, Volume 20, Issue 1, pp 33–48 | Cite as

Metformin as a geroprotector: experimental and clinical evidence

  • Veronika Piskovatska
  • Nadiya Stefanyshyn
  • Kenneth B. Storey
  • Alexander M. VaisermanEmail author
  • Oleh LushchakEmail author
Review Article


Apart from being a safe, effective and globally affordable glucose-lowering agent for the treatment of diabetes, metformin has earned much credit in recent years as a potential anti-aging formula. It has been shown to significantly increase lifespan and delay the onset of age-associated decline in several experimental models. The current review summarizes advances in clinical research on the potential role of metformin in the field of geroprotection, highlighting findings from pre-clinical studies on known and putative mechanisms behind its beneficial properties. A growing body of evidence from clinical trials demonstrates that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, cancer, chronic inflammation, and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain cancer types. Moreover, due to the ability of metformin to induce autophagy by activation of AMPK, it is regarded as a potential hormesis-inducing agent with healthspan-promoting and pro-longevity properties. Long-term intake of metformin is associated with low risk of adverse events; however, well-designed clinical trials are still warranted to enable potential use of this therapeutic agent as a geroprotector.


Metformin Age-related disease Longevity Hormesis Model organism Type 2 diabetes Cardiovascular disease Inflammation 



This work was partially supported via a Grant from the Ministry of Education and Science of Ukraine to OL (#0117U006426) and discovery grant from the Natural Sciences and Engineering Research Council of Canada (#6793) to KBS.


  1. Abrat OB, Storey JM, Storey KB, Lushchak VI (2018) High amylose starch consumption induces obesity in Drosophila melanogaster and metformin partially prevents accumulation of storage lipids and shortens lifespan of the insects. Comp Biochem Physiol A 215:55–62. Google Scholar
  2. Adak T, Samadi A, Ünal AZ, Sabuncuoğlu S (2018) A reappraisal on metformin. Regul Toxicol Pharmacol 92:324–332. Google Scholar
  3. Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila) 5:536–543. Google Scholar
  4. American Diabetes Association (2002) Implications of the United Kingdom prospective diabetes study. Diabetes Care 25(suppl 1):s28–s32. Google Scholar
  5. American Diabetes Association (2018) Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care 41(Suppl 1):S73–S85. Google Scholar
  6. An H, He L (2016) Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol 228:97–106. Google Scholar
  7. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40:685–693. Google Scholar
  8. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV (2008) Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7:2769–2773. Google Scholar
  9. Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA (2010a) Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle 9:188–197. Google Scholar
  10. Anisimov VN, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Egormin PA, Yurova MV, Rosenfeld SV, Semenchenko AV, Kovalenko IG, Poroshina TE, Berstein LM (2010b) Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging (Albany NY) 2:945–958. Google Scholar
  11. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE (2011) If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY) 3:148–157. Google Scholar
  12. Bailey CJ (2017) Metformin: historical overview. Diabetologia 60:1566–1576. Google Scholar
  13. Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, Mukherjee J, Currie CJ (2014) Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab 16:1165–1173. Google Scholar
  14. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (2016) Metformin as a tool to target aging. Cell Metab 23:1060–1065. Google Scholar
  15. Batandier C, Guigas B, Detaille D, El-Mir MY, Fontaine E, Rigoulet M, Leverve XM (2006) The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr 38:33–42. Google Scholar
  16. Berstein LM (2012) Metformin in obesity, cancer and aging: addressing controversies. Aging (Albany NY) 4:320–329. Google Scholar
  17. Björkhem-Bergman L, Asplund AB, Lindh JD (2011) Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis. J Psychopharmacol 25:299–305. Google Scholar
  18. Bonnet F, Scheen A (2017) Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metab 19:473–481. Google Scholar
