期刊
AGING CELL
卷 19, 期 8, 页码 -出版社
WILEY
DOI: 10.1111/acel.13195
关键词
aging; inflammation; mitochondria; senescence; T cell
资金
- Gilead Sciences Asia Ltd
- Chungnam National University Hospital
- National Research Foundation of Korea [2017K1A1A2013124, 2017R1E1A1A01075126, 2018R1C1B6004439, 2019M3E5D1A02068575]
- National Research Foundation of Korea [2017R1E1A1A01075126, 2018R1C1B6004439, 2019M3E5D1A02068575, 2017K1A1A2013124] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 ofGDF15as 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 hepaticGdf15expression. Mendelian randomization links reducedGDF15expression 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 inGdf15-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.
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