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A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan - PubMed

  • ️Fri Jan 01 2021

Review

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

Ibrahim Mohammed et al. Front Endocrinol (Lausanne). 2021.

Abstract

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

Keywords: AMP-Kinase; aging; calorie restriction mimetic; cancer; cardiovascular and neurodegenerative diseases; diabetes; healthspan and lifespan; metformin.

Copyright © 2021 Mohammed, Hollenberg, Ding and Triggle.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

Metformin inhibits mitochondrial complex 1. In this schematic, metformin is transported into the cell via the organic cation transporters, OCT 1, 2 and 3 and the plasma membrane monoamine transporter (PMAT). The transport of metformin out of the cell is mediated through the multidrug and toxin extrusion (MATE1/2) transporters. Metformin is thought to mediate most of its cellular effects via activation of AMPK and, in this schematic, metformin inhibits the electron transport chain of mitochondrial complex 1, which leads to a reduction in ATP levels, increasing the AMP/ATP ratio, thus increasing AMPK activation and also reduces the generation of reactive oxygen species (ROS). AMPK activation leads to an inhibition of the mTOR pathway, which would contribute to the antitumor effects of metformin. Metformin also has been shown to activate AMPK via the serine-threonine liver kinase B1 (LKB1) where phosphorylation (p) (activation) of AMPK occurs. The protein product of SIRT1, sirtuin1, is an upstream deacetylase, which activates LKB1 via deacetylation as indicated in the figure by loss of ac, at times of cellular stress and decreased cellular energy, when NAD+/NADH ratio is high and is also a putative site of action for metformin.

Figure 2
Figure 2

Metformin protects endothelial function. Pre-clinical and clinical data indicates that metformin has direct effects to protect the endothelium from diabetes-induced dysfunction and treatment results in improved function of endothelial nitric oxide synthase (eNOS), the generation of nitric oxide (NO) and improved blood flow that facilitates glucose disposal. Based on in vitro data, the effects of metformin are dependent on the expression of the NAD+ dependent deacetylase, sirtuin1, which targets lysine residues on eNOS as reflected in the figure by removal of ac, the activation of AMPK, and the nuclear orphan receptor, NR4A1. The latter has important links to the regulation of metabolism. OCT3 transporter expression in nuclear membrane facilitates metformin transport into the nucleus (183).

Figure 3
Figure 3

Potential cellular targets for metformin that affect healthspan and lifespan. The figure depicts how metformin may affect cell aging and indicates a potential action in the gut where, prior to absorption, merformin modulates the microbiome as well as enhances release of glucagon-like factor 1 (GLP-1). Important links are also indicated to the insulin (IRS: Insulin Receptor Substrate) and insulin-like growth factor-1 (IGF-1) signaling pathways as well as to tumor suppressors including p53, and inflammation and cytokine signaling. (PI3K: Phosphatidylinositol 3-kinase); (AKT: protein kinase B); (FOXO: Forkhead Box O3); (SIRT1: NAD-dependent deacetylase sirtuin-1); (Bax: Bcl-2-associated X protein). As a result of metformin moderating the cellular signaling pathways mediated by insulin, IGF-1, and cytokines, both, healthspan and lifespan are increased. Metformin also, inhibits the inflammatory pathway and increases AMPK activation, which inhibits mTOR, a primary target for cell aging modulation. Inflammation, apoptosis, autophagy, cell survival, and protein synthesis are all affected by these mechanisms and are all linked to accelerated aging.

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