  19. Bridgeman SC, Ellison GC, Melton PE, Newsholme P, Mamotte CDS (2018) Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab 20:1553–1562. Google Scholar
  20. Burkewitz K, Zhang Y, Mair WB (2014) AMPK at the nexus of energetics and aging. Cell Metab 20:10–25. Google Scholar
  21. Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–239. Google Scholar
  22. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJ, Savinko T, Wong AK, Viollet B, Sakamoto K, Fagerholm SC, Foretz M, Lang CC, Rena G (2016) Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 119:652–665. Google Scholar
  23. Campbell JM, Bellman SM, Stephenson MD, Lisy K (2017) Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev 40:31–44. Google Scholar
  24. Canto C, Auwerx J (2010) AMP-activated protein kinase and its downstream transcriptional pathways. Cell Mol Life Sci 67:3407–3423. Google Scholar
  25. Caughey GE, Roughead EE, Vitry AI, McDermott RA, Shakib S, Gilbert AL (2010) Comorbidity in the elderly with diabetes: identification of areas of potential treatment conflicts. Diabetes Res Clin Pract 87:385–393. Google Scholar
  26. Chen W, Liu X, Ye S (2016) Effects of metformin on blood and urine pro-inflammatory mediators in patients with type 2 diabetes. J Inflamm (Lond) 13:34. Google Scholar
  27. Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT (2012) Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat 135:639–646. Google Scholar
  28. De Haes W, Frooninckx L, Van Assche R, Smolders A, Depuydt G, Billen J, Braeckman BP, Schoofs L, Temmerman L (2014) Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci USA 111:E2501–E2509. Google Scholar
  29. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3:1451–1461. Google Scholar
  30. Demirovic D, Rattan SI (2013) Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis. Exp Gerontol 48:94–98. Google Scholar
  31. Diamanti-Kandarakis E, Alexandraki K, Piperi C, Aessopos A, Paterakis T, Katsikis I, Panidis D (2007) Effect of metformin administration on plasma advanced glycation end product levels in women with polycystic ovary syndrome. Metabolism 56:129–134. Google Scholar
  32. Dowling RJ, Niraula S, Chang MC, Done SJ, Ennis M, McCready DR, Leong WL, Escallon JM, Reedijk M, Goodwin PJ, Stambolic V (2015) Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res 17:32. Google Scholar
  33. Eriksson L, Nyström T (2015) Antidiabetic agents and endothelial dysfunction-beyond glucose control. Basic Clin Pharmacol Toxicol 117:15–25. Google Scholar
  34. Florez JC (2011) Does metformin work for everyone? A genome-wide association study for metformin response. Curr Diab Rep 11:467–469. Google Scholar
  35. Florez JC (2017) The pharmacogenetics of metformin. Diabetologia 60:1648–1655. Google Scholar
  36. Fougère B, Boulanger E, Nourhashémi F, Guyonnet S, Cesari M (2017) Chronic inflammation: accelerator of biological aging. J Gerontol A 72:1218–1225. Google Scholar
  37. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A 69(1):S4–S9. Google Scholar
  38. Franciosi M, Lucisano G, Lapice E, Strippoli GFM, Pellegrini F, Nicolucci A (2013) Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS ONE 8:e71583. Google Scholar
  39. Gao Y, Li Y, Xue J, Jia Y, Hu J (2010) Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol 635:231–236. Google Scholar
  40. Garg G, Singh S, Singh AK, Rizvi SI (2017a) Metformin alleviates altered erythrocyte redox status during aging in rats. Rejuvenation Res 20:15–24Google Scholar
  41. Garg G, Singh S, Singh AK, Rizvi SI (2017b) Antiaging effect of metformin on brain in naturally aged and accelerated senescence model of rat. Rejuvenation Res 20:173–182Google Scholar
  42. Garimella S, Seshayamma V, Rao HJ, Kumar S, Kumar U, Saheb SH (2016) Effect of metformin on lipid profile of type II diabetes. Int J Intg Med Sci 3:449–453. Google Scholar
  43. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consesus report. Diabetes Care 33:1674–1685. Google Scholar
  44. Gore DC, Wolf SE, Sanford A, Herndon DN, Wolfe RR (2005) Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. Ann Surg 241:334–342. Google Scholar
  45. Gowans GJ, Hardie DG (2014) AMPK: a cellular energy sensor primarily regulated by AMP. Biochem Soc Trans 42:71–75. Google Scholar
  46. Griffin SJ, Leaver JK, Irving GJ (2017) Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 60:1620–1629. Google Scholar
  47. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226. Google Scholar
