Grant: Operating Grant

Normal human cells explanted from human tissues grow under experimental conditions in the laboratory for a defined number of cell divisions and then irreversibly stop dividing. This is known as replicative senescence. Although controversial, there is accumulating evidence that cellular senescence and organismal aging are related, namely that senescent cells accumulate as we age. Replicative senescence is a property of most human cells and is thought to provide a natural barrier against the accumulation of the multiple mutations that lead to tumour development. p53 plays a critical role in signalling cells to enter senescence; in the absence of p53, this barrier is lost and human cells can grow for an extended period during which they undergo further changes leading to genetic instability and cancer. Cells from patients with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS) undergo premature senescence when grown in culture. This too seems to be dependent on p53. The genetic defect that causes HGPS is known (a mutation in the lamin A gene). We want to understand how p53 becomes activated to induce replicative senescence in normal cells and in response to defective lamin A in HGPS cells. Our work has implications in the area of aging and cancer.