Age-Related Metabolic Reprogramming in Cancer Cell Plasticity

Metabolic plasticity is a defining hallmark of cancer cells, enabling them to adapt dynamically to fluctuating demands for energy, biosynthesis, and redox balance throughout tumor progression—from escaping oncogene-induced senescence (OIS) to rapid proliferation, local invasion, and distant metastasis. The selection of metabolic pathways is shaped not only by intrinsic cellular needs but also by extrinsic factors such as substrate availability within the tumor microenvironment (TME). Dysregulated metabolism, a hallmark of aging, creates unique metabolic landscapes characterized by altered nutrient levels (glucose, amino acids, lipids) and increased levels of reactive oxygen species and inflammatory metabolites. While an excess of certain nutrients (e.g., sugars and lipids) may facilitate OIS escape and tumor cell proliferation, other age-related metabolic stresses, such as oxidative damage, chronic inflammation, and nutrient depletion, drive cancer cells to switch toward an invasive phenotype, thereby promoting metastasis. Despite aging being the most significant risk factor for cancer, its influence on tumor cell metabolic and phenotypic plasticity remains incompletely understood. This review synthesizes current literature on how age-associated metabolic changes in the TME modulate cancer cell metabolism and enhance phenotypic plasticity to promote tumor progression. We emphasize unresolved mechanistic questions regarding how aging predisposes cancer cells to more aggressive behavior via metabolic remodeling and discuss potential therapeutic strategies targeting these age-specific vulnerabilities to improve outcomes in elderly cancer patients.