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Figure 10.2 Hypothetical change in allele frequency for a human aging gene. If many individuals from a variety of ages are genotyped and the allele frequency is plotted as a function of donor age, the relative frequency of the allele that promotes longevity (Allele B) will increase as homozygous carriers of the allele that does not confer a longevity benefit (Allele A) die early, and only homozygous carriers of the beneficial allele achieve extremely old age.

the role this gene plays in determining human longevity is related to the ability of centenarians to escape cardiovascular disease.

Another method for identifying polymorphisms correlated with longevity is a high-throughput SNP-typing approach, where allele frequencies are determined for a large number of SNPs from individuals of many different ages. Under this design, alleles that result in disease susceptibility are expected to decrease in frequency with donor age, while alleles that are important for longevity should increase in frequency (Figure 10.2).

An isoleucine-to-valine polymorphism in the protein kinase A-anchoring protein AKAP2 was found to correlate with decreased longevity and cardiac disease in one study of this type (Kammerer et al., 2003). Unfortunately, no large-scale search for age-related changes in SNP frequencies has yet been reported.

Both approaches described above have the advantage of being unbiased, in the sense that no assumptions about the identity of the putative longevity gene are required. It is possible, however, that these types of unbiased approaches will be unable to detect polymorphisms that influence aging if disease alleles, particularly alleles protective for heart disease and cancer, give a more robust signal than allelic variation in genes that affect the aging process at a more fundamental level. In order to get around this potential limitation, researchers are beginning to look for polymorphisms that alter the function of conserved aging genes identified from simple eukaryotes. For example, an allelic variant in the human SIRT3 gene, resulting in decreased expression of the protein in vitro, has been reported to correlate with

Figure 10.2 Hypothetical change in allele frequency for a human aging gene. If many individuals from a variety of ages are genotyped and the allele frequency is plotted as a function of donor age, the relative frequency of the allele that promotes longevity (Allele B) will increase as homozygous carriers of the allele that does not confer a longevity benefit (Allele A) die early, and only homozygous carriers of the beneficial allele achieve extremely old age.

failure to attain extreme longevity (Bellizzi et al, 2005). SIRT3 was chosen as a candidate human aging gene based on reports that increased expression of SIRT3 homologs increases life span in yeast (Kaeberlein et al., 1999), worms (Tissenbaum and Guarente, 2001), and flies (Rogina and Helfand, 2004). The insulin/IGF-1 signaling pathway is another highly conserved longevity-determining pathway that has been screened for longevity-associated polymorphisms in people (van Heemst et al., 2005). As additional conserved aging genes are identified, further studies of this type will shed light on the role of specific genetic variation in human aging.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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