Abstract
An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the “oldest old” Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate-buffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.
Highlights
While life-style factors such as obesity have been identified as limiting factors in life expectancy [1], genetic factors have been implicated in, and are considered central to, the process of aging
Previous research showed that the frequency of deleterious genotype of some age-related disease decreases its prevalence as the population ages, as expected, since subjects with deleterious genotype are weeded out due to mortality
Our findings suggest that individuals with the favorable longevity genotype can have just as many deleterious aging genotypes as the rest of the population because their longevity genotype protects them from the harmful effects of the other
Summary
While life-style factors such as obesity have been identified as limiting factors in life expectancy [1], genetic factors have been implicated in, and are considered central to, the process of aging. The long list of biological processes associated with aging has not permitted all the causes of mammalian aging to be determined Monogenetic disorders such as abnormalities in the LDL receptor gene [5,6], the rare helicase gene defects in Werner syndrome that prevent subjects from attaining normal lifespan [7], and the more common BRCA1 and BRCA2 genes in breast cancer [8], all represent genetically determined phenotypic defects associated with early mortality. These are not necessarily common mechanisms of aging, and despite the evidence for a substantial genetic component, the inherited biological factors [9] that define lifespan in long-lived humans remain unknown. In our Ashkenazi Jewish study, the Editor: Pinchas Cohen, University of California Los Angeles, United States of America
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