The virtual aging brain: Causal inference supports interhemispheric dedifferentiation in healthy aging

•VAB mechanistically confirm the hypothesis that inter-hemispheric SC serves as a pivotal basis for homotopic FC.•Global neuromodulation increases with age and with SC deterioration, but it is negatively related to verbal memory and concept shifting.•Increased SC-FC tethering might suggest an amplification of loss of dynamical flexibility, especially in poor cognitive performers.•Global modulation increase seems not to happen for the high performing group, likely due to better brain maintenance.•SBI confirms the increase of SC neuromodulation with aging and retrieves working points with the same age-declining FC and FCD features. The mechanisms of cognitive decline and its variability during healthy aging are not fully understood, but have been associated with reorganization of white matter tracts and functional brain networks. Here, we built a brain network modeling framework to infer the causal link between structural connectivity and functional architecture and the consequent cognitive decline in aging. By applying in-silico interhemispheric degradation of structural connectivity, we reproduced the process of functional dedifferentiation during aging. Thereby, we found the global modulation of brain dynamics by structural connectivity to increase with age, which was steeper in older adults with poor cognitive performance. We validated our causal hypothesis via a deep-learning Bayesian approach. Our results might be the first mechanistic demonstration of dedifferentiation during aging leading to cognitive decline.