The Complex Relationship Between CRP and Longevity

CRP, short for C-reactive protein, is an important part of the immune system. It’s mainly made in the liver and released into the blood in response to injury, inflammation, and infection [R].

It works as a pattern recognition protein, which means that its job is to recognize and bind invading microbes and damaged or altered (i.e. cancer) cells. In essence, CRP tags microbes and defective cells for destruction so they can be cleared away by white blood cells [R, R, R]. 

Once the cause of the disturbance has been taken care of, CRP levels usually drop back to normal. However, when there’s chronic low-grade inflammation in the body, CRP levels remain slightly increased [R].

CRP’s main role is to tag microbes and damaged or altered cells for destruction. CRP levels increase in the short-term with injury, infection, and inflammation and decrease once the disturbance has been taken care of. CRP levels can remain slightly increased in those with chronic low-grade inflammation.

CRP and Heart Disease

Scientists have found that higher CRP levels can help predict the future risk of heart (cardiovascular) disease even in apparently healthy people [R, R, R].

You can read more about CRP levels and heart disease risk here.

There are several explanations for this. 

Firstly, we know that CRP levels increase in chronic inflammatory states, such as [R, R]:

• High blood pressure (hypertension)
• Obesity
• Diabetes
• Heart disease 

Secondly, CRP can also create inflammation on its own. Scientists have found that CRP can damage blood vessels by increasing the release of inflammatory molecules from white blood cells [R].

Finally, CRP can also directly inhibit insulin signaling and prevent blood sugar from entering the muscles, thereby increasing insulin resistance [R].

Scientists have found a link between higher CRP levels and heart disease. Elevated CRP indicates there’s chronic inflammation in the body. CRP can also damage blood vessels and increase insulin resistance. 

CRP and Longevity

After establishing CRP’s role in heart disease, scientists next looked at the link between CRP and longevity. They found that elevated CRP levels were associated with a higher chance of dying (all-cause mortality), especially due to heart disease (cardiovascular mortality) [R, R].

But when it comes to CRP gene variants and longevity, the story gets much more complex. 

Why is the relationship between CRP gene variants and longevity not straightforward?

For a start, there are many factors that may influence how well someone ages, and how long they can live. Genes likely 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 [R, R]. 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). 

Furthermore, studies suggest that there are many (over 100) 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 CRP is one such gene.

In addition, while we may be tempted to conclude that lower CRP levels are generally better based on the studies that looked at CRP blood levels. However studies that have looked at SNPs in this gene often disagree.

Most importantly, we know that lifestyle, dietary, and other non-genetic factors have a greater impact on CRP levels than genetic variants — which is why actual CRP levels in the blood are predictive when it comes to heart disease but CRP gene variants are not.

The takeaway here is that lifestyle, dietary, and other non-genetic factors are ultimately way more important when it comes to longevity than genes.

CRP gene is only one of a multitude of genes that each play a minor, modest role when it comes to longevity. Furthermore, CRP levels are influenced by lifestyle, dietary, and other non-genetic factors and not just genetic variants. That’s why the relationship between CRP gene and longevity is complex.

rs1205 and Longevity

Take for example a commonly-studied SNPs in the CRP gene, rs1205 (also known as the “1846 G>A” polymorphism). The ‘C’ allele has been linked with higher and the ‘T’ allele with lower CRP levels.

A small study looked at 284 Finish people over the age of 90, and found ‘T’ carriers, who in theory should have lower CRP levels, were more likely to live longer [R]. This was more or less expected.

This was supported by studies which found that:

• ‘T’ seemed protective for heart disease (a meta-analysis of 22 studies) [R]
• ‘C’ was linked to high blood sugar (a study of 945 siblings from 330 families) [R]
• Elderly with the ‘TT’ genotype were more likely to have multiple health conditions, compared to those with the ‘CC’ genotype (a study in over 1.7k Chinese aged 70-84 years) [R].

However, in another study of over 5k people, researchers found that having the ‘T’ allele was associated with [R]:

• A lower risk of death from heart disease over the next couple of years 
• A HIGHER risk of mortality that’s not associated with heart disease, particularly death from cancer.

They found this relationship in blacks but not in whites!

Furthermore, a study of over 3.7k older Australians found that those with the ‘T’ variant were more likely to be frail compared to those carrying the ‘C’ variant (and especially the ‘CC’ genotype) [R] — and frailty is a known enemy of longevity [R].

A meta-analysis of 21 studies with over 26k people found that the ‘TT’ genotype was associated with a slightly higher incidence of colon cancer, but lower incidence of breast cancer [R].

Scientists think that the ‘T’ variant, which is associated with lower CRP levels, may prevent the elderly from mounting an efficient immune response, which is why the ‘T’ variant has been associated with frailty and mortality that’s not due to heart disease [R, R].

According to some studies, the ‘T’ variant of the rs1205 SNP in the CRP gene has been associated with longevity and lower mortality due to heart disease. However, this variant has also been associated with frailty and higher mortality due to causes other than heart disease.

You can see your genotype for several CRP SNPs in the table below. However, remember that CRP 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!

CRP rs1205

• ‘T’ = Associated with lower CRP levels, longevity and lower heart disease mortality. However, it’s also been associated with higher mortality due to causes other than heart disease and frailty.
• ‘C’ = Associated with higher CRP levels and higher heart disease mortality. Has been associated with lower risk of frailty and lower mortality due to some types of cancer.

Every third person carries the ‘T’ allele (33%) (‘CT’ or ‘TT’ genotype). This allele is more common in East Asians (57%) and less common in Africans (17%).

CRP rs1800947

• ‘G’ = Associated with higher CRP levels and possibly higher mortality and heart disease. 
• ‘C’ = Associated with lower CRP levels. 

A study of over 900 people with heart failure found that the ‘G’ allele was associated with a higher risk of dying [R].

Similarly, in over 900 people with heart disease, the ‘GG’ genotype was associated with further adverse events during the three years of follow up [R].

However, there are also studies that didn’t find a link between this SNP and heart disease [R, R].

The ‘G’ allele is found in less than 3% of the population. It’s slightly more common in East Asians (6%) and Europeans (5%), and less common in Africans (0.2%). 

CRP rs11265263  

• ‘A’ = Associated with higher CRP and possibly increased mortality.
• ‘C’ = Associated with lower CRP levels.
• ‘T’ = Effect unknown.

In a single study of 900 people with heart failure, ‘A’ allele was associated with higher mortality risk [R]. 

‘A’ variant is found in 9% of people. It’s more common in East Asians (20%) and less common in Africans (1%). ‘T’ variant is extremely rare — less than 0.1% of people have it.