Aging and longevity are undoubtedly determined by multiple, interacting genetic loci. In multicellular organisms, longevity-influencing genes may act at any of several levels, including individual cells. Higher organisms contain two types of cells that differ in their proliferative potential: 1) postmitotic cells, which never divide; 2) mitotically competent cells, which divide (continually or occasionally) throughout life. Most mitotically competent cells cannot divide indefinitely -- certainly in culture, and very probably in vivo. This is due to cellular or replicative senescence, a process driven by progressive telomere shortening. There is increasing evidence that cellular senescence may contribute to aging in higher, muticellular organisms. One line of evidence stems from studies of Werner syndrome (WS), an autosomal recessive premature aging syndrome. Individuals with WS develop many age-associated disorders two or three decades prematurely, and cells from WS donors senesce prematurely. Thus, WRN, the gene defective in WS, may be a longevity-assurance gene that delays cell senescence and several age-associated pathologies. We recently found that a related gene, BLM, which is defective in the cancer-prone Bloom syndrome (BS), also delays the senescence of human cells. WRN and BLM belong to a small family of human genes encoding DNA helicases having homology to RECQ, a gene important for recombination and DNA repair in E. coli. Unlike the E. coli gene, very little is known about how human RECQ-Iike genes function, the presumed recombination or repair pathways in which they participate, much less their roles in aging and longevity. Our preliminary data suggest that the Wrn protein is also an exonuclease, suggesting it participates in a (as yet uncharacterized) DNA repair pathway, and Blm interacts with a telomere binding protein. We propose cellular and biochemical experiments to elucidate the mechanisms and pathways by which the human WRN and BLM genes regulate the replicative life span of human cells. It is not yet clear whether the mouse will be a suitable model for WS or BS, but if it is we will extend our cell studies to include transgenic mice. We will search for Wrn and Blm-interacting proteins in order to identify the complexes and pathways in which Wrn and Blm function, and uncover additional genes that modulate replicative life span. In collaboration with the Jazwinski laboratory, we will explore the role of the yeast Wrn- interacting protein Sap 1 in human and yeast replicative life span. The long range goal is to identify human longevity assurance genes and to know enough about their function to develop rational strategies for therapeutics or interventions.
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