An accurate prediction of the Remaining Useful Life (RUL) of aircraft engines plays a fundamental role in the aerospace field since it is both mission and safety critical. In fact, a reliable estimate of the RUL can effectively reduce the maintenance costs while fostering safety. This paper proposes a novel data-driven method to increase accuracy of the RUL prediction for real-time prognostic systems, considering multiple degradation mechanisms and making the model easy to implement. The proposed method exploits a novel modified k-Nearest Neighbors Interpolation (kNNI) with an a posteriori Least Square Smoothing (LSS) automatically optimized to obtain the minimum prediction error. The LSS novel formulation was also generalized and proved to be equivalent to a Cumulative and Moving Average (CMA) mixture filter, which can be easily implemented online. The method was developed and validated based on a new NASA dataset generated by the dynamic model Commercial Modular Aero-Propulsion System Simulation (N-CMAPSS) with run-to-failure data related to a small fleet of aircraft engines under realistic flight conditions. Finally, a reference kNN-based method already known in the literature was compared to the novel proposed one to demonstrate the goodness of the results and the performance improvements.