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

Authors

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

Publication Date

7-7-2020

Journal

Cell Metabolism

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

Adult, Aging, Autophagy, Humans, Hypoglycemic Agents, Inflammation, Metformin, Middle Aged, Mitochondria, inflammaging, T cells, autophagy

Comments

Supplementary Materials

PMID: 32402267