Systems biology and systems neurophysiology generate comprehensive mechanistic models of the spatial-temporal evolution of body system networks from physiological to pathophysiological conditions. Alzheimer's disease (AD)-related pathophysiological alterations converge with overexpressed age-related functional decline, i.e. aging, which is induced by genetic- and stochastic time-dependent events. Accumulation of cellular senescence has a casual role in aging-related disease and senotherapeutic drugs have already shown encouraging results for counteracting the detrimental effect of senescence. However, the non-linear complex nature of AD pathophysiology calls for a systems-level integration of aging dynamics, from molecules until large-scale networks. We need a holistic systems-wide comprehensive model of aging which is constituted by a non-linear spatial-temporal weakening of adaptive responses resulting in the activation of compensatory mechanisms that ensure biological robustness, resilience, and finally preserve homeodynamics. After exceeding the threshold of compensated (resilient) aging, a cascade of decompensatory events occurs, ultimately triggering irreversible systems failure that, at some advanced stages, reflect widespread "pathophysiological hallmarks of AD". The gap in the comprehensive understanding of aging, resilience, and AD pathophysiological evolution will be filled through a quantitative, flexible, and integrative modeling approach to detect multiple spatial-temporal patterns and for dissecting causal mechanisms and downstream cascades throughout the aging-AD continuum. Novel technological and conceptual advances, will enable the systems-level integration of aging signatures as well as compensatory mechanisms that provide resilience to early functional decline. This will provide new systems-scaled outcomes and endpoints to map and therapeutically enhance resilience, accomplishing a long-lasting compensated aging.
