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

Area of Science:

• Immunology
• Gerontology
• Metabolic Disease Research

Background:

• Aging is linked to chronic inflammation (inflammaging), a risk factor for age-associated diseases.
• CD4+ T cells exhibit distinct inflammatory profiles with age, resembling those seen in diabetes.
• Older individuals show impaired T cell autophagy and mitochondrial function, contributing to redox imbalance.

Purpose of the Study:

• To investigate the role of metformin in modulating age-related T cell inflammation.
• To explore the connection between autophagy, mitochondrial function, and the Th17 inflammaging profile.
• To define a novel inflammaging signature in T cells and its link to diabetes.

Main Methods:

• Comparative cytokine profiling and bioinformatic analysis of T cells from younger and older subjects.
• Assessment of autophagy and mitochondrial bioenergetics in T cells.
• Experimental manipulation using metformin, autophagy-targeting siRNA, and mitophagy-targeting siRNA.
• Analysis of STAT3 activation and IL-17A/F promoter binding.

Main Results:

• Older T cells displayed a pro-inflammatory Th17 profile with impaired autophagy and mitochondrial function.
• Metformin treatment improved T cell autophagy and mitochondrial bioenergetics, reducing the Th17 inflammaging signature.
• Disrupting autophagy in young T cells activated the Th17 profile via STAT3, while mitophagy disruption did not.
• The observed inflammaging profile in aging T cells mirrors that associated with diabetes.

Conclusions:

• Metformin ameliorates a specific T cell inflammaging profile by enhancing autophagy and mitochondrial function.
• Autophagy is a key regulator of the Th17 master regulator STAT3 and subsequent IL-17 production in T cells.
• This study defines a novel inflammaging profile in T cells that is responsive to metformin and relevant to diabetes-associated inflammation.