It has long been suspected that polymorphisms in the cholesterol ester transfer protein (CETP) gene confer important longevity benefits. This post is prompted by recent news about the gene. The post reviews what is known about the actions of the gene and its variants, and speculates about how this knowledge could lead to a new anti-aging intervention.
CEPT inhibition and coronary heart disease
The interest in the CEPT gene goes back a long time. A 2000 publication states “Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that mediates the transfer of cholesteryl ester from high density lipoproteins (HDL) to triglyceride-rich lipoproteins in exchange for triglycerides. — Several genetic variants at CETP locus have been identified and they have been generally associated with increased HDL-cholesterol concentrations.” Thus, it was originally thought that these gene variations could be life-extending because the higher HDL would be cardioprotective. Interest developed in drugs that limit the expression of CEPT, the hope being that they would have a profound effect on raising HDL cholesterol. “In our view, CETP inhibitors in combination with statins will be profoundly beneficial in reducing human atherosclerosis, primarily because they normalize HDL particles and prevent the transfer of cholesteryl ester from HDL to atherogenic lipoproteins(ref).” “A relative new strategy for raising HDL cholesterol, inhibition of cholesteryl ester transfer protein (CETP), is markedly effective. CETP inhibitors prevent the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride. One inhibitor, torcetrapib, binds to CETP on HDL, markedly increases HDL cholesteryl ester, — (ref) .“
Unfortunately torcetrapib had serious problems. “A large clinical trial in patients with CAD who were taking atorvastatin was recently stopped prematurely because of excess mortality in those receiving torcetrapib versus placebo, and 2 other trials reported no benefit of torcetrapib on coronary atherosclerosis or carotid intima-media thickness as compared with subjects on atorvastatin alone. The adverse effects of torcetrapib may be compound specific, and because the crystal structure of CETP is now known, it should be possible to develop more optimal CETP inhibitors that do not form a nonproductive complex with CETP on the HDL particle, as has been reported for torcetrapib(ref).” A 2009 report indicates ”Recently, Phase III clinical studies of torcetrapib, one of the CETP inhibitors developed by researchers at Pfizer, were unexpectedly terminated because of an increase in cardiovascular events and mortality. Torcetrapib has some compound-specific and off-target effects, such as raising blood pressure and aldosterone, which could affect an increase in cardiovascular events and mortality.”
The abandonment of torcetrapib due to side effects dealt a mighty blow to the area of pharmacologic CETP inhibition, although not necessarily a fatal one. See JTT-705: is there still future for a CETP inhibitor after torcetrapib? Also, “Dalcetrapib (JTT-705) and anacetrapib, which have not been reported to have the off-target effects of torcetrapib, are currently in Phase III. They are expected to reveal whether CETP inhibition is beneficial for atherosclerosis-related diseases(ref).” Results of the safety and tolerability study of Dalcetrapib were promising(ref). A clinical trial of the Tolerability and Efficacy of Anacetrapib for patients with coronary heart disease is ongoing(ref).
CEPT gene variations and cardiovascular diseases
Most of the studies of CEPT have looked at the CEPT gene and its variants in the context of HDL and impact on cardiovascular disease processes. The 2009 report Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18 245 initially healthy women from the Women’s Genome Health Study looks at whether CEPT and HDL-C have causal roles in atherothrombosis. “One method to evaluate this issue is to examine whether polymorphisms in the CETP gene that impact on HDL-C levels also impact on the future development of myocardial infarction. METHODS AND RESULTS: In a prospective cohort of 18 245 initially healthy American women, we examined over 350 000 singe-nucleotide polymorphisms (SNPs) first to identify loci associated with HDL-C and then to evaluate whether significant SNPs within these loci also impact on rates of incident myocardial infarction during an average 10-year follow-up period. Nine loci on 9 chromosomes had 1 or more SNPs associated with HDL-C at genome-wide statistical significance (P<5×10(-8)). However, only SNPs near or in the CETP gene at 16q13 were associated with both HDL-C and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the CETP gene was associated with a per-allele increase in HDL-C levels of 3.1 mg/dL and a concordant 24% lower risk of future myocardial infarction (age-adjusted hazard ratio, 0.76; 95% CI, 0.62 to 0.94), consistent with recent meta-analysis. Independent and again concordant effects on HDL-C and incident myocardial infarction were also observed at the CETP locus for rs4329913 and rs7202364. Adjustment for HDL-C attenuated but did not eliminate these effects. CONCLUSIONS: In this prospective cohort of initially healthy women, SNPs at the CETP locus impact on future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDL-C mediated pathway.”
A 2006 study I405V polymorphism of the cholesteryl ester transfer protein (CETP) gene in young and very old people reports “We recruited 100 healthy young people (median age 31 years) and 100 very old people (median age 89 years) and analysed their DNA for the presence of I405V polymorphism. — The frequency of the VV genotype in very old people was more than double that in the young population. Subjects with this genotype had lower serum concentrations of CETP. Young people with the V/V genotype had a less atherogenic lipoprotein profile (lower total cholesterol, LDL cholesterol, Apo B, and Apo B/Apo A-I ratio) than those with the I/V or I/I genotypes. The older subjects, particularly the older women with the V/V genotype, had larger LDL than the young people. The prevalence of clinical endpoints was much lower among the very old people with the V/V genotype. In conclusion, the V/V genotype of the I405V CETP polymorphism is more frequent among very old people than young ones, and is associated with a lower incidence of vascular damage.”
