December 29, 2006
CETP Gene Variant Slows Brain Aging

A variation in the enzyme cholesterol ester transfer protein (CETP) slows general aging and brain aging.

ST. PAUL, Minn -- A gene variation that helps people live into their 90s and beyond also protects their memories and ability to think and learn new information, according to a study published in the December 26, 2006, issue of Neurology, the scientific journal of the American Academy of Neurology.

The gene variant alters the cholesterol particles in the blood, making them bigger than normal. Researchers believe that smaller particles can more easily lodge themselves in blood vessel linings, leading to the fatty buildup that can cause heart attacks and strokes.

The study examined 158 people of Ashkenazi, or Eastern European, Jewish descent, who were 95 years old or older. Those who had the gene variant were twice as likely to have good brain function compared to those who did not have the gene variant. The researchers also validated these findings in a group of 124 Ashkenazi Jews who were between age 75 and 85 and found similar results.

"It's possible that this gene variant also protects against the development of Alzheimer's disease," said study author Nir Barzilai, MD, the director of the Institute for Aging Research at Albert Einstein College of Medicine in Bronx, NY.

Work is underway to develop a drug that emulates the effect of this life-extending version of the CETP gene. But I'd much rather get a gene therapy that'd enhance my liver cells to express the genetic variant for CETP that slows aging.

I've long thought the liver a key target for slowing whole body aging because it regulates blood lipid, lipoprotein, and cholesterol levels. This CETP gene variant (called CETP VV) is likely just one of many genetic variations waiting to be found that are expressed in the liver and can raise life expectancy. Another example genetic variation with life extending capabilities is Apolipoprotein A-I Milano high density lipoprotein (Apo A-I Milano HDL for short) clears out artery plaque and would also be a very beneficial gene with which to enhance one's liver.

Since livers age and become cancerous what we need are genetically engineered youthful replacement livers. The maximum benefit way to extend one's life through liver genetic engineering would be to grow a youthful replacement liver that has beneficial genes added. We can not do this yet. But in 10 or 20 years we should be able to take some existing liver cells, select out cells that have the least amount of accumulated DNA aging damage, do gene therapy on those cells in culture, then grow the cells up into a replacement liver. Next swap out your aged liver for a genetically enhanced younger liver. Your blood lipids will get changed by the new liver to slow the aging of your brain and body.

Seniors who have the CETP VV genetic variant have higher odds of reaching 100 years lower odds of developing dementia.

Led by Dr. Nir Barzilai, director of the Institute for Aging Research at Einstein, the researchers examined 158 people of Ashkenazi (Eastern European) Jewish descent who were 95 or older. Compared with elderly subjects lacking the gene variant, those who possessed it were twice as likely to have good brain function based on a standard test of cognitive function.

Later the researchers validated their findings independently in a younger group of 124 Ashkenazi Jews between the ages of 75 and 85 who were enrolled in the Einstein Aging Study led by Dr. Richard Lipton. Within this group, those who did not develop dementia at follow up were five times more likely to have the favorable genotype than those who developed dementia.

Dr. Barzilai and his colleagues had previously shown that this gene variant helps people live exceptionally long lives and apparently can be passed from one generation to the next. Known as CETP VV, the gene variant alters the Cholesterol Ester Protein. This protein affects the size of “good” HDL and “bad” LDL cholesterol, which are packaged into lipoprotein particles. Centenarians were three times likelier to possess CETP VV compared with a control group representative of the general population and also had significantly larger HDL and LDL lipoproteins than people in the control group.

People with the CETP VV variant had more HDL cholesterol and bigger particles in their blood.

The genetic variation causes people to produce less of a protein called cholesterol ester transfer protein (CETP). Barzilai says that CETP has two functions: it helps move cholesterol from the arteries to the liver, and it helps control the size of cholesterol particles circulating in the blood. People with the protective gene variant have higher levels of "good" HDL cholesterol and also produce bigger cholesterol particles, which scientists believe may not stick to blood-vessel walls as easily as small particles do.

CETP is on one of the 3 pathways that transfer cholesterol from HDL particles in the blood into the liver. So CETP is involved in regulating the amount of cholesterol in the blood.

Plasma high density lipoprotein (HDL) levels show an inverse relationship to atherogenesis, in part reflecting the role of HDL in mediating reverse cholesterol transport. The transfer of HDL cholesterol to the liver involves 3 catabolic pathways: the indirect, cholesteryl ester transfer protein (CETP)–mediated pathway, the selective uptake (scavenger receptor BI) pathway, and a particulate HDL uptake pathway. The functions of the lipid transfer proteins (CETP and phospholipid transfer protein) in HDL metabolism have been elucidated by genetic approaches in humans and mice. Human CETP deficiency is associated with increased HDL levels but appears to increase coronary artery disease risk.

Each tweak on genes causes many effects. CETP modification might or might not be the most effective way to improve blood lipids and slow brain and body aging. We might eventually find that CETP VV has side effects that are undesirable and that ApoA-I Milano will accomplish the same beneficial effects without some undesirable side effects. Or we might find CETP VV is better than ApoA-I Milano or some other genetic variants not yet discovered are better than either of them. Or maybe ApoA-I Milano and CETP VV work together synergistically to slow aging even more.

