Life, services and activities within cities have commonly been studied by separate disciplines, each one independent from the others. One such approach is the computer simulation, which enables in-depth modelling and cost-effective evaluation of city phenomena. However, the adoption of integrated city simulations faces several barriers, such as managerial, social, and technical, despite its potential to support city planning and policymaking. This paper introduces the City Physiology: a new conceptual framework to facilitate the integration of city layers when designing holistic simulators. The physiology is introduced and applied through a process of three steps. Firstly, a literature review is offered in order to study the terminology and the progress already made towards integrated modelling of different urban systems. Secondly, interactions between urban systems are extracted from the approaches studied before. Finally, the pipeline to carry out the integration strategy is described. In addition to providing a conceptual tool for holistic simulations, the framework enables the discovery of new research lines generated by previously unseen connections between city layers. Being an open framework, available to all researchers to use and broaden, the authors of this paper envisage that it will be a valuable resource in establishing an exact science of cities.