Multimodal Cancer Therapy and Accelerated Brain Aging: Mechanisms, Biomarkers, and Clinical Consequences

Advances in cancer therapy have markedly improved survival rates; however, long-term neurological sequelae represent a significant clinical challenge. Cancer treatment-related cognitive impairment (CRCI), commonly referred to as "chemobrain", affects a substantial proportion of cancer survivors and encompasses a broad spectrum of neuropsychiatric and cognitive symptoms, including anxiety, depression, fatigue, balance disturbances, and deficits in attention, memory, processing speed, and executive function. Increasing evidence suggests that these manifestations reflect accelerated biological aging of the brain, rather than merely transient toxic effects. This review synthesizes current clinical, molecular, and neuroimaging evidence supporting the concept of accelerated brain aging associated with multimodal cancer therapy. We summarize key molecular and cellular mechanisms including oxidative stress, neuroinflammation, blood-brain barrier dysfunction, mitochondrial impairment, cellular senescence with a senescence-associated secretory phenotype, and epigenetic remodeling that overlap with physiological brain aging hallmarks. Particular attention is given to circulating molecular biomarkers of accelerated aging, such as inflammatory mediators, senescence markers, endothelial and neuronal injury indicators, and epigenetic age acceleration, and their potential translational relevance. We discuss clinical and neuropsychological data alongside structural and functional magnetic resonance imaging findings demonstrating cortical thinning, altered gyrification, white matter microstructural changes, disrupted functional connectivity, and increased brain age estimates following cancer therapy. Framing CRCI within an accelerated brain aging paradigm may improve risk stratification, guide biomarker development, and inform personalized survivorship care.