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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Available from: Gil Atzmon, Sep 29, 2015
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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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    ABSTRACT: The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease, and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4,114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p< 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly LLFS subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in ENCODE; however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.
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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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    • "Additional genes show promise of great relevance to healthy aging. A variant at CETP, for example, though inconsistently associated with longevity in different populations (reviewed by (Christensen et al. 2006)), in 213 Ashkenazi Jewish individuals of average age 98 is associated not only with longevity but also with additional aging-related phenotypes including a desirable lipid profile (Barzilai et al. 2003) and preservation of cognitive function (Barzilai et al. 2006). Other recent studies with extensive replication data are also encouraging. "
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