Project 1: Genetic Contributions to Longevity
Life maintenance in extreme old age is the problem we address by initiating a genetic analysis of human aging using a novel approach. Associative genetics constitutes the first tool applied, but the candidate genes that will be analyzed have already passed the muster of causal connection to the aging process in genetic model organisms. The association of specific alleles of these genes with human longevity will provide probes for the verification of longevity gene function at the molecular level and clues to the molecular mechanisms of aging. Our focus will initially be the genes LAG1Hs and c-H-ras-1, which have been validated in yeast longevity studies, and the APOE locus. We will test the hypothesis, for each of these genes, that certain alleles of a gene are more frequent in centenarians than in younger controls.
The research will be carried out in several steps. First, we will assess the underlying genetic structure of our population by searching for polymorphisms in these genes. Second, we will determine the level of variation in the centenarian population compared to the control, in our candidate longevity selected (i.e. replication in other longevous cohorts). We will also supply a panel of ethnic affiliation markers to control for the confounding effects of population admixture. This analysis, in conjunction with the tests in other populations, may suggest the existence of longevous haplotypes in the population, a possibility which will be explored further. Finally, we will examine the functional significance of any allelic variants detected at higher frequency in centenarians, using the yeast genetic model system. This will involve the determination of the effect on yeast longevity of corresponding mutations in the yeast gene. The embodiment of this genetic study with its emphasis on metabolic control and stress responses and its accent on nervous system function in the context of this Program Project with its nutrition, neuropathology, and neuropsychology components will facilitate identification of genetic correlates, and the elucidation of features important for maintenance of functional health in old age. Thus, these studies should help to improve the quality of life in old age.
Project 1 Investigators:
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Mark Batzer, Ph.D. Senior Investigator Louisiana State University |
