A genotype of exceptional longevity is associated with preservation of cognitive function

Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Neurology (Impact Factor: 8.29). 12/2006; 67(12):2170-5. DOI: 10.1212/01.wnl.0000249116.50854.65
Source: PubMed


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.
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.
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.
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.

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    • "Several genes were selected for investigation because they were previously implicated in aging, and SNPs within these genes were suggested to be linked with longevity. These included PON1 (Bonafe et al. 2002; Rea et al. 2004; Franceschi et al. 2005; Marchegiani et al. 2006; Tan et al. 2006), insulin-like growth factor 1 (IGF-1) (Bonafe et al. 2003; Kojima et al. 2004; van Heemst et al. 2005), PAPR-1, cytokine genes, genes that code for enzymatic antioxidants such as superoxide dismutases (Andersen et al. 1998; Mecocci et al. 2000), and components of lipid metabolism (Barzilai et al. 2006; Vergani et al. 2006). Other genes that have been implicated in human aging, and not only longevity, are updated on the Aging Gene Database (see genomics .senescence.info/genes). "
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    • "CETP V405 homozygosity was associated with slower memory decline and lower incidence of dementia and Alzheimer disease risk in healthy older adults compared with controls in the Einstein Aging Study (Sanders et al., 2010). In Ashkenazi Jews from the Longevity Gene Study, high levels of HDL and its large lipoprotein sizes were over represented in centenarians, as well as the prevalence of homozygosity for I405V-CETP and 641C-APOC3 in both centenarians and their offspring than in the controls (Barzilai et al., 2006; Bergman et al., 2007). We also found high levels of HDL and a borderline higher prevalence of homozygosity for 641C-APOC3 (rs2542052: p = 0.06) in the healthy LLFS subjects as compared to an independent data from the Family Heart Study (N = 3794 European-Americans) that has approximately half families CVDselected and the other half families randomly-selected. "
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    • "Aging-associated disorders include immune dysfunction (Candore et al., 2006; Sansoni et al., 2008), cognition degeneration (Barzilai et al., 2006; Mehta, 2007), cardiovascular disease (Dominguez and Barbagallo, 2007) and metabolic syndrome (Maggi et al., 2008). Increasing evidence suggests that aging increases the risk of degeneration of the nervous system, which mostly affects the moral and physiological life of the elderly. "
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