MOLECULAR MECHANISMS OF METFORMIN ACTION: FROM METABOLIC EFFECTS TO LIFESPAN EXTENSION AND HEALTHSPAN PROMOTION
Metformin’s Molecular Effects on Aging and Healthspan
Keywords:
Anti-aging; AMPK; Longevity; Metformin; Mitochondria; mTOR
Abstract
Background :
Metformin, a biguanide primarily used for the treatment of type 2 diabetes mellitus, has attracted significant attention for its potential anti-aging effects. As aging becomes the primary risk factor for chronic diseases, interventions targeting fundamental aging processes are gaining traction in biomedical research.
Mechanisms of Action:
Accumulating evidence suggests that metformin exerts geroprotective effects through multiple interconnected pathways. These include activation of AMP-activated protein kinase (AMPK), inhibition of the mechanistic target of rapamycin (mTOR), attenuation of oxidative stress, modulation of mitochondrial biogenesis, and reduction of low-grade systemic inflammation. Together, these actions address key hallmarks of aging such as cellular senescence, dysregulated nutrient sensing, and altered proteostasis.
Preclinical and Clinical Evidence:
Animal studies have consistently shown that metformin extends both lifespan and healthspan. In humans, retrospective epidemiological data indicate reduced incidence of cancer, cardiovascular disease, and cognitive decline among metformin users. The TAME (Targeting Aging with Metformin) trial represents the first large-scale attempt to formally assess aging-related outcomes in a non-diabetic population.
Challenges and Perspectives:
Despite promising data, uncertainties remain regarding optimal dosing, long-term safety, and applicability in healthy aging populations. Furthermore, individual variability in response to metformin suggests the need for precision medicine approaches.
Conclusion:
Metformin stands at the intersection of metabolic regulation and aging biology. While not a panacea, its favorable safety profile and multi-targeted actions make it a leading candidate for repurposing as an anti-aging therapy. Continued clinical validation is essential to translate these insights into practice.
References
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2. Leser JM, Harriot A, Buck HV, Ward CW, Stains JP. Aging, Osteo-Sarcopenia, and musculoskeletal Mechano-Transduction. Front Rehabil Sci. 2021;2. https://doi.org/10.3389/fresc.2021.7828483.
3. Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023;8(1). https://doi.org/10.1038/s41392-023-01502-8
4. Kang C. Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases. Mol Cells. 2019;42(12):821–827.
5. Davalli P, Mitic T, Caporali A, Lauriola A, D’Arca D. ROS, cell senescence, and novel molecular mechanisms in aging and Age‐Related diseases. Oxid Med Cell Longev. 2016;2016:3565127. https://doi.org/10.1155/2016/3565127
6. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms regulating longevity and aging. Cell. 2016 Aug 11;166(4):822–839.
7. Harman D. Aging: Overview. Department of Medicine, University of Nebraska College of Medicine, 68198-4635.
8. Lopes-Paciencia S, Saint-Germain E, Rowell M, Ruiz AF, Kalegari P, Ferbeyre G. The senescence-associated secretory phenotype and its regulation. Cytokine. 2019;117:15–22. https://doi.org/10.1016/j.cyto.2019.01.013
9. World Health Organization. Ageing and health [Internet]. Geneva: WHO; 2024 [cited 2025 Aug 5]. Available from: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
10. Tang B, Li Z, Hu S, Xiong J. Economic implications of health care burden for elderly population. INQUIRY J Health Care Organ Provision Financ. 2022;59. https://doi.org/10.1177/00469580221121511
11. Asejeje FO, Ogunro OB. Deciphering the mechanisms, biochemistry, physiology, and social habits in the process of aging. Arch Gerontol Geriatr Plus. 2023;1(1):100003. https://doi.org/10.1016/j.aggp.2023.100003
12. Palmel AK, Gustafson B, Kirkland JL, Smith U. Cellular senescence: at the nexus between ageing and diabetes. Diabetologia. 2019;62:1835–1841.
13. Pontzer H, Yamada Y, Sagayama H, et al. Daily energy expenditure through the human life course. Science. 2021;373(6556):808–812. https://doi.org/10.1126/science.abe5017
14. Palmer AK, Jensen MD. Metabolic changes in aging humans: current evidence and therapeutic strategies. J Clin Invest. 2022;132(16). https://doi.org/10.1172/jci158451
15. Ma S, Gladyshev VN. Molecular signatures of longevity: insights from cross-species comparative studies. Semin Cell Dev Biol. 2017;70:190–203.
16. Fraser HC, Kuan V, Johnen R, et al. Biological mechanisms of aging predict age‐related disease co‐occurrence in patients. Aging Cell. 2022;21(4). https://doi.org/10.1111/acel.13524
17. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278. https://doi.org/10.1016/j.cell.2022.11.001
18. Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol. 2007;292:R18–R36.
