The Pro/Pro genotype of the p53 codon 72 polymorphism modulates PAI-1 plasma levels in ageing

Plasminogen activator inhibitor 1 (PAI-1) is over-expressed during ageing and it has been linked to cellular senescence. Recently, PAI-1 has been also identified in vitro as a critical downstream target of p53. TP53, the p53 gene, has a common functional polymorphism at codon 72 which influences the capability to modulate both apoptosis and cell senescence. In the attempt to demonstrate an in vivo role of p53 in the relationship between PAI-1 and age, we studied PAI-1 on 570 healthy subjects (aged from 18 to 92yrs.). PAI-1 showed significant relationship with age (r=0.12, p=0.02). Stratifying by genotype, it became evident that the association between PAI-1 and age was mainly due to Pro/Pro subjects (partial r=0.75, p<0.01). These results have been confirmed by a validation study on an independent sample population of 496 subjects (aged from 18 to 94yrs.). This is the first demonstration of an in vivo role of TP53 polymorphism in PAI-1 regulation, supporting the hypothesis that the effects of this polymorphism are age-dependent. In particular, our results indicate that Pro/Pro genotype plays a pivotal role in determining PAI-1 levels in aged subjects, while in Arg carriers PAI-1 levels are associated to the known insulin related determinants.