Cellular Aging: DNA Polymorphisms

The wide variation in the maximum life span, even among mammalian species, is well established and is related to the genetic endowment of each species. There are also qualitative and quantitative differences in the phenotype of aging among mammalian species. For example, the extensive atherosclerotic involvement of the arterial system associated with extensive morbidity (illness) and mortality with advancing age is virtually unique to humans. On the other hand, the extent to which genetic differences are responsible for the variation in longevity between individuals within a species is unknown. The variation of individual life spans is evident in populations of inbred organisms, indicating that environmental factors and, very likely, chance events contribute to this variability. However, the extent of the genetic contribution to this interindividual variation in the manifestation of aging and maximum survivability remains to be established.

It is generally accepted that aging and life span are regulated by multiple genes. Although the precise number is not known, it has been speculated that relatively few genes may be directly involved in this process. The most direct approach to the identification of aging and longevity genes would be to search for quantitative trait loci (QTL). These loci contain genes that regulate traits, such as blood pressure, that can be defined in specific units of measurement (in the case of blood pressure, the units would be millimeters of mercury) and are, in most cases, regulated by multiple genes. Longevity, which can be measured in units of time (e.g., days or years), is another example of a quantitative trait. A QTL study of aging might, for example, involve strains of laboratory mice that exhibit significantly different maximum life spans. Genetic loci that effect the phenotype (in this case, longevity) and their relative contribution, can be identified by a sophisticated analysis of data derived from the segregation pattern of polymorphic markers in relation to the phenotype (longevity) of the offspring from crosses between the strains, and from back crosses.

This type of genetic analysis is not realistically feasible with human subjects. However, association studies, another experimental approach to the identification of "aging genes," can be carried out in human subjects. Such studies involve the search for linkage between a specific polymorphic allele(s) or DNA polymorphism(s) and a specific trait. For example, one could compare the frequency of polymorphic alleles of a gene in an exceptionally long-lived population (e.g., centenarians) and a well-defined control population. A number of studies have been carried out with the human leukocyte antigen (HLA) loci in the major histocompatibility complex (MHC), one of the most polymorphic class of genes in the mammalian genome. These studies have yielded conflicting results, probably due to a number of methodological problems, including inaccurate identification of specific alleles in the pregenomic era. Similar studies designed to establish linkage between the incidence of a specific age-associated disease and specific alleles of a polymorphic locus have provided new information of considerable interest. For example, the association of the e4 allele of the apolipoprotein E gene, a gene that codes for a protein involved in lipid transport in the vascular system, with an elevated risk of developing Alzheimer's disease is now well established.

Clearly demonstrable associations, such as that between apolipoprotein B and Alzheimer's disease, are infrequent. More subtle associations are difficult to detect because of the relative paucity of genetic markers (e.g., SNPs) that, up to this time, have been identified in the human genome. Moreover, aging and the regulation of life span are multifactorial phenotypic traits, regulated by multiple genes interacting with the environment. Therefore, it is unlikely that polymorphic variants at a single locus will have a profound effect on the aging process or longevity; what is more likely is that combinations of alleles (haplotypes) will be associated with specific aging phenotypes. As indicated above, highly efficient methods to determine the frequency of SNPs in human populations are being developed, which will make the haplotyping of large numbers of individuals within a population feasible. The task may be simplified by the emerging observation that human genetic diversity is surprisingly limited. Theoretically there could be hundreds, even thousands, of variants at each locus, but in reality the number of alleles at most loci appears to be small, only two or three in many cases.