ADVANTAGES AND DISADVANTAGES OF USING METFORMIN IN AGING RELATED DISEASES
Main Article Content
This review aimed to explore the anti-aging effects of metformin, which lowers glucose, slows down cell aging through regulating intracellular signaling molecules and activating AMPK, and protects against aging-related diseases. The activation of AMPK by Metformin allows it to control inflammatory conditions, improve oxidative status, regulate differentiation pathways of various cells, and ultimately provide positive therapeutic effects on these cells. Metformin plays a role in several cardiovascular diseases, neurological disorders, cancer, and fragile X syndrome by improving several parameters in some of these disease conditions. Metformin provides benefits in aging-related diseases, but further studies with various methods and samples are needed to assess the effectiveness and consider the side effects of metformin in diabetic and non-diabetic patients, as well as involving genetic factors associated with metformin.
Keywords:
Aging
Metformin
Aging-Related Diseases
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20. Isop LM, Neculau AE, Necula RD, Kakucs C, Moga MA, Dima L. Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders. Pharmaceuticals. 2023;16(12):1714. https://doi.org/10.3390/ph16121714.
21. Samaras K, Makkar S, Crawford JD, Kochan NA, Wen W, Draper B, et al. Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care. 2020;43:2691-2701. https://doi.org/10.2337/dc20-0892.
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24. Battini V, Cirnigliaro G, Leuzzi R, Rissotto E, Mosini G, Benatti B, et al. The Potential Effect of Metformin on Cognitive and Other Symptom Dimensions in Patients with Schizophrenia and Antipsychotic-Induced Weight Gain: A Systematic Review, Meta-Analysis, and Meta-Regression. Front Psychiatry. 2023;14:1215807. https://doi.org/10.3389/fpsyt.2023.1215807.
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26. Yang R, Yu H, Wu J, Chen H, Wang M, Wang S, et al. Metformin treatment and risk of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus in Beijing, China. Front. Endocrinol. 2023;14:1082720. https://doi.org/ 10.3389/fendo.2023.1082720.
27. Huang KH, Chang YL, Gau SY, Tsai TH, Lee CY. Dose–Response Association of Metformin with Parkinson’s Disease Odds in Type 2 Diabetes Mellitus. Pharmaceutics. 2022;14:946. https://doi.org/10.3390/ pharmaceutics14050946.
28. Serra MC, Kancheria V, Khakharia A, Allen LL, Phillips LS, Rhee MK, et al. Long-term metformin treatment and risk of peripheral neuropathy in older Veterans. Diabetes Res Clin Pract. 2020;170:108486. https://doi.org/10.1016/j.diabres.2020.108486.
29. Kakarlapudi Y, Kondabolu SK, Tehseen Z, Khemani V, Srilakshmi KJ, Nousherwani MD, et al. Effect of Metformin on Vitamin B12 Deficiency in Patients With Type 2 Diabetes Mellitus and Factors Associated With It: A Meta-Analysis. Cureus 2022;14(12):e32277. https://doi.org/10.7759/cureus.32277.
30. Karedath J, Batool S, Arshad A, Khalique S, Raja S, Lai B, et al. The Impact of Vitamin B12 Supplementation on Clinical Outcomes in Patients With Diabetic Neuropathy: A Meta-Analysis of Randomized Controlled Trials. Cureus. 2022;14(11):e31783. https://doi.org/10.7759/cureus.31783.
31. Didangelos T, Karlafti E, Kotzakioulafi E, Margariti E, Giannoulaki P, Batanis G, et al. Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2021;13(2):395. https://doi.org/ 10.3390/nu13020395.
32. Hamudin A, Atik N. Mechanism of action of metformin as an anti-aging agent: a literature review. Intisari Sains Medis. 2021;12(2): 453-458 P-ISSN: 2503-3638, E-ISSN: 2089-9084.
33. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti- Aging Drug That Enhances Healthspan and Extends Lifespan. Frontiers in Endocrinology. 2021;12, Article 718942. https://doi.org/10.3389/fendo.2021.718942.
34. Kulkarni AS, Brutsaert EF Anghel V, Zhang K, Bloomgarden N, Pollak M, et al. Metformin regulates metabolic and non-metabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell. 2018;17:e12723. https://doi.org/10.1111/acel.12723.
35. Luo S, Wong ICK, Chui CSL, Zheng J, Huang Y, Schooling CM, et al. Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank. Lancet Healthy Longev. 2023;4:e337-44. https://doi.org/10.1016/S2666-7568(23)00085-5.
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37. Chen YH, Wang PH, Chen PN, Yang SF, Hsiao YS. Molecular and Cellular Mechanisms of Metformin in Cervical Cancer. Cancers. 2021;13(11):2545. https://doi.org/10.3390/cancers13112545.
