Can This Gene Influence your Lifespan? (CFH)

The immune system is essential to prevent diseases caused by invading microbes (pathogens). One of the ways it fights off infections is by promoting inflammation. Unfortunately, chronic or uncontrolled inflammation can have negative consequences on the body, and may even reduce lifespan!

For this reason, it’s important to fine-tune the immune system so that it’s only activated when needed. In this post, we will be looking at the CFH (complement factor H) gene, which can be a key player in inflammation by blocking some of the processes that trigger the immune response [R].

The Complement System

The immune system is a complex network with multiple pathways. One of them is called the “complement system” because it supports (or “complements”) the function of other immune components. The main functions of the complement system are to trigger inflammation and target pathogens for elimination by white blood cells [R, R].

The complement system can be activated in three different ways [R, R]:

• The “classical” pathway: activated when antibodies recognize pathogens
• The lectin pathway: activated when lectins recognize pathogens
• The “alternative” pathway: activates itself when its key component, C3, changes its structure, either spontaneously or in response to infections 

Although each of them is important to the immune system, CFH specifically blocks the “alternative” pathway.

In this pathway, C3 binds to another protein called factor B to form the enzyme C3 convertase. This enzyme converts inactive C3 into its two active forms [R, R]:

• C3a, a strong pro-inflammatory protein
• C3b, which enhances pathogen elimination by white blood cells and binds to factor B to produce more C3 convertase

C3 convertase also triggers the production of other pro-inflammatory and antimicrobial proteins (such as C4a, C5a, C5b, and membrane attack complex) [R, R].

What Does the CFH Gene Do?

The CFH gene encodes a key regulator also called CFH that blocks the alternative pathway. CFH reduces C3 convertase production through two mechanisms [R, R]:

• Preventing the binding of factor B to C3 and C3b
• Promoting the deactivation of C3b (by a protein called complement factor I)

Additionally, CFH blocks an activator of the alternative pathway: C-reactive protein (CRP) [R, R].

Overall, variants in the CFH gene determine its ability to block the complement system. How may this be important for longevity? Well, the immune system can contribute to diseases depending on how and when inflammation is triggered. 

Two ways by which chronic immune system activation can be harmful is by directly damaging the tissues or causing the build-up of immune system waste products. This may have an impact on your overall health and, ultimately, on your lifespan [R].

The CFH gene codes for complement factor H, a protein that blocks the activation of the “complement system”. This may protect the tissues from chronic inflammation, ultimately increasing lifespan.

Your CFH Results for Longevity

Because the CFH gene has a lot of known polymorphisms, most people will probably have a mix of variants that each increase or decrease the activation of the complement system. It’s therefore important to look at as many SNPs as possible to see which way you lean.

Additionally, polymorphisms in the CFH gene can have different effects in specific parts of the body. This is probably why some individual SNPs in this gene have been associated with various specific health conditions, as we will discuss below.

Nevertheless, all these conditions have been reported to involve the immune response in one way or another. Therefore, looking at these SNPs together may give you some insight into your overall immune system function.

You can see your genotypes for some select CFH SNPs in the table below. However, keep in mind that these results are based on association studies suggesting that certain genetic variants are relatively more common in people with certain health outcomes. More research will still be needed to know what role, if any, these variants may play in actually causing these health outcomes. Therefore, just because you have one of these genotypes does not necessarily mean you are at increased risk of developing one of the specific medical or health conditions, it has been linked to!

Primary SNP:

CFH rs1061170:

• ‘T’ = Relatively more common among longer-lived people.
• ‘C’ = Relatively less common among longer-lived people.

Population Frequency:

• Almost 56% of the world population has ‘TT’ (homozygous major).
• Only 0.6% of people with East Asian ancestry have ‘CC’ (homozygous minor).

Other Important SNPs:

CFH rs1061147:

• ‘C’ = Relatively more common among people with end-stage kidney damage. 
• ‘A’ = Relatively less common among people with end-stage kidney damage.

Population Frequency:

• 36% of the world population has one copy of each allele (the “heterozygous” genotype).
• 91% of East Asian descendants have ‘CC’.

Out of the above SNPs, the only polymorphism that has been directly associated with longevity is rs1061170. Almost 45% of the world population has at least one copy of its minor ‘C’ allele, which makes the CFH protein less able to block the complement system activator CRP (which could in turn contribute to increased overall immune system activity) [R].

The minor ‘C’ allele has been associated with reduced lifespan in a follow-up study on 90-year-olds. The authors of this study proposed that long-term hyperactivation of the immune system may end up reducing its ability to fight off infections (which can be especially dangerous in older age) [R].

Regarding this SNP’s links to death from heart disease, the results are mixed. One study in people above 85 years old reported an association of the minor ‘C’ allele with an increased mortality rate from heart disease [R]. However, while some studies found an increased frequency of heart disease in carriers of this allele, others found no association [R, R, R, R]. A meta-analysis even concluded that the ‘C’ allele may only be associated with higher blood triglyceride levels, rather than any direct effect on heart disease or lifespan itself [R].

Finally, a study associated the ‘C’ allele with increased mortality rates from strokes. According to this study’s authors, the resulting over-activation of the immune system may contribute to worse medical outcomes in stroke patients by damaging red blood cells and weakening the blood-brain barrier — each of which could worsen bleeding in the brain and make it harder for the brain to recover [R].

All in all, a number of studies provide suggestive evidence for this SNP’s association with overall lifespan, although more research will still be needed to figure out for sure what exact mechanisms might be responsible for producing these differences in longevity.

Kidney failure is a serious complication of many inflammatory diseases (such as lupus or Berger’s disease). If left untreated, it can lead to death.

The major allele (‘C’) of rs1061147 produces a version of the CFH protein less likely to bind to C3b and block the complement system. This allele was associated with end-stage kidney disease in older African Americans (roughly 60+ years of age, both diabetic and non-diabetic) [R].

Other polymorphisms in this gene (such as rs1061170, rs1065489, rs6677604, and rs800292) have been linked to increased chances of kidney damage from lupus, Berger’s disease, and diabetes [R, R, R, R, R, R]. However, their overall contribution to longevity based on their associations to these specific health conditions remains unclear, which is why we have not analyzed these SNPs here — but we will update this post as science uncovers more about these variants!

All in all, while this SNP has not been directly linked with longevity per se, some studies suggest that it may indirectly affect overall lifespan by increasing the risk of certain potentially serious health problems — especially in older age.