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FoxO3 Allele Associated with Reduced All-Cause Mortality Across Populations

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I'm usually reluctant to post studies that try to associate single nucleotide polymorphisms (SNPs) with health or longevity outcomes. There are several reasons to be skeptical of such gene studies, including:

  • They often fail to replicate across different populations
  • The effects of individual SNP variations are often quite small - since there are usually many genes and polymorphisms that contribute to any important health/longevity outcome
  • Often it's not even clear from the study what the specific allele variation(s) the authors are evaluating
  • You often can't even find out what variant of an allele you have - since only some of us have our own genetic data and even that is only partial coverage through 23andMe.
  • There is nothing you can do about it anyway - your genes are your genes.
  • These polymorphisms and their effects often have nothing to do with CR.

But this new meta-analysis [1] posted by Al Pater (thanks Al!) seems to suffer from none of these shortcomings. It focuses on a SNP in the FoxO3 gene (rs2802292) which has been previously associated with longevity - is it overrepresented in centenarians [2], as discussed here, and summarized as:


[T]he odds ratio for reaching 100 years of age for rs2802292(G;G) vs (T;T) carriers was 2.75 (p = 0.00009; adjusted p = 0.00135). One's odds of living to 100 with one copy of 'G' for rs2802292 (i.e. G:T), appears to be about 1.5-2 times greater than people with T:T.


Those results were encouraging, but  didn't address causality, and was limited to a homogeneous population of men. Plus it only seemed relevant for people without other 'gotchas' (genetic or otherwise) that might kill them off long before reaching 100. What about the rest of us mortals, who may not be destined to live that long? Does having copies of the 'G' allele for rs2802292 do the rest of us any good on the way to extreme longevity?


Apparently - Yes!


Study [1] followed three pretty large groups of Americans with Japanese (N ≈ 3600), Caucasian (N ≈ 1600), or African (N ≈ 1000) ancestory for 17 years to assess the association between SNP rs2802292 status and mortality.  Interestingly, the frequency of being a lucky 'G' Allele Carrier (GAC)  for this SNP varied between the three populations - 47% of Japanese, 58% of Caucasian and 92% of African ancestry folks were GACs.


Across all three populations, being a GAC was associated with a 10% reduction in all-cause mortality over the 17 year follow-up, with virtually all of the benefit resulting from a 26% reduction in heart disease mortality. Here is the most important figure from the free full text:




As you can see the effect was quite consistent across the three populations. The difference in the confidence interval for the three groups was a result of the different population sizes.


The cool thing is that those of us with 23andMe data can find out our status for SNP rs2802292. Simply log in to 23andMe and follow this link. I'm fortunate to be in the ~60% of caucasian people who is a 'G' carrier for this allele (I've got one copy). 


But for anyone who isn't lucky enough to be a GAC for this allele, there is still hope. Why? Because FoxO3 gene activity is something we know quite a bit about, including ways of boosting its activity, like the G allele for rs2802292 apparently does. Curiously, cider vinegar appears to upregulate DAF-16, the C. Elegans equivalent of FoxO3, which in turn resulted in the worms living 25% longer, as discussed here. So maybe cider vinegar is worth including in one's diet. I do.


But even more relevant, we know that both CR and cold exposure increase FoxO3 gene expression largely by upregulating SIRT1, as discussed recently here.


So everybody wins!




