Aging attenuates brain metastasis in lung cancer through the MT1G/NF-κB/SPARC signaling

Aging is a major risk factor for cancer, with incidence and mortality increasing significantly with age across most cancer types. With the global population aged over 60 projected to rise from 12-22 percent by 2050, understanding the relationship between aging and cancer is critically important. Aging and cancer share several hallmarks-including cumulative genetic damage, immune senescence, altered nutrient sensing, and chronic low-grade inflammation. This overlap implies that age-related biological changes may not only correlate with increased cancer incidence but also influence tumor progression and metastasis. Despite this preconceived notion, population-based epidemiological studies have revealed an inverse association between aging and brain metastasis incidence in lung cancer, with unclear molecular mechanism(s). Here, we show a significantly lower incidence of brain metastasis in aged lung cancer patients compared to younger patients or those with brain metastasis from other cancers, based on analysis of the SEER population-based cancer registry. Mechanistically, aging activates MT1G/NFκB signaling in reactive astrocytes within the brain, leading to increased secretion of SPARC from A1 type reactive astrocytes, which suppresses tumor growth by inhibiting ITGB1 signaling in tumor cells, thereby limiting brain colonization. Notably, therapeutic targeting of ITGB1 using liposome-encapsulated SPARC peptide effectively suppresses brain tumor growth and metastasis, supporting its tumor-suppressive role. These findings uncover an age-associated protective mechanism and provide a compelling rationale for developing targeted therapies to prevent or treat brain metastasis in younger lung cancer patients.