Clinical perspectives and concerns of metformin as an anti‐aging drug

Abstract

As percentages of elderly people rise in many societies, age‐related diseases have become more prevalent than ever. Research interests have been shifting to delaying age‐related diseases by delaying or reversing aging itself. We use metformin as an entry point to talk about the important molecular and genetic longevity‐regulating mechanisms that have been extensively studied with it. Then we review a number of observational studies, animal studies, and clinical trials to reflect the clinical potentials of the mechanisms in lifespan extension, cardiovascular diseases, tumors, and neurodegeneration. Finally, we highlight remaining concerns that are related to metformin and future anti‐aging research.

Metformin: Is it a drug for all reasons and diseases?

“…There is a substantive literature, often controversial, that has investigated the putative benefits of metformin as an anti-aging drug with data derived from a number of species ranging from C. elegans, to Drosophila melangaster, to rodents and humans. A number of reviews that supports the benefits of metformin are available [189,[324][325][326] as well as several that are more critical of the evidence [280,[327][328][329].…”

Metformin: Sex/Gender Differences in Its Uses and Effects—Narrative Review

“…The mechanisms of cellular action of MTF are still poorly understood. Various molecular responses are elicited by MTF and apparently some are influenced by sex hormones ( Figure 1 ) [ 10 , 11 , 12 , 13 ]. The normoglycemic effect of MTF results mainly from a decrease in hepatic glucose production by inhibition of gluconeogenesis and by an action on glucose-6-phosphatase [ 2 ].…”

“… Molecular responses that are elicited by MTF; some are influenced by sex hormones. Insulin-like Growth Factor-1, INS: Insulin, IGF-1-R: Insulin-like Growth Factor-1-Receptor, INS-R: Insulin Receptor, PI3K: Phosphoinositide 3-kinase, Akt: Serine/threonine protein kinase B, AMPK: AMP-activated protein kinase, SIRT1: Sirtuin 1, FOXO1: Forkhead box protein O1, FOXO2: Forkhead box protein O2, p53: Tumor protein p53, NFκB: Nuclear factor kappa-light-chain-enhancer of activated B cells, mTOR: Mammalian target of rapamycin, p21: Cyclin-dependent kinase inhibitor 1, ROS: Reactive oxygen species, E2: Estradiol, ERβ: Estrogen receptor β, (+): activation, (−): inhibition, drawn with data from [ 10 , 11 , 12 , 13 ]. …”

Modulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs

“…In addition, epidemiological and association studies show that metformin is linked to reduced incidences and all-cause mortalities in several age-related diseases, such as age-associated cancers and AD ( Barzilai et al, 2016 ; Campbell et al, 2017 ; Valencia et al, 2017 ). Based on these promising results, the “targeting aging with metformin” (TAME, ClinicalTrials.gov Identifier: NCT02118727) study currently investigates metformin’s potential in aging and its therapeutical potential in age-related diseases ( Campisi et al, 2019 ; Wang et al, 2020 ).…”