Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation

Leena P. Bharath; Madhur Agrawal; Grace McCambridge; Dequina A. Nicholas; Hatice Hasturk; Jing Liu; Kai Jiang; Rui Liu; Zhenheng Guo; Jude Deeney; Caroline M. Apovian; Jennifer Snyder-Cappione; Gregory S. Hawk; Rebecca M. Fleeman; Riley M.F. Pihl; Katherine Thompson; Anna C. Belkina; Licong Cui; Elizabeth A. Proctor; Philip A. Kern; Barbara S. Nikolajczyk

doi:10.1016/j.cmet.2020.04.015

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation

Leena P. Bharath, Madhur Agrawal, Grace McCambridge, Dequina A. Nicholas, Hatice Hasturk, Jing Liu, Kai Jiang, Rui Liu, Zhenheng Guo, Jude Deeney, Caroline M. Apovian, Jennifer Snyder-Cappione, Gregory S. Hawk, Rebecca M. Fleeman, Riley M.F. Pihl, Katherine Thompson, Anna C. Belkina, Licong Cui, Elizabeth A. Proctor, Philip A. KernBarbara S. Nikolajczyk

Research output: Contribution to journal › Article › peer-review

275 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	44-55.e6
Journal	Cell Metabolism
Volume	32
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2020.04.015
State	Published - Jul 7 2020

Bibliographical note

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.

Keywords

T cells
autophagy
inflammaging
metformin
mitochondria

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cmet.2020.04.015

Cite this

Bharath, L. P., Agrawal, M., McCambridge, G., Nicholas, D. A., Hasturk, H., Liu, J., Jiang, K., Liu, R., Guo, Z., Deeney, J., Apovian, C. M., Snyder-Cappione, J., Hawk, G. S., Fleeman, R. M., Pihl, R. M. F., Thompson, K., Belkina, A. C., Cui, L., Proctor, E. A., ... Nikolajczyk, B. S. (2020). Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation. Cell Metabolism, 32(1), 44-55.e6. https://doi.org/10.1016/j.cmet.2020.04.015

@article{4166b4f8728d430d8924ec411f39567b,

title = "Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation",

abstract = "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.",

keywords = "T cells, autophagy, inflammaging, metformin, mitochondria",

author = "Bharath, {Leena P.} and Madhur Agrawal and Grace McCambridge and Nicholas, {Dequina A.} and Hatice Hasturk and Jing Liu and Kai Jiang and Rui Liu and Zhenheng Guo and Jude Deeney and Apovian, {Caroline M.} and Jennifer Snyder-Cappione and Hawk, {Gregory S.} and Fleeman, {Rebecca M.} and Pihl, {Riley M.F.} and Katherine Thompson and Belkina, {Anna C.} and Licong Cui and Proctor, {Elizabeth A.} and Kern, {Philip A.} and Nikolajczyk, {Barbara S.}",

note = "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: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jul,

day = "7",

doi = "10.1016/j.cmet.2020.04.015",

language = "English",

volume = "32",

pages = "44--55.e6",

number = "1",

}

Bharath, LP, Agrawal, M, McCambridge, G, Nicholas, DA, Hasturk, H, Liu, J, Jiang, K, Liu, R, Guo, Z, Deeney, J, Apovian, CM, Snyder-Cappione, J, Hawk, GS, Fleeman, RM, Pihl, RMF, Thompson, K, Belkina, AC, Cui, L, Proctor, EA, Kern, PA & Nikolajczyk, BS 2020, 'Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation', Cell Metabolism, vol. 32, no. 1, pp. 44-55.e6. https://doi.org/10.1016/j.cmet.2020.04.015

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.

KW - T cells

KW - autophagy

KW - inflammaging

KW - metformin

KW - mitochondria

UR - http://www.scopus.com/inward/record.url?scp=85085355154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85085355154&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2020.04.015

DO - 10.1016/j.cmet.2020.04.015

M3 - Article

C2 - 32402267

AN - SCOPUS:85085355154

SN - 1550-4131

VL - 32

SP - 44-55.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this