Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging

Abstract Metabolic diseases and age-related disorders represent a major global health burden driven by the increasing prevalence of obesity and obesity-associated complications. These disorders are characterized by chronic disturbances in energy homeostasis. A key feature linking metabolic disease and aging is the activation of stress-related pathways, which contribute to progressive metabolic dysfunction. Among the endocrine mediators of cellular stress, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) have emerged as key regulators of metabolic homeostasis. Both are induced by similar stress conditions, including nutrient imbalance, inflammation, oxidative and endoplasmic reticulum (ER) stress and mitochondrial dysfunction, and are elevated in pathophysiological conditions such as obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD) and aging. FGF21 and GDF15 also share overlapping regulatory pathways and complementary functions, suggesting a potential coordinated regulation and functional interplay. However, the extent and physiological relevance of this possible interrelationship remain incompletely understood. This review summarizes current knowledge on the regulation, tissue sources, and signaling mechanisms of FGF21 and GDF15 across metabolic diseases and aging, with particular attention to their roles as mediators of adaptive metabolic responses and their overlapping biological actions. We further discuss their context-dependent effects under acute and chronic stress and their relevance as biomarkers of metabolic dysfunction and disease progression. Collectively, this work highlights FGF21 and GDF15 as integrated stress signals linking cellular stress to systemic metabolic adaptation, providing a conceptual framework for understanding their cooperative roles and regulation in metabolic and age-related diseases, which may have therapeutic potential.