seniors exercising on beach 2048 x 1370

There is a famous research project, the Longevity Genes Project, at Albert Einstein College of Medicine, that is trying to uncover the genes which endow centenarians (people living to 100 years and older) with their prodigious lifespan. The project, led by Dr. Nir Barzilai, has so far enrolled over 500 Ashkenazi Jews. The reason for focusing on this ethnic cohort is their relative genetic homogeneity, which makes it easier to tease out information on rare genes out of the genetic background “noise”.

There are four “big killers” that account for most cases of mortality: cardiovascular disease (hypertension, atherosclerosis, congestive heart failure, myocardial infarction), diabetes, cancer, and cognitive decline. One gene, CETP, seems to be important in two of them: cardiovascular disease and cognitive decline (including Alzheimer’s Disease).


What is CETP?

This gene codes for the protein Cholesteryl Ester Transfer Protein. What it normally does is not very beneficial; it mediates the transfer of cholesterol from HDL particles (that’s the “good” cholesterol) to LDL (“bad” cholesterol), and, in exchange, it transfers triglycerides from LDL to HDL.

This is a double whammy because cholesterol on HDL is eliminated, whereas cholesterol on LDL is deposited in the wall of the blood vessels, causing atherosclerosis and its consequent cardiac effects. To add insult to injury, the transfer of triglycerides out of the LDL particles reduces their size, and small LDL is more injurious to the intima, or the endothelial layer of the vessel wall.

So how does CETP figure in longevity? The nucleotides of the gene code for the amino acids that make up CETP. Every gene contains two copies of the sequence called alleles. When the two alleles are identical, they are homozygous. And when the two alleles are different in some way, they are called heterozygous.

When there is a mutation in one of the nucleotides, the variability is called SNP (pronounce snip), or single nucleotide polymorphism. In normal CETP, the amino acid in position 405 of the sequence is isoleucine; in the SNP mutation, it is changed to valine (hence, V405). This innocent-looking change causes a profound change in the activity of the protein—downward; the homozygous V405 variant of CETP has a fraction of the non-mutated protein; the heterozygous has less of a reduction in activity. That’s how V405 CETP confers on its owner’s protection from cardiovascular disease. But there is more. A later publication by the Albert Einstein group found that the same SNP, V405, also confers on the homozygous protection from cognitive decline and an astounding 70% decrease in risk of Alzheimer’s Disease.

Before we go on, it should be emphasized that other markers found more frequently among the Super Agers include a variant of the APOE gene that protects against atherosclerosis and Alzheimer’s, a variant of the FOXO3A gene that protects against tumor formation and leukemia, and a variant of the APOC3 gene that protects against cardiovascular disease and diabetes. (This variant alone has been associated with an average life extension of four years.) Having long telomeres—regions at the ends of chromosomes that shorten as you age—is another kind of marker, acting as an instant-read longevity thermometer; the longer the telomeres, the longer the lifespan. Apparently, the biochemical mechanism that maintains the length of the telomeres is better in Super Agers than in us, normal mortals. There’s evidence, as well, that small stature among the Super Agers may reflect the influence of a protective factor seen throughout nature; ponies live longer than horses. So, who said size doesn’t matter?


Can we get around the CETP hurdle?

Most of us are not blessed with being homozygous CETP V405. So is the fix in? Not so fast.

It turns out that one of the most powerful non-pharmacological influences on the distribution of cholesterol in the blood is exercise. It shows a dose-related influence on increasing HDL-cholesterol and reducing LDL-cholesterol; the more vigorous and longer the exercise, the more pronounced is the effect on cholesterol. Thirty minutes of moderate exercise a day, five days a week, has a great beneficial effect on lipid profile in the blood. Increasing the intensity and/or the length of the exercise can add to the increase in the ratio of HDL/LDL.

Exercise has many other benefits such as cardiac, pulmonary, gastrointestinal, and even the brain. Can the effect of exercise counteract the curse of CETP on cognition and dementia? Probably not completely. It has been demonstrated that exercise increases problem-solving capacity and memory. It even elevates mood. But the evidence on the effect on dementia and Alzheimer’s disease is not yet in.


Is there a pill?

A specific inhibitor of CETP, Torcetrapib (who is in charge of naming these drugs?), together with Lipitor showed an unexpected 60% increase in mortality over Lipitor alone. The trial was terminated in Phase III, after an expenditure of over $800 million. Did that mark the end of the pursuit of specific CETP inhibitors? Not quite. Merck is still in phase III with its own drug.

But there is another drug, which is actually a vitamin—niacin, vitamin B3, or nicotinic acid (no, it’s not nicotine!). It increases HDL-cholesterol and decreases LDL-cholesterol; it even reverses the decrease in LDL particle size. It almost looks like a CETP inhibitor—in outcome, if not in actual mechanism. So what’s not to like? It causes a flush that can be very uncomfortable. There is a slow-release formulation, Niaspan, which markedly improves this side effect. So why aren’t physicians prescribing more of this drug? The short answer is always the same: Follow the money. Niacin, per se, cannot be patented, so the barrier to entry is low—anybody can get into the field at very low expense. And the profit margin is low. So why should any pharmaceutical company get into it when they can invent a CETP inhibitor and make a fortune on it? How big the potential profit is can be inferred from the ready willingness to risk the loss of $800 million on a failed study.

Still, why aren’t physicians prescribing the drug? The embarrassing answer is that most physicians rely on drug-industry information to keep up, and there is no financial incentive to push niacin.


There are no shortcuts

Niaspan is good as far as it goes. There is no evidence that it makes any difference in the risk of cognitive decline and Alzheimer’s disease. It does not have the effects on pulmonary function, GI health, and brain function that exercise has. So the conclusion is obvious, isn’t it?

Exercise, exercise, exercise!

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. Since my husband (Brian Klepper) began his struggle with high cholesterol, I have always thought that meds’ ridiculous names sound like some medieval story.

    Once upon a time, King Zocor and Queen Zetia ruled over the tiny kingdom of eastern Niaspan. One day they were attacked by an army of evil Lipitors who were in search of hidden treasures. But King Zocor called out his army of giant Vytorin warriors who crushed the Lipitors. The king bestowed the highest honor, the order of the Crestor, upon his army and they all lived happily ever after.

    Stay tuned for the story of the three headed Torceptrapib.

    PS Do taxane and carboplatin maybe sound like fossil fuels?


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