Is This Triglyceride Gene Related To Lifespan? (APOC3)

The APOC3 gene plays an important role in cholesterol management by coding for a protein called apo-CIII (short for apolipoprotein C-III). This apo-CIII protein is responsible for inhibiting several enzymes that help break down triglycerides [R].

Studies have found that certain genetic variants of APOC3 are much more common in people who have exceptionally long lifespans. According to some researchers, these gene variations may improve longevity by improving cardiovascular health [R].

Blocking Triglyceride Removal

Triglycerides are a type of fat that the body uses to store energy. There are several enzymes in the body that break down and remove triglycerides from the blood, such as lipoprotein lipase (LPL) and hepatic lipase (HL). These enzymes are important because high triglyceride levels in the blood can lead to atherosclerosis, a buildup of plaque in the arteries [R].

The main function of apo-CIII is to inhibit these enzymes, including LPL and HL. This means that apo-CIII activity ultimately leads to increased triglyceride levels in the blood. On the other hand, research shows that reduced apo-CIII activity can result in lower triglyceride levels [R, R].

The protein apo-CIII inhibits enzymes that eliminate triglycerides from the blood, ultimately leading to higher triglyceride levels.

Other Effects

There is some evidence that apo-CIII may have several other mechanisms, all of which appear to also promote atherosclerosis. These other potential effects include [R]:

• Promoting the adhesion of monocytes to endothelial cells, essentially making the wall of the blood vessels “stickier” and more prone to form plaque
• Increasing the concentration of platelets, which normally play a role in blood clotting
• Disrupting the activity of HDL, which may prevent its normally beneficial effects

Connecting Longevity and APOC3

How exactly does APOC3 affect longevity? So far we’ve discussed how apo-CIII activity may lead to atherosclerosis by increasing triglyceride levels. Atherosclerosis, in turn, is a strong risk factor for the development of cardiovascular diseases, like heart attack and stroke [R].

According to some researchers, certain genetic variants in APOC3 that reduce the activity of apo-CIII may improve longevity by protecting against atherosclerosis and potentially preventing deadly cardiovascular diseases [R, R].

This is supported by research looking at rare mutations that result in a loss-of-function in the APOC3 gene. Researchers found that these genetic variants result in lower triglyceride levels and are associated with lower rates of heart disease [R, R].

Certain genetic variants of APOC3 reduce the activity of apo-CIII, which may improve longevity by potentially protecting against atherosclerosis.

Supporting Evidence

There are two main types of research that support the association between APOC3 and longevity. The first type consists of longevity research that directly compares the frequency of APOC3 genotypes with lifespan. The second type of research looks at the association between cardiovascular disease and APOC3, which may serve as an indirect marker for longevity.

In the following sections, we’ll go further into these two types of studies. We’ll also discuss the conflicting evidence that questions the connection between the APOC3 gene and longevity.

Longevity Studies

Currently, there is only one study that directly compares APOC3 genotypes with lifespan. This study looked at the SNP rs2542052 and compared 429 Ashkenazi Jews (a group that originates from Eastern Europe) with control groups. The results suggest that the ‘CC’ genotype may be more common in people who live past 100 years old [R].

The ‘CC’ genotype at rs2542052 may be associated with a longer lifespan in certain Jewish groups.

Cardiovascular Studies

There are a number of studies that associate certain genetic variants of APOC3 with cardiovascular disease, especially stroke. Stroke is an important example because it is associated with poor long-term outcomes and increased risk of death [R].

One study of 895 stroke patients suggests that both the ‘CC’ genotype in rs5128 and the ‘TT’ genotype in rs4520 may be associated with a greater frequency of strokes. However, these associations were only found in women from a Northern Han Chinese population [R].

According to a different study of 812 stroke patients, the ‘CC’ genotype in rs2854116 may be associated with higher rates of stroke as well. This evidence is also based on a Northern Han Chinese population, but this association was found in both men and women [R].

Specific genetic variants in rs5128, rs4520, and rs2854116 may be associated with lower rates of stroke in certain Chinese groups.

Conflicting Evidence

Not all research supports the link between APOC3 and longevity. For example, one study looked at 749 American Caucasians who have exceptionally long lifespans and found no association between rs2542052 and longevity [R].

There is also conflicting research when it comes to cardiovascular studies. A meta-analysis of 79 studies looked at the link between stroke and APOC3, along with many other related genes. According to the researchers, the SNPs rs4520, rs5128, and rs2854116 all have no association with stroke [R].

There is research that suggests there may be no connection between APOC3 and longevity.

Primary SNP: 

APOC3 rs2542052:

• ‘CC’ (homozygous minor) = More common in those that live exceptionally long lives
• ‘AC/AA’ = No association with longevity
• About 21% of people have the ‘CC’ genotype
• The association between the ‘CC’ genotype and longevity has so far only been reported in certain Jewish groups

Other Important SNPs:

APOC3 rs5128:

• ‘CC’ (homozygous major) = More common in those that have experienced a stroke
• ‘GC/GG’ = No association with stroke
• About 60% of people have the ‘CC’ genotype
• The association between the ‘CC’ genotype and stroke has so far only been reported in certain Chinese women

APOC3 rs4520:

• ‘TT’ (homozygous minor) = More common in those that have experienced a stroke
• ‘CT/CC’ = No association with stroke
• About 18% of people have the ‘TT’ genotype
• The association between the ‘TT’ genotype and stroke has so far only been reported in certain Chinese women

APOC3 rs2854116:

• ‘CC’ (homozygous major) = More common in those that have experienced a stroke
• ‘TC/TT’ = No association with stroke
• About 31% of people have the ’CC’ genotype
• The association between the ‘CC’ genotype and stroke has so far only been reported in certain Chinese groups