A quantitative model for age-dependent expression of the p16INK4a tumor suppressor

Recent work has shown that expression of the p16(INK4a) tumor suppressor increases with chronological age. Expression is accelerated by gerontogenic behaviors such as tobacco use and physical inactivity, and is also influenced by allelic genotype of a polymorphic single nucleotide polymorphism (SNP) rs10757278 that is physically linked with the p16(INK4a) ORF. To understand the relationship between p16(INK4a) expression, chronologic age, subject characteristics and host genetics, we sought to develop a mathematical model that links p16(INK4a) expression with aging. Using an annotated dataset of 170 healthy adults for whom p16(INK4a) expression and subject genotypes were known, we developed two alternative stochastic models that relate p16(INK4a) expression to age, smoking, exercise and rs10757278 genotype. Levels of p16(INK4a) increased exponentially and then saturated at later chronologic ages. The model, which best fit the data, suggests saturation occurs because of p16(INK4a)-dependent attrition of subjects at older chronologic ages, presumably due to death or chronic illness. An important feature of our model is that factors that contribute to death in a non p16(INK4a)-dependent manner do not affect our analysis. Interestingly, tobacco-related increases in p16(INK4a) expression are predicted to arise from a decrease in the rate of p16(INK4a)-dependent death. This analysis is most consistent with the model that p16(INK4a) expression monotonically increases with age, and higher expression is associated with increased subject attrition.