A Mathematical Model of p16INK4a and Aging

While the exact causes of mammalian aging are not known, the decline in replicative capacity of cells appears to be a factor. Activation of a particular gene, p16INK4a, causes the cell to arrest in a state of senescence at once suppressing cancer while attenuating its ability to replicate. Thus p16 may function via aging as a cancer suppressor.

Previous research has already shown that levels of p16INK4a increase exponentially with age, and recent research shows that inactivation of p16INK4a alleviates progeriod (early aging) symptoms in mice, suggesting that p16INK4a expression has an effect in the aging process.

The data used in this model of p16INK4a is taken from blood samples of 170 individuals. The level of p16INK4a was measured in blood cells of a limited lifespan, as such the model had to account for declines in p16INK4a due to apoptosis or immune clearance. Two models were created for the level of expression, the first which viewed the level of p16INK4a in a synthesis/degredation dynamic and the second which only accounted for p16INK4a loss after saturation. Both models are designed to account for the exponential increase in p16INK4a, even at an early age, leading into what is seen as an asymptotic “saturation” of p16INK4a expression. Despite some attrition, not all p16 senescent cells are cleared and many remain in the body for years.

The model also contained clinical factors which all had an effect on p16INK4a expression. Namely: smoking, exercise, and the rs10757278 genotype (Single nucleotide polymorphism). As found previously p16INK4a expression is considerably higher in those who smoke and levels of p16INK4a are considerably lower if those who exercise, but the exercise works only till age 65. The reason for this is not clear. Whether exercise loses its effect or the amount of exercise people attempt after age 65 drops considerably. The rs10757278 SNP reduces the level of p16INK4a but the exact mechanism is not known. The authors speculate that it is by activating other cell cycle control mechanisms p15INK4b and ARF which increases the death rate of cells inactivated by p16INK4a.

The use of the model allows for a way to predict molecular aging on the basis of genetics and lifestyle factors. The authors conclude stating they will work to create a better model as the amount of their data increases.

Denis Tsygankova, Yan Liub, Hanna K. Sanoffb, Norman E. Sharplessb, & Timothy C. Elston (2009). A quantitative model for age-dependent expression of the p16INK4a tumor suppressor PNAS, 106 (39)