Illustration showing possible mechanisms of p16^INK4a and ARF induction and the role of these proteins in aging. The accumulation of persistent and increasing DNA damage in senescent cells in response to telomere shortening, DNA damage, inappropriate activation of signaling pathways, and production of ROS during aging results in transcriptional activation of the INK4a/ARF locus. Mitogen stimulation may amplify the signals of DNA damage. Alternative stochastic mechanisms of aging that lead to p16^INK4a/ARF induction might also exist. Upregulation of p16^INK4a and ARF activates pRB and p53 pathways, which in turn lead to cell cycle arrest and regenerative defects. In addition, p16^INK4a/ARF upregulation might influence cellular functions in mitotically inactive organs during aging. Cyc D, cyclin D; BMI1, B lymphoma Mo-MLV insertion region; ID1, inhibitor of DNA binding 1; ETS1, v-ets erythroblastosis virus E26 oncogene homolog 1.