Background Science
Genetic contributions to longevity across species
Experiments in C. elegans, Drosophila, and mice suggest that a few alleles influence life-span and senescence. A few mutations in C. elegans) increase the longevity of these nematodes by 35 to 110% (14, 18-21). For example, Kenyon discovered that mutations in daf-2 doubles the life-span of C. elegans and prolongs its youthful activity (21). daf-2 regulates life-span through a pathway very similar to human insulin and IGF-1 signaling pathways (57). Diverse types of studies indicate that 22% to 50% of the variability in human longevity or susceptibility to mortality is heritable (6-8)). Studies estimate that somewhere between a 'a few' to 250 genes determine human longevity.(9=iceland study; 10). However, we wish to avoid the tendency to generalize from worms to humans, or to "nematomorphize" the aging process. Most lower animals die of unknown causes, not specific diseases. Worms, for example, do not develop pneumonia, suffer myocardial infarction, break their hips, or develop dementia; indeed, they do not even have lungs, a circulatory system, or bones. Protein products that have similar functions at cellular levels may have different effects at the level of the organism. And although the reactive oxygen species model is often cited as the best developed theory of aging (1), the effects of anti-oxidants in humans have been disappointing (26-29). The degree to which findings in non-human species can be applied to human longevity and frailty will be addressed by the Consortium.
This effort may influence paradigms of aging and disease
Most biological and clinical research has been conducted by specialists focused on specific diseases. Clinical policy now focuses on prevention by modifying risk factors for individual diseases. This is important: Stamler estimated that the 5% to 10% of middle-aged people without the major risk factors for coronary heart disease have a 6 to 9 year longer life-expectancy than average. We do not plan to focus on genes for specific diseases but on those that affect life-span or that influence susceptibility to several diseases. The discovery of biological pathways that influence longevity independently of specific diseases would have a profound effect on our concepts of disease, aging and prevention. These discoveries would raise possibilities of interventions to prolong active life in ways besides the prevention of specific diseases.
Laboratory and human studies have complementary roles in the discovery, confirmation, and explanation of genes that influence longevity and frailty.
Schachter and colleagues suggested that candidate genes for longevity in humans should be sought in genes with homologues that influence life-span in other species or that mediate cellular maintenance and repair (2, 47). Indeed, many of the genes that control life-span in C. elegans, Drosophila, and mice have human homologues. These ancient genes, which are well conserved across species, are generally involved in fundamental cellular processes, such as energy metabolism, stress response, and repair of macromolecules (3, 11, 48-51). Laboratory studies are needed to identify biological effects of candidate genes- such as changes in the pattern of gene expression in murine muscle that occur with aging (52)-and suggest pathways for intervention, such as via caloric restriction. We have also included specialized populations (Iceland and centenarians) because studies in these populations may identify candidate genes for longevity and frailty whose biological relevance can be tested in laboratory experiments, and whose clinical relevance can be confirmed in large, more diverse populations. An advantage of our approach is that many of the participating cohort studies have made key aging-related measurements, which are often quite expensive, in substantial numbers of subjects. All also have frozen serum samples and DNA available for subsequent analyses. These samples can be used to test specific theories of aging by measuring markers of oxidative damage such as oxidized lipids, or levels of stress and inflammation. The identification of endocrinological or biochemical phenotypes that are associated with longevity in these cohorts may inspire a search for genetic determinants of those levels.