CETP, longevity, and brain health

What we know about CETP levels, genetic variants, and therapeutics

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the exchange of lipids, specifically cholesteryl esters and triglycerides, between lipoproteins like High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL). Lower CETP activity is linked to better cardiovascular health, whereas higher CETP activity can increase LDL-C levels, potentially contributing to plaque buildup.

Role of CETP in lipid metabolism. CETP mediates the transfer of cholesteryl ester (CE) and triglyceride (TG) between lipoproteins. The transfer of CE into apolipoprotein B–containing LDL particles contributes to the maturation of VLDL particles to more atherogenic, more readily oxidized LDL particles, which contribute to macrophage foam cell formation. ABCA1, ABCG1, and SR-BI mediate efflux of cholesterol out of the peripheral macrophage to nascent, pre-β HDL, which matures to larger HDL via the esterification of cholesterol by LCAT. CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-level density lipoprotein; LCAT, lecithin: cholesterol acyltransferase; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. Citation: https://doi.org/10.1038/clpt.2011.271

CETP genetic variants are linked with lower CETP activity, lower risk of heart attack, and lower LDL cholesterol (bad cholesterol).

CETP and longevity

These genetic variants are also associated with living past 100 (centenarians) according to a study published by Dr. Nir Barzalai and colleagues. People who had two copies of the CETP gene with a one letter difference occurred in 24.8% of centenarians compared to 8.6% among controls.

If you’d had whole genome sequencing analysis with NeuroAge, you can find out if you have the CETP longevity variant in your genetic resilience dashboard.

CETP and brain health

A separate study in an Ashkenazi Jewish population showed that people without dementia were 5X more likely to have this genetic variant than people with dementia. Studies in other populations had mixed results for association of dementia with this variant^10–14.

This is yet another link between heart health and brain health. Many of the genes involved with cardiovascular health are also associated with less dementia risk.

CETP therapeutics

Clinical trials for CETP inhibitors, which increase HDL and lower LDL and ApoB, have been ongoing since 2006. Early trials of various CETP inhibitors (Torcetrapib, Dalcetrapib, Evacetrapib, Anacetrapib) for cardiovascular disease failed due to adverse events or were discontinued due to lack of superior efficacy compared with statins.

Obicetrapib, a newer, highly potent CETP inhibitor designed to overcome the limitations of previous compounds is currently in phase 3 clinical trials.

CETP inhibitors are also being explored for other indications. A meta-analysis of clinical trials showed that they can significantly reduce the incidence of new-onset diabetes. They are also being tested in combination with SGLT2 inhibitors to improve glycemic control.

Preclinical studies in mice suggest that CETP inhibition, by modulating cholesterol distribution in the brain, may affect brain health. Obicetrapib is being investigated for this application.

How to decrease your CETP levels

Apparently, CETP levels are lower in alcoholics according to a few studies. This does not seem to be the case for moderate drinking though so I would not recommend drinking in excess to lower CETP.

I was not able to find any randomized control trials of supplements or other interventions that measured CETP levels.

It seems that until the next generation of CETP inhibitors are available, the best way to lower CETP levels is through a heart healthy diet and exercise.