Cancer incidence increases exponentially with age, suggesting that a common mechanism contributes to both of these biological processes. One such mechanism is thought to be oxidative stress, due to an imbalance between the production of reactive oxygen species (ROS, e.g. O2.- and H2O2, arising from O2 metabolism), and their removal by the antioxidant network. A majority of aging-research is focused on understanding the mechanisms regulating replicative lifespan (Hayflick limit), which is attributed to telomere shortening and mitotic attrition. In the previous period of support (R01 CA111365), we discovered a novel mode of cellular aging (chronological lifespan), which is independent of both mitotic attrition and telomerase activity. We define chronological lifespan as the duration in which quiescent cells retain their capacity to re-enter the proliferative cycle and transit back to quiescence. Our data show that molecular and pharmacologically induced overexpression of manganese superoxide dismutase (MnSOD) suppresses age-associated increase in mitochondrial injury, and extends chronological lifespan. We also observed that MnSOD overexpression inhibits age-associated increases in the ability of quiescent fibroblasts to stimulate the proliferation of neighboring epithelial cancer cells. Finally, our recent preliminary results suggest that MnSOD-induced regulation of cell cycle regulatory pathways including the redox-sensitive phosphatase, DUSP1, and the chemokine, CCL5, could mediate chronological lifespan in human fibroblasts. These observations have now led us to test the specific hypothesis that MnSOD and ROS (O2.- and H2O2) regulate the chronological lifespan of human fibroblasts as well as their ability to influence the proliferation of epithelial cancer cells via edox-sensitive cell cycle regulatory pathways involving DUSP1 and CCL5. To investigate this hypothesis we will determine if: (a) MnSOD dependent expression of DUSP1 and CCL5 regulates the chronological lifespan of normal human fibroblasts;(b) cellular quiescence and redox-sensitive post-transcriptional mechanisms regulate MnSOD, DUSP1, and CCL5 expression;and (c) the aging of quiescent fibroblasts regulates the proliferation of epithelial cancer cells in co-cultures via the secretion of CCL5. A better understanding of the redox-biology of chronological lifespan and its effect on epithelial cancer progression will be of significance to aging and cancer research because this knowledge can greatly facilitate the development of novel nutritional and antioxidant-based approaches to promote healthy aging and suppress age-related cancer progression.
An understanding of the redox-biology of chronological lifespan will be of significance to aging and cancer research because this knowledge can greatly facilitate the development of novel nutritional and antioxidant- based approaches to promote healthy aging and suppress age-related cancer progression.
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