In mice genetically engineered to contain a human form of CETP a high fat high cholesterol diet turned up production of liver CETP from the CETP gene.

In three lines of transgenic mice the tissues expressing the human CETP mRNA were similar to those in humans (liver, spleen, small intestine, kidney, and adipose tissue); in two lines expression was more restricted. There was a marked (4-10-fold) induction of liver CETP mRNA in response to a high fat, high cholesterol diet. The increase in hepatic CETP mRNA was accompanied by a fivefold increase in transcription rate of the CETP transgene, and a 2.5-fold increase in plasma CETP mass and activity.

Brain rejuvenation is going to be the hardest rejuvenation task to accomplish. Anything that slows down brain aging is doubly beneficial. First off, your brain will function at a higher level longer during your working career and into retirement. That makes for better success at work and a happier life all around. Also, since the brain is going to be the hardest organ to rejuvenate we need to preserve it longer while we wait for effective brain rejuvenation biotechnologies.

More generally, while we desperately need therapies that do repair and replacement of aged parts we should not ignore the benefits and potential of slowing the aging process. Liver genetic engineering as an approach to slow the aging process is appealing because it looks much easier to do than full body gene therapy. If liver genetic engineering could buy us one or two decades of additional life that might be just the time we need to live long enough to still be alive when full body rejuvenation becomes possible.

Share |      Randall Parker, 2006 December 29 12:06 PM  Aging Brain Genetic Studies


Comments
rsilvetz said at December 29, 2006 6:20 PM:

As I am fond of pointing out, it's not your cholesterol or your lipids that are the issue. The biggest issue is whether or not you are inflamed. If you are NOT inflamed, high cholesterol will do butkus, won't injure you, and probably will prevent cancer in you because peroxidized lipids are selectively toxic to cancer cells. Hand in hand with that, if your homocysteine levels are on the floor, you will not get heart disease regardless of your cholesterol level.

Since NO studies of cholesterol lowering drugs have ever bothered to correct for inflammation or measure for it, we are in the crazy situation of trying to correct a secondary and not-too-important variable by CoQ10-depleting, congestive-failure-inducing statins. If you thought cox-inhibitor class actions lawsuits were big, wait till the wave of heart-induced failure from statins hits...

And yes, you will live longer if you are not inflamed. Chronic inflammation has immense, off-the-chart correlation, with weird and funky transpositions in the DNA... which invariably destroy function and certainly lead either to heart disease or cancer, depending on which chaotic attractor you are in.

I would love to know if this gene variant is associated say with low TNF production, or with more powerful inflammation-stopping mechanisms...

carl said at December 30, 2006 12:04 PM:

rsilvetz -

I wish you were a little less glib with your comments here. Although cholesterol lowering drugs do deplete coq10, unless I'm remembering completely wrong the statin data includes survival numbers, not just cholesterol lowering numbers. That doesn't mean that other alternatives aren't a better choice in a lot of cases, and it doesn't mean that you shouldn't supplement with coq10 -- you should anyway IMO -- but if you have a persistent cholesterol problem the data suggest you take statins.

There is a lot of talk about inflammation and the cycle between inflamation and oxygen radicals (e.g., on the lef site) but I'm not sure about the strength of these claims. I don't discount them -- and I take a lot of lef supplements aimed at these targets -- but I don't think the science is as clear as you seem to think. I'd be overwhelmed with gratitude if you could fill in the missing data for me.

When you say "Chronic inflammation has immense, off-the-chart correlation, with weird and funky transpositions in the DNA" what exactly are you referring to?

I think it's also worth pointing out that in the study in question the gene variant led to less dementia. So I'm not sure why the fact that this involves cholesterol is an argument against the impact of the gene rather than an argument for the role of cholesterol.

Fly said at December 31, 2006 3:17 PM:

The gene-engineered cells might die-off and the treatment would need to be repeated periodically. Gene engineering could interfere with other liver cell functions either because the DNA is inserted in a harmful place or because expression of the new gene interfered with other molecular pathways. (E.g., extra microRNA production could block the DICER processing of liver microRNA’s.)

As an alternative, genetically engineered bacteria could be grown in microcapsules that allowed the inflow of nutrients and outflow of wastes and desired biomolecules. It should be easier to optimize the product levels. The capsules could be easily removed or replaced. The microcapsules could be placed directly in the tissues where the enhancement is desired. (E.g., in specific brain regions for increased neuron generation.)

It might be costly to genetically engineer each person’s unique liver cells and the side effects might be difficult to predict. The microcapsules should work in all people and should be far cheaper.

The microcapsules could be used in conjunction with rejuvenated organs.

rsilvetz said at December 31, 2006 3:57 PM:

Carl -- Two seperate issues:

Issue 1- I'm not saying this gene isn't good. I think it's great that we are identifying important nexi in the DNA to start modifying ourselves to live longer. Identification of these genes is a crucial first step. Kudos to the researchers. Thanks to Randall for keeping us upto date.

