Trait#100: FOXO3 and longevity

Monday, June 21, 2021. Author FitnessGenes

Trait#100: FOXO3 and longevity

Could you live until 100?

Despite promising research to combat it, ageing is an inevitable fact of human life.

As we get older, we all gradually accumulate damage to cell components, DNA, proteins, and other important molecules. Over time, this damage starts to compromise tissue and organ function, causing a gradual decline in physical and mental capacity, an increased risk of age-related diseases (such as cancer, high blood pressure, osteoarthritis, dementia) and, eventually, death.

Of course, the process of biological ageing and the rate at which we accumulate cell and molecular damage varies from person to person.  Some of us may reach advanced chronological age with much better physical and mental health and less ageing-related damage than others.

The way we live our lives undoubtedly plays an important role in ageing. Physical inactivity, psychological stress, under and overnutrition, smoking, and exposure to environmental pollutants can all accelerate ageing.

By contrast, someone who takes moderate amounts of exercise, eats a healthy, well-balanced diet, refrains from smoking, gets enough sleep, practises caloric restriction/fasting, and lives a predominantly stress-free life, may benefit from slowed cellular ageing.

 

Source: Awofala, A., & Ogundele, O. Genetic and Environmental Contributions to Human Longevity. Arşiv Kaynak Tarama Dergisi, 25(2), 191-206.

 

But lifestyle isn’t the only piece of the puzzle. The genes we inherit also substantially affect ageing and have a strong influence on our lifespan. Family studies suggest that between 20 -50% of variation in human lifespan can be explained by genetic differences.

In terms of higher-than-average lifespans, commonly referred to as human “longevity”, roughly 25% of the variation is attributed to genetic factors, with genes exerting more of an effect at older ages and in men compared to women.

When it comes to individual genes that confer longevity, one of the most promising candidates is FOXO3 – the forkhead box O3 gene. It encodes a transcription factor that switches on other genes that protect against oxidative stress, promote DNA repair, and stimulate cell renewal – all of which may prevent cell ageing.

In this 100th FitnessGenes trait, you’ll find out whether you carry a FOXO3 gene variant that is overrepresented in exceptionally long-lived people (aged 95 years or older) from various ethnic backgrounds.

Do you have the genes of a centenarian?

 

KEY POINTS

  • Ageing results from the accumulation of cell damage over time.
  • Both environmental factors (including our lifestyle) and genetic factors influence our lifestyle.
  • Longevity refers to higher-than-average lifespans (often defined as 90 years+ in studies).
  • About 25% of variation in long lifespans can be explained by genes.
  • FOXO3 is one of the few well-studied candidate longevity genes.

 

What causes ageing?

Before we look at the potential anti-ageing effects of the FOXO3 gene, it’s useful to get an idea of what causes cellular ageing in the first place.

The cliff note answer is that ageing is caused by the accumulation of cell damage over time.

A deeper look into the academic literature reveals that there are at least nine different cellular and molecular hallmarks of ageing. These are illustrated in the diagram below.

 

Source: Singh, P. P., Demmitt, B. A., Nath, R. D., & Brunet, A. (2019). The genetics of aging: a vertebrate perspective. Cell, 177(1), 200-220.

 

Let’s take a brief look at each of the above hallmarks of ageing individually.

 

- Genomic instability

Genomic instability essentially refers to damage to our DNA molecules.

Throughout life, our DNA sustains lots of different types of damage. Some of these sources of damage are external to the body. For example, if we we’re to sit outside on a summer’s day, UV radiation from the sun would damage our DNA, often by causing neighbouring nucleotides in the DNA sequence to abnormally bond together (the technical term is ‘thymine dimerization’). Another external source of DNA damage is exposure to ionising radiation, such as X-rays, which can cause breaks across both strands of the DNA molecule (known as a double-strand break).

Our DNA also gets damaged by normal biological processes within the body. Reactive oxygen species (ROS), which are generated through cell respiration, inflammation, and other chemical reactions in the body, can damage nucleotide bases or cause abnormal linkages between DNA strands.

Another common source of DNA damage is cell replication. When cells divide and make copies of themselves, they can commit errors copying their genetic material, leading to DNA damage.

The accumulation of all these various kinds of DNA damage is thought to contribute to ageing.

 

Source: Dexheimer, T. S. (2013). DNA repair pathways and mechanisms. In DNA repair of cancer stem cells (pp. 19-32). Springer, Dordrecht.

