The highway bridge infrastructure system within the United States is rapidly deteriorating and a significant percentage of these bridges are approaching the end of their useful service life. Deterioration mechanisms affect the load resisting capacity of critical structural components and render aging highway bridges more vulnerable to earthquakes compared to pristine structures. While past literature has traditionally neglected the simultaneous consideration of seismic and aging threats to highway bridges, a joint fragility assessment framework is needed to evaluate the impact of deterioration mechanisms on bridge vulnerability during earthquakes. This research aims to offer an efficient methodology for accurate estimation of the seismic fragility of aging highway bridges. In addition to aging, which is a predominant threat that affects lifetime seismic reliability, other stressors such as repeated seismic events or simultaneous presence of truck traffic are also incorporated in the seismic fragility analysis. The impact of deterioration mechanisms on bridge component responses are assessed for a range of exposure conditions following the nonlinear dynamic analysis of three-dimensional high-fidelity finite element aging bridge models. Subsequently, time-dependent fragility curves are developed at the bridge component and system level to assess the probability of structural damage given the earthquake intensity. In addition to highlighting the importance of accounting for deterioration mechanisms, these time-evolving fragility curves are used within an improved seismic loss estimation methodology to aid in efficient channeling of monetary resources for structural retrofit or seismic upgrade. Further, statistical learning methods are employed to derive flexible parameterized fragility models conditioned on earthquake hazard intensity, bridge design parameters, and deterioration affected structural parameters to provide significant improvements over traditional fragility models and aid in efficient estimation of aging bridge vulnerabilities. In order to facilitate bridge management decision making, a methodology is presented to demonstrate the applicability of the proposed multi-dimensional fragility models to estimate the in-situ aging bridge reliabilities with field-measurement data across a transportation network. Finally, this research proposes frameworks to offer guidance to risk analysts regarding the importance of accounting for supplementary threats stemming from multiple seismic shocks along the service life of the bridge structures and the presence of truck traffic atop the bridge deck during earthquake events.