Issue 2 - Subtext of the post is about cholesterol. Well cholesterol is mostly irrelevant. It's not causal. It's a symptom. Cholesterol rises if your simple carb/insulin system is out of whach. Period. End of story. To treat a symptom and not causal factor of disease is to throw away the primary achievement of Western Medicine: That diseases have causes and you have to remove the cause to cure a disease. To not do so when the cause is known is criminal.

I'm not being glib.

It is categorically wrong to ascribe to cholesterol the causation of heart-disease.

The homocysteine and inflammatory causes of heart disease are clear in the literature. To treat a number (cholesterol level) as something causal regarding heart disease, is absurd medically. To create a drug that induces congestive heart failure as its ultimate outcome (unless you get enough CoQ10) and not warn the users is criminal. Kudos to Canadian FDA forcing the CoQ10 issue. Watch and wait for the class action lawsuit here in the U.S.

And yes, the science is damn well there. I'm not going to review it for the nth time. You can find a big chunk of it at lef.org. It is mind-numbing to me that my erstwhile medical brethren discuss "angels on the head of pin" e.g. statin types and benefits, while missing the whole big picture right under their noses and has been there in various levels of certainty from 1960-onwards. Understand this - 100% of the people on statins for heart disease die of the heart disease they have. They just live a little longer. This is an improvement of the same kind as moving from 5-yr survival curves to 6-yr survival curves in cancer. It's criminal when the obvious therapy should be as below:

What should be happening is aggressive conversion to fish/vegetarianism for these people. Lots of excersize with glutamine supplementation. Statins short-term with CoQ10 supplementation. Aspirin 80 mg BID. Every known TNF and NF-Kb suppressor should be aggressively used. Massive homocysteine lowering doses of TMG, B12,B6, carnosine, carnitine should not hesitated to be used. Even the slightest hint of metabolic syndrome attacked. Additionally, Japanese docs routinely use LDL-apheresis to remove plaque. It works almost 100% of the time. Instead of fem-pop grafts for peripheral vascular disease, those sturdy enough to take LDL-apheresis clear out their lower vasculature (and heart!). We should be doing the same here.

And for folks that have real issues with their heart vessels, move to the Brazilian laser therapy, 100 zaps into the heart to form 100 seperate auxillary chanels. Then do all the above.

Have a Great New Year Everyone. Party TIME!

Randall Parker said at December 31, 2006 3:58 PM:

Fly,

I'm assuming a method for inserting genes into the genome that does not cause damage. Otherwise the risk of cancer would be too high to make gene therapy safe.

I'm also assuming we will get down the cost of gene therapy and of organ growing. Think robotics.

Fly said at January 1, 2007 2:40 PM:

Randall,

I’m imagining a future where new genetic advances are made every year. Should we be tinkering with the cell genome for each separate enhancement? The genetic modifications would be made to only a fraction of the cells. Controlling what fraction of the cells had a specific modification might be difficult over many years. After a decade a person might have an unpredictable mishmash of modified cells.

Another approach would be to rejuvenate the existing cells. Take a tissue sample and create a stem cell culture. Correct the accumulated damage and inherited genetic flaws and reset the epigenetic factors. Use the repaired and rejuvenated stem cell culture to gradually replace the body’s existing stem cell reserves. (The line between genetic enhancement and repairing inherited genetic flaws is blurry.) This yields a basic, rejuvenated human. (Slow turnover of somatic brain cells might cause significant memory loss but I’m willing to retrain and re-educate myself.)

This basic human model could then be modified with targeted enhancements that could be removed or updated. That is where microcapsules and cybernetic implants come into play. I favor modifications that could be reversed if unforeseen problems arise or if a better enhancement becomes available.

Randall Parker said at January 1, 2007 6:48 PM:

Fly,

Yes, I see the same future. But think about how we handle computer upgrade choices today. We could buy a new computer every 6 months. Or every 2 years. Or every 3 years. Or we could upgrade parts. What makes sense depends on lots of things including the size of the recent advances and what your needs are.

Some enhancements are going to yield much bigger benefits. Others will yield smaller benefits. Some enhancements will require changing most or all of an organ. Others will require only a small fraction of the cells in, say, the liver to be modified to get the benefit.

If I just got a new liver that slows my rate of aging to give me 10 more years I'm not going to upgrade again a year later to get a new liver that gives me a much smaller advantage. I'm guessing as we go along sometimes we'll discover enhancements that give big benefits and other times we'll discover enhancements to the same organ that provide only small benefits.

But as your liver gets older at some point you'll be better off getting a complete new one even if you could wait yet another year and get a still better liver. Ditto for other body parts. Ditto for stem cell therapies.

Rejuvenation of existing cells is much harder when we are talking about the brain. How to fix the accumulated damage to genomes for 100 billion neurons in the brain? We probably won't have to replace the entire genome of each cells. But we might need to replace dozens or hundreds of genes and perhaps some regulatory areas in genomes as well. How to do that? It is way harder than stem cell therapy and way way harder than growing replacement livers or replacement pancreases.

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