38. Morale MG, Tamura RE, Rubio IGS. Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models. Biomolecules. 2022;12(3):357. https://doi.org/10.3390/biom12030357.
39. Corleto KA, Strandmo JL, Giles ED. Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies. Pharmaceuticals. 2024;17(3):396. https://doi.org/10.3390/ph17030396.
40. Kim HS, Kim JH, Jang HJ, Lee J. The addition of metformin to systemic anti-cancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials. Int J Med Sci. 2020;17(16):2551-2560. https://doi.org/10.7150/ijms.50338.
41. Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, et al. Effect of Metformin Versus placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer. Journal of Clinical Oncology. 2023;41(35):5356–5362. https://doi.org/10.1200/JCO.23.00296.
42. Sonnenblick A, Aqbor-Tahr D, Bradbury I, Di Cosimo S, Azim Jr HA, Fumagalli D, et al. Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2–Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial. Journal of Clinical Oncology. 2017; 35(13):1421-1429. https://doi.org/10.1200/JCO.2016.69.7722.
43. Protic D, Hagerman R. State-of-the-art therapies for fragile X syndrome. Dev Med Child Neurol. 2024;00:1-9. https://doi.org/10.1111/dmcn.15885.
44. Lozano R, Salto N, Reed D, Eldeeb M, Schneider A, Hessl D, et al. Aging in Fragile X Premutation Carrier. Cerebellum. 2016;15(5):587-594. https://doi.org/10.1007/s12311-016-0805-x.
45. Watkins LV, Moon S, Burrows L, Tromans S, Barwell J, Shankar R. Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence. Expert Opinion On Pharmacotherapy. 2024;25(3):301-313. https://doi.org/10.1080/14656566.2024.2323605.
46. Elhawary NA, Aljahdali IA, Abumansour IS, Azher ZA, Falemban AH, Madani WM, et al. Phenotypic variability to medication management: an update on fragile X syndrome. Human Genomics. 2023;17:60. https://doi.org/10.1186/s40246-023-00507-2.
47. Tassanakijpanich N, Cabal-Herrera AM, Salcedo-Arellano MJ, Hagerman RJ. Fragile X Syndrome and Targeted Treatments. Journal of Biomedicine and Translational Research. 2020;6(1):23-33. https://doi.org/10.14710/jbtr.v6i1.7321.
48. Dy ABC, Tassone F, Eldeeb M, Salcedo-Arellano MJ, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet. 2018;93:216–22. https://doi.org/ 10.1111/cge.13039.
2. Xiong Y, Zhou L. The Signaling of Cellular Senescence in Diabetic Nephropathy. Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 7495629. https://doi.org/10.1155/2019/7495629.
3. Tenchov R, Sasso JM, Wang X, Zhou QA. Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACS Chem. Neurosci. 2024;15(1):1-30. https://doi.org/10.1021/acschemneuro.3c00531.
4. Saito Yuki, Yamamoto Sena, Chikenji Takako S. Role of cellular senescence in inflammation and regeneration. Inflamm Regener 44, 28 (2024). https://doi.org/10.1186/s41232-024-00342-5.
5. Sanz P, Serratosa JM, Sanchez MP. Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease. Int J Mol Sci. 2021;22(10):5351. https://doi.org/10.3390/ijms22105351.
6. Hu D, Xie F, Xiao Y, Lu C, Zhong J, Huang D, et al. Metformin: A Potential Candidate for Targeting Aging Mechanisms. Aging Dis. 2021;12(2):480-493. https://doi.org/10.14336/AD.2020.0702.
7. El Sayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Supplement_1):S140–S157. https://doi.org/10.2337/dc23-S009.
8. Froldi G. View on Metformin: Anti-diabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences. Pharmaceuticals. 2024;17(4):478. https://doi.org/10.3390/ph17040478.
9. LaMoia TE, Shulman GI. Cellular and Molecular Mechanisms of Metformin Action. Endocrine Reviews. 2021;42(1):77–96. https://doi.org/10.1210/endrev/bnaa023.
10. Zhu H, Jia Z, Li YR, Danelisen I. Molecular mechanisms of action of metformin: latest advances and therapeutic implications. Clin Exp Med. 2023;4:1-11. https://doi.org/ 10.1007/s10238-023-01051-y.
11. Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nature Reviews Endocrinology. 2023;19:460–476. https://doi.org/ 10.1038/s41574-023-00833-4.
12. Stage TB, Brosen K, Hougaard Christensen MM. A Comprehensive Review of Drug–Drug Interactions with Metformin. Clin Pharmacokinet. 2015;54(8). https://doi.org/10.1007/s40262-015-0270-6.
13. Li JZ, Li YR. Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research. Cardiology. 2023;148(4): 374–384. https://doi.org/ 10.1159/000531432.
