Genetic causes underlying healthy aging

A small proportion of our population is fortunate to live to the age of 85, and only a minority of these achieves this age free of major age-related diseases such as cancer, cardiovascular disease, pulmonary disease, diabetes or Alzheimer`s while maintaining a good quality of life. People who reach the age of 85 in good health may represent a group who may either lack susceptibility factors that contribute to disease in the majority of people, or may possess resistance factors that enhance their ability to resist disease and prolong lifespan. We consider healthy aging to be a complex phenotype that is determined intrinsically by genes for which expression and physiological consequences are modified by extrinsic factors such as lifestyle and environment, and that variation in these genes contributes to a variety of processes that result in long-term good health. The main objectives of this study are to identify genes involved in long-term good health and to identify whether single nucleotide polymorphisms (SNPs) in these genes are associated with resistance to age-related diseases. This will be achieved by A) selecting up to 20 candidate "healthy aging" genes, derived both from studies in C. elegans and by comprehensive literature evaluation and B) assessing whether genetic variation in these genes is associated with healthy aging by performing a population-based genetic association study comparing exceptionally healthy seniors to ordinary middle-aged controls. Candidate genes for this study will be selected using expression profiling work already performed in C. elegans. We have had early access to C. elegans serial analysis of gene expression (SAGE) data and have mined these SAGE data for longevity genes. Specifically, we looked for genes that are differentially expressed at various adult time points in daf-2 (long-lived mutant) versus wild-type control worms. These analyses have yielded new types of genes that we think are fundamentally involved in regulating metabolic changes and mechanisms associated with longevity. Human orthologs of these genes will be identified for use as candidate genes in the proposed human association study under the hypothesis that they have also fundamental and analogous roles in humans. Additionally, candidate genes are being identified by critically reviewing the current aging literature. Subsequently, we will propose an integrated hypothesis including SAGE data and insights from the literature as a working model for our human association study. A case-control approach will be used as the genetic association study design to test SNPs found in our candidate genes for statistical association with successful aging. Polymorphisms in these "susceptibility genes" are hypothesized to directly influence an individual`s likelihood of living a long and healthy life.