TY - JOUR
T1 - Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation
AU - Bharath, Leena P.
AU - Agrawal, Madhur
AU - McCambridge, Grace
AU - Nicholas, Dequina A.
AU - Hasturk, Hatice
AU - Liu, Jing
AU - Jiang, Kai
AU - Liu, Rui
AU - Guo, Zhenheng
AU - Deeney, Jude
AU - Apovian, Caroline M.
AU - Snyder-Cappione, Jennifer
AU - Hawk, Gregory S.
AU - Fleeman, Rebecca M.
AU - Pihl, Riley M.F.
AU - Thompson, Katherine
AU - Belkina, Anna C.
AU - Cui, Licong
AU - Proctor, Elizabeth A.
AU - Kern, Philip A.
AU - Nikolajczyk, Barbara S.
N1 - Funding Information:
We thank Dr. Sara Santa Cruz Calvo for critical reading of the manuscript. This work was supported by grants R01DK108056 and U 01DE025383 (B.S.N.), UL1TR001998 from NCATS (P.A.K.), University of Kentucky College of Medicine (B.S.N.), University of Kentucky Markey Cancer Center and Flow Cytometry Core P30CA177558 (B.S.N.), Boston University Flow Cytometry Core Facility T32AI089673 , and Boston University Medical Center , Metabolism, Endocrinology and Obesity training grant T32DK007201 . This work was also supported by the College of Health Sciences , Faculty Development grant (FDG) and Sakowich Center for Undergraduate Research and Creative Activities grant (SCURCA), Merrimack College (L.P.B.).
Funding Information:
We thank Dr. Sara Santa Cruz Calvo for critical reading of the manuscript. This work was supported by grants R01DK108056 and U01DE025383 (B.S.N.), UL1TR001998 from NCATS (P.A.K.), University of Kentucky College of Medicine (B.S.N.), University of Kentucky Markey Cancer Center and Flow Cytometry Core P30CA177558 (B.S.N.), Boston University Flow Cytometry Core Facility T32AI089673, and Boston University Medical Center, Metabolism, Endocrinology and Obesity training grant T32DK007201. This work was also supported by the College of Health Sciences, Faculty Development grant (FDG) and Sakowich Center for Undergraduate Research and Creative Activities grant (SCURCA), Merrimack College (L.P.B.). Conceptualization, B.S.N. and L.P.B.; Methodology, L.P.B. J.L. L.C. and A.C.B.; Investigation, L.P.B. M.A. G.M. D.N.A. Z.G. K.J. R.M.F.P. R.L. and A.C.B.; Formal Analysis, J.L. L.C. R.M.F. E.A.P. A.C.B. and K.T.; Supervision and Fund Acquisition, B.S.N.; Writing ? Review & Editing, L.P.B. and B.S.N.; Resources, H.H. J.D. C.M.A. J.S.C. and P.A.K. The authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/7/7
Y1 - 2020/7/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2020.04.015
DO - 10.1016/j.cmet.2020.04.015
M3 - Article
C2 - 32402267
AN - SCOPUS:85085355154
VL - 32
SP - 44-55.e6
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -