# Metformin Therapy for Ischemic Insult and Reperfusion Injury in Aging

> **NIH NIH R33** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $380,395

## Abstract

In aging, myocardial injury is increased during ischemia-reperfusion and accelerates the
transition to post-infarction heart failure. In addition, most therapeutic strategies that effectively
decrease cardiac injury in younger hearts fail in aged hearts. Thus, it is a critical unmet need to
find an effective approach to decrease cardiac injury in the high risk aged heart during
myocardial infarctions and their treatment. Metformin is a currently approved drug for the
treatment of type II diabetes. We found that metformin is a reversible inhibitor of electron
transport chain complex I. Metformin (2 mM) decreased complex I activity in ischemia-damaged
heart mitochondria. Administration of metformin (2 mM) acutely during early reperfusion
decreased infarct size in both in vitro and in vivo murine models. The protection of metformin
was independent of AMPK activation, since cardiac injury was also decreased in the metformin-
treated AMPK kinase dead mouse. Thus, we propose to repurpose metformin as a complex I
inhibitor to decrease cardiac injury in aged hearts during the acute phase of reperfusion. AMPK
is also a critical stress-activated kinase that exerts longer-term cardiac protection during
prolonged recovery periods of reperfusion following myocardial infarction. Aging attenuates
AMPK activation and subsequently enhances cardiac injury during ischemia and reperfusion.
Sestrin2 is a scaffold protein critical to the activation of AMPK. Sestrin2 deficiency in the aging
heart leads to decreased AMPK activation and impairs protective autophagy and mitochondrial
biogenesis. We hypothesize that metformin treatment will activate AMPK in aged hearts through
modulation of sestrin 2 during prolonged reperfusion. Thus, we propose that high dose
metformin treatment provides acute protection in aged hearts during early reperfusion by
transiently inhibiting complex I and decreasing mitochondrial-driven injury. Modulation of
sestrin2-dependent AMPK activation in aged hearts by continued metformin treatment during
longer term reperfusion should provide prolonged protection and consolidate the benefit during
longer term recovery and decrease the transition to heart failure. Taken together, metformin
presents an attractive opportunity to repurpose a currently approved drug for a new use to
potentially attenuate both phases of the enhanced injury following a heart attack in the aged
heart in order to improve outcomes in the high risk elderly patient.

## Key facts

- **NIH application ID:** 10896309
- **Project number:** 5R33AG071249-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Edward J Lesnefsky
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,395
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896309

## Citation

> US National Institutes of Health, RePORTER application 10896309, Metformin Therapy for Ischemic Insult and Reperfusion Injury in Aging (5R33AG071249-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10896309. Licensed CC0.

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