GDF15 connecting ageing and cancer: Mechanistic insights and therapeutic opportunities

Growth Differentiation Factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, is highly expressed in response to cellular stress, ageing, and various pathological conditions. As a key component of the senescence-associated secretory phenotype, it plays important roles in modulating inflammation, mitochondrial dysfunction, energy metabolism, and appetite. It signals through the glial-derived neurotrophic factor receptor alpha-like receptor in the brainstem to suppress appetite and modulate energy balance. Increasing evidence supports that GDF15 exhibits dual and context-dependent functions in cancer, contributing to both tumor suppression and progression through its regulation of cellular proliferation, metastasis, and interactions within the tumor microenvironment. Elevated GDF15 levels have been observed in cardiovascular diseases, metabolic disorders, neurodegenerative diseases, and numerous malignancies, making it a potential biomarker and therapeutic target for a spectrum of age-related and pathological conditions, including cancer. Emerging therapeutic strategies targeting GDF15 encompass the use of agonists for obesity and antagonists for cachexia, either alone or in combination with immunotherapy, reflecting its complex role in disease. A comprehensive understanding of its context-dependent roles may shed light on fundamental disease mechanisms, offering a foundation for the development of innovative and personalized therapeutic approaches.