"Evolutionary theory can be summarized as the study of how genetic variation within a population is translated into variation between populations in response to natural selection, i.e., differential reproduction over the course of many generations. Similar principles can be applied to the study of changes in the genetic makeup of populations in response to differential survival over the course of one, or two overlapping generations. Differential survival in response to mortality will therefore be reflected in the prevalence of genotypes underlying the process of aging and longevity." (Bergman et al. 2007).Personally, I don't agree with the basis for this. The author's argument is that genes associated with "exceptional longevity" (over 95 years) are being selected for. I'm not sure if this is the case because all of the individuals that were studied would have been in their 50s and if female would have been past reproductive age, so if they already had surviving offspring how is this natural selection. They argue that the phenotype is "exceptional longevity", which is rare, that those without the "longevity genes" are "weeded out" (their term) due to chronic disease, and that these "longevity genes" are buffering this subpopulation from chronic disease. They argue only the latter half of natural selection and not the survival of offspring, which is the true measure of fitness. So unless some of these centenarians are popping Viagra and breeding like rabbits it unlikely that this is being caused by selection. It is more likely being buffered by culture and then possibly enhanced through drift. There are a number of neutrality test statistics that would have allowed them to test this and demonstrate its statistical significance.
The far more interesting portions of their article have to do with the hypothesis that genes associated with "exceptional longevity" are buffering against chronic disease. Figure 3 in the article shown below (I love open access) does a good example of showing this with the U-shaped distribution. The article also does a decent job of explaining some of the genotypes may be associated with this. This helps explains an interesting trend in epidemiology which demonstrated that a number of traits associated with heart disease seem to increase with chronic diseases such as congestive heart failure. As the age of the general population has increased a number of these have noted the increase of traits considered to be risk factors actually end up appearing to be beneficial in older populations. This article does a good job of demonstrating a genetic component to these finding.
Citation: Bergman A, Atzmon G, Ye K, MacCarthy T, Barzilai N (2007) Buffering Mechanisms in Aging: A Systems Approach Towards Uncovering the Genetic Component of Aging. doi:10.1371/journal.pcbi.0030170.eor
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 over 1200 subjects between the 6th and 11th decade 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 sub-network 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.
Future Article URL: http://dx.doi.org/10.1371/journal.pcbi.0030170
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