Does the Aging Brain Become Resistant to Metastasis? A Vascular Co-Option and Perivascular-Niche Hypothesis

Several studies suggest that, in small cell lung cancer (SCLC), increasing age is associated with a lower incidence of brain metastases. This is conventionally explained by younger patients living long enough to develop them, an interpretation that fits poorly with the rapid course and short survival of SCLC. We propose a biological alternative grounded in the mechanics of brain-metastatic colonization. Because early colonization depends on the arrest of circulating tumour cells at microvessels, their perivascular survival, and outgrowth by co-option of the existing vasculature within a supportive perivascular niche, we hypothesize that the aging brain becomes a relatively resistant soil: microvascular rarefaction, endothelial senescence, chronic hypoperfusion and senescence of the perivascular niche reduce the competence of the brain to host metastatic colonization. We further propose that macroscopic cerebral atrophy is a radiologic surrogate of this reduced competence and should therefore be inversely associated with brain-metastatic incidence. The hypothesis is falsifiable, testable in matched radiologic cohorts and age-controlled experimental models, and clinically consequential for the selection of patients for prophylactic cranial irradiation.