@article{a416a230f70f4ec09700ff8aaf80ca86,
title = "Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice",
abstract = "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.",
keywords = "T cell, aging, inflammation, mitochondria, senescence",
author = "Moon, {Ji Sun} and Goeminne, {Ludger J.E.} and Kim, {Jung Tae} and Tian, {Jing Wen} and Kim, {Seok Hwan} and Nga, {Ha Thi} and Kang, {Seul Gi} and Kang, {Baeki E.} and Byun, {Jin Seok} and Lee, {Young Sun} and Jeon, {Jae Han} and Minho Shong and Johan Auwerx and Dongryeol Ryu and Yi, {Hyon Seung}",
note = "Funding Information: This work was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning, Korea (NRF-2018R1C1B6004439, NRF-2019M3E5D1A02068575), Gilead Sciences Asia Ltd and CNUH Research Fund, 2018. M.S and S.K.K were also supported by the NRF (NRF-2017K1A1A2013124 and NRF-2017R1E1A1A01075126). D.R. was supported by Samsung Research Fund, Sungkyunkwan University, 2019. J.A. was supported by grants from the EPFL, the European Research Council (ERC-AdG-787702), the Swiss National Science Foundation (SNSF 31003A_179435), and a GRL grant of the National Research Foundation of Korea (NRF 2017K1A1A2013124). L.J.E.G. was supported by a Swiss Government Excellence Scholarship (FCS ESKAS-Nr. 2019.0009). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina - Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). The GTEx datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v8.p2. Funding Information: This work was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning, Korea (NRF‐2018R1C1B6004439, NRF‐2019M3E5D1A02068575), Gilead Sciences Asia Ltd and CNUH Research Fund, 2018. M.S and S.K.K were also supported by the NRF (NRF‐2017K1A1A2013124 and NRF‐2017R1E1A1A01075126). D.R. was supported by Samsung Research Fund, Sungkyunkwan University, 2019. J.A. was supported by grants from the EPFL, the European Research Council (ERC‐AdG‐787702), the Swiss National Science Foundation (SNSF 31003A_179435), and a GRL grant of the National Research Foundation of Korea (NRF 2017K1A1A2013124). L.J.E.G. was supported by a Swiss Government Excellence Scholarship (FCS ESKAS‐Nr. 2019.0009). The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina ‐ Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). The GTEx datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v8.p2. Publisher Copyright: {\textcopyright} 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd",
year = "2020",
month = aug,
day = "1",
doi = "10.1111/acel.13195",
language = "English",
volume = "19",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "8",
}
