Longevity, Immunity, and IL6

Interleukin-6 (IL-6) is a cytokine — a signaling molecule released by cells to interact and communicate with other cells, mainly those of the immune system. As such, IL-6 plays important roles in the immune response. Research shows that, depending on the situation, IL-6 can have either pro- or anti-inflammatory properties [R].

Being on the crossroads of both pro- and anti-inflammatory pathways, it’s really important for IL-6 levels to be balanced. Studies suggest that having low IL-6 levels may impair immune function and may make people more vulnerable to infections. High IL-6 levels, on the other hand, have been linked to chronic inflammation and inflammatory disease [R].

In the absence of infection or inflammation, the activity of the IL6 gene is low and IL-6 levels are not normally detectable in the blood. However, scientists have discovered that IL6 gene activity and blood IL-6 levels gradually increase as we age [R, R].

There are studies that suggest that this age-related increase in IL-6 may be associated with chronic inflammation — a process called “inflammaging” — which may possibly contribute to the physical and mental decline that can come with aging [R, R].

IL-6 is involved in immune system function, and can be both pro- or anti-inflammatory. Baseline levels of IL-6 are low, but gradually increase with age. Studies suggest that higher levels of IL-6 may be associated with age-related physical and mental decline.

There are many factors that may influence how well someone ages, and how long they can live. As it turns out, genes may only have a relatively small effect on overall longevity! For example, it is estimated that less than 10% of the variation in human lifespan is determined by genetics — and which genes, and exactly how they contribute to longevity, are not yet well-understood [R, R]. Furthermore, this 10% refers to the population level and doesn’t apply to any single person as an individual: in other words, just because you may have a “bad” genetic variant does not mean your lifespan will get reduced by 10% (and that’s 10% of the variance between lifespans, not 10% of a human lifespan). The takeaway here is that lifestyle, dietary, and other non-genetic factors are ultimately way more important when it comes to longevity than genes — so at the end of the day, your best bet for living a longer life is to focus on the factors that you can control!

When it comes to the genetic aspects of longevity, studies suggest that there are many genes associated with lifespan. However, any single one of these genes generally plays only a very modest and limited role in the overall picture — and IL6 is one such gene.

In addition to its relatively minor contribution, the relationship between IL6 and lifespan is not a simple one. While we may be tempted to conclude that lower IL-6 levels are generally better based on the studies that looked at IL-6 blood levels, studies that have looked at SNPs in this gene and longevity suggest otherwise.

According to research, genetic factors may be responsible for about 10% of individual differences in longevity. In addition, IL6 is only one of many genes that each play minor, modest roles in determining overall longevity — so make sure to take your results for any single gene or SNP with a grain of salt!

rs1800795 and Longevity

Take for example one of the most commonly-studied SNPs in the IL6 gene, rs1800795 (also known as the “−174 G>C” polymorphism). The ‘G’ allele of this SNP has been linked with higher levels of IL-6, while the ‘C’ allele has been associated with lower IL-6 levels.

A meta-analysis found that it was in fact the ‘G’ allele that may be associated with exceptional longevity (>85 years), although the size of these effects were relatively modest [R].

Similarly, in a Danish study, scientists found that the ‘GG’ genotype was relatively more common in the very oldest of old people, which led these researchers to suggest that this genotype may somehow be advantageous for longevity [R].

It’s important to point out that studies often disagree when it comes to this SNP, as there are also studies which have reported that the ‘C’ allele is more advantageous in certain populations. Furthermore, other studies have found no association between IL6 and longevity at all [R, R, R, R].

It’s therefore plausible that different alleles may be beneficial in different settings and populations, depending on other genetic and non-genetic factors. That’s why you should take the association of IL6 with longevity as tentative and with a grain of salt.

Several studies suggest that the major ‘G’ allele of rs1800795 may be associated with longevity, but the overall evidence is still somewhat weak.

A Complex Relationship

Scientists suggests that for successful aging there needs to be a balance between pro- and anti-inflammatory processes. For example, aging is accompanied by both a decline in immune function (“immunosenescence”) and an increase in chronic low-grade inflammation (“inflammaging“) [R]. IL-6 is a good example of a factor that can influence both.

It is plausible that higher or lower baseline IL-6 levels interact with various genetic and environmental cues in different populations to differentially impact longevity. For example, higher IL-6 activity may protect against infections and may keep the immune system in better shape, while lower IL-6 activity may decrease inflammation and “inflammaging”. Which of these is more beneficial may depend on the lifestyle and other genetic and environmental factors of the population in question. However, it’s all conjecture at this point.

What we do know is that when it comes to rs1800795, both the ‘G’ and the ‘C’ alleles have their relatively advantages and drawbacks. For example, some studies suggest that the ‘C’ allele is associated with obesity, diabetes, blood clots, hardening of the arteries (atherosclerosis), and heart disease [R, R, R, R, R, R]. The ‘G’ allele, on the other hand, is linked to inflammatory conditions such as periodontitis (inflammation of the gums) and rheumatoid arthritis [R, R, R].

At this point in time, there isn’t enough evidence to draw any solid conclusions. Larger and more comprehensive studies will be needed to clarify the link between IL6 and longevity.

Successful aging requires a sensitive balance between pro- and anti-inflammatory processes. It’s possible that’s where IL6 comes into play. However, there isn’t enough evidence yet to draw any solid conclusions.

You can see your genotype for several IL6 SNPs in the table below. However, remember that IL6 is only one of many genes that together influence longevity, and that its effects are modest at best. It’s also important to keep in mind that these results are based on association studies suggesting that certain genetic variants are more common in people with longer lifespans. However, more research will be needed to know what role, if any, these variants play in directly causing certain people to live longer — so take these results with a grain of salt!

IL6 rs1800795:

• ‘G’ = Higher IL6 gene activity (expression) and circulating IL-6 levels. May be beneficial for longevity.
• ‘C’ = Potentially lower IL6 activity (expression) and circulating IL-6 levels. Possibly disadvantageous for longevity.

About 23% of people in the world carry the minor ‘C’ allele for this SNP. This variant, however, is much more common in Europeans, where the majority of people (69%) carry the ‘C’ allele.

IL6 rs2069837:

• ‘A’ = Higher IL6 gene activity (expression) and circulating IL-6 levels. Potentially beneficial for longevity.
• ‘G’ = Lower IL6 activity (expression) and circulating IL-6 levels. Potentially disadvantageous for longevity.

A study found that the minor ‘G’ allele was less frequent among Chinese who were over 100 years old [R].

About 22% of people carry the minor ‘G’ allele, which is slightly more common in Asians.

IL6 rs2069827:

• ‘G’ = Unknown effect on IL6 gene activity. Potentially less advantageous for longevity.
• ‘T’ = Unknown effect on IL6 gene activity. Potentially beneficial for longevity.

One study suggests that old people with the ‘T’ allele (‘TT’ and ‘GT’ genotypes) may live slightly longer on average (around 0.7 years) [R].

Less than 7% of people in the world carry the minor ‘T’ variant, which is more common in In Europe (21%).