RNA editing, one of the steps in the process by which genetic material, DNA, controls protein synthesis. It's something every cell in the body needs to do in order to function.

What happened? Their abstract makes the exciting claim that
18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study ... We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity.
But read the whole paper and the picture is a little more complex. For ADARB1, they looked at 31 variants (SNPs). In the New England sample, which was the largest, 5 of them were statistically significantly more common in old people compared to the controls. However, none of these were significantly associated in any of the other samples, although for 3 of the 5 variants, there was some evidence of an effect in the same direction in the other samples.

In ADARB2, out of 114 variants, 10 were significantly associated in the New England sample. Of these, 4 were independently significant in the Italian sample, and in the combined New England/Italian sample all 10 were still associated. But the Jewish and the Japanese samples showed a rather different picture: only 1 of the 10 associations was significant in the Jews, although several were weakly associated in the same direction, and in a pooled New England/Italian/Jewish analysis 9 were still significant. In the Japanese sample, one association was replicated but another variant was associated in the wrong direction.

They also did some lab work and found that in nematode worms (C. Elegans), mutants lacking the worm equivalent of the ADARB1 and ADARB2 genes had a 50% reduced lifespan - 10 days, instead of the normal 20 - despite no obvious symptoms of illness. Hmm.

I'm not quite sure what to make of this data. They looked at 4 separate, large samples, which is an excellent size by the standards of candidate gene association studies. The evidence implicating ADARB1 and (especially) ADARB2 variants in longevity is fairly convincing, although the most consistent effects came from the European-ancestry samples, suggesting that different things might be going on in other populations. This is the first research looking at these genes; ultimately, we won't know for sure until we get more. The worm data is a nice touch, but I'd like to see evidence from animals with a bit more similarity to humans, say mice.

Still, suppose that these genes are associated with long life; suppose they they control the rate of the ageing process, protecting you from dying from "natural causes" too early. That doesn't mean that you'll live to an old age - it just makes it possible. If you get hit a truck or fall of a cliff, you're dead, anti-ageing genes or not.

Frenchwoman Jeanne Calment, born 1875, died 1997, is the oldest person on record, at 122 years. But we'll never know whether someone with the genetic potential to outlive her died in WW2, or the Cultural Revolution, or just got hit by a truck. Calment presumably had the right genes, but she was also lucky.

So a trait's being genetically heritable doesn't make it pre-ordained and immutable. IQ, for example, most likely has a heritability of around 50% - some people likely have a higher potential for intellectual achievement than others. But if you're born into an abusive family, or deep poverty, or you never get a chance to go to school, you may never reach that potential. There's always that truck.

ResearchBlogging.orgSebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, Sedgewick A, Arai Y, Bergman A, Barzilai N, Terry DF, Riva A, Anselmi CV, Malovini A, Kitamoto A, Sawabe M, Arai T, Gondo Y, Steinberg MH, Hirose N, Atzmon G, Ruvkun G, Baldwin CT, & Perls TT (2009). RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PloS one, 4 (12) PMID: 20011587

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