Cited by 614Autophagy in Disease and TherapyGenetics, Aging, and Longevity in Model OrganismsMetabolism, Diabetes, and Cancer

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

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Bharath, Leena P., Agrawal, Madhur, McCambridge, Grace, Nicholas, Dequina A., Hasturk, Hatice, Liu, Jing, Jiang, Kai, Liu, Rui, Guo, Zhenheng, Deeney, Jude, Apovian, Caroline M., Snyder-Cappione, Jennifer, Hawk, Gregory S., Fleeman, Rebecca M., Pihl, Riley M.F., Thompson, Katherine, Belkina, Anna C., Cui, Licong, Proctor, Elizabeth A., Kern, Philip A., Nikolajczyk, Barbara S.·2020·Cell Metabolism

DOI 10.1016/j.cmet.2020.04.015PMC PMC7217133

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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.

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Authors: 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., Kern, P. A., & Nikolajczyk, B. S.
Affiliations: Merrimack College (US)
University of Kentucky (US)
University of California San Diego (US)
Boston University (US)
Pennsylvania State University (US)
Corresponding author: Nikolajczyk, Barbara S.
ORCID: Bharath, Leena P.
Agrawal, Madhur
Nicholas, Dequina A.
Liu, Jing
Jiang, Kai
Guo, Zhenheng
Deeney, Jude
Apovian, Caroline M.
Snyder-Cappione, Jennifer
Hawk, Gregory S.
Fleeman, Rebecca M.
Pihl, Riley M.F.
Thompson, Katherine
Belkina, Anna C.
Cui, Licong
Proctor, Elizabeth A.
Kern, Philip A.
Nikolajczyk, Barbara S.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2020-07
Volume: 32
Issue: 1
Pages: 44-55.e6
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2020.04.015
PMC: PMC7217133
OpenAlex: W3024177706
Cited by: 614
References: 90
Citations by year: 2026: 66 · 2025: 123 · 2024: 110 · 2023: 120 · 2022: 83 · 2021: 81 · 2020: 29
FWCI: 56.30
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
Locations: Cell Metabolism (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
UKnowledge (University of Kentucky) (submittedVersion)
Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders: National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: metformin, autophagy, mitochondrial function, inflammaging, Th17 cells, CD4+ T cells, aging, STAT3, IL-17A, redox imbalance, mitophagy, healthspan
MeSH terms: Adult, Aging, Autophagy, Humans, Hypoglycemic Agents, Inflammation, Metformin, Middle Aged, Mitochondria

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

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