Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

Abstract

Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.

Keywords: Metformin; aging; aging-related diseases; clinical application; molecular mechanism..

Figure 1

Metformin chemistry, pharmacokinetics and side effects. Metformin contains a double salt group and is synthesized from dimethylamine chloride and dicyandiamide. The oral dose of metformin is 500-1000mg, and the absolute bioavailability of oral metformin hydrochloride is relatively low (about 50-60%), and its absorption process is mainly in the proximal intestine, including the duodenum and jejunum. The T_max is about 2.5 hours. Its typical peak plasma concentration (C_max) is about 2 μg/ml, and rarely exceeds 4 μg/ml. And the state concentration range is 0.3-1.5 μg/ml. The absorption of metformin in the gastrointestinal tract (GIT) is slow and incomplete. Metformin is not metabolized by the liver. Plasma protein binding is negligible and widely distributed (usual volume of distribution [V_d], 100-300l). Metformin has an elimination half-life (T_1/2) of ~6-7h. The main way of elimination is rapid excretion through the kidneys, where 30-50% of the metformin is eliminated and remains unchanged in the urine. The most common side effects include gastrointestinal irritation, lactic acidosis and vitamin B12 deficiency. Adapted from Bailey et al. .

Figure 2

The effect of metformin in the treatment of musculoskeletal diseases. Metformin plays an important role in the treatment of musculoskeletal diseases such as osteoarthritis (OA), osteoporosis (OP), intervertebral disc degeneration (IVDD), periodontitis (PD), ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteosarcoma (OS) by inhibiting the effect of inflammatory response, cartilage degeneration, mechanical hyperalgesia, cellular senescence, osteoclastic activity, oxidative stress, fibroblast ossification, cellular proliferation and migration, reducing body weight or improving osteogenic activity.

Figure 3

Targets of metformin among the hallmarks of aging. Metformin attenuates aging and aging-related diseases by targeting nine hallmarks of aging, including (1) four primary hallmarks (loss of proteostasis, telomere attrition, genomic instability and epigenetic alterations); (2) three antagonistic hallmarks (deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence); (3) two integrative hallmarks (altered intercellular communication and stem cell exhaustion).

Figure 4

Multiple pathways of metformin targeting aging and aging-related diseases. Metformin alleviates aging and aging-related diseases by targeting aging hallmarks through following signaling pathways: (1) Metformin is transported into cells through organic transporter 1 (OCT1). Then metformin inhibits mitochondrial respiratory-chain complex 1 and thereby oxidative phosphorylation, resulting in increased AMP/ATP and NAD⁺/NADH ratios, causing activation of AMPK and up-regulation of SIRT1. AMPK-dependent mechanisms lead to the inhibition of mTOR, reactive oxygen species (ROS), DNA Methylation (DNMT) and histone acetyltransferase (HAT)/ histone deacetylase (HDAC), and the increase of PGC1α and DICER1. Metformin also up-regulates ataxic telangiectasis mutation (ATM) protein kinase and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to the inhibition of DNA damage and increase of glutathione peroxidase 7 (GPx7). (2) Metformin regulates the insulin and IGF-1 signaling and thereby the phosphorylation of insulin receptor substrate-1/2 (IRS-1/2) and PI3K/AKT/mTOR signaling. Activation of AMPK also inhibits mTOR signaling. (3) Metformin inhibits NF-κB signaling induced by pro-inflammatory cytokines. Up-regulation of SIRT1 further inhibits NF-κB signaling. Adapted from Kulkarni et al.