Grant: Operating Grant: Geroscience Demonstration Grants

The question: Major questions remain unanswered as to how and why we age, and whether we can intervene in the aging process. Recent technological advances in molecular biology and genetics have opened new avenues to investigate how genes function to influence aging at the cellular, tissue and whole body level. Remarkably, in certain cases these gene functions can now be manipulated, either genetically or chemically, to induce aged cells within tissues to be selectively removed to improve the function of tissues, and even improve health outcomes in mammals. This emerging new field of research is called geroscience. The approach: In this proposal, we will take advantage of CRISPR-based gene editing technology to understand how individual genes in the human genome contribute to cellular aging. We will focus on a central mechanism by which human cells age, namely through erosion of their chromosome protective caps, called telomeres. The research we propose will address the important question of whether removal of telomere-eroded "old" or senescent cells could also improve health outcomes. Our preliminary result have identified candidate gene functions whose absence appears to selectively impede the growth of cells with eroded telomeres. We have also identified chemicals that mimic this genetic sensitivity. We will extend these exciting preliminary results to comprehensively identify gene functions and chemicals that permit the removal of old cells that arise due to telomere erosion, and to test how the removal of these cells may improve the health of a mouse model engineered to possess human-like telomeres. Significance of the study: Since cellular senescence due to telomere erosion is already known to be critically important in age-associated human disease, our results may provide new clinical approaches to ameliorate the manifold effects of aging on human health.