[1] The FoxO3 gene and cause-specific mortality.
Willcox BJ, Tranah GJ, Chen R, Morris BJ, Masaki KH, He Q, Willcox DC,
Allsopp RC, Moisyadi S, Poon LW, Rodriguez B, Newman AB, Harris TB, Cummings
SR, Liu Y, Parimi N, Evans DS, Davy P, Gerschenson M, Donlon TA.
Aging Cell. 2016 Apr 13. doi: 10.1111/acel.12452. [Epub ahead of print]
Free Article
The G allele of the FOXO3 single nucleotide polymorphism (SNP) rs2802292
exhibits a consistently replicated genetic association with longevity in
multiple populations worldwide. The aims of this study were to quantify the
mortality risk for the longevity-associated genotype and to discover the
particular cause(s) of death associated with this allele in older Americans
of diverse ancestry. It involved a 17-year prospective cohort study of 3584
older American men of Japanese ancestry from the Honolulu Heart Program
cohort, followed by a 17-year prospective replication study of 1595 white
and 1056 black elderly individuals from the Health Aging and Body
Composition cohort. The relation between FOXO3 genotype and cause-specific
mortality was ascertained for major causes of death including coronary heart
disease (CHD), cancer, and stroke. Age-adjusted and multivariable Cox
proportional hazards models were used to compute hazard ratios (HRs) for
all-cause and cause-specific mortality. We found G allele carriers had a
combined (Japanese, white, and black populations) risk reduction of 10% for
total (all-cause) mortality (HR = 0.90; 95% CI, 0.84-0.95; P = 0.001). This
effect size was consistent across populations and mostly contributed by 26%
lower risk for CHD death (HR = 0.74; 95% CI, 0.64-0.86; P = 0.00004). No
other causes of death made a significant contribution to the survival
advantage for G allele carriers. In conclusion, at older age, there is a
large risk reduction in mortality for G allele carriers, mostly due to lower
CHD mortality. The findings support further research on FOXO3 and FoxO3
protein as potential targets for therapeutic intervention in aging-related
diseases, particularly cardiovascular disease.
FOXO3; heart disease; longevity; mortality
PMID: 27071935 
[2] Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92. doi:
10.1073/pnas.0801030105. Epub 2008 Sep 2.
FOXO3A genotype is strongly associated with human longevity.
Willcox BJ(1), Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC,
Rodriguez B, Curb JD.
Author information:
(1)Pacific Health Research Institute, 846 South Hotel Street, Honolulu, HI 96813,
USA. bjwillcox@phrihawaii.org
Human longevity is a complex phenotype with a significant familial component, yet
little is known about its genetic antecedents. Increasing evidence from animal
models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important,
evolutionarily conserved biological pathway that influences aging and longevity.
However, to date human data have been scarce. Studies have been hampered by small
sample sizes, lack of precise phenotyping, and population stratification, among
other challenges. Therefore, to more precisely assess potential genetic
contributions to human longevity from genes linked to IIS signaling, we chose a
large, homogeneous, long-lived population of men well-characterized for aging
phenotypes, and we performed a nested-case control study of 5 candidate longevity
genes. Genetic variation within the FOXO3A gene was strongly associated with
human longevity. The OR for homozygous minor vs. homozygous major alleles between
the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived
men also presented several additional phenotypes linked to healthy aging,
including lower prevalence of cancer and cardiovascular disease, better
self-reported health, and high physical and cognitive function, despite
significantly older ages than controls. Several of these aging phenotypes were
associated with FOXO3A genotype. Long-lived men also exhibited several biological
markers indicative of greater insulin sensitivity and this was associated with
homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene,
human longevity and other aging phenotypes is warranted in other populations.
PMCID: PMC2544566
PMID: 18765803
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It looks like I come up GG on the rs2802292, but your words of caution are well advised. After all, the claim is that 92% folks of African ancestry are GACs, and only 47% of Japanese ancestry - but then when you look at actual survivability statistics, people of Japanese ancestry consistently come out near the top, whereas the opposite is true for African ancestry; this holds even when stratified by age group, so f.ex. if you are 80 years old, your odds of living longer are greater if you are of Japanese ancestry vs African (stratifying by age group strongly attenuates variables like "death by firearms" which might otherwise skew statistics for, say, the 20-25 year old cohort). I haven't looked up the statistics, but I believe the same holds for prevalence of heart disease at advanced ages, and controlled for things like smoking, in the two groups - which is supposedly the strength of this variant "benefit resulting from a 26% reduction in heart disease mortality" - not if you look at the relevant statistics of mortality from heart disease in older age groups for Japanese and African. As you say "There are several reasons to be skeptical of such gene studies".

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The reduction in mortality reported in PMID 27071935 were relative to others in the same cohort during the 17 year follow-up - e.g. Japanese GACs vs. Japanese non-GACs. Of course there are many factors contributing to mortality, including other genetic traits as well as diet and lifestyle differences between different groups of people that can have much larger effects on mortality than the 10% difference apparently associated with SNP rs2802292.