19. De Almeida AJP, De Oliveira JCPL, Da Silva Pontes LV, et al. ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways. Oxid Med Cell Longev. 2022;2022:1–23. https://doi.org/10.1155/2022/1225578
20. Graham C, Stefanatos R, Yek AEH, et al. Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies. GeroScience. 2022;44(4):1961–1974. https://doi.org/10.1007/s11357-022-00555-x
21. Vitale M, Sanz A, Scialò F. Mitochondrial redox signaling: a key player in aging and disease. Aging. 2023. https://doi.org/10.18632/aging.204659
22. Maldonado E, Morales-Pison S, Urbina F, Solari A. Aging hallmarks and the role of oxidative stress. Antioxidants. 2023;12(3):651. https://doi.org/10.3390/antiox12030651
23. Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972;20(4):145–147. https://doi.org/10.1111/j.1532-5415.1972.tb00787.x
24. Biswas SK. Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox? Oxid Med Cell Longev. 2016;2016:5698931. https://doi.org/10.1155/2016/5698931
25. Ramos-Tovar E, Muriel P. Molecular mechanisms that link oxidative stress, inflammation, and fibrosis in the liver. Antioxidants. 2020;9(12):1279. https://doi.org/10.3390/antiox9121279
26. Reznick RM, Zong H, Li J, et al. Aging-Associated reductions in AMP-Activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 2007;5(2):151–156. https://doi.org/10.1016/j.cmet.2007.01.008
27. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2011;11(2):230–241. https://doi.org/10.1016/j.arr.2011.12.005
28. Han X, Tai H, Wang H, et al. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD+ elevation. Aging Cell. 2016;15:416–427.
29. Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48:e245.
30. Gelino S, Hansen M. Autophagy - An Emerging Anti-Aging Mechanism. J Clin Exp Pathol. 2012 Jul 12;Suppl 4:006.
31. Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 2015; 15(2): 196–207.
32. Link W. Introduction to FOXO Biology. Methods Mol Biol 2018; 1–9.
33. Milman S, Huffman DM, Barzilai N. The somatotropic axis in human aging: framework for the current state of knowledge and future research. Cell Metab 2016; 23(6): 980–989.
34. Zhang WB, Ye K, Barzilai N, Milman S. The antagonistic pleiotropy of insulin‐like growth factor 1. Aging Cell 2021; 20(9).
35. Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, et al. Low insulin‐like growth factor‐1 level predicts survival in humans with exceptional longevity. Aging Cell 2014; 13(4): 769–771.
36. McCubrey JA, Lertpiriyapong K, Steelman LS, Abrams SL, Yang LV, Murata RM, et al. Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs. Aging 2017; 9(6): 1477–1536.
37. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, et al. mTOR as a central regulator of lifespan and aging. F1000Res 2019; 8: 998.
38. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria R, Alimonti A. Cellular senescence: aging, cancer, and injury. Physiol Rev 2019; 99: 1047–1078.
39. Dodig S, Čepelak I, Pavić I. Hallmarks of senescence and aging. Biochem Med (Zagreb) 2019; 29(3): 483–497.
40. Moiseeva O, Simard XD, Germain E, Igelmann S, Huot G, Cadar AE, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 2013; 12: 489–498.
41. Smieszek A, Strek Z, Kornicka K, Grzesiak J, Weiss C, Marycz K. Antioxidant and anti-senescence effect of metformin on mouse olfactory ensheathing cells (mOECs) may be associated with increased brain-derived neurotrophic factor levels—an ex vivo study. Int J Mol Sci 2017; 18(4): 872.
42. Blagosklonny MV. Anti-aging: senolytics or gerostatics (unconventional view). Oncotarget 2021; 12(18): 1821–1835.
43. Dasgupta N, Arnold R, Equey A, Gandhi A, Adams PD. The role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression. NPJ Aging 2024; 10(1).
44. Fu TE, Zhou Z. Senescent cells as a target for anti-aging interventions: from senolytics to immune therapies. J Transl Intern Med 2025; 13(1): 33–47.
45. Kulkarni AS, Brutsaert EF, Anghel V, Zhang K, Bloomgarden N, Pollak M, et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 2018; 17: e12723.
46. Roberts C, Raabe N, Wiegand L, Shahib AK, Rastegar M. Diverse applications of the anti-diabetic drug metformin in treating human disease. Pharmaceuticals 2024; 17(12): 1601.
47. Romero R, Erez O, Huittemann M, Maymon E, Panaitescu B, Agudelo AC, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 2017; 217(3): 282–302.
48. Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J 2015; 471: 307–322.
49. Fujita Y, Inagaki N. Metformin: new preparations and nonglycemic benefits. Curr Diab Rep 2017; 17(1): 5.
50. Podhorecka M, Ibanez B, Dmoszynska A. Metformin – its potential anti-cancer and anti-aging effects. Postepy Hig Med Dosw (Online) 2017; 71: 170–175.
51. Rangel ES, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia 2017; 60(9): 1586–1593.
52. Saisho Y. Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 2015; 15: 196–205.
53. Hur KY, Lee MS. New mechanisms of metformin action: focusing on mitochondria and the gut. J Diabetes Investig 2015; 6: 600–609.
54. Algire C, Moiseeva O, Simard XD, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 2012; 5(4): 536–543.
55. Blagosklonny MV. Validation of anti‐aging drugs by treating age‐related diseases. Aging (Albany NY) 2009; 1(3): 281–288.
56. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY) 2010; 2(11): 760–774.
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2025/10/27
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