 

Luckily, our cells also have and assortment of DNA repair mechanisms to fix different types of DNA damage. For example, we have specialised proteins, called Fanconi anaemia proteins, that are able to repair abnormal cross-links between DNA strands.  We also have various enzymes that are able to selectively remove (excise) damaged nucleotide bases from the DNA molecule – a process known as base excision repair.  

Failure of these DNA repair mechanisms, however, also contributes to DNA damage and cellular ageing.

 

- Telomere attrition

Telomeres, which we encountered in your Telomere-linked ageing (TERC) trait, are stretches of DNA at the end of chromosomes. They act as buffers to prevent important genetic information from being lost every time cells replicate.  

As explained in the accompanying Telomere-linked ageing (TERC) trait article, telomeres get shorter and sacrificed with every cycle of cell replication. They also get shorter due to damage from oxidative stress. This process of telomeres shortening over time is known as 'telomere attrition'.

 

If telomeres become too short, further cell replication would cause important genetic material to be lost instead, in turn causing irreparable cell damage.

Therefore, once telomeres reach a certain critical length, cells receive a signal to permanently stop dividing or enter a process of programmed cell death.

The shortening of telomeres towards this critical length is one of the hallmarks of ageing.

 

- Epigenetic alterations

Epigenetic alterations refer to changes that affect gene activity without altering the DNA sequence. For example, a process called methylation, which involves adding a methyl group to DNA, causes genes to be switched off and not converted into proteins.

Certain patterns of methylation, such as increased methylation of tumour suppressor genes, may be a hallmark of ageing. Other epigenetic alterations associated with ageing include structural changes to histones – proteins which act as spools for DNA to wrap around into tight coils.

 

- Loss of proteostasis

Proteostasis is the process by which cells maintain the building, stabilisation, and turnover of proteins.

For proteins to maintain their structure and function effectively, they need to be folded correctly. To assist with this, our cells produce specialised molecules, known as chaperone proteins, that guide and protect proteins throughout the folding process. This allows proteins to be stabilised.

Source: López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

 

Incorrectly folded proteins, as well as other unstable or damaged proteins, are typically refolded by chaperone proteins (e.g. heatshock proteins [HSP]) or otherwise destroyed (degraded) or recycled.

It’s thought that disturbances to the function of chaperone proteins, as well as impaired degradation of misfolded proteins, can lead to the aggregation of misfolded and unfolded proteins. This, in turn, has been linked to cell ageing.

 

- Deregulated nutrient sensing

Dietary restriction has been widely observed across several species to extend lifespan. Similarly, reduced protein and fat intake has been linked to longevity and a reduced risk of ageing-related diseases such as cardiovascular disease and cancer.  

By contrast, high nutrient availability stimulates anabolic pathways, such as the mTOR pathway (discussed in the Muscle hypertrophy (mTOR) trait article) or the IGF-1 signalling pathway (discussed in the Muscle growth (IGF-1) trait article, which are shown to accelerate cell-ageing. 

 

Source: Mirzaei, H., Suarez, J. A., & Longo, V. D. (2014). Protein and amino acid restriction, aging and disease: from yeast to humans. Trends in Endocrinology & Metabolism, 25(11), 558-566.

 

Changes in these nutrient-sensing metabolic pathways are thought to be hallmarks of ageing.

 

- Mitochondrial dysfunction

As we age, the efficiency of our mitochondria at producing energy starts to decline.

Mitochondria, which are responsible for cell respiration, become less effective at producing ATP and, as a result, also generate more reactive oxygen species (ROS). (You can read more about the mechanisms by which mitochondria generate ROS in the Protection against reactive oxygen species (UCP2) trait article).

ROS generated by dysfunctional mitochondria go on to inflict cell damage, causing cell ageing.

Another hallmark of ageing is reduced production of new mitochondria (mitochondrial biogenesis). On this note, endurance training and alternate-day fasting have both been shown to delay cell ageing, an effect possibly due to enhanced production and/or recycling of mitochondria. 

 

- Cellular senescence

If cells sustain sufficient damage, or if telomeres reach a critical length (explained previously), cells stop growing and dividing. This state of permanent growth arrest is known as senescence.

Senescence is often beneficial, as it stops the growth and proliferation of damaged cells. In order for tissue and organ function not to suffer, however, senescent cells need to be removed and replaced with younger cells.

