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FOXO3

Are You Genetically Predisposed to Live a Longer Life? (FOXO3)

Written by Jasmine Foster, BSc, BEd on August 30th, 2019

One of the best-studied longevity genes, one variant in FOXO3 can affect your lifespan as much as smoking a pack a day for 25 years. Are you at risk? What can you do to live a longer life? Read on to find out.

Who Wants to Live Forever?

Human beings have been looking for ways to increase our lifespan since at least the beginning of recorded history. Before the advent of modern science, people told each other stories of a Fountain of Youth; more recently, stem cells and cryogenic freezing have inspired dreams of immortality [R, R, R].

The average life expectancy on Earth has been rising for generations due to improvements in medical knowledge and procedures, but some of the reasons we do or don’t live for a long time are purely genetic. Your DNA is estimated to make up about 25% of the factors that influence your lifespan, where the other 75% comes from your environment and experiences [R, R].

The Forkhead of Youth

One of the best-studied longevity genes is FOXO3, which codes for forkhead box protein O3. It is a member of the forkhead box (FOX) family of genes, which all encode transcription factors: proteins which regulate the expression of other genes. The FOXO subclass, of which FOXO3 is a member, regulates insulin signalling and protein metabolism in muscles [R].

In the last decade or so, a large body of research has linked certain variants in the FOXO3 gene with longer lifespan [R, R, R, R, R].

FOXO3 is involved in tumor suppression, immune function, DNA repair, and resistance to oxidative stress [R, R, R].

As Impactful as Smoking Cigarettes?

Some variations in the FOXO3 gene are enormously beneficial, while others are risky. At rs2802292, which has the greatest effect of any single SNP yet studied in FOXO3, the TT genotype confers the same risk as smoking a pack a day for 25 years, having 20 mmHg higher systolic blood pressure, or having 20 mg dL-1 higher fasting blood sugar [R].

Another SNP, rs2802288, boasts a similar impact on longevity. This isn’t surprising, given that the two variations are physically very close to each other in the DNA sequence; they are inherited together almost 100% of the time [R].

FOXO3 regulates insulin signalling and protein metabolism in muscles. Surprisingly, some variants in FOXO3 have as much of an effect on longevity as smoking a pack of cigarettes per day for 25 years.

How Does FOXO3 Increase Your Lifespan?

In worm and fly models, increased FOXO3 expression increased lifespan. FOXO3 appears to promote tissue regeneration, autophagy (the cellular recycling system), and the growth of stem cells [R, R].

In rodents, FOXO3 also appears to increase the production of regulatory T cells (Tregs), which regulate the immune response, promote tolerance of harmless proteins, and prevent autoimmunity. Mice without a functional FOXO3 gene were also many times more likely to develop cancer and die young [R].

FOXO3 also plays a role in managing oxidative stress. Mice without FOXO3 are highly susceptible to reactive oxygen species in their bones, resulting in decreased bone mass and increased risk of fracture (osteoporosis). The antioxidant effect of FOXO3 has not yet been investigated in aged mice [R, R].

In animals, FOXO3 promotes tissue regeneration, autophagy, and the growth of stem cells. Mice and rats without a functional FOXO3 gene tend to develop osteoporosis and die young of cancer.

Your FOXO3 Results for Longevity

Frequency Data

How common or rare are the beneficial alleles? Where on Earth are they most common?

FOXO3 rs2802288

‘A’ = Longer than average lifespan, more likely to live past 100
‘G’ = Less likely to live past 100

FOXO3 rs12212067

‘G’ = Longer than average lifespan, more likely to live past 100
‘T’ = Less likely to live past 100

FOXO3 rs9398171

‘C’ = Longer than average lifespan, more likely to live past 100
‘T’ = Less likely to live past 100

FOXO3 rs9400239

‘T’ = Longer than average lifespan, more likely to live past 100
‘C’ = Less likely to live past 100

FOXO3 rs2802292

‘G’ = Longer than average lifespan, more likely to live past 100
‘T’ = Less likely to live past 100

FOXO3 rs4946936

‘T’ = Longer than average lifespan, more likely to live past 100
‘C’ = Less likely to live past 100

SNP Table

variant	genotype	frequency	risk allele
rs2802288
rs12212067
rs9398171
rs9400239
rs2802292
rs4946936

Recommendations

Lifestyle

Exercise induces FOXO3 and its closely related cousin FOXO1, another transcription factor important for insulin signalling and reducing fat storage. This helps explain why people who are physically active tend to live longer! To increase FOXO3, commit to a fitness plan and focus on some forms of endurance training [R, R].

