General Description

Metformin, a commonly prescribed antihyperglycemic medication, has gained attention for its potential in targeting biological aging beyond glycemic control. Its multifaceted mechanisms involve inhibiting hepatic glucose production, enhancing insulin sensitivity, and modulating pathways related to metabolism, oxidative stress, and inflammation. By activating AMP-activated protein kinase (AMPK) and influencing mitochondrial function, metformin plays a crucial role in regulating cellular processes associated with aging. While generally well-tolerated, metformin can cause gastrointestinal discomfort and, rarely, serious conditions like metformin-associated lactic acidosis. Monitoring for side effects and considering individual risk factors are essential when utilizing metformin for managing diabetes and potentially addressing aging-related processes.

Figure 1. Metformin

Mechanisms in Targeting Biological Aging

Metformin, a widely used antihyperglycemic agent, has garnered attention for its potential in targeting biological aging beyond its primary function in glycemic control. The mechanisms through which metformin influences fundamental pathways in aging and disease are multifaceted and not fully elucidated. Metformin's primary antihyperglycemic action involves the suppression of hepatic glucose production by inhibiting mitochondrial glycerophosphate dehydrogenase and fructose-1,6-bisphosphatase-1, leading to reduced gluconeogenesis. Additionally, metformin reduces glucose absorption in the intestine, enhances insulin secretion in pancreatic beta cells, and improves insulin-mediated glucose uptake in peripheral tissues. In targeting biological aging, metformin acts through three main mechanisms: metabolic, oxidative, and inflammatory. Metformin inhibits mitochondrial complex I, leading to increased AMP:ATP ratio and subsequent activation of AMP-activated protein kinase (AMPK). AMPK-dependent pathways inhibit mTORC1, promote mitochondrial biogenesis, regulate autophagy, and modulate gene expression. AMPK-independent effects include reducing reactive oxygen species (ROS), advanced glycation end products (AGEs), and inflammation. Metformin's cellular uptake is facilitated by organic cationic transporters, allowing it to accumulate in mitochondria and inhibit complex I activity. This inhibition triggers a cascade of metabolic and non-metabolic effects involved in the aging process. Metformin's AMPK-dependent and -independent actions further contribute to its anti-aging properties by regulating nutrient sensing, mitochondrial function, inflammation, and cellular senescence. Moreover, metformin's role in modulating gut microbiota and branched-chain amino acid availability highlights its impact on intercellular signaling and inflammation, crucial aspects of biological aging. Recent studies suggest that metformin's effects on energy balance and body weight are mediated through growth differentiation factor 15 (GDF15), underscoring its potential in targeting biological aging through various molecular pathways. While the precise mechanisms of metformin in combating biological aging are not fully understood, its diverse actions on cellular processes and signaling pathways offer promising avenues for further research and potential therapeutic interventions in age-related conditions. ¹

Side Effects

Metformin, a widely used antihyperglycemic agent, is generally well-tolerated, but it can cause some side effects that are important to monitor. Common minor side effects of metformin include gastrointestinal discomfort such as abdominal pain, early satiety, decreased appetite, and diarrhea. These symptoms typically resolve within 1 to 2 weeks of starting the medication. However, persistent diarrhea, although rare in about 3% of users, may necessitate discontinuation of the drug. Changes in the gut microbiome, possibly due to metformin use, could contribute to these gastrointestinal side effects. In rare cases, metformin can lead to a serious condition known as metformin-associated lactic acidosis (MALA), particularly in individuals with pre-existing conditions such as severe kidney, liver, or heart disease. Patients experiencing symptoms like anxiety, sleeplessness, fast breathing, or elevated lactate levels after taking metformin should discontinue the medication and seek medical advice. Additionally, chronic use of metformin may lead to reduced levels of vitamin B12 in some individuals, although the exact mechanism is not fully understood. Regular monitoring of vitamin B12 levels and supplementation may be necessary for a subset of patients. It is crucial for healthcare providers and patients to be aware of these potential side effects of metformin and to monitor for any adverse reactions while reaping the benefits of this medication in managing diabetes and potentially attenuating the hallmarks of aging. ²

Reference

1. Kulkarni AS, Gubbi S, Barzilai N. Benefits of Metformin in Attenuating the Hallmarks of Aging. Cell Metab. 2020; 32(1): 15-30.

2. Triggle CR, Mohammed I, Bshesh K, et al. Metformin: Is it a drug for all reasons and diseases?. Metabolism. 2022; 133: 155223.