The Cdkn2a locus and aging. (A) In young mice, the amount of p16Ink4a and p19Arf is quite low and in balance. (B) As animals age, p16Ink4a and p19Arf accumulate in the same tissue, with p19Arf attempting to counter-balance the pro-aging effects of p16Ink4a. With time, the balance shifts towards a state of aging. (C) In scenarios where p19Arf is not present to counteract p16Ink4a, the absolute levels of p16Ink4a increase dramatically, further promoting a pro-aging microenvironment. (D) When p16Ink4a is absent, p19Arf does not accumulate. Aging is delayed and the induction of p19Arf is not required.