p16^INK4a reporter mice reveal age-promoting effects of environmental toxicants

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Abstract

While murine-based systems to identify cancer-promoting agents (carcinogens) are established, models to identify compounds that promote aging (gerontogens) have not been described. For this purpose, we exploited the transcription of p16^INK4a, which rises dynamically with aging and correlates with age-associated disease. Activation of p16^INK4a was visualized in vivo using a murine strain that harbors a knockin of the luciferase gene into the Cdkn2a locus (p16^LUC mice). We exposed p16^LUC mice to candidate gerontogens, including arsenic, high-fat diet, UV light, and cigarette smoke and serially imaged animals to monitor senescence induction. We show that exposure to a high-fat diet did not accelerate p16^INK4a expression, whereas arsenic modestly augmented, and cigarette smoke and UV light potently augmented, activation of p16^INK4a-mediated senescence. This work provides a toxicological platform to study mammalian aging and suggests agents that directly damage DNA promote molecular aging.

Authors

Jessica A. Sorrentino, Janakiraman Krishnamurthy, Stephen Tilley, James G. Alb Jr., Christin E. Burd, Norman E. Sharpless