As I was wandering the net today I found a very nice writeup about the 2009 report of an association between the FOXO3A gene and human aging. I found the article at the apparently quite popular but new-to-me blog Singularity Hub.

We mentioned this work in a brief post last year. The overall conclusion is that natural variants in this gene that are associated with extreme longevity. (The FOXO3A gene is a homolog of DAF-16, a longevity determinant in worms.) The 2009 paper describes a study of German centenarians, and is consistent with similar results in Japanese-Americans, published in 2008. Other genetic variants associated with lifespan include the hTERT and hTERC loci, recently described in a study of Ashkenazi Jewish centenarians.

Mostly I’m writing this post to introduce our readers to an interesting site: Singularity Hub contains a lot of excellent biogerontology coverage (in their longevity category). Much of the writing on that topic is by senior editor Aaron Saenz, who does a great job of critically addressing the newest findings in a very reader-friendly and accessible style. I’m going to subscribe to their feed and start reading regularly. Overall it’s a very professional and well-written site, and I’d recommend it to Ouroboros readers.

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In my first contribution to Ouroboros, I reviewed a paper in which the authors found an allele of FOXO3A associated with long lived Japanese men. So it seemed highly appropriate that I wrote the review for a follow-up paper: Flachsbart et al. analyzed 16 polymorphisms in the FOXO3A allele in 1,031 long-lived individuals (95-110 years old, 388 centenarians included) and 731 younger controls. They found that polymorphisms in the FOXO3A gene were significantly associated with German centenarians and human longevity.

Association of FOXO3A variation with human longevity confirmed in German centenarians
Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.

The next exciting advances in our knowledge of the molecular function of the FOXO3A protein will address how these polymorphisms affect protein function to impart this long-lived phenotype. FOXO3A (a human homo of the worm gene daf-16, whose function is necessary for lifespan extension conferred by daf-2/IGF-I pathway mutations) has been shown to play a role in insulin sensitivity, coronary heart disease, and diabetes which implicates FOXO3A as a “master regulator” that can regulate a wide variety of downstream targets which can have large effects on extending lifespan.

(Editor’s note: Liz will be taking a hiatus from blogging while she finishes her thesis. Let’s all wish her luck!)

ResearchBlogging.orgFlachsbart, F., Caliebe, A., Kleindorp, R., Blanche, H., von Eller-Eberstein, H., Nikolaus, S., Schreiber, S., & Nebel, A. (2009). Association of FOXO3A variation with human longevity confirmed in German centenarians Proceedings of the National Academy of Sciences, 106 (8), 2700-2705 DOI: 10.1073/pnas.0809594106

Mutations in genes involved in the insulin/IGF-1 signaling pathway (IIS) improve longevity in animal models, but there is minimal evidence that mutations in human homologues of genes in this pathway are associated with a long-lived phenotype.

In order to find such evidence, one could take a traditional forward genetics approach and study populations of centenarians. A recent paper in PNAS by Willcox et al. looked at a population of long-lived Japanese men. DNA samples were taken from men enrolled in the Honolulu Heart Program/Honolulu Asia Aging Study (HHP/HAAS). These men enrolled in the study throughout 1991-1993, and had a mean age of 77.9. From this population of volunteers, “long-lived” participants were defined as those who survived to 95 years old or older (n= 213) and “average-lived” controls as those who died before 81 years (n=402).  

The researchers then used a candidate approach to select the genes to analyze as potential “longevity genes” from the insulin/IGF-1 pathway. They selected this pathway to focus their candidate search because insulin signaling is conserved through evolution; furthermore, from mutation analysis and knockout models in many model organisms, we know that decreasing insulin/IGF-1 signaling increases lifespan.  These phenotypes occur through regulation of FOXO transcription factors and their homologues. The authors hypothesized that single nucleotide polymorphisms (SNPs) in FOXO related genes could be responsible for the differing longevity phenotypes between the long-lived and average-lived cohorts. Five genes, ADIPOQ, FOXO1A, FOXO3A, SIRT1, and COQ7 were selected as candidates, and three SNPs were analyzed per gene. Despite the small number of genes and SNPs analyzed, the researchers identified FOXO3A as being significantly associated with the long-lived phenotype. Genotype analysis revealed that long-lived study participants had one or more copies of the “G” allele in the FOXO3A gene. The authors state that this finding is especially exciting because the FOXO family of proteins are closely related to the C. elegans protein, DAF-16, which has been shown to protect cells from oxidative stress, which could be a “plausible mechanism of action for modification of human aging.”

Additionally, these long-lived men also had significantly lower plasma insulin, low cancer incidence, cardiovascular disease, had good self reported health, and had high physical and cognitive function at the time of their enrollment regardless of their genotype. The decreased incidence of cardiovascular disease and cancer was also associated with the presence of the “G” allele. It is possible that remaining healthy phenotypes could be regulated by alternative genes not analyzed in this study.

As the authors address in their introduction, many previously published searches for longevity genes do not show reproducibility across populations (“with the exception of APOE”), so it will be intriguing to determine if this FOXO3A “G” allele will transcend various populations of centenarians. 

Resveratrol decreases tobacco-induced inflammation in the lungs of smokers, suggesting that SIRT1 is involved in regulating the inflammatory response to cigarette smoke. Further evidence for a role for sirtuins in this process comes from Rajendrasozhan et al., in a study that confirms and extends the results of previous work.

The authors show once again that SIRT1 levels are low in the lungs of smokers, and that these levels diminish further in response to cigarette smoke. Smoke-exposed lung cells and macrophages exhibited increased inflammatory signaling (assayed primarily by looking at IL-8), as do cells in which SIRT1 has been artificially knocked out. Consistent with this, the RelA subunit of the master inflammation regulator NF-κB is hyperacetylated — recall that SIRT1 is a deacetylase — and consequently more active. Conversely, overexpression of SIRT1 decreases inflammatory cytokine production, echoing earlier results that described SIRT1 activation by resveratrol treatment.

Thus, a key longevity-assurance gene is also involved in restricting inflammation, which is a risk factor for some of smoking’s worst complications — chronic obstructive pulmonary disease (COPD) — as well as tumorigenesis. Tobacco is a major public health issue, so it’s not surprising that SIRT1 is getting attention in this context, but there is reason to believe that the phenomenon is general to organs other than the lung — e.g., see this review from Salminen et al., which describes how signaling from SIRT1 and FoxO transcription factors (mammalian homologs of the worm longevity gene DAF-16) can inhibit NF-κB signaling in a variety of systems. The authors close the circle by discussing the connection between longevity assurance and the mitigation of one specific age-related phenotype, inflammaging.

COPD is a leading cause of death worldwide, and it arises not only in smokers but in members of their households, as well as people exposed to environmental pollutants. A host of other inflammatory diseases, such as arthritis, beset the elderly and decrease quality of life. Increasing evidence that SIRT1 activity could mitigate the health harms of runaway inflammation point to even more potential uses for the new class of sirtuin-activating drugs that are currently under consideration as therapies against diabetes and metabolic syndrome.