Interestingly, 75% of Japanese Americans, 52% of Caucasians Americans, 54% of Africans Americans died during the 17-year follow-up. So the African Americans didn't exhibit increased overall mortality in this study. The Japanese American's increased mortality may have been a result of starting out 4 years older on average at the beginning of the study relative to the other two populations (~77 vs. ~74).



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Oops, I missed that it was in-group comparisons. So I take back my remarks :)


Although you'd think if GACs are more prevalent in the African ancestor demographic it would translate into lower CVD mortality for that demographic compared to the Japanese ancestry - and I believe the opposite is the case.

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I was looking up various SNPs on snpedia, and I came across this summary for rs2802292:




FWIW, they also highlighted the conflict between longevity data in the Japanese vs African background populations, so I was not the only one:


"No-one should consider this association to be definitive until it's been replicated in independent cohorts. Secondly, the effects of this variant are likely to differ between groups. According to the HapMap database the frequency of the "die early" (T) version of the variant varies substantially between populations: it's around 76% in Japanese, slightly more common (81%) in Chinese, less common (58%) in Europeans, and quite rare (17%) in West Africans. Given that the Japanese have the highest life expectancy of any of these populations, this is a counter-intuitive result, which reinforces the fact that there are many genes and other factors influencing variation in longevity."

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  • 5 months later...
Guest bgmarcks

In 2011, Boston researchers reported on the DNA longevity results of a 114 year old male and a 114 year old female.  They had Tables of about 25 SNP's they considered as Exceptional Longevity SNP variants, among which were 5 FOXO3A SNP variants.  The male had the longevity variant for all 5 FOXO3A SNP's.  I looked up my raw DNA data from 23andme and found I also was homozygous for all of the longevity SNP variants.  I researched the literature on FOXO3A and found 3 more FOXO3A SNP's for which I was homozygous for the longevity variant.  The authors of the study said there was nothing unusual or uncommon about the number of longevity SNPs, but I had a better number of the good variants than he did.  So, maybe I will break the male record of 120 years if I continue to live right, being 76 in Oct. already.  The woman did not have any of the FOXO3A longevity variants, but it has been shown that most of them confer male only longevity.  Women are apparently more reliant on FOXO1A for longevity, while men do not benefit from FOXO1A like women.  Most of the longevity variants are minor alleles.

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  • 6 months later...
Guest Bradley Willcox



I just came across your post. Very interesting discussion.


I was also intrigued by what appears to be a counter-intuitive finding that we saw in our research - that most blacks we studied are carriers of the longevity-associated allele (G allele) of the FOXO3 gene - SNP rs2802292.


Interestingly, it is not so counter-intuitive when one considers some other interesting facts. The refs for the points I make below are easily searchable. 

- blacks live longer than whites in the VA Medical Care system (where they have relatively equal access to health care) (a paper in "Circulation" a couple of years ago) 

- blacks have lower coronary calcium scores than whites, indicating less coronary heart disease (CHD) than whites (several studies). I suspect that a lot of supposed black CHD mortality on death certificates (having filled out quite a few and studied a lot more) is not really due to CHD but hypertensive heart disease, leading to enlarged hearts, which can lead to sudden cardiac death. This is often mislabeled as CHD.

blacks have lower overall mortality and lower coronary heart disease (CHD) mortality after the age of 80 years than whites, as quoted below:

"Black persons had higher mortality rates than Whites at young-old age (65-80 years) but had significantly lower mortality rates after age 80. Black persons age 80 or older had a significantly lower risk of all-cause mortality (HR of Blacks vs Whites, 0.75; 95% confidence interval [CI] = 0.62, 0.90) and of CHD mortality (HR 0.44: 95% CI = 0.30, 0.66)" from Am J Public Health. 1999 Mar;89(3):308-14.

- blacks are the longest lived of all ethnic groups in the US after the age of 90 years (multiple studies)


I speculate that FOXO3 may have something to do with black longevity.


Brad Willcox, MD

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