GDF-15 Expression is Induced by Inflammatory Cell Stress and Promotes Aging
Chronic, unresolved inflammation is a feature of aging. Many of the forms of molecular damage associated with aging provoke an inflammatory response from cells, including the signaling generated by senescent cells and mitochondrial dysfunction leading to mislocalized mitochondrial DNA. Short-term inflammation is necessary for regeneration and defense against pathogens, but inflammation becomes harmful when sustained for the long term. It is disruptive to tissue structure and function, and accelerates the onset and progression of age-related conditions.
In today's open access paper, researchers note one interesting example of the way in which chronic inflammation provokes maladaptive responses. GDF-15 is an immune regulator expressed in response to inflammation, and which can dampen excessive inflammation. This is normal and beneficial in the short term. When inflammation becomes lasting, however, the constant presence of GFD-15 becomes harmful to cell function. An important goal in the treatment of aging is to find ways to suppress unwanted, chronic inflammation without suppressing necessary, transient inflammation - so far a challenge, as it appears they depend on the same pathways and systems of regulation.
GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process
The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging.
In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process.
GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.