GDF15 Helps to Resist Age-Related Chronic Inflammation
Aging is accompanied by rising levels of sustained inflammation, a chronic overactivation of the immune system. This inappropriate activity on the part of immune cells disrupts tissue function in numerous ways, contributing to onset and progression of all of the common and ultimately fatal age-related conditions, from atherosclerosis to Alzheimer's disease. Ways to control this inflammation without disrupting other, necessary immune functions are thus likely to be broadly beneficial. Numerous age-related changes contribute to chronic inflammation; one of the most relevant for near term intervention is the accumulation of senescent cells in tissues throughout the body. These cells are near all destroyed quite rapidly in youth, with with age the processes of removal become less efficient. Senescent cells secrete pro-inflammatory signal molecules, and the more of them there are, the worse the outcome. Fortunately, senolytic therapies to selectively destroy senescent cells are presently in active development. Other approaches to inflammation will also be needed, however.
Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals.
In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression.
Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.
It's unbelievable that there hasn't been more R&D into making immune suppression agents for inflammation. There may be some drugs in transplantation that are used to avoid immune rejection that can be modified.
Anyone help with my confusion? This article says GDF-15 deficiency is bad, reduced expression causes inflammation. That it's indispensable.
Yet other articles say things like:
"The stress-induced cytokine GDF15 (growth differentiation factor 15; also known as macrophage inhibitory cytokine-1) is an atypical member of the transforming growth factor beta superfamily. It circulates at high levels in humans, with the majority of its expression occurring in the liver, lung, kidney and placenta.Serum levels have been shown to increase with age, smoking, intense exercise, cancer, and a range of other disease states5."
Intense excercise and smoking both contributing?
So is it it good or bad, how does one balance it?