Turning Back the Ageing Clock? Brain Age in Neuroprotective and Clinical Interventions

Neuroimaging-derived brain age has emerged as an intuitive marker of brain health and cognitive longevity. The difference between brain age and chronological age, termed brain-predicted age difference (brain-PAD), quantifies deviation from normative brain ageing and may help evaluate whether interventions could attenuate brain ageing trajectories. This review synthesizes the methodological foundations of brain age estimation, factors linked to brain-PAD across healthy ageing and disease, evidence from clinical interventions, and emerging translational applications in clinical trials. Across non-clinical and clinical populations, older-appearing brains are associated with poorer cognitive and physical function, greater physiological burden, higher mortality risk, cardiometabolic vulnerability, and a range of neurological and psychiatric disorders. Evidence from interventions remains limited and heterogeneous. Exercise provides the clearest proof-of-concept that brain-PAD is potentially modifiable, whereas dietary interventions and multidomain lifestyle programmes have produced suggestive but preliminary evidence; cognitive, sleep, and mind-body interventions have yielded sparse or mixed findings. In clinical settings, brain-PAD shows promise for predicting disease conversion, disability progression, and treatment response, and may support trial stratification, enrichment and monitoring. Evidence that medication, neuromodulation, or other interventions reliably normalize brain-PAD, however, remains inconsistent. We argue that brain-PAD is a useful but biologically nonspecific, model-derived biomarker. Its interpretation critically depends on pipeline choice, harmonization, age-bias correction, and longitudinal validity. For now, brain-PAD is best regarded as a complementary biomarker and exploratory outcome rather than a validated surrogate endpoint. Future progress will require standardized methods, validation in representative populations and prespecified longitudinal cohorts that links brain-age changes to meaningful clinical outcomes.