Effect of Metformin on Cardiac Metabolism and Longevity in Aged Female Mice.

Xudong Zhu,Zhenyu Ju,Zhu Liu,Ruikun He,Xuguang Zhang,Likun Ma,Wei Xiong,Shihao Sheng,Weiyan Shen

doi:10.3389/fcell.2020.626011

Abstract

The antidiabetic drug metformin exerts pleiotropic effects on multiple organs, including the cardiovascular system. Evidence has shown that metformin improves healthspan and lifespan in male mice, yet its lifespan lengthening effect in females remains elusive. We herein demonstrated that metformin fails to extend the lifespan in female mice. Compared to 2-month-old young controls, 20-month-old female mice showed a spectrum of degenerative cardiac phenotypes alongside significant alterations in the extracellular matrix composition. Despite lowered reactive oxygen species production, long-term metformin treatment did not improve cardiac function in the aged female mice. In contrast, RNA sequencing analyses demonstrated that metformin treatment elevated the extracellular matrix-related gene while lowering oxidative phosphorylation-related gene expression in the heart. In addition, metformin treatment induced metabolic reprogramming that suppressed mitochondrial respiration but activated glycolysis (i.e., Warburg effect) in cultured primary cardiomyocytes and macrophages, thereby sustaining an inflammatory status and lowering ATP production. These findings suggest the unexpected detrimental effects of metformin on the regulation of cardiac homeostasis and longevity in female mice, reinforcing the significance of comprehensive testing prior to the translation of metformin-based novel therapies.

Highlights

Cardiac function declines with advancing age, thereby increasing cardiovascular diseases in the geriatric population (Gude et al, 2018)
To evaluate whether these age-related degenerative indices link to impaired exercise capacity, we examined the 15-min-run tolerance between young and old females
Aged mice could not maintain the speed and struggled to catch up with the set speed, experiencing a high frequency of electric shock (Figure 1E). These data suggest that 20-month-old female mice have already exhibited phenotypes of age-associated cardiac degeneration, the outer appearance is far from advanced aging

Summary

Introduction

Cardiac function declines with advancing age, thereby increasing cardiovascular diseases in the geriatric population (Gude et al, 2018). Metformin (Met) was initially introduced for the treatment of type II diabetes mellitus in 1957, which has been found salutary in reducing cardiovascular mortality and morbidity (Vasamsetti et al, 2015; Bergmark et al, 2019) The benefit of this old drug in cardiovascular diseases may be attributed to its classical AMPK-dependent metabolic signaling pathways (Nafisa et al, 2018) or anti-inflammatory effect (Cameron et al, 2016) via the suppression of NF-kB or attenuation of endothelial dysfunction via the inhibition of LOX-1 (Xu et al, 2013) or antioxidant effect via inhibiting TRAF3IP2 (Valente et al, 2014) and NOX4 (Sato et al, 2016). Data on whether female mice can benefit from Met’s cardioprotective and life-extending effects remain elusive

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