Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15): a new marker of all‐cause mortality

Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15) is a member of the TGF‐b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC‐1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC‐1/GDF15 may be a marker of all‐cause mortality. To determine whether serum MIC‐1/GDF15 estimation is a predictor of all‐cause mortality, we examined a cohort of 876 male subjects aged 35–80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC‐1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same‐sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL‐6) and C‐reactive protein (CRP) available. Patients were followed for up to 14 years and had cause‐specific and all‐cause mortality determined. Serum MIC‐1/GDF15 levels predicted mortality in the all‐male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38–8.26). This finding was validated in the twin cohort. Serum MIC‐1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL‐6 and CRP. Additionally, serum MIC‐1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC‐1/GDF15 is a novel predictor of all‐cause mortality.

[1]  M. Haluzík,et al.  Association of macrophage inhibitory cytokine-1 with nutritional status, body composition and bone mineral density in patients with anorexia nervosa: the influence of partial realimentation , 2010, Nutrition & metabolism.

[2]  Linda Partridge,et al.  Extending Healthy Life Span—From Yeast to Humans , 2010, Science.

[3]  A. Salmon,et al.  Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? , 2010, Free radical biology & medicine.

[4]  D. Richardson,et al.  Iron Chelator-Mediated Alterations in Gene Expression: Identification of Novel Iron-Regulated Molecules That Are Molecular Targets of Hypoxia-Inducible Factor-1α and p53 , 2010, Molecular Pharmacology.

[5]  Peter Dalgaard,et al.  R Development Core Team (2010): R: A language and environment for statistical computing , 2010 .

[6]  L. Donehower Using mice to examine p53 functions in cancer, aging, and longevity. , 2009, Cold Spring Harbor perspectives in biology.

[7]  R. Dietrich,et al.  Potential of deoxynivalenol to induce transcription factors in human hepatoma cells. , 2009, Molecular nutrition & food research.

[8]  F. Wright,et al.  Transcriptional response of rat frontal cortex following acute In Vivo exposure to the pyrethroid insecticides permethrin and deltamethrin , 2008, BMC Genomics.

[9]  M. Olschewski,et al.  Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. , 2008, American journal of respiratory and critical care medicine.

[10]  D. Leahy,et al.  Functionally significant insulin-like growth factor I receptor mutations in centenarians , 2008, Proceedings of the National Academy of Sciences.

[11]  J. Carrero,et al.  Telomere attrition is associated with inflammation, low fetuin‐A levels and high mortality in prevalent haemodialysis patients , 2008, Journal of internal medicine.

[12]  Rolf-Edgar Silber,et al.  Potential biomarkers of ageing , 2008, Biological chemistry.

[13]  David Hinkley,et al.  Bootstrap Methods: Another Look at the Jackknife , 2008 .

[14]  L. Wallentin,et al.  Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. , 2007, European heart journal.

[15]  G. Mcclearn,et al.  Telomere length predicts survival independent of genetic influences , 2007, Aging cell.

[16]  W. D. Fairlie,et al.  Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1 , 2007, Nature Medicine.

[17]  G. Fonarow,et al.  CARDIOVASCULAR AND SURVIVAL PARADOXES IN DIALYSIS PATIENTS: Reverse Epidemiology beyond Dialysis Patients: Chronic Heart Failure, Geriatrics, Rheumatoid Arthritis, COPD, and AIDS , 2007, Seminars in dialysis.

[18]  Xiao-yan Li,et al.  Celecoxib induces apoptosis in COX-2 deficient human gastric cancer cells through Akt/GSK3beta/NAG-1 pathway. , 2007, Cancer letters.

[19]  P. Tak,et al.  Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: a potential marker of erosive joint destruction. , 2007, Arthritis and rheumatism.

[20]  H. Johnen,et al.  Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer. , 2006, Cancer research.

[21]  A. Cataldi,et al.  p53 and p66 Proteins Compete for Hypoxia-Inducible Factor 1 Alpha Stabilization in Young and Old Rat Hearts Exposed to Intermittent Hypoxia , 2006, Gerontology.

[22]  G. Hampton,et al.  Measurement of Serum Levels of Macrophage Inhibitory Cytokine 1 Combined with Prostate-Specific Antigen Improves Prostate Cancer Diagnosis , 2006, Clinical Cancer Research.

[23]  S. Badve,et al.  The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells. , 2005, Carcinogenesis.

[24]  J. Kench,et al.  The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. , 2005, Cancer research.

[25]  Seong-ho Lee,et al.  Identification of Nonsteroidal Anti-inflammatory Drug-activated Gene (NAG-1) as a Novel Downstream Target of Phosphatidylinositol 3-Kinase/AKT/GSK-3β Pathway* , 2004, Journal of Biological Chemistry.

[26]  Pär Stattin,et al.  H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. , 2004, Journal of the National Cancer Institute.

[27]  C. Franceschi,et al.  Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. , 2003, The Journal of clinical endocrinology and metabolism.

[28]  K. Unsicker,et al.  Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways* , 2003, The Journal of Biological Chemistry.

[29]  J. Welsh,et al.  Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P. Lichtenstein,et al.  The Swedish Twin Registry: a unique resource for clinical, epidemiological and genetic studies , 2002, Journal of internal medicine.

[31]  S. Breit,et al.  Antibody-based approach to high-volume genotyping for MIC-1 polymorphism. , 2002, BioTechniques.

[32]  W. D. Fairlie,et al.  Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study , 2002, The Lancet.

[33]  Stephen N. Jones,et al.  p53 mutant mice that display early ageing-associated phenotypes , 2002, Nature.

[34]  H. Vogel,et al.  Analysis of ku80-Mutant Mice and Cells with Deficient Levels of p53 , 2000, Molecular and Cellular Biology.

[35]  Lynda Chin,et al.  p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis , 1999, Cell.

[36]  Sandy Chang,et al.  Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice , 1999, Cell.

[37]  B Johansson,et al.  Substantial genetic influence on cognitive abilities in twins 80 or more years old. , 1997, Science.

[38]  S. Covey,et al.  Substantial Genetic Influence on Cognitive Abilities in Twins 80 or More Years Old , 1997 .

[39]  J. Hanley,et al.  A method of comparing the areas under receiver operating characteristic curves derived from the same cases. , 1983, Radiology.