Model of p16^INK4A in aging in AML. The expression of p16^INK4A mRNA increases with advancing age to ensure that potentially dangerous lesions, resulting from accumulated DNA damage, do not lead to malignancy. The increased expression of p16^INK4A mRNA has the potential to negatively modulate stem cell function through the induction of apoptosis or senescence. This concept, a decline in regenerative potential of tissues caused by a decline in functional stem cells mediated by stress-induced senescence, is a leading dogma in aging. Our data illustrate the importance of this p16^INK4A-dependent mechanism because AML samples of older patients have a lower instead of higher expression of p16^INK4A mRNA compared with AML samples of younger patients and compared with CD34⁺ cells of healthy controls. So we hypothesize that suppression of defense mechanisms, which protect older stem cells against accumulated cellular and DNA damage, facilitates the development of AML in older persons.