recent studies have revealed that the reduced proliferative potential of stem cells and the subsequent depletion of the stem cell pool are correlated with age-related diseases such as rheumatoid arthritis, osteoarthritis, refractory hypertension (78, 79). More clearly, an animal model revealed that premature depletion of the stem cell pool by massive tissue damage and subsequent major repair is strongly associated with the premature aging phenotype (80). These data indicate that dysfunction of stem cells or depletion of an adequate pool of stem cells may be closely related to aging and/or aging related symptoms (such as degenerative diseases). On the other hand, uncontrolled proliferation of stem cells by constant stimulation or loss of tumor suppressor activity is suggested to be the origin of tumors such as intestinal cancer (81) and malignant astrocytoma (82). Therefore, well-defined tumor suppressors such as p16Ink4a, 19Arf and p53 have been extensively studied in a variety of stem cell systems and have a role in regulating the cellular fate of stem cells such as aging or senescence (83–86), tumorigenesis (87, 88) and stemness or self-renewality (89, 90).