As we age, the number of senescent cells in tissues starts to accumulate. This is partly due to impaired removal and replacement of senescent cells. Furthermore, senescent cells are shown to stimulate the release of pro-inflammatory molecules, which can cause damage to other cells and cause cell ageing.

 

- Stem cell exhaustion

Stem cells are specialized cells with the potential to develop into several different types of cells of in the body.

For example, haemopoietic stem cells found in bone marrow are capable of developing into red blood cells, mast cells, different kinds of white blood cell, or platelets. The presence of stem cells allows tissues to regenerate and organ function to be maintained.

Source: Franco, S. S., Raveh-Amit, H., Kobolák, J., Alqahtani, M. H., Mobasheri, A., & Dinnyes, A. (2015). The crossroads between cancer stem cells and aging. BMC cancer, 15(1), 1-15.

 

As we get older, however, the number of stem cells in various tissues starts to decline and, along with it, the regenerative capacity of our tissues. This may partly explain why it takes longer for injuries to heal in older individuals compared to younger people.

Similarly, as with other cell types, stem cells also sustain damage over time. This damage can impair the function of stem cells, again leading to ageing.   

 

- Altered intercellular communication

Falling under the banner of ‘altered intercellular communication’ is inflammation.

Chronic inflammation involves the prolonged release of pro-inflammatory molecules (‘cytokines’) that recruit various immune cells to sites of tissue injury. Rather than helping to resolve tissue injury, chronic inflammation can perpetuate cell and tissue damage by causing oxidative stress. In turn, this inflammatory cell damage contributes to ageing: a phenomenon known as “inflammaging.”

 

KEY POINTS

  • There are thought to be 9 different hallmarks of ageing - which includes damage to DNA, reduced mitochondrial function, aggregation of toxic, unfolded proteins, shortening of telomeres, reduced numbers of stem cells, inflammation, and changes to metabolic pathways.

 

What is FOXO3?

FOXO3 (also known as FOXO3A) is a gene that codes for a protein called forkhead box O3.

This protein belongs to a class of molecules known as transcription factors. Transcription factors help to switch certain genes ‘on’ and ‘off’ by binding to nearby DNA.

Remember that genes code for proteins. When genes are switched on, their genetic instructions are read, and protein production is ramped up. This, in turn, effects changes in a cell’s activity and behaviour.

In particular, the forkhead box O3 transcription factor switches on genes involved in response to cellular stress.

Cellular stress refers to damage from changes in a cell’s environment: for example, from changes in temperature, reduced oxygen availability (hypoxia), the presence of toxins, oxidative stress from the build-up of reactive oxygen species (ROS), or from mechanical damage.

 

Source: van der Horst, A., & Burgering, B. M. (2007). Stressing the role of FoxO proteins in lifespan and disease. Nature reviews Molecular cell biology, 8(6), 440-450.

 

As part of a response to these types of damage, cells activate genes that help to protect against further injury and oxidative stress, repair cell and DNA damage, recycle damaged cell components, alter cell metabolism, cause programmed cell-death (apoptosis) of badly damaged cells, and promote overall cell survival.

By switching on these stress response genes, it’s thought that the FOXO3 gene helps to protect against the accumulation of cell damage that causes ageing. On this note, FOXO3 is one of the few genes that has been consistently linked to longevity in humans.

 

KEY POINTS

  • FOXO3 is a gene which switches on other genes that protect against cell stress/cell damage.
  • The action of FOXO3 may help protect against the cell damage that causes ageing.

 

How does FOXO3 protect against ageing?

Some of the first evidence for the role of FOXO3 in ageing comes from studies of C.elegans – a species of nematode worm with a typical lifespan of about 2 – 3 weeks. This worm contains a version of the FOXO gene called DAF16.

When the activity DAF16 gene has been experimentally enhanced, the lifespan of C.elegans gets significantly extended. Similar findings have been found with FOXO genes in other organisms too. For example, genetically engineering Drosophila fruitflies to overexpress the FOXO gene also increases their lifespan.

Another line of evidence come from studies of dietary restriction in mice, which involves reducing calorie intake without causing malnutrition. Dietary restriction has been widely demonstrated across species to promote longevity.

 

Source: Cameron, K. M., Miwa, S., Walker, C., & von Zglinicki, T. (2012). Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction. Longevity & healthspan, 1(1), 1-9.

