From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin’s Anticancer and Anti-Aging Effects
Abstract
1. Introduction
2. Materials and Methods
2.1. Literature Search and Study Selection
2.2. Data Synthesis
3. Results and Discussion
3.1. Metformin-Mediated Inhibition of Mitochondrial Activity, Nuclear Pore Function, and ACAD10 Induction
3.2. Insulin- and IGF1-Dependent Mechanisms
3.3. AMPK-Dependent Mechanisms
3.4. AMPK-Independent Mechanisms
3.4.1. Direct Antineoplastic Effects: Beyond the AMPK Paradigm
3.4.2. Indirect Systemic Mediators
3.5. Stress-Induced Effects
3.6. Autophagy, Apoptosis Induction, and Cell Cycle Arrest
3.7. Metformin in Therapy Combinations and Dose-Dependent Clinical Effects
4. Clinical Evidence and Translational Implications
5. Future Directions
6. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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| Context of Use | Model/Study Type | Typical Dose Range | Reported Effect |
|---|---|---|---|
| Lifespan/Healthspan | C. elegans, Drosophila; rodent models | 10–100 μM (in medium); 50–300 mg/kg/day (oral) | Increased lifespan via AMPK activation; reduced ROS; improved healthspan; delayed tumorigenesis [72,73,74] |
| Cancer research | In vitro cancer cell lines (breast, colon, leukemia, osteosarcoma); xenograft mouse models; clinical studies (adjuvant use) | 1–20 mM; 100–300 mg/kg/day; 500–2000 mg/day (oral) | Autophagy and apoptosis induction; cell cycle arrest; tumor growth inhibition; improved therapy response and survival outcomes [62,65,66,67,69] |
| Metabolic/Classical Use | T2DM patients | 500–2000 mg/day (oral) | Glycemic control; reduced insulin resistance [70,71] |
| Clinical Evidence (Cancer/Aging Outcomes) | Essential Mechanism | Study Type | Translational Significance | Reference |
|---|---|---|---|---|
| Reduced overall cancer risk in T2DM patients (Scottish population study) | Systemic insulin/IGF-1 reduction; indirect mTOR inhibition | Population-based cohort | Supports chemopreventive potential in metabolically dysregulated populations | [8] |
| 31% reduction in overall tumor incidence and 34% reduction in cancer-related mortality in diabetic patients | AMPK activation; mTOR suppression; metabolic reprogramming | Meta-analysis of diabetic cohorts | Rationale for repurposing as adjunct anticancer therapy in T2DM patients | [13] |
| Decreased incidence of gastrointestinal cancers (colon, liver, pancreas) | Reduced hyperinsulinemia; IGF-1 signaling attenuation | Observational diabetic cohorts | May justify targeted prevention strategies in high-risk GI cancer patients with T2DM | [16] |
| Improved overall survival in metformin users (dose-dependent effect) | Energy stress induction; systemic metabolic modulation | Observational diabetic cohorts | Suggests dose optimization could enhance oncologic outcomes | [12] |
| No significant survival benefit in colorectal cancer with T2DM (HR 1.06; 95% CI 0.80–1.40) | Heterogeneous response; context-dependent metabolic effects | CRC patients with T2DM | Highlights need for biomarker-driven patient stratification | [17] |
| Most pronounced survival benefit in breast cancer; moderate in colorectal and prostate cancers (meta-analysis of 80 studies) | Combined AMPK/mTOR and insulin-lowering mechanisms | Meta-analysis (80 observational studies); aggregated populations | Indicates tumor-type-specific responsiveness and supports precision and targeted oncology approaches | [18] |
| Reduced cancer incidence (adjusted HR 0.68; 95% CI 0.51–0.90); no change in cancer mortality | Glucose lowering; reduced oxidative stress and IGF-1 | T2DM cohort | Suggests preventive potential, rather than therapeutic clinical application | [86] |
| Reduced inflammatory markers (IL-6, NF-κB) independent of diabetes status | Anti-inflammatory AMPK/NF-κB modulation | Human study | Reinforces potential role in addressing inflammation-driven tumorigenesis and aging | [90] |
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Vujovic, S.; Perovic, S.; Vlaovic, M.; Scepanovic, A.; Scepanovic, S. From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin’s Anticancer and Anti-Aging Effects. Curr. Issues Mol. Biol. 2026, 48, 286. https://doi.org/10.3390/cimb48030286
Vujovic S, Perovic S, Vlaovic M, Scepanovic A, Scepanovic S. From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin’s Anticancer and Anti-Aging Effects. Current Issues in Molecular Biology. 2026; 48(3):286. https://doi.org/10.3390/cimb48030286
Chicago/Turabian StyleVujovic, Slavica, Svetlana Perovic, Milorad Vlaovic, Andjelka Scepanovic, and Stasa Scepanovic. 2026. "From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin’s Anticancer and Anti-Aging Effects" Current Issues in Molecular Biology 48, no. 3: 286. https://doi.org/10.3390/cimb48030286
APA StyleVujovic, S., Perovic, S., Vlaovic, M., Scepanovic, A., & Scepanovic, S. (2026). From Metabolism to Longevity: Molecular Mechanisms Underlying Metformin’s Anticancer and Anti-Aging Effects. Current Issues in Molecular Biology, 48(3), 286. https://doi.org/10.3390/cimb48030286
