study, we utilized our two-dimensional gene scanning (TDGS) technology platform to screen two populations of centenarians for polymorphic variation in the BRCA1 breast cancer susceptibility gene. This gene is involved in genome maintenance and we found differences in BRCA1 genotype frequencies between the centenarian populations and controls. Our findings suggest that a genetic epidemiological approach could lead to new insights regarding the basic mechanisms of aging and longevity, as well as identifying new targets to prevent or retard some of the late-age adverse effects.

The success of the human genome project, combined with new technologies of genetic analysis, has greatly facilitated the identification of genes with inherited mutations that predispose to various age-related disorders, including specific cancers. Such genes are often involved in genome stability pathways to maintain DNA integrity. Examples include the DNA mismatch repair genes MLH1 and MSH2, heritable mutations in which predispose to colon cancer, and the breast cancer susceptibility genes BRCA1 and BRCA2.

Increased genomic instability and mutation accumulation are causally related to the increased risk of cancer observed in individuals with heritable defects in these genes. Genomic instability in organs and tissues has also been considered a major cause of aging, leading to tissue atrophy, neoplasms, and increased loss of cellular function. This process could be driven by oxygen free radicals and other sources of spontaneous DNA damage, although unambiguous evidence for such a causal relationship is still lacking.

Oxidative stress induces genome rearrangement mutations such as large deletions, inversions or translocations. These types of mutation have been demonstrated to accumulate during aging in various tissues of normal mice. In this respect, it has been speculated that a relatively small number of such large mutations could destabilize the genome, leading to dysregulation of normal patterns of gene expression.

Ultimately, the quality of genome stability systems determines the rate and spectrum of mutation accumulation during aging. Evidence is accumulating that defects in those systems that control the frequency of large DNA rearrangement mutations are associated with symptoms of accelerated senescence, in both mice and humans. This is the case for mice with defects in double-strand break repair genes, which can be expected to greatly accelerate the rate of illegitimate recombinations. Recent evidence indicates that mice with inactivated genes involved in non-homologous end joining, i.e., Ku86, prematurely exhibit symptoms of age-related degeneration in various tissues, including liver, skin, and bone.

The possible role of genomic instability in aging is further exemplified by recent work investigating telomere maintenance in the preservation of tissue functioning during aging. In a study of third-generation telomerase-deficient mice, shortened life span was found to be accompanied by reduced capacity to respond to stresses such as wound healing, hematopoietic ablation, and an increased incidence of spontaneous malignancies. The results of these studies underscore that in proliferative organs, the early initiation of genetic instability due to telomere erosion can greatly accelerate age-related loss of cell viability and increase tumor formation.

An important body of evidence that large genomic mutations are causally related to the degenerative aspects of the aging process has been derived from human syndromes of accelerated aging, such as Werner syndrome. Werner syndrome is caused by a heritable mutation in a human homologue of the bacterial RecQ gene, termed WRN in humans. Cultured somatic cells from patients with Werner syndrome display an increased rate of somatic mutations and a variety of cytogenetic abnormalities.

TABLE 1 summarizes the pathways and some of the genes thus far identified that are involved in the suppression of large genomic mutations. Defects in many of these genes have been found associated with accelerated senescence but not always and not to the same extent. It is possible to test this by creating mouse models with a variety of knock-in variants of the relevant genome stability genes. However, an alternative and reasonable approach would be to compare frequencies of the various alleles of loci involved in genome maintenance and repair and more specifically the pathways listed in TABLE 1 in different human populations with characteristic aging-related phenotypes.

Thus far, association studies have been based on single polymorphisms in candidate genes. The best-known example in this respect is the observed lower frequency of the APOE4 variant in centenarians, a higher frequency of which had previously been found associated with sporadic Alzheimer's disease. However, any positive result could be due to an effect of the polymorphism on the function of the candidate gene or some other gene variant that is in linkage disequilibrium with the marker locus. It has recently been shown that the distances over which linkage disequilibrium acts are small, typically less than 3 kb, although these data have recently been challenged.