Ink4a/Arf links senescence and aging

The mammalian INK4a/ARF locus encodes two linked tumor suppressor proteins, p16(INK4a) and ARF, which respectively regulate the retinoblastoma (RB) and p53 pathways. Genetic data have firmly established that both proteins possess significant in vivo tumor suppressor activity. In addition to their non-overlapping roles in preventing cancer, one or both proteins are induced under certain circumstances in most cultured murine and human cell types, and thereby are critical effectors of senescence. Likewise, data from murine models have suggested that this anti-cancer growth inhibitory activity of the locus can similarly affect permanent growth arrest in vivo. When such in vivo senescence occurs in a cell possessing self-renewal potential (e.g. a tissue stem cell), there is an attendant decline in the regenerative capabilities of the organ maintained by that stem cell. In turn, the concomitant decline of this stem cell reserve is a cardinal feature of mammalian aging. Expression of the INK4a/ARF locus, therefore, appears not only to be a major suppressor of cancer, but also an effector of mammalian aging. (C) 2004 Elsevier Inc. All rights reserved.