Efficient ageing: Simulated lesion of the structural connectome reveals optimised decline in the healthy ageing brain

Healthy ageing is associated with widespread white-matter change and altered connectome organisation, yet the link between local microstructural decline and whole-brain network communication remains unclear. Here we combined tract-based spatial statistics (TBSS) with probabilistic tractography and graph analysis to quantify the connectome-level consequences of age-sensitive white-matter hotspots. In two independent diffusion MRI datasets of healthy young and older adults (n = 144 total; Dataset 1: 77 participants; Dataset 2: 67 participants), we first identified age-sensitive fractional anisotropy clusters and then used them as constraints in a cross-dataset simulated-lesion framework. This allowed us to estimate how strongly each structural connection depended on age-sensitive tissue and to test the resulting network effects against matched-mass null lesions. Across both datasets, ageing hotspot lesioning reduced global efficiency, but consistently less than expected under the null model, indicating a less-than-random disruption of network integration. Age-sensitive tissue was disproportionately embedded in the brain’s integrative backbone: proportional degree loss was strongest in high-degree nodes, rich-club connections showed the greatest hotspot dependence, and nodewise losses were concentrated in frontal, cingulate and subcortical association systems, whereas posterior sensory and temporo-limbic regions were relatively spared. These findings suggest that healthy ageing reflects a selective and constrained reconfiguration of structural connectivity rather than simply pointing to uniform decline.