A number of other studies have supported a possible life-extending role for CEPT polymorphisms, but always in the contexts of lipids, raising HDL, and preventing cardiovascular diseases. See, for example, this list of citations.
Latest news: CEPT and dementia
A break in the pattern was reported two days ago. Going back a couple of years, researchers at the Albert Einstein College of Medicine of Yeshiva University conducted a study where they searched for the presence of “longevity genes” in a cohort of aged Ashkenazi Jews. As reported in a 2008 Science Daily article “Participating in the study were 305 Ashkenazi Jews more than 95 years old and a control group of 408 unrelated Ashkenazi Jews. — All participants were grouped into cohorts representing each decade of lifespan from the 50’s on up. Using DNA samples, the researchers determined the prevalence in each cohort of 66 genetic markers present in 36 genes associated with aging. — The Einstein researchers were able to construct a network of gene interactions that contributes to the understanding of longevity. In particular, they found that the favorable variant of the gene CETP acts to buffer the harmful effects of the disease-causing gene Lp(a).”
A January 13 2010 report ‘Longevity Gene’ Helps Prevent Memory Decline and Dementia in Science Daily discusses a January report on JAMA describing further investigations by the same researchers relating the CEPT gene in the Ashkenazi Jews to the risks of Alzheimer’s Disease. The JAMA report is entitled Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (CETP) Gene With Memory Decline and Incidence of Dementia. “Objective To test the hypothesis that a single-nucleotide polymorphism (SNP) at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including Alzheimer disease (AD).” “The researchers of the current study hypothesized that the CETP longevity gene might also be associated with less cognitive decline as people grow older. To find out, they examined data from 523 participants from the Einstein Aging Study, an ongoing federally funded project that has followed a racially and ethnically diverse population of elderly Bronx residents for 25 years. — At the beginning of the study, the 523 participants — all of them 70 or over — were cognitively healthy, and their blood samples were analyzed to determine which CETP gene variant they carried. They were then followed for an average of four years and tested annually to assess their rates of cognitive decline, the incidence of Alzheimer’s disease and other changes. - – “We found that people with two copies of the longevity variant of CETP had slower memory decline and a lower risk for developing dementia and Alzheimer’s disease,” says Amy E. Sanders, M.D., assistant professor in the Saul R. Korey Department of Neurology at Einstein and lead author of the paper. “More specifically, those participants who carried two copies of the favorable CETP variant had a 70 percent reduction in their risk for developing Alzheimer’s disease compared with participants who carried no copies of this gene variant. — The favorable gene variant alters CETP so that the protein functions less well than usual(ref).”
The new news is in fact not completely new. A December 2006 news report states “An Israeli study involving 158 people who lived to 95 or beyond has found that those who inherit a particular version of the gene CETP are twice as likely to have a sharp and alert brain when they are elderly. — They are also five times less likely than people with a different version of CETP to develop Alzheimer’s disease and other forms of dementia, according to the study by a team at the Albert Einstein College of Medicine at Yeshiva University. — About 8 per cent of people aged 70 have the CETP variant, but this rises to 25 per cent among centenarians. This is thought to play a key role in explaining why some people live to very old ages. The research, published in the journal Neurology, found that those with CETP VV were twice as likely as the others to have good brain function. — A separate investigation of 124 Ashkenazi Jews aged between 75 and 85 found that CETP VV appeared to protect against dementia: those with the variant were five times less likely to suffer from it.”
The researchers at the Albert Einstein College of Medicine also have found that telomere maintenance plays a very important role in maintaining the longevity of the centenarian Ashkenazi Jews, as reported in the November 2009 blog entry Timely telomerase tidbits. From a November 2009 Science Daily story: “As we suspected, humans of exceptional longevity are better able to maintain the length of their telomeres,” said Yousin Suh, Ph.D., associate professor of medicine and of genetics at Einstein and senior author of the paper. “And we found that they owe their longevity, at least in part, to advantageous variants of genes involved in telomere maintenance. — More specifically, the researchers found that participants who have lived to a very old age have inherited mutant genes that make their telomerase-making system extra active and able to maintain telomere length more effectively. For the most part, these people were spared age-related diseases such as cardiovascular disease and diabetes, which cause most deaths among elderly people.”
So, variants in the CEPT gene appear to be protective against cardiovascular diseases and also protective against memory decline and dementia. Further, drugs are in Phase III clinical trials that may mimic the effects of these gene variants. As usual several questions are still to be answered including:
· Do variations in the CEPT gene actually confer overall additional longevity or simply accompany longevity conferred by other genes? If so, which variations are most effective and how much additional longevity can they provide?
· In the centenarians, what is the relationship between having extraordinary telomerase- maintenance genes and CEPT polymorphic genes? Is it coincidental or in any sense causative that some centenarians have both of these kinds of gene variations?
· In the event that effective and safe pharmacological means are established to inhibit CEPT expression (Dalcetrapib or Anacetrapib), will these be longevity-enhancing drugs?
· If so, how will they work: by maintaining high HDL levels and protecting cardiovascular health, by protecting mental functioning and preventing dementia, and/or by additional means yet to be characterized?
· Are there nutraceuticals that inhibit CEPT expression and that could provide similar benefits?