With an increasingly older population there is a significant interest to recognize potential risk factors and develop effective strategies to prevent, postpone or slow down disorders common in elderly. These efforts may depend, in part, on our abilities to unravel patterns of normal aging and to critically resolve, whether common underlying mechanisms govern the physiology and pathology of aging. A powerful approach to investigate the mechanism of human aging is to identify and characterize the biological functions of genes in human genetic disorders that result in premature aging. Information from these studies may have far-reaching implications, as it is conceivable, that these genes may play a role in the rate and variability of normal aging process and the vulnerability to the effect of aging or age-related disorders. Werner syndrome is perhaps the single Mendelian disorder that most closely produces a phenotype resembling to human aging. This disorder is one of a class of human progerias, which is due to loss-of-function mutations in a single gene (Wrn). While the encoded Werner protein (WRN) shows significant homology to the RecQ family of DNA helicases, its precise cellular function is poorly understood. We propose that WRN protein may be part of multiple protein complexes with dynamically changing composition and subcellular/subnuclear distribution, thereby participating in diverse cellular functions. In this project we describe our findings and plans to discern the mechanisms, which may link WRN protein directly to DNA replication. These experiments are expected to provide insights into the mechanism(s) by which mutations in Wrn gene promote genetic instability due to a critical role of WRN protein on replication fork progression. In addition, we describe the strategy to characterize several genes and their encoded proteins, some without known homology or function that were isolated by their virtue to bind specifically to the WRN protein and may have significance in vivo. This information may uncover new directions in searching for aging- and longevity-related, genes. Furthermore, mutations and/or polymorphisms of these genes may define specific pathomechanisms of common disorders of the elderly. This project is expected to define features of genome and cellular maintenance that are particularly susceptible to the effects of normal aging. It is designed to provide an advanced training for the applicant and to enable her to develop an independent carrier in academic gerontology with a focus on the molecular mechanism of aging.