Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation
- Cell Metab. 2020 Jul 7;32(1):44-55.e6. doi: 10.1016/j.cmet.2020.04.015.
- 1. Department of Nutrition and Public Health, Merrimack College, North Andover, MA, USA.
- 2. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA.
- 3. Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of California, San Diego, San Diego, CA, USA.
- 4. Forsyth Institute, Cambridge, MA, USA.
- 5. Department of Computer Science, University of Kentucky, Lexington, KY, USA.
- 6. Department of Physiology, University of Kentucky, Lexington, KY, USA.
- 7. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
- 8. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
- 9. Department of Medicine, Endocrinology, Diabetes & Nutrition, Boston University School of Medicine, Boston, MA, USA.
- 10. Department of Microbiology, Boston University School of Medicine, Boston, MA, USA; Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, USA.
- 11. Department of Statistics, University of Kentucky, Lexington, KY, USA.
- 12. Departments of Neurosurgery and Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
- 13. Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, USA.
- 14. Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
- 15. Department of Computer Science, University of Kentucky, Lexington, KY, USA; School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA.
- 16. Departments of Neurosurgery and Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA; Departments of Biomedical Engineering, and Engineering Science & Mechanics and Center for Neural Engineering, Pennsylvania State University, University Park, PA, USA.
- 17. Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA; Department of Medicine, University of Kentucky, Lexington, KY, USA.
- 18. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA. Electronic address: [email protected].
Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in Autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing Autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves Autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.