Nitrile butadiene rubbers (NBR) are widely used in sealing applications, such as O-rings inside the pneumatic system of the French high-speed train (TGV). In this application, a strong hardening of the NBRs alters the sealing function. Predicting the evolution of the mechanical properties during service life, especially the material hardening, is therefore a strategic issue to optimize time in maintenance operations of the TGV's pneumatic system. The main goal of this study is to reproduce the aging observed on a train's pneumatic system by performing thermo-oxidative accelerated aging tests with different commercial nitrile rubbers at several temperatures and up to 2016 h. After achieving similar degradation to specimens aged on trains, aging mechanisms and effects have been investigated through different characterization techniques: infrared spectroscopy, swelling tests, X-ray fluorescence spectrometry, differential scanning calorimetry, thermogravimetric analysis, and micro-hardness measurements. The results obtained enabled us to identify and to relate aging mechanisms to aging conditions and to precisely determine and quantify the effects of physicochemical state evolution on the mechanical properties of each NBR considered. Extra crosslinks and oxidative functionalities form in the different elastomers, making them hard and brittle, and thus impacting the sealing function.