The fundamental question in the biology of aging is-why do humans age? Many hypotheses have been put forth to answer this question. Among these are """"""""oxidative damage theories"""""""" and """"""""telomere theories"""""""" of aging. """"""""Oxidative damage theories"""""""" state that aging occurs, in part, because normal biologic processes release reactive oxygen species that can damage cellular components. """"""""Telomere theories"""""""" state that aging occurs that aging occurs in part, because telomere erosion occurs with each cell division in body cells that don't express telomerase. This loss of telomere sequence results in eventual cellular dysfunction. The research proposed is designed to clarify a simple question related to both of these """"""""theories""""""""does oxidative stress contribute to telomere sequence loss in vivo? This question attempts to unite """"""""telomere theories"""""""" and """"""""oxidative"""""""" damage theories"""""""" of aging-oxidative stress may influence age associated changes through an effect on the rate of telomere sequence loss. A seemingly simple question, it has not been simple to answer given the limitations of the individual experimental systems in which the question has been tested. Although a number of studies have demonstrated an accelerated rate of loss of telomeric repeats dependent on the level of exogenous oxidative stress in cells grown in tissue culture in vitro, the significance of these findings to processes occurring in vivo has been unclear. In the studies proposed herein, genetically manipulated mice will be used to test the significance of these findings in vivo. Mice cohorts heterozygous for the manganese superoxide dismutase gene and homozygous for telomerase RNA deletion will be bred, and rates of telomere loss in these cohorts relative to appropriate controls will be determined. By studying rates of telomere sequence loss in mice also lacking the Werner syndrome gene, the role of the Werner syndrome gene product in this process also will be determined.
