What is the functional role and the mechanism of induction of p16INK4a and ARF during aging?
The study by Krishnamurthy et al. (14) appears to be of general interest, since the development of reliable biomarkers of aging will certainly be immensely useful in various areas of medicine. It is tempting to speculate that p16INK4a and/or ARF are not only good candidate biomarkers of aging, but that they may in fact have a functional role in the aging process. p16INK4a and ARF have both been linked to the induction of cell cycle arrest in response to DNA damage (21, 22). This finding seems of particular interest, since there are several connections among the different senescence stimuli that point to DNA damage as a major factor inducing senescence: (a) telomere shortening induces senescence by activation of the DNA-damage response (16); (b) ROS increase the rate of telomere shortening and induces multiple forms of DNA damage (23, 24); and (c) mitogen stimulation cooperates with telomere shortening to induce a DNA-damage response (25). It has recently been shown that DNA damage accu