In mice, heat stress increased FOXO3 expression. This result suggests that using a sauna could help induce FOXO3 and extend lifespan. Indeed, some evidence has shown that people who regularly take sauna baths live longer lives [R, R].

Finally, intermittent fasting and calorie restriction activate FOXO3 [R].

Diet

Many polyphenols commonly found in plants we eat (especially fruits and vegetables) are capable of inducing FOXO3.

While we don’t usually get a large concentration of any single polyphenol in the diet, we do get many of them in smaller concentrations, and they have synergistic effects.

A promising polyphenol to induce FOXO3 is EGCG, which is found primarily in green tea at reasonable concentrations [R].

Theaflavins, a class of polyphenols found in black tea, stimulated FOXO3 activity in multiple cell studies [R, R].

In worms, epicatechins (which are found in the highest concentrations in cocoa) induce FOXO and improves the animals’ resistance to stress. In human athletes, drinking chocolate milk after exercise increases FOXO3 expression [R, R].

The longest living person ever, Jeanne Calment, lived to 122.5 years old! She used to enjoy cocoa daily, sometimes indulging in a kilogram (2.2 lb) per week. She was able to do this despite smoking, probably because the cocoa increased her FOXO3 [R]!

So, good news: eating a moderate amount of chocolate could increase your lifespan.

Other polyphenols that have induced FOXO3 in a lab include [R, R]:

Resveratrol found in grapes, wine, peanuts, Japanese Knotweed
Curcumin [R]
Quercetin, abundant in capers, apples, berries, broccoli, onions, and many other sources [R]
Luteolin, abundant in carrots, cabbage, artichokes, tea, celery, and apples [R]
Apigenin, abundant in celery, onions, oranges, and many herbs [R]

A diet rich in polyphenols may help induce FOXO3 and extend your lifespan. Many fruits and vegetables contain helpful polyphenols like quercetin, luteolin, and apigenin; they are particularly abundant in apples, onions, and many herbs.

Supplements

Some polyphenols can be taken as supplements; if you have lots of risk alleles in the table above, you may want to consider taking one or more of these compounds, each of which have been found to induce FOXO3:

Curcumin and EGCG were able to extend lifespan in flies and worms [R, R, R].

One review study found that resveratrol supplements extended the lives of about 60% of animal models; however, results varied widely from one species to another. Researchers don’t currently agree on whether resveratrol significantly affects human lifespan [R].

Jasmine Foster

BSc, BEd

Jasmine received her BS from McGill University and her BEd from Vancouver Island University.

Jasmine loves helping people understand their brains and bodies, a passion that grew out of her dual background in biology and education. From the chem lab to the classroom, everyone has the right to learn and make informed decisions about their health.

Disclaimer

The information on this website has not been evaluated by the Food & Drug Administration or any other official medical body. This information is presented for educational purposes only, and may not be used to diagnose or treat any illness or disease.

Also keep in mind that the “Risk Score” presented in this post is based only on a select number of SNPs, and therefore only represents a small portion of your total risk as an individual. Furthermore, these analyses are based primarily on associational studies, which do not necessarily imply causation. Finally, many other (non-genetic) factors can also play a significant role in the development of a disease or health condition — therefore, carrying any of the risk-associated genotypes discussed in this post does not necessarily mean you are at increased risk of developing a major health condition.

Always consult your doctor before acting on any information or recommendations discussed in this post — especially if you are pregnant, nursing, taking medication, or have been officially diagnosed with a medical condition.

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Content

Who Wants to Live Forever? The Forkhead of Youth How Does FOXO3 Increase Your Lifespan? Your FOXO3 Results for Longevity

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Are You Genetically Predisposed to Live a Longer Life? (FOXO3)

Who Wants to Live Forever?

The Forkhead of Youth

As Impactful as Smoking Cigarettes?

How Does FOXO3 Increase Your Lifespan?

Your FOXO3 Results for Longevity

Frequency Data

SNP Table

Recommendations

Lifestyle

Diet

Supplements

Disclaimer

More inflammation & autoimmunity blogs

Content

Unlock Personalized Results And So Much More!

Essential Bundle

Essential

Bundle

Limited time offer 25% off

Ultimate Bundle

Policies

About

Navigation

Health reports