Does This Cholesterol-Related Gene Affect Lifespan? (APOC1)

The APOC1 gene is named after the protein it codes for — apolipoprotein C-I (or just “apoC-1” for short). The apoC-1 protein belongs to the apolipoprotein C family of proteins, which all play a role in regulating cholesterol and fat in the body [R].

There is some evidence that certain variations in the APOC1 gene are associated with longevity. According to some researchers, these genetic variants may contribute to a longer lifespan by preventing several common age-related health conditions such as heart disease, stroke, and Alzheimer’s disease [R, R].

The apoC-1 protein has several mechanisms, and not all of them are fully understood. In general, apoC-1 helps regulate the activity of lipoproteins, which are proteins that are responsible for transporting cholesterol and fat around the body [R].

We’ll go into detail about some of these mechanisms in the following sections.

Blocking Lipoprotein Receptors

Lipoproteins, such as LDL and VLDL, carry cholesterol and fat through the bloodstream. These lipoproteins have corresponding receptors, such as the LDL receptor (LDL-R) that they can bind to. Once attached to these receptors, these lipoproteins are removed from the blood, which will also remove cholesterol and fat from the bloodstream [R, R].

One of the main functions of apoC-1 is blocking the binding of lipoproteins to their respective receptors, including LDL-R, VLDL-R, and LRP. By inhibiting these receptors, the lipoproteins remain in the bloodstream. The end result is that increased apoC-1 activity leads to increased cholesterol and fat levels in the blood [R, R].

The apoC-1 protein works by blocking lipoprotein receptors, ultimately increasing cholesterol and fat levels in the blood.

Effects on Lipoprotein Enzymes

The protein apoC-1 increases the activity of an enzyme called lecithin–cholesterol acyltransferase (LCAT). This enzyme facilitates the conversion of cholesterol into cholesteryl ester, a more transportable form of cholesterol. This ultimately promotes the movement of cholesterol in the body [R, R].

On the other hand, apoC-1 reduces the activity of cholesteryl ester transfer protein (CETP), which is responsible for moving cholesteryl ester to different lipoproteins. Reducing the activity of CETP may result in reduced cholesterol elimination, increased HDL levels, and decreased LDL levels [R, R].

The apoC-1 protein also changes the activity of enzymes like LCAT and CETP, which can have various effects on cholesterol metabolism.

Effects In the Brain

There’s some evidence that apoC-1 has specific effects on the immune system in the brain. More specifically, apoC-1 activity may help suppress immune system activity by reducing the expression of cytokines, including TNF-α and IL-6 [R].

According to some researchers, this suppression of cytokines may help prevent the formation of amyloid plaques, which are thought to be a major contributor to Alzheimer’s disease [R].

The apo-C1 protein may help suppress immune system activity in the brain.

Research shows there may be a potential link between the APOC1 gene and longevity. According to researchers, certain genetic variants in APOC1 may extend lifespan by preventing age-related diseases, such as cardiovascular disease and Alzheimer’s disease [R].

The Research

Multiple genome-wide studies looking at the APOC1 gene have reported that the ‘AA’ (homozygous major) genotype for rs4420638 is significantly more common in those who live exceptionally long lives. However, one important limitation is that these studies have only found this association in Caucasian and European groups — so it remains an open question whether this effect carries over to other ethnic populations as well [R, R, R, R].

Another study reported that the SNP at rs56131196 may also be associated with longevity. In this study, the ‘GG’ (homozygous major) genotype was found to be more common in those that live to 80 years or older. However, this finding is also based on data from Caucasian and European groups, and additional studies will be needed to verify the effect of this genotype in other populations [R].

Finally, according to a different study, the ‘AA’ genotype for rs445925 is more common in Chinese people with longer lifespans. However, this is dependent on individuals having specific genotypes at 9 other nearby SNPs in a region known as the TOMM40/APOE/APOC1 region, which we’ll discuss in more detail in the next section [R].

Several SNPs in APOC1, including certain variants at rs4420638, rs56131196, and rs445925, are associated with longevity — but only in certain ethnic groups.

Relation To Other Genes

The APOC1 gene is located closely next to two other genes: TOMM40 and APOE. Because of their close proximity, genetic variations in these genes are often inherited together. These genes are usually referred to collectively as the TOMM40/APOE/APOC1 region [R].

These genes also have similar associations, with all three being linked to cholesterol levels, Alzheimer’s disease, and longevity. Studies show that their associations are sometimes affected by one another [R, R].

For example, as previously mentioned, certain genotypes for rs445925 in the APOC1 gene may be associated with longevity only when specific alleles are present at TOMM40 and APOE [R].

Genetic variations in APOC1 are often inherited together with certain variants in two other nearby genes — TOMM40 and APOE.

You can see your genotypes for these three APOC1 SNPs in the table below. However, keep in mind that these associations are based on studies from certain ethnic populations, so you should interpret your results with caution if you are not descended from one of these specific groups!

Primary SNP:

APOC1 rs4420638:

• ‘AA’ (homozygous major) = More common in those who live exceptionally long lives
• ‘AG’ / ‘GG’ = No association with longevity
• About 72% of people have the ‘AA’ genotype
• The association between the ‘AA’ genotype and longevity has so far only been reported in certain Caucasian and European groups

Other Important SNPs:

APOC1 rs56131196:

• ‘GG’ (homozygous major) = More common in those who live exceptionally long lives
• ‘AG’ / ‘AA’ = No association with longevity
• About 73% of people have the ‘GG’ genotype
• The association between the ‘GG’ genotype and longevity has so far only been reported in certain Caucasian and European groups

APOC1 rs445925:

• ‘AA’ = More common in those who live exceptionally long lives
• ‘AG’ / ‘GG’ = No association with longevity
• About 3% of people have the ‘AA’ genotype
• The association between the ‘AA’ genotype and longevity has so far only been reported in certain Chinese groups