Metformin longevity
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Metformin and Longevity: A Comprehensive Review
Introduction to Metformin and Longevity
Metformin, a widely prescribed antidiabetic drug, has garnered significant attention for its potential anti-aging properties. Originally used to manage type 2 diabetes, metformin's benefits may extend beyond glycemic control, potentially influencing longevity and healthspan. This article synthesizes current research on metformin's effects on lifespan and aging-related processes.
Metformin's Mechanisms of Action in Longevity
Activation of Longevity Pathways
Research indicates that metformin modulates several key pathways associated with aging. In a study involving prediabetic subjects, metformin was shown to enhance the expression of SIRT1, a gene linked to longevity, and improve insulin sensitivity. Additionally, metformin increased AMP-activated protein kinase (AMPK) activity, which is known to play a crucial role in cellular energy homeostasis and longevity .
Mitohormesis and Reactive Oxygen Species (ROS)
Metformin's lifespan-extending effects may also be mediated through a process known as mitohormesis. This involves the production of reactive oxygen species (ROS) that, paradoxically, promote cellular stress resistance and longevity. In Caenorhabditis elegans, metformin-induced ROS production was found to activate the antioxidant peroxiredoxin PRDX-2, which in turn extended lifespan.
Lysosomal Pathway and AMPK Activation
Further elucidating metformin's mechanisms, studies have shown that it acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 inhibition and AMPK activation. This dual action contributes to lifespan extension in model organisms. Additionally, metformin's ability to mimic dietary restriction by engaging AMPK and the oxidative stress-responsive transcription factor SKN-1/Nrf2 has been demonstrated in C. elegans.
Evidence from Model Organisms
Effects in Mice
In mice, metformin has been shown to extend both healthspan and lifespan when administered at appropriate doses. Long-term treatment with metformin improved physical performance, increased insulin sensitivity, and reduced oxidative damage and inflammation, mimicking some benefits of calorie restriction. Another study reported that metformin extended the lifespan of female SHR mice by reducing body weight and delaying age-related decline in reproductive function.
Effects in Nematodes and Fish
Metformin's impact on lifespan has also been studied in nematodes and fish. In C. elegans, metformin extended lifespan through mechanisms involving AMPK and oxidative stress response pathways. In the short-lived fish Nothobranchius guentheri, metformin prolonged lifespan and improved cognitive abilities by reducing inflammation and oxidative stress.
Human Studies and Clinical Trials
Preliminary Findings and Controversies
While preclinical studies provide promising insights, the evidence for metformin's longevity benefits in humans remains mixed. Clinical trials such as the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin) are ongoing to assess metformin's potential as an anti-aging drug. Preliminary results suggest that metformin may induce anti-aging transcriptional changes, but its protective effects in disease-free individuals are still debated.
Cellular Aging and Healthspan
In human cellular models, metformin has been shown to delay cellular senescence by upregulating the antioxidant enzyme GPx7 through the Nrf2 pathway. This suggests that metformin may have direct anti-aging effects at the cellular level. Additionally, metformin's ability to improve healthspan by reducing early mortality associated with diseases such as diabetes, cardiovascular disease, and cancer has been well-documented.
Conclusion
Metformin holds promise as a potential anti-aging intervention, with evidence supporting its ability to extend lifespan and improve healthspan in various model organisms. Its mechanisms of action involve key longevity pathways, including AMPK activation, mitohormesis, and lysosomal signaling. While preliminary human studies are encouraging, further research is needed to fully understand metformin's impact on human aging and to establish its efficacy as a longevity-promoting drug.
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