SNPwatch: Mounting Evidence That FOXO3A Contributes To Human Longevity

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

Want to live long enough to get a birthday wish from Willard Scott?  It may depend on more than just eating right and getting plenty of exercise.  Your DNA could play a part too.

Last year a report showed that variations in the FOXO3A gene are associated with longevity in Japanese men.  Now a separate research group has confirmed these findings in a European population.  These results, published online this week in the Proceedings of the National Academy of Sciences, add credence to the idea that FOXO3A is, as the authors call it, a “ susceptibility gene for prolonged survival” – a condition that many of us hope to develop.

Flachsbart et al. looked at a collection of FOXO3A variations in a sample of German men and women.  They found that several variations slightly increased the odds of being long-lived (aged 95-100).  When the sample was split into nonagenarians (people in their 90s) and centenarians (those 100+), the researchers found that the effects of the FOXO3A SNPs were much stronger in those that had made it to the century mark.  For example, having one or two As at rs2802288 increased the odds of making it to 100 by about 1.5 times.

“Centenarians may be particularly enriched for beneficial variants in ‘longevity assurance genes’,” the authors write.

Rs2802288 is located very close to rs2802292, which was one of the SNPs found in the September 2008 report by Willcox et al on Japanese men living in Hawaii.  In that study, men with an A at rs2802292 had 1.91 times odds of living to 95 or older compared to those with two Cs; two As increased the odds by 2.75 times.  Unlike in the German study, where two copies of the long-lived version had no more effect than one, each copy of rs2802292 appeared to increase the odds of longevity in the Japanese sample.

The authors investigated several FOXO3A SNPs in French and Dutch samples.  There was no statistically significant association between the SNPs and longevity in these groups, although there were some suggestive results in the French sample.

According to the authors, there is good reason to believe that variations in FOXO3A could contribute to healthy aging.  The protein encoded by the gene has been shown to control insulin sensitivity and influence risk for coronary heart disease and type 2 diabetes.  The fact that the association has now been observed in two genetically diverse groups makes the evidence even stronger.  More work will be needed to work out all the details, however.

“The future challenge is to investigate whether the observed discrepancies in the strength and kind of the FOXO3A effect can be verified and, if so, to clarify whether they are caused by study design, population-and/or gender-specific difference, or some other factors.”

(23andMe customers can look up their data for rs2802288 using the Browse Raw Data feature. This SNP is located very close to rs2802292, which is not currently available.  Customers with Japanese ancestry can use rs2802288 as a proxy for rs2802292, keeping in mind that while the A version of rs2802288 also indicates increased chances of longevity, the exact odds will differ from those cited in the September 2008 study by Willcox et al.)


  • Mark

    The v3 data seems to have rs2802292 available, but browsing it I note that it can only be G or T… this article says you want to see one or two A’s there. Eh?

    “In that study, men with an A at rs2802292 had 1.91 times odds of living to 95 or older compared to those with two Cs; two As increased the odds by 2.75 times. “

    • http://23andme.com Shwu

      Hi Mark,

      23andMe always reports data from the “positive” strand of DNA (DNA is a double-stranded molecule with one strand designated as the positive strand and the other as the negative strand). Other sources may report from the negative strand, in which case the versions of the SNPs mentioned will be the complementary DNA base. “A” pairs with “T” and “G” pairs with “C,” so if the article or paper says the “A” version is associated with something and 23andMe data reports G or T for that SNP, that means a “T” on 23andMe corresponds to the “A” mentioned in the article/paper (and the “G” corresponds to the “C”). Keep in mind that for SNPs that can be either A or T, or SNPs that can be G or C, you will need to know what strand the other source is reporting from to know if the your 23andMe data can be matched directly to information reported by the other source, or if you need to “flip” the letters.

      Hope this clears things up!

  • eastcarolinatarheel

    Shwu:

    So if 23andMe reports AG for me at rs2802288, what does that tell me in relation to this study and gene?

    • http://23andme.com Shwu

      @eastcarolinatarheel, “having one or two As at rs2802288 increased the odds of making it to 100 by about 1.5 times.” So you have somewhat higher odds of living to 100, based on your having an AG genotype! Of course, there are other factors involved, so it remains to be seen whether you actually do make it that far. But every little bit helps, eh? :)

  • Phil Goetz

    All these SNPs are in introns, while AFAIK all the regulators of FOXO3a (eg Akt1) interact with the protein. What interacts with the FOXO3a gene directly?

    • http://23andme.com Shwu

      Hi Phil,

      Not sure if I’m interpreting your question correctly, but here’s some info that might help. Genetic variations in introns of genes may still influence the biological processes that their proteins are involved in. For example, regulatory sequences in the introns may influence how much of the gene (and therefore protein) is expressed in the cell. If one of these sequences is disrupted by a variant, the protein may be produced in different amounts. It’s also possible that these variants are simply “tagging” — or correlated with — the actual variants that are directly involved in the gene’s activity. Hope this information is useful!

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