  48. Ha J, Guan KL, Kim J (2015) AMPK and autophagy in glucose/glycogen metabolism. Mol Aspects Med 46:46–62. Google Scholar
  49. Haddad M, Knani I, Bouzidi H, Berriche O, Hammami M, Kerkeni M (2016) Plasma levels of pentosidine, carboxymethyl-lysine, soluble receptor for advanced glycation end products, and metabolic syndrome: the metformin effect. Dis Mark 2016:6248264. Google Scholar
  50. Hans H, Lone A, Aksenov V, Rollo CD (2015) Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension? Age (Dordr) 37:31. Google Scholar
  51. Hardie DG (2015) AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol 33:1–7. Google Scholar
  52. Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG (2017) Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia 60:1639–1647. Google Scholar
  53. Hegazy SK (2015) Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 33:207–212. Google Scholar
  54. Hervás D, Fornés-Ferrer V, Gómez-Escribano AP, Sequedo MD, Peiró C, Millán JM, Vázquez-Manrique RP (2017) Metformin intake associates with better cognitive function in patients with Huntington’s disease. PLoS ONE 12:e0179283. Google Scholar
  55. Hindupur SK, González A, Hall MN (2015) The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Med 7:a019141. Google Scholar
  56. Holman RR, Sanjoy KP, Bethel MA, Matthews DR, Neil AW (2008) 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589. Google Scholar
  57. Hostalek U, Gwilt M, Hildemann S (2015) Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 75:1071–1094. Google Scholar
  58. Hou YC, Hu Q, Huang J, Fang JY, Xiong H (2017) Metformin therapy and the risk of colorectal adenoma in patients with type 2 diabetes: a meta-analysis. Oncotarget 8:8843–8853. Google Scholar
  59. Hur KY, Lee MSh (2015) New mechanisms of metformin action: focusing on mitochondria and the gut. J Diabetes Investig 6:600–609. Google Scholar
  60. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S (2012) Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression. Horm Metab Res 44:891–895. Google Scholar
  61. Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schönbeck U, Libby P (2006) Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26:611–617. Google Scholar
  62. Jenkins AJ, Welsh P, Petrie JR (2018) Metformin, lipids and atherosclerosis prevention. Curr Opin Lipidol 29:346–353. Google Scholar
  63. Kaeberlein M, Rabinovitch PS, Martin GM (2015) Healthy aging: the ultimate preventative medicine. Science 350:1191–1193. Google Scholar
  64. Kane DA, Anderson EJ, Price JW, Woodlief TL, Lin CT, Bikman BT, Cortright RN, Neufer PD (2010) Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free Radic Biol Med 49:1082–1087. Google Scholar
  65. Kuan YC, Huang KW, Lin CL, Hu CJ, Kao CH (2017) Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry 79:77–83. Google Scholar
  66. Larsen JR, Dima L, Correll CU, Manu P (2018) The pharmacological management of metabolic syndrome. Expert Rev Clin Pharmacol 11:397–410. Google Scholar
  67. Lei Y, Yi Y, Liu Y, Liu X, Keller ET, Qian CN, Zhang J, Lu Y (2017) Metformin targets multiple signaling pathways in cancer. Chin J Cancer 36:17. Google Scholar
  68. Li X, Li T, Liu Z, Gou S, Wang C (2017) The effect of metformin on survival of patients with pancreatic cancer: a meta-analysis. Sci Rep 7:5825. Google Scholar
  69. Liu Q, Li S, Quan H, Li J (2014) Vitamin B12 status in metformin treated patients: systematic review. PLoS ONE 9:e100379. Google Scholar
  70. Madeo F, Zimmermann A, Maiuri MC, Kroemer G (2015) Essential role for autophagy in life span extension. J Clin Invest 125:85–93. Google Scholar
  71. Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel V, Kibbey RG, Shulman GI (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546. Google Scholar
  72. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112:2902–2909. Google Scholar
  73. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192. Google Scholar
  74. McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract. Diabetologia 59:426–435. Google Scholar
  75. Meireles CG, Pereira SA, Valadares LP, Rêgo DF, Simeoni LA, Guerra ENS, Lofrano-Porto A (2017) Effects of metformin on endometrial cancer: systematic review and meta-analysis. Gynecol Oncol 147:167–180. Google Scholar
  76. Memisogullari R, Turkeli M, Bakan E, Akcay F (2008) Effect of metformin or giclazide on lpidperoxidation and antioxidant levels in patients with diabetes mellitus. Turk J Med Sci 38:545–548Google Scholar
