Longevity & AgingGDF15 Emerges as a Master Regulator of Metabolic and Heart Disease
GDF15, a TGF-β superfamily stress cytokine, is elevated in obesity, diabetes, cardiovascular disease, cachexia, and aging. It acts primarily through its brainstem receptor GFRAL to suppress appetite and regulate energy balance. This 2025 review synthesizes the multilayered regulation of GDF15 expression—including transcription factors ATF4/CHOP, NRF2, p53, EGR1, and epigenetic silencer EZH2—and its interactions with metabolic hormones like FGF21, GLP-1, and leptin. Diet, exercise, metformin, and natural compounds all modulate GDF15 levels. Drug development targeting the GDF15/GFRAL axis, including monoclonal antibodies and fusion proteins, is actively advancing for obesity, heart failure, and cachexia.
