GDF-15

Growth differentiation factor 15 (GDF15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor beta superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. ^[1] GDF15 is recently emerging not only as a stress-related mitokine but also as a key player in the aging process, being one of the most up-regulated proteins with age and associated with a variety of age-related diseases. ^[2] Physiological expression is barely detectable in most somatic tissues in humans but is abundant in placenta, and a moderate increase in blood levels is observed with age. ^[3]

GDF15 binds to the glial-cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and recruits the receptor tyrosine kinase RET in the hindbrain to reduce food intake and body mass, largely independently of other appetite-regulating hormones. ^[1] It is a stress-response cytokine whose levels increase in response to cell stress, and it may also exert anti-inflammatory effects. ^{[4] [1]} GDF15 may be a pleiotropic factor with protective roles during stress and aging that can turn detrimental when chronically elevated in old age. ^[2]