 

The graph above, for instance, shows how male (M) and female (F) mice undergoing dietary restriction (DR) survive longer than those allowed to have food ad libitum (AL). This lifespan-increasing effect in mice is thought to be dependent on activity of the FOXO gene.

So, how does the FOXO3 gene slow down cell ageing and promote longevity?

As discussed earlier in the “What causes ageing?” section, cell ageing results from the accumulation of cell and molecular damage, with nine hallmarks of this damage identified. Studies suggest that the FOXO3 gene may help to prevent ageing by activating genes that protect against these nine ageing-related processes.

 

Source: Morris, B. J., Willcox, D. C., Donlon, T. A., & Willcox, B. J. (2015). FOXO3: a major gene for human longevity-a mini-review. Gerontology, 61(6), 515-525.

 

For example, FOXO3 is shown to upregulate genes involved in DNA repair, which protects against genomic instability (i.e. damage to DNA).

FOXO3 also switches on genes that:

- Protect against oxidative stress

Oxidative stress refers to the accumulation of harmful reactive oxygen species (ROS) substances, which can inflict damage to DNA, proteins, fats, and other key molecules. FOXO3 can protect against oxidative stress by upregulating various antioxidant enzymes (e.g. SOD2), which can help to neutralise and clear ROS. 

 

- Renew stem cells

As previously mentioned, stem cell exhaustion is one of the features of ageing. FOXO3 helps tissues to maintain a steady pool of stem cells, thereby allowing tissues to regenerate. For example, studies have shown that FOXO3 stimulates the renewal and prevents the decline in numbers of satellite cells – stem cells found in skeletal muscle.

 

- Stimulate proteostasis and autophagy

Proteostasis, as described earlier, refers to the maintenance and turnover of proteins. Loss of proper proteostasis, another hallmark of ageing, can lead to the aggregation of toxic mis- and unfolded proteins, causing cell damage.

FOXO3 is thought to activate genes that help to remove these toxic proteins. Similarly, FOXO3 stimulates autophagy – the process by which cells remove and recycle damaged components (e.g. damaged mitochondria).

 

- Counteract nutrient-sensing pathways that promote ageing

Stimulation of certain anabolic signalling pathways, such as the mTOR and insulin/IGF-1 signalling pathways, are shown to enhance cell ageing.

In very general terms, FOXO3 acts to inhibit these pathways, thereby preventing ageing.  

 

KEY POINTS

  • FOXO3 switches on genes that promote: DNA repair, clearance of toxic, unfolded proteins, renewal of stem cells, recycling of damaged cell components, resistance to oxidative stress, and inhibition of metabolic/nutrient-sensing pathways linked to ageing.
  • By switching on these stress response genes, FOXO3 can help to minimise and protect against ageing-related cell damage.

 

What FOXO3 gene variants do you look at in this trait?

There are thought be around 40 SNPs (Single Nucleotide Polymorphisms) within the FOXO3 gene that are linked to longevity in various ethnic populations. Many of these SNPs are in strong linkage disequilibrium with another, meaning they are often inherited together.

One of the most widely studied SNPs, rs2802292, creates two FOXO3 gene variants/alleles: the ‘G’ allele and the ‘T’ allele.

It is the ‘G’ allele that is linked to longevity, with several studies demonstrating that is overrepresented in people aged 90 years old and over.

In your FOXO3 and longevity trait, you’ll find out whether you carry one, two, or no copies of the ‘G’ allele linked to longevity.

 

KEY POINTS

  • Your FOXO3 and longevity trait looks at the rs2802292 SNP, which creates two different FOXO3 variants: 'G' and 'T'.
  • The 'G' allele / variant is linked to longevity.
  • Other SNPs in the FOXO3 gene are often coinherited along with the rs2802292 SNP. Depending on what genetic data you have available, TrueTrait may analyse these linked (proxy) SNPs instead.

 

What do studies say about FOXO3 gene variants and human longevity?

Several studies into long-lived populations have found that they are more likely to carry the ‘G’ allele (rs2802292) of the FOXO3 gene compared to those with average lifespans.

One of the first studies to find this association was the Hawaii Lifespan Study, which followed the lives of roughly 10,000 Japanese-American men born between 1900 and 1919.

The researchers split subjects into two groups:

  • longevity cases - those who had survived past 95 years old (mean attained age = 97.9 years).
  • average-lived controls – those who died before 81 years old (mean attained age = 78.5 years).  

