Toward Understanding the Molecular Mechanisms of Skin Stem Cell Aging
2013 new Scholar Award in aging
The number of adults over the age of 65 is predicted to triple in the next 40 years, and with that the incidence of age-related diseases is expected to increase sharply worldwide. Understanding the molecular basis of aging is critical to finding new methods for prevention and treatment of age-related diseases that will have positive health and economic impacts. Recent studies have suggested that alterations in stem cell function are responsible for age-related pathologies, with the root of the problem appearing to be increased expression of the Ink4ap16 and Ink4bp15 cell cycle inhibitors. We and others have shown that the Polycomb chromatin complex represses the Ink4a/b locus in various adult stem cells and p15/p16 upregulation during aging is linked to loss of Polycomb repression. However, the mechanisms responsible for activation of Ink4a/b, and how the resulting p16/p15 accumulation leads to tissue aging remain unknown. We have generated mice that lack Polycomb repressive activity in skin epithelium and presented premature aging phenotypes. Interestingly, we detected upregulation of p16 and p15 in Polycomb-null skin epithelial stem cells in young mice where it is normally detected only in aged animals. With the support of the Ellison Foundation New Scholar Award we propose to elucidate the role of p16/p15 in induction of skin aging pathologies and to determine the mechanisms of loss of Polycomb repression at Ink4a/b during aging. Uncovering these mechanisms will be potentially applicable to other adult stem cells where p16/p15 has been proposed to be a major effector of age-related pathologies, and will have a significant impact on delaying or preventing aging.