14. Feng X, Chen W, Ni X, Little PJ, Xu S, Tang L, et al. Metformin, Macrophage Dysfunction and Atherosclerosis. Front Immunol. 2021;12:682853. https://doi.org/ 10.3389/fimmu.2021.682853.
15. Sardu C, Paolisso P, Sacra C, Mauro C, Minicucci F, Portoghese M, et al.. Effects of Metformin Therapy on Coronary Endothelial Dysfunction in Patients With Prediabetes With Stable Angina and Non-obstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study. Diabetes Care. 2019;42:1946–55. https://doi.org/10.2337/dc18-2356.
16. Roumie CL, Chipman J, Min JY, Hackstadt AJ, Hung AM, Greevy RA, et al.. Association of Treatment With Metformin Vs Sulfonylurea With Major Adverse Cardiovascular Events Amon G Patients With Diabetes and Reduced Kidney Function. AMA.2019;322(12):1167-77. https://doi.org/10.1001/jama.2019.13206.
17. Seneviratne A, Cave L, Hyde G, Moestrup SK, Carling D, Mason JC, et al.. Metformin Directly Suppresses Atherosclerosis in Normoglycemic Mice Via Haematopoietic Adenosine Monophosphate-Activated Protein Kinase (AMPK). Cardiovasc Res.2020;117(5):1295–308. https://doi.org/10.1093/cvr/cvaa171.
18. Mohan M, Al-Talabany S, McKinnie A, Mordi IR, Singh JSS, Gandy SJ, et al.. A Randomized Controlled Trial of Metformin on Left Ventricular Hypertrophy in Patients With Coronary Artery Disease Without Diabetes: The MET-REMODEL Trial. Eur Heart J. 2019;40:3409–17. https://doi.org/10.1093/eurheartj/ehz203.
19. Sardu C, Morella M, D’Onofrio N, Mureddu S. Metformin Therapy Effects on the Expression of Sodium-Glucose Cotransporter 2, Leptin, and SIRT6 Levels in Pericoronary Fat Excised from Pre-Diabetic Patients with Acute Myocardial Infarction. Biomedicines. 2021;9(904). https://doi.org/10.3390/biomedicines9080904.
20. Isop LM, Neculau AE, Necula RD, Kakucs C, Moga MA, Dima L. Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders. Pharmaceuticals. 2023;16(12):1714. https://doi.org/10.3390/ph16121714.
21. Samaras K, Makkar S, Crawford JD, Kochan NA, Wen W, Draper B, et al. Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care. 2020;43:2691-2701. https://doi.org/10.2337/dc20-0892.
22. Zhang QQ, Li WS, Liu Z, Zhang HL, Ba YG, Zhang RX. Metformin Therapy and Cognitive Dysfunction in Patients with Type 2 Diabetes: A Meta-Analysis and Systematic Review. Medicine 2020;99:e19378. https://doi.org/10.1097/MD.0000000000019378.
23. Zhou JB, Tang X, Han M, Yang J, Simó R. Impact of Anti-diabetic Agents on Dementia Risk: A Bayesian Network Meta-Analysis. Metabolism. 2020;109:154265. https://doi.org/10.1016/j.metabol.2020.154265.
24. Battini V, Cirnigliaro G, Leuzzi R, Rissotto E, Mosini G, Benatti B, et al. The Potential Effect of Metformin on Cognitive and Other Symptom Dimensions in Patients with Schizophrenia and Antipsychotic-Induced Weight Gain: A Systematic Review, Meta-Analysis, and Meta-Regression. Front Psychiatry. 2023;14:1215807. https://doi.org/10.3389/fpsyt.2023.1215807.
25. Malazi OT, Bandarian F, Qorbani M, Mohseni S, Mirsadeghi S, Peiman M, et al. The Effect of Metformin on Cognitive Function: A Systematic Review and Meta-Analysis. J Psychopharmacol. 2022;36:666-679. https://doi.org/10.1177/02698811211057304.
26. Yang R, Yu H, Wu J, Chen H, Wang M, Wang S, et al. Metformin treatment and risk of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus in Beijing, China. Front. Endocrinol. 2023;14:1082720. https://doi.org/ 10.3389/fendo.2023.1082720.
27. Huang KH, Chang YL, Gau SY, Tsai TH, Lee CY. Dose–Response Association of Metformin with Parkinson’s Disease Odds in Type 2 Diabetes Mellitus. Pharmaceutics. 2022;14:946. https://doi.org/10.3390/ pharmaceutics14050946.
28. Serra MC, Kancheria V, Khakharia A, Allen LL, Phillips LS, Rhee MK, et al. Long-term metformin treatment and risk of peripheral neuropathy in older Veterans. Diabetes Res Clin Pract. 2020;170:108486. https://doi.org/10.1016/j.diabres.2020.108486.