  77. Meng X, Chu G, Yang Z, Qiu P, Hu Y, Chen X, Peng W, Ye C, He FF, Zhang C (2016) Metformin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury by down-regulating MAD2B. Cell Physiol Biochem 40:477–485. Google Scholar
  78. Meng F, Song L, Wang W (2017) Metformin improves overall survival of colorectal cancer patients with diabetes: a meta-analysis. J Diabetes Res 2017:5063239. Google Scholar
  79. Miles JM, Rule AD, Borlaug BA (2014) Use of metformin in diseases of aging. Curr Diab Rep 14:490. Google Scholar
  80. Mofo Mato EP, Guewo-Fokeng M, Essop MF, Owira PMO (2018) Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes: a systematic review. Medicine 97:e11349. Google Scholar
  81. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51:2074–2081. Google Scholar
  82. Nesti L, Natali A (2017) Metformin effects on the heart and the cardiovascular system: a review of experimental and clinical data. Nutr Metab Cardiovasc Dis 27:657–669. Google Scholar
  83. Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL, Halter JB, Barzilai N (2016) Strategies and challenges in clinical trials targeting human aging. J Gerontol A 71:1424–1434. Google Scholar
  84. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B (2014) Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 41:61–68. Google Scholar
  85. Niafar M, Hai F, Porhomayon J, Nader ND (2015) The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med 10:93–102. Google Scholar
  86. Novelle MG, Ali A, Diéguez C, Bernier M, de Cabo R (2016) Metformin: a hopeful promise in aging research. Cold Spring Harb Perspect Med 6:a025932. Google Scholar
  87. Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS ONE 5:e8758. Google Scholar
  88. Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A (2014) Role of advanced glycation end products in cellular signaling. Redox Biol 2:411–429. Google Scholar
  89. Papanas N, Maltezos E, Mikhailidis DP (2012) Metformin and heart failure: never say never again. Expert Opin Pharmacother 13:1–8. Google Scholar
  90. Perla V, Jayanty SS (2013) Biguanide related compounds in traditional antidiabetic functional foods. Food Chem 138:1574–1580. Google Scholar
  91. Pernicova I, Korbonits M (2014) Metformin-mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10:143–156. Google Scholar
  92. Rattan SI (2008) Hormesis in aging. Ageing Res Rev 7:63–78. Google Scholar
  93. Rojas LB, Gomes MB (2013) Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 5:6. Google Scholar
  94. Ruderman NB, Carling D, Prentki M, Cacicedo JM (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Investig 123:2764–2772. Google Scholar
  95. Safe S, Nair V, Karki K (2018) Metformin-induced anticancer activities: recent insights. Biol Chem 399:321–335. Google Scholar
  96. Saisho Y (2015) Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 15:196–205Google Scholar
  97. Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11:230–241. Google Scholar
  98. Salminen A, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M (2011) AMP-activated protein kinase: a potential player in Alzheimer’s disease. J Neurochem 118:460–474. Google Scholar
  99. Samocha-Bonet D, Debs S, Greenfield JR (2018) Prevention and treatment of type 2 diabetes: a pathophysiological-based approach. Trends Endocrinol Metab 29:370–379. Google Scholar
  100. Schlender L, Martinez YV, Adeniji C, Reeves D, Faller B, Sommerauer C, Al Qur’an T, Woodham A, Kunnamo I, Sönnichsen A, Renom-Guiteras A (2017) Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing. BMC Geriatr 17(Suppl 1):227. Google Scholar
  101. Seifarth C, Schehler B, Schneider HJ (2013) Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 121:27–31. Google Scholar
  102. Slack C, Foley A, Partridge L (2012) Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila. PLoS ONE 7:e47699. Google Scholar
  103. Smith DL, Elam CF, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB (2010) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci 65:468–474. Google Scholar
  104. Song R (2016) Mechanism of metformin: a tale of two sites. Diabetes Care 39:187–189. Google Scholar
  105. Stage TB, Brøsen K, Christensen MM (2015) A comprehensive review of drug-drug interactions with metformin. Clin Pharmacokinet 54:811–824. Google Scholar
  106. Stevens RJ, Ali R, Bankhead CR, Bethel MA, Cairns BJ, Camisasca RP, Crowe FL, Farmer AJ, Harrison S, Hirst JA, Home P, Kahn SE, McLellan JH, Perera R, Plüddemann A, Ramachandran A, Roberts NW, Rose PW, Schweizer A, Viberti G, Holman RR (2012) Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomized clinical trials. Diabetologia 55:2593–2603. Google Scholar
