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

TL;DR

Cancer treatments can cause long-term brain aging-like effects, leading to cognitive and neurological issues in survivors.

Contribution

The paper proposes that cancer treatment-related cognitive impairment reflects accelerated brain aging rather than temporary toxicity.

Findings

Multimodal cancer therapy induces brain aging processes like oxidative stress and inflammation.

Brain imaging shows structural and functional changes consistent with accelerated aging.

Circulating biomarkers indicate aging-related damage linked to cancer treatments.

Abstract

Cancer therapies have improved survival, but many survivors develop long-term cognitive and neurological problems known as cancer treatment-related cognitive impairment (CRCI or “chemobrain”). Symptoms include memory and attention deficits, fatigue, mood changes, and balance problems. Growing evidence suggests these effects reflect accelerated brain aging rather than temporary toxicity. This review summarizes clinical, molecular, and neuroimaging data showing that cancer therapy induces processes similar to normal brain aging, including oxidative stress, inflammation, mitochondrial dysfunction, cellular senescence, and epigenetic changes. Brain imaging reveals structural and functional alterations, while circulating biomarkers indicate aging-related damage. Viewing CRCI as accelerated brain aging may improve diagnosis, biomarker development, and personalized rehabilitation strategies.

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.

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