29. Kakarlapudi Y, Kondabolu SK, Tehseen Z, Khemani V, Srilakshmi KJ, Nousherwani MD, et al. Effect of Metformin on Vitamin B12 Deficiency in Patients With Type 2 Diabetes Mellitus and Factors Associated With It: A Meta-Analysis. Cureus 2022;14(12):e32277. https://doi.org/10.7759/cureus.32277.
30. Karedath J, Batool S, Arshad A, Khalique S, Raja S, Lai B, et al. The Impact of Vitamin B12 Supplementation on Clinical Outcomes in Patients With Diabetic Neuropathy: A Meta-Analysis of Randomized Controlled Trials. Cureus. 2022;14(11):e31783. https://doi.org/10.7759/cureus.31783.
31. Didangelos T, Karlafti E, Kotzakioulafi E, Margariti E, Giannoulaki P, Batanis G, et al. Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2021;13(2):395. https://doi.org/ 10.3390/nu13020395.
32. Hamudin A, Atik N. Mechanism of action of metformin as an anti-aging agent: a literature review. Intisari Sains Medis. 2021;12(2): 453-458 P-ISSN: 2503-3638, E-ISSN: 2089-9084.
33. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti- Aging Drug That Enhances Healthspan and Extends Lifespan. Frontiers in Endocrinology. 2021;12, Article 718942. https://doi.org/10.3389/fendo.2021.718942.
34. Kulkarni AS, Brutsaert EF Anghel V, Zhang K, Bloomgarden N, Pollak M, et al. Metformin regulates metabolic and non-metabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell. 2018;17:e12723. https://doi.org/10.1111/acel.12723.
35. Luo S, Wong ICK, Chui CSL, Zheng J, Huang Y, Schooling CM, et al. Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank. Lancet Healthy Longev. 2023;4:e337-44. https://doi.org/10.1016/S2666-7568(23)00085-5.
36. Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res. 2019;11:3295-3313. https://doi.org/10.2147/CMAR.S200059.
37. Chen YH, Wang PH, Chen PN, Yang SF, Hsiao YS. Molecular and Cellular Mechanisms of Metformin in Cervical Cancer. Cancers. 2021;13(11):2545. https://doi.org/10.3390/cancers13112545.
38. Morale MG, Tamura RE, Rubio IGS. Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models. Biomolecules. 2022;12(3):357. https://doi.org/10.3390/biom12030357.
39. Corleto KA, Strandmo JL, Giles ED. Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies. Pharmaceuticals. 2024;17(3):396. https://doi.org/10.3390/ph17030396.
40. Kim HS, Kim JH, Jang HJ, Lee J. The addition of metformin to systemic anti-cancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials. Int J Med Sci. 2020;17(16):2551-2560. https://doi.org/10.7150/ijms.50338.
41. Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, et al. Effect of Metformin Versus placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer. Journal of Clinical Oncology. 2023;41(35):5356–5362. https://doi.org/10.1200/JCO.23.00296.
42. Sonnenblick A, Aqbor-Tahr D, Bradbury I, Di Cosimo S, Azim Jr HA, Fumagalli D, et al. Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2–Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial. Journal of Clinical Oncology. 2017; 35(13):1421-1429. https://doi.org/10.1200/JCO.2016.69.7722.
43. Protic D, Hagerman R. State-of-the-art therapies for fragile X syndrome. Dev Med Child Neurol. 2024;00:1-9. https://doi.org/10.1111/dmcn.15885.
44. Lozano R, Salto N, Reed D, Eldeeb M, Schneider A, Hessl D, et al. Aging in Fragile X Premutation Carrier. Cerebellum. 2016;15(5):587-594. https://doi.org/10.1007/s12311-016-0805-x.
45. Watkins LV, Moon S, Burrows L, Tromans S, Barwell J, Shankar R. Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence. Expert Opinion On Pharmacotherapy. 2024;25(3):301-313. https://doi.org/10.1080/14656566.2024.2323605.
46. Elhawary NA, Aljahdali IA, Abumansour IS, Azher ZA, Falemban AH, Madani WM, et al. Phenotypic variability to medication management: an update on fragile X syndrome. Human Genomics. 2023;17:60. https://doi.org/10.1186/s40246-023-00507-2.
47. Tassanakijpanich N, Cabal-Herrera AM, Salcedo-Arellano MJ, Hagerman RJ. Fragile X Syndrome and Targeted Treatments. Journal of Biomedicine and Translational Research. 2020;6(1):23-33. https://doi.org/10.14710/jbtr.v6i1.7321.
48. Dy ABC, Tassone F, Eldeeb M, Salcedo-Arellano MJ, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet. 2018;93:216–22. https://doi.org/ 10.1111/cge.13039.
