Genes predisposing to exceptional longevity

It is practically intuitive to state that centenarians outlive those who are relatively predisposed to age-related fatal illnesses and that they are less likely to have environmental and genetic exposures that contribute to death at earlier ages. This selection phenomenon, called demographic selection, is exemplified by the fact that the apolipoprotein E e4 allele, associated with heart disease and Alzheimer's disease, is rare in centenarians, whereas the prevalence of an alternative allele, e2, is relatively high (Schachter et al., 1994). Along the same lines, it is likely that there are certain environmental exposures that are rare among centenarians as well, such as tobacco, obesity and bullets. Richard Cutler, in what is now a classic paper in gerontology, proposed that persons who achieve extreme old age do so in great part because they have genetic variations that affect the basic mechanisms of aging and that result in a uniform decreased susceptibility to age-associated diseases (Cutler, 1975). Our studies and those of others researching the oldest old have noted that persons who achieve extreme old age probably lack many of the variations (the ''disease genes'') that substantially increase risk for premature death by predisposing persons to various fatal diseases, both age-associated and non-age-associated (Schachter, 1998). More controversial is the idea that genetic variations might confer protection against the basic mechanisms of aging or age-related illnesses (the ''longevity-enabling genes'') (Perls et al., 2002a). The progressive selecting out of more and more genetically fit persons of very old age lays the foundation for a simpler model for sorting out the genetics of aging and longevity.

The discovery of genetic variations that explain even 5% to 10% of the variation in survival to extreme old age could yield important clues about the cellular and biochemical mechanisms that affect basic mechanisms of aging and susceptibility to age-associated diseases. The elevated relative survival probability values found among the siblings of centenarians (Table 8.1) supported the utility of performing genetic studies to determine what genetic region or regions, and ultimatelywhat genetic variations, centenarians and their siblings have in common that confers their survival advantage (McCarthy et al., 1998). Centenarian sibships from the New England Centenarian Study were included in a genome-wide sibling-pair study of 308 persons belonging to 137 families with exceptional longevity. According to nonparametric analysis, significant evidence for linkage was noted for a locus on chromosome 4, near microsatellite D4S1564 (Puca et al., 2001).

The interval on chromosome 4 spanned 12 million base pairs and contained approximately 50 putative genes. In order to identify the specific gene and gene variants impacting lifespan, our genetics colleagues Drs Annibale Puca, Bard Geesaman, Louis Kunkel and Mark Daly performed a haplotype-based fine mapping study of the interval. A detailed haplotype map was created of the chromosome 4 locus that extended over

12 million base pairs and involved the genotyping of over 2000 single nucleotide polymorphism (SNP) markers in 700 centenarians and 700 controls. The study identified a haplotype, approximating the gene microsomal transfer protein (MTP), defined by two SNPs that accounted for all of the statistical distortion detected in the region. Statistically, the result appears to be robust, with a relative risk of nearly 2 (p<2 x 10~9). With interest narrowing in on a single gene, all known SNP polymorphisms for MTP and its promoter were genotyped in 200 centenarians and 200 controls (young individuals). After haplotype reconstruction of the area was completed, a single haplotype, which was under-represented in the long-lived individuals, accounted for the majority of the statistical distortion at the locus (~15% among the long lived individuals versus 23% in the controls). MTP is a rate limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study supports the feasibility of fine mapping linkage peaks using association studies and the power of using the centenarian genome to identify genes impacting longevity and the diseases of aging (Puca et al., 2001).

Dr Nir Barzilai and his colleagues studying Ashkenazi Jewish centenarians and their families recently found another cardiovascular pathway and gene that is differentiated between centenarians and controls (Barzilai et al., 2003). In Dr Barzilai's study, controls are the spouses of the centenarians' children. It was noted that high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly larger among the centenarians and their offspring and the particle size also differentiated between subjects with and without cardiovascular disease, hypertension and metabolic syndrome. In a candidate gene approach the researchers then searched the literature for genes that impact upon HDL and LDL particle size and the came up with hepatic lipase and cholesteryl ester transfer protein (CETP). Comparing centenarians and their offspring against controls, one variation of CETP was noted to be significantly increased among those with or predisposed to exceptional longevity. Given our findings that cardiovascular disease is significantly delayed among the offspring of centenarians and that 88% of centenarians either delay or escape cardiovascular disease and stroke beyond the age of 80 years, it makes sense that the frequency of genetic polymorphisms that play a role in the risk for such diseases (such as Apolipoprotein E e-4) would be differentiated between long lived individuals and the general population (Rebeck et al., 1994; Schachter et al., 1994; Tilvis et al., 1998; Smith, 2000; van Bockxmeer, 1994).

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