  107. Sumantri S, Setiati S, Purnamasari D, Dewiasty E (2014) Relationship between metformin and frailty syndrome in elderly people with type 2 diabetes. Acta Med Indones 46:183–188Google Scholar
  108. Takahashi N, Shibata R, Ouchi N, Sugimoto M, Murohara T, Komori K (2015) Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model. J Vasc Surg 561:489–496. Google Scholar
  109. Tang YL, Zhu LY, Li Y, Wang J, Zeng XX, Hu KX, Liu JY, Xu JX (2017) Metformin use is associated with reduced incidence and improved survival of endometrial cancer: a meta-analysis. Biomed Res Int 2017:5905384. Google Scholar
  110. Tolosa MJ, Chuguransky SR, Sedlinsky C, Schurman L, McCarthy AD, Molinuevo MS, Cortizo AM (2013) Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin. Diabetes Res Clin Pract 101:177–186. Google Scholar
  111. Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signalling. Circ Res. 1100:328–341. Google Scholar
  112. Tseng CH (2016) Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus. Aging (Albany NY) 8:1636–1649. Google Scholar
  113. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP (2015) Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350:g7607. Google Scholar
  114. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865. Google Scholar
  115. Vaiserman A, Lushchak O (2017) Implementation of longevity-promoting supplements and medications in public health practice: achievements, challenges and future perspectives. J Transl Med 15:160. Google Scholar
  116. Vaiserman AM, Lushchak OV, Koliada AK (2016) Anti-aging pharmacology: promises and pitfalls. Ageing Res Rev 31:9–35. Google Scholar
  117. Van Leeuwen N, Swen JJ, Guchelaar HJ (2013) The role of pharmacogenetics in drug disposition and response of oral glucose-lowering drugs. Clin Pharmacokinet 52:833–854. Google Scholar
  118. Verdaguer E, Junyent F, Folch J, Beas-Zarate C, Auladell C, Pallàs M, Camins A (2012) Aging biology: a new frontier for drug discovery. Expert Opin Drug Discov 7:217–229. Google Scholar
  119. Wang CP, Lorenzo C, Espinoza SE (2014) Frailty attenuates the impact of metformin on reducing mortality in older adults with type 2 diabetes. J Endocrinol Diabetes Obes 2:1031Google Scholar
  120. Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L, Huang Q (2017) Metformin: a review of its potential indications. Drug Des Devel Ther 11:2421–2429. Google Scholar
  121. Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, Xie J, Tao M, Mao Y (2015) Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis. Oncologist 20:1236–1244. Google Scholar
  122. Yamagishi S, Maeda S, Matsui T, Ueda S, Fukami K, Okuda S (2012) Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes. Biochim Biophys Acta 1820:663–671. Google Scholar
  123. Yu H, Yin L, Jiang X, Sun X, Wu J, Tian H, Gao X, He X (2014) Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS ONE 9:e116327. Google Scholar
  124. Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE (2012) Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab 97:2347–2353. Google Scholar
  125. Zheng J, Woo SL, Hu X, Botchlett R, Chen L, Huo Y, Wu C (2015) Metformin and metabolic diseases: a focus on hepatic aspects. Front Med 9:173–186. Google Scholar
  126. Zhou L, Liu H, Wen X, Peng Y, Tian Y, Zhao L (2017a) Effects of metformin on blood pressure in nondiabetic patients: a meta-analysis of randomized controlled trials. J Hypertens 35:18–26. Google Scholar
  127. Zhou XL, Xue WH, Ding XF, Li LF, Dou MM, Zhang WJ, Lv Z, Fan ZR, Zhao J, Wang LX (2017b) Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies. Oncotarget 8:55622–55631. Google Scholar
  128. Zimmermann A, Bauer MA, Kroemer G, Madeo F, Carmona-Gutierrez D (2014) When less is more: hormesis against stress and disease. Microb Cell 1:150–153. Google Scholar

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© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Clinic for Heart SurgeryUniversity Clinic of the Martin Luther UniversityHalleGermany
  2. 2.Department of Biochemistry and BiotechnologyVasyl Stefanyk Precarpathian National UniversityIvano-FrankivskUkraine
  3. 3.Institute of BiochemistryCarleton UniversityOttawaCanada
  4. 4.D.F. Chebotarev Institute of GerontologyNAMSKievUkraine

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