p16INK4a reporter mice reveal age-promoting effects of environmental toxicants

J Clin Invest. 2014 Jan;124(1):169-73. doi: 10.1172/JCI70960. Epub 2013 Dec 16.

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 p16INK4a, which rises dynamically with aging and correlates with age-associated disease. Activation of p16INK4a was visualized in vivo using a murine strain that harbors a knockin of the luciferase gene into the Cdkn2a locus (p16LUC mice). We exposed p16LUC 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 p16INK4a expression, whereas arsenic modestly augmented, and cigarette smoke and UV light potently augmented, activation of p16INK4a-mediated senescence. This work provides a toxicological platform to study mammalian aging and suggests agents that directly damage DNA promote molecular aging.

MeSH terms

  • Aging*
  • Animals
  • Arsenic / toxicity*
  • Biomarkers / metabolism
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • DNA Damage
  • Diet, High-Fat / adverse effects
  • Environmental Exposure
  • Genes, Reporter
  • Luciferases, Firefly / biosynthesis
  • Luciferases, Firefly / genetics
  • Lung Diseases / etiology
  • Lung Diseases / pathology
  • Mice
  • Mice, Transgenic
  • Mutagens / adverse effects
  • Mutagens / toxicity*
  • Promoter Regions, Genetic
  • Skin Diseases / etiology
  • Skin Diseases / pathology
  • Smoke / adverse effects*
  • Tobacco
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / radiation effects
  • Ultraviolet Rays / adverse effects*
  • Whole Body Imaging

Substances

  • Biomarkers
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Mutagens
  • Smoke
  • Luciferases, Firefly
  • Arsenic