Grant: Operating Grant

One of the most fascinating of human aging syndromes is Werner syndrome (WS). WS is a recessive disorder characterized by genomic instability and the premature onset of several age-related diseases. The precise function of the WS protein (WRN) in genomic stability is not fully understood but data in the literature points toward a role of WRN in DNA recombination/repair pathways during replication or even transcription in cells. Importantly, we have found that loss of WRN protein in human cells affects the expression of genes involved in cellular metabolism and oxidative stress response. Correspondingly, the current theory is that oxidative stress is the culprit of several diseases associated with aging. Thus, the understanding of the mechanism by which WRN prevents oxidative stress will open the route to possible intervention not only in premature aging diseases but also normal aging. Hence, the first aim of this proposal is to determine whether the WRN protein regulates the expression of these genes by interacting directly with their regulatory sequences. Such results will be confirmed in mouse models of WS. Our laboratory has two WS mouse line. One line produces a stable mutant protein with abnormal enzymatic activities. These mice have a reduced health and life span. The other line does not synthesize a WRN protein but has less severe age-related pathologies. The second aim is to understand why mice with a stable mutant WRN protein have more severe pathologies than mice without any WRN protein. Finally, we found that vitamin C supplementation reverses aging in WRN mutant mice. Our third aim will be to cross all our WRN mutant lines with mouse line that lacks the enzyme required for vitamin C synthesis. Such mice will rely entirely on vitamin C provided in the diet like humans. Results obtained from our mice supplemented with vitamin C will be clinically relevant for the prevention or treatment of premature aging syndrome as well as normal human aging.