Grant: Operating Grant

The human body ages in part because the cells within the body age. These tissues generally age as the cells age, replacing dead cells as needed. Cellular aging is a complex process, controlled by a combination of factors within the cell and the cellular environment. For example, vascular cells (which line our blood vessels) that are exposed to various types of stress (e.g., chemicals or mechanical strain) deteriorate faster than they can be replaced and a atherosclerotic plaque can develop, leading to a heart attack or stroke. Aged cells are more susceptible to cellular stress, which is a reason why age is the most important factor in predicting whether an individual will have a stroke or heart attack. Unfortunately, there is still much that scientists do not understand about cellular aging. We are studying patients with a disease called Progeria, in which the children's cells and bodies age very rapidly. They loose their hair, develop wrinkles, arthritis, and become skinny as they loose fat and muscle mass - all by the age of 6-8. Worse yet, they develop hardening of the arteries (atherosclerosis) by the same age and usually die from a heart attack or stroke around age 13. We have generated stem cells from these patients by reprogramming their skin cells. We have differentiated the stem cells into different cell types and shown that we can model their disease (cellular aging) in culture dishes. We discovered that Progeria vascular and cartilage cells are very sensitive to reactive oxygen species (ROS) which are known to contribute to cellular aging. We have found that ROS leads to difficulty for the cells to divide into daughter cells. We propose to perform experiments to learn why ROS leads to stress in cell division and how that impacts gene and protein expression in Progeria patient cells. As these mechanisms are fundamental to aging and the diseases of aging, we believe our research will benefit patients suffering from a multitude of age-related diseases.