They then compared FOXO3 genotypes between the groups, to see if any particular genotype or allele was overrepresented.

The researchers found that longevity cases were 2.75 times more likely to have two copies of the ‘G’ allele (the GG genotype) compared to no copies (the TT genotype).

Furthermore, the ‘G’ allele was also linked to better overall health in older age, greater mobility, better insulin sensitivity, and lower prevalence of cardiovascular disease.

Subsequent studies, using a similar case-control methodology, have also supported an association between the ‘G’ allele and longevity.

A 2014 meta-analysis, which collated the findings of 11 individual studies, found that longevity cases (aged 90 years and above) were 1.36 times more likely to carry the ‘G’ allele compared to the ‘T’ allele. This is illustrated in the Forest plot below.

 

Source: Bao, J. M., Song, X. L., Hong, Y. Q., Zhu, H. L., Li, C., Zhang, T., ... & Chen, Q. (2014). Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis. Asian journal of andrology, 16(3), 446.

 

Further analysis suggests the ‘G’ allele has an ‘additive effect’ on longevity. This means that inheriting two copies of the ‘G’ allele (i.e. having the GG genotype) confers greater benefits for lifespan compared to inheriting just one copy (i.e. the GT genotype).

On this note, the meta-analysis found that longevity cases were 1.97 times more likely to have the GG genotype compared to the TT genotype, but only 1.38 times more likely to have the GT genotype.

 

KEY POINTS

  • The 'G' allele of the FOXO3 gene is overrepresented in long-lived populations (>90 years old) compared to average-lived populations.
  • Long-lived individuals are more likely to have the GG and GT genotypes compared to the TT genotype.
  • The GG genotype is more strongly linked to longevity compared to the GT genotype.

 

How does the ‘G’ allele (rs2802292) confer benefits for ageing?

It isn’t completely clear why the ‘G’ allele of the FOXO3 gene is linked to longevity. We know that the FOXO3 gene is involved in protective responses to cellular stress, all of which may help to prevent cell damage linked to ageing.

Studies in cell lines taken from ‘G’ allele carriers have found that the ‘G’ allele may result in the increased expression of FOXO3 in response to cellular stress.

The increased expression of FOXO3 may also underlie a “healthy ageing phenotype” whereby individuals are likely to maintain better physical and mental health into old age, and have a lower risk of age-related diseases.

On this note, a study which followed the lives of 3,584 older American men linked the ‘G’ allele to a 10% lower risk of death from any cause (all cause mortality), including a 26% reduced risk of coronary heart disease.

Another study in Danes aged 92-93 years old found that ‘G’ allele carriers had higher scores for activities of daily living and a lower risk of bone fractures. (This review paper is a good overview of other studies into the FOXO3 gene and longevity/healthy ageing).

It’s worth pointing out, however, that the beneficial effect of the ‘G’ allele is likely to vary between different ethnic populations and across the sexes. More specifically, the ‘G’ allele is shown to have less of a beneficial effect in women compared to men.

This may be because women tend to have longer lifespans than men, so the effect of a single gene variant is likely to be relatively weaker. In accordance with this, it has been hypothesised that the presence of oestrogen also enhances FOXO3 expression, meaning that the ‘G’ allele exerts relatively less influence on FOXO3 activity.

 

KEY POINTS

  • The 'G' allele may increase the expression of FOXO3 in response to cellular stress - helping to counteract ageing.
  • The 'G' allele may contribute to a "healthy ageing phenotype" characterised by better physical and mental health in older age.
  • The effect of FOXO3 on longevity and ageing is weaker in women compared to men.

 

Your FOXO3 and longevity trait

Your FOXO3 and longevity trait analyses several linked SNPs within the FOXO3 gene, including rs2802292.

Depending on your DNA results, you will be placed into one of three groups:

  • Increased – you have two copies of the ‘G’ allele (or other linked SNPs) associated with longevity. Your genotype is GG, which is overrepresented in long-lived (>90 years old) populations.
  • Moderately increased – you have one copy of the ‘G’ allele (or other linked SNPs) associated with longevity. Your genotype is GT, which is also overrepresented in long-lived (>90 years old) populations.
  • Average – you do not carry the ‘G’ allele (or other linked SNPs) associated with longevity. Your genotype is TT.

To find out your result, please login to Truefeed.

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