I recently became aware of the Rs5882(G,G) SNP, sometimes called a longevity gene which is fairly common among Ashkenazic Jews, among whom it was discovered. From SNPedia:
Rs5882(G;G)
This SNP has been related to exceptional long life. A study in Ashkenazi Jews showed that individuals with this genotype have significantly longer lifespans, and better cognitive function [PMID 17190939])
Another study shows that this homozygote has and average 70% lower risk of dementia and Alzheimer's disease.
Associated with longer lifespan, 0.28x lower risk of dementia, 0.31x lower risk of Alzheimer's.
Even a single copy of the gene confers protection against dementia, and against heart disease. From Pubmed:
Neurology. 2006 Dec 26;67(12):2170-5.
A genotype of exceptional longevity is associated with preservation of cognitive function.
Barzilai N, Atzmon G, Derby CA, Bauman JM, Lipton RB.
Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. barzilai@aecom.yu.edu
Abstract
OBJECTIVE: To test whether cholesterol ester transfer protein (CETP) genotype (VV homozygosity for I405V) is associated with preservation of cognitive function in addition to its association with exceptional longevity.
METHODS: We studied Ashkenazi Jews with exceptional longevity (n = 158; age 99.2 +/- 0.3 years) for the associations of CETP VV genotype and lipoprotein phenotype, using the Mini-Mental State Examination (MMSE). To confirm the role of CETP in a younger cohort, we studied subjects from the Einstein Aging Study (EAS) for associations between CETP VV and cognitive impairment.
RESULTS: Subjects with MMSE > 25 were twice as likely to have the CETP VV genotype (29% vs 14%, p = 0.02), and those with the VV genotype were more likely (61% vs 30%, p = 0.02) to have MMSE > 25. Subjects with the VV genotype had lower levels of CETP (1.73 +/- 0.11 vs 2.12 +/- 0.10 mug/mL, p = 0.01), higher high-density lipoprotein (HDL) levels (p = 0.02), and larger lipoprotein particles (p = 0.03). In the EAS cohort, an approximately fivefold increase in the VV genotype (21% vs 4%, p = 0.02), higher HDL levels, and larger lipoprotein particle sizes were associated with less dementia and improved memory.
CONCLUSIONS: Using two independent cohorts, we implicate the longevity CETP gene as a modulator of age-related cognitive function. A specific CETP genotype is associated with lower CETP levels and a favorable lipoprotein profile. It has not been determined whether modulation of this gene prevents age-related decline or AD.
PMID: 1719093
This gene functions as a CETP inhibitor. It increases the size of one's HDL lpoproteins, and also increases the size of VLDL lipoproteins. Apparently larger HDL particles are more efficient at clearing out ones arteries and capilaries, and larger VLDL particles do not form plaques that lead to heart disease, strokes and various dementias including Alzheimers.
Drug companies have been testing CETP inhibitors in the hope of replicating the effect for those without the lucky gene. The first of these CETP inhibotors, Torcetrapib (Pfizer), was associated with excessive all cause mortality in the treatment group receiving a combination of atorvastatin and Torcetrapib. Testing was discontinued. It looked like this approach to treating hypercholesterolemia might be a dead end, but a second CETP inhibitor Anacetrapib (Merck) apparently does not have adverse side effects. Recent publicity has suggested this may be a block-buster drug ofr Merck. Though intended to treat high cholesterol levels, the effects of the Rs5882suggest that even in people with normal cholesterol levels it may lengthen life and prevent dementia.
At this point, I wondered if any currently available supplements might function as CETP inhibitors. I found one, fenofibrate, which is prescribed alone or in combination with metformin (a putative CR mimetic) for diabetes. Apparently fenofibrate has a favorable effect on lipid profiles, as well as normalizing blood glucose, improving insulin sensitivity and generally reversing what is referred to as "metabolic syndrome."
J Cardiovasc Pharmacol Ther. 2010 Jun;15(2):196-202. Epub 2010 Mar 23.
Selective CETP inhibition and PPARalpha agonism increase HDL cholesterol and reduce LDL cholesterol in human ApoB100/human CETP transgenic mice.
Hansen MK, McVey MJ, White RF, Legos JJ, Brusq JM, Grillot DA, Issandou M, Barone FC.
Discovery Research, GlaxoSmithKline, King of Prussia, PA, USA. mkhansen99@yahoo.com
Abstract
Cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) cholesterol metabolism, but normal mice are deficient in CETP. In this study, transgenic mice expressing both human apolipoprotein B 100 (ApoB-100) and human CETP (hApoB100/hCETP) were used to characterize the effects of CETP inhibition and peroxisome proliferator-activated receptor alpha (PPARalpha) agonism on lipid profiles. Torcetrapib (3, 10, and 30 mg/kg), a CETP inhibitor, fenofibrate (30 mg/kg), a weak PPARalpha agonist, and GW590735 (3 and 10 mg/kg), a potent and selective PPARalpha agonist were given orally for 14 days to hApoB100/hCETP mice and lipid profiles were assessed. The average percentages of HDL, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol fractions in hApoB100/hCETP mice were 34.8%, 61.6%, and 3.6%, respectively, which is similar to those of normolipidemic humans. Both torcetrapib and fenofibrate significantly increased HDL cholesterol and reduced LDL cholesterol, and there was a tendency for torcetrapib to reduce VLDL cholesterol and triglycerides. GW590735 significantly increased HDL cholesterol, decreased LDL and VLDL cholesterol, and significantly reduced triglycerides. Maximal increases in HDL cholesterol were 37%, 53%, and 84% with fenofibrate, torcetrapib, and GW590735, respectively. These results, in mice that exhibit a more human-like lipid profile, demonstrate an improved lipid profile with torcetrapib, fenofibrate, and GW590735, and support the use of selective PPARalpha agonism for the treatment of lipid disorders. In addition, these data demonstrate the use of hApoB100/hCETP transgenic mice to identify, characterize, and screen compounds that increase HDL cholesterol.
PMID: 20332533
At this point I am wondering if use of fenofibrate would be a viable strategy for prolonging one's life while waiting for other, more effective interventions?
