# The Biological Mechanisms of Metformin Effects on Aging-Associated Inflammation

> **NIH NIH R56** · UNIVERSITY OF KENTUCKY · 2020 · $380,433

## Abstract

Inflammation rises in aging to promote age-associated diseases including type 2 diabetes, cardiovascular
disease, and cognitive decline and is thus recognized as a significant cause of death across the globe.
Metformin broadly alleviates age-associated inflammation, or inflammaging. The proposed project will identify
mechanisms of metformin action on age-associated changes in CD4+ T cell function. Focus on this cell type is
justified by data herein that used bioinformatics to uncover a Th17 cytokine profile preferentially produced by
CD4+ T cells from sexagenarians. This inflammaging profile is strikingly similar to the profile that characterizes
a major challenge to healthspan, type 2 diabetes. Our new data show that physiologically achievable amounts
of metformin ameliorate the Th17 inflammaging profile by improving mitochondrial bioenergetics and/or
autophagy in CD4+ T cells from older subjects. Metformin concurrently increased non-mitochondrial glycolysis
and thus lactate production, but had none of these effects on cells from younger subjects. Data herein
challenge dogmas that glycolysis fuels inflammation, and raise the possibility that metformin can target either
one of the two required inflammatory pathways to lower age-related inflammation. We will test the central
hypothesis that metformin ameliorates a Th17 inflammaging profile through targeting one of two critical
mechanisms, non-mitochondrial autophagy or excessive mitochondrial OXPHOS, to increases lactate and
block age-related Th17 cytokine production.
We will analyze CD4+ T cells from overweight/obese subjects 60-85 yrs of age, with cytokine profiles as our
primary outcome. Some studies will use cells from younger adults to test conclusion from aged cells. We will
inhibit/activate each step of the hypothesized pathway in cells stimulated in the presence/absence of
metformin, and measure effects on downstream elements with rigorous statistical and bioinformatic tests to
query similarities/differences in cytokine profiles. This approach will establish cause/effect relationships
amongst metformin and mechanisms that drive age-related inflammation. Finally, comparison of mechanistic
changes in T cells from older subjects exposed to metformin in vitro and in vivo, the latter from people who
take metformin as part of their clinical care, will establish clinical relevance of our in vitro mechanistic work to
meet our main objective: to pinpoint mechanisms by which metformin lowers inflammaging en route to
improving healthspan.

## Key facts

- **NIH application ID:** 10231303
- **Project number:** 1R56AG069685-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Barbara Nikolajczyk
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,433
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231303

## Citation

> US National Institutes of Health, RePORTER application 10231303, The Biological Mechanisms of Metformin Effects on Aging-Associated Inflammation (1R56AG069685-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231303. Licensed CC0.

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