Metformin and Aging: A Review

Abstract

Metformin is sometimes proposed to be an “anti-aging” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has “frailty” as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B<sub>12</sub> and B<sub>6</sub> deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

“…Metformin, a widely prescribed first-line oral drug to treat type 2 diabetes, inhibits cellular senescence in vitro and in animal models via multiple molecular and cellular mechanisms [103][104][105]. For example, metformin inhibits oncogene-induced SASP by blocking nuclear factor-κB activation in human diploid fibroblasts [106].…”

A proposed mechanism for the possible therapeutic potential of Metformin in COVID-19

“…Two crucial membrane compartments for the maintenance and regulation of endosomal acidic pH, are Vacuolar ATPase (V-ATPase) as proton pumping or acidifier compartment, and endosomal Na+/H+ exchangers (eNHEs) as proton leaking or alkalizing compartment on the endosomal membrane [5]. It is not crystal clear but several studies have suggested that Metformin can directly act on the eNHEs and/or the V-ATPase via its guanidine scaffold similar to Amiloride, then leads to the inhibition of viral infection through increasing the cellular pH and subsequently interfering with the endocytic cycle [5][6][7].…”

Repurposing Antidiabetic Drugs for Cardiovascular Disease

“…is an important mechanism for the glucose-lowering effect of metformin (Glossmann and Lutz, 2019). An immunometabolism-based beneficial effect of metformin may also contribute to the improved outcome in nondiabetic HF patients (Rena and Lang, 2018).…”

“…Apart from its effect on diabetes and the heart, metformin treatment was shown to extend the lifespan in mice, highlighting a potential anti-aging effect of the drug (Martin-Montalvo et al, 2013). However, this effect was not found in other species (Glossmann and Lutz, 2019). Further results for a potential anti-aging effect of metformin may be expected from the Targeting Aging with Metformin (TAME) trial, which specifically investigates the effect of metformin on the onset of aging-related diseases (MI, congestive HF, stroke, cancer, dementia, death), however, the trial was not yet listed in ClinicalTrials.gov as of May 2020.…”

“…Questions about the molecular target also remain for metformin although it is used in clinical practice since about 25 years. It is widely proven that metformin treatment induces phosphorylation and activation of AMPK (Glossmann and Lutz, 2019). Mechanistically, this has been linked to the ability of metformin to inhibit the activity of mitochondrial complex 1 (MC-1) in the respiratory chain, resulting in an increased AMP/ATP ratio, which triggers AMPK phosphorylation (Glossmann and Lutz, 2019;Soukas et al, 2019).…”