1932

Abstract

Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-051920-093829
2022-01-06
2024-12-10
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/62/1/annurev-pharmtox-051920-093829.html?itemId=/content/journals/10.1146/annurev-pharmtox-051920-093829&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Gevers D, Knight R, Petrosino JF, Huang K, McGuire AL et al. 2012. The Human Microbiome Project: a community resource for the healthy human microbiome. PLOS Biol 10:e1001377
    [Google Scholar]
  2. 2. 
    Ursell LK, Clemente JC, Rideout JR, Gevers D, Caporaso JG, Knight R. 2012. The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J. Allergy Clin. Immunol. 129:1204–8
    [Google Scholar]
  3. 3. 
    Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. 2007. The human microbiome project. Nature 449:804–10
    [Google Scholar]
  4. 4. 
    Marchesi JR, Ravel J 2015. The vocabulary of microbiome research: a proposal. Microbiome 3:31
    [Google Scholar]
  5. 5. 
    Lederberg J, McCray AT. 2001.. ‘ Ome sweet ‘omics—a genealogical treasury of words. Scientist 15:8
    [Google Scholar]
  6. 6. 
    Berg G, Rybakova D, Fischer D, Cernava T, Verges MC et al. 2020. Microbiome definition re-visited: old concepts and new challenges. Microbiome 8:103
    [Google Scholar]
  7. 7. 
    Scepanovic P, Hodel F, Mondot S, Partula V, Byrd A et al. 2019. A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals. Microbiome 7:130
    [Google Scholar]
  8. 8. 
    Flores GE, Caporaso JG, Henley JB, Rideout JR, Domogala D et al. 2014. Temporal variability is a personalized feature of the human microbiome. Genome Biol 15:531
    [Google Scholar]
  9. 9. 
    Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J et al. 2021. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat. Metab. 3:274–86
    [Google Scholar]
  10. 10. 
    Gilbert JA. 2015. Our unique microbial identity. Genome Biol 16:97
    [Google Scholar]
  11. 11. 
    Honda K, Littman DR. 2012. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30:759–95
    [Google Scholar]
  12. 12. 
    Baquero F, Nombela C. 2012. The microbiome as a human organ. Clin. Microbiol. Infect. 18:Suppl. 42–4
    [Google Scholar]
  13. 13. 
    Niemeyer-van der Kolk T, van der Wall HEC, Balmforth C, Van Doorn MBA, Rissmann R. 2018. A systematic literature review of the human skin microbiome as biomarker for dermatological drug development. Br. J. Clin. Pharmacol. 84:2178–93
    [Google Scholar]
  14. 14. 
    Gevers D, Knight R, Petrosino JF, Huang K, McGuire AL et al. 2012. The human microbiome project: a community resource for the healthy human microbiome. PLOS Biol 10:e1001377
    [Google Scholar]
  15. 15. 
    Hum. Microbiome Proj. Consort 2012. A framework for human microbiome research. Nature 486:215–21
    [Google Scholar]
  16. 16. 
    Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ et al. 2006. Metagenomic analysis of the human distal gut microbiome. Science 312:1355–59
    [Google Scholar]
  17. 17. 
    Neish AS. 2009. Microbes in gastrointestinal health and disease. Gastroenterology 136:65–80
    [Google Scholar]
  18. 18. 
    Verstraelen H. 2008. Cutting edge: the vaginal microflora and bacterial vaginosis. Verh. K. Acad. Geneeskd. Belg. 70:147–74
    [Google Scholar]
  19. 19. 
    Faner R, Sibila O, Agusti A, Bernasconi E, Chalmers JD et al. 2017. The microbiome in respiratory medicine: current challenges and future perspectives. Eur. Respir. J. 49:1602086
    [Google Scholar]
  20. 20. 
    Frank DN, St. Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR 2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. PNAS 104:13780–85
    [Google Scholar]
  21. 21. 
    Nayfach S, Roux S, Seshadri R, Udwary D, Varghese N et al. 2020. A genomic catalog of Earth's microbiomes. Nat. Biotechnol. 39:499–509
    [Google Scholar]
  22. 22. 
    Almeida A, Nayfach S, Boland M, Strozzi F, Beracochea M et al. 2021. A unified catalog of 204,938 reference genomes from the human gut microbiome. Nat. Biotechnol. 39:105–14
    [Google Scholar]
  23. 23. 
    Gebbers JO, Laissue JA. 1989. Immunologic structures and functions of the gut. Schweiz. Arch. Tierheilkd 131:221–38
    [Google Scholar]
  24. 24. 
    Ley RE, Peterson DA, Gordon JI. 2006. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:837–48
    [Google Scholar]
  25. 25. 
    Ursell LK, Clemente JC, Rideout JR, Gevers D, Caporaso JG, Knight R. 2012. The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J. Allergy Clin. Immunol. 129:1204–8
    [Google Scholar]
  26. 26. 
    Whitman WB, Coleman DC, Wiebe WJ 1998. Prokaryotes: the unseen majority. PNAS 95:6578–83
    [Google Scholar]
  27. 27. 
    Berg RD. 1996. The indigenous gastrointestinal microflora. Trends Microbiol 4:430–35
    [Google Scholar]
  28. 28. 
    Dickson RP, Erb-Downward JR, Huffnagle GB. 2015. Homeostasis and its disruption in the lung microbiome. Am. J. Physiol. Lung Cell Mol. Physiol. 309:L1047–55
    [Google Scholar]
  29. 29. 
    Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C et al. 2018. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359:1156–61
    [Google Scholar]
  30. 30. 
    Savage D. 1977. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31:107–33
    [Google Scholar]
  31. 31. 
    Tannock GW. 1999. Analysis of the intestinal microflora: a renaissance. Antonie Van Leeuwenhoek 76:265–78
    [Google Scholar]
  32. 32. 
    Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L et al. 2005. Diversity of the human intestinal microbial flora. Science 308:1635–38
    [Google Scholar]
  33. 33. 
    Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. 2005. Host-bacterial mutualism in the human intestine. Science 307:1915–20
    [Google Scholar]
  34. 34. 
    Muller CA, Autenrieth IB, Peschel A. 2005. Innate defenses of the intestinal epithelial barrier. Cell Mol. Life Sci. 62:1297–307
    [Google Scholar]
  35. 35. 
    Nava GM, Stappenbeck TS. 2011. Diversity of the autochthonous colonic microbiota. Gut Microbes 2:99–104
    [Google Scholar]
  36. 36. 
    Peterson LW, Artis D. 2014. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14:141–53
    [Google Scholar]
  37. 37. 
    Abrams GD, Bauer H, Sprinz H. 1963. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Investig. 12:355–64
    [Google Scholar]
  38. 38. 
    Bry L, Falk PG, Midtvedt T, Gordon JI 1996. A model of host-microbial interactions in an open mammalian ecosystem. Science 273:1380–83
    [Google Scholar]
  39. 39. 
    Alam M, Midtvedt T, Uribe A. 1994. Differential cell kinetics in the ileum and colon of germfree rats. Scand. J. Gastroenterol. 29:445–51
    [Google Scholar]
  40. 40. 
    Sommer F, Bäckhed F. 2013. The gut microbiota—masters of host development and physiology. Nat. Rev. Microbiol. 11:227–38
    [Google Scholar]
  41. 41. 
    Gordon HA, Bruckner-Kardoss E. 1961. Effect of normal microbial flora on intestinal surface area. Am. J. Physiol. 201:175–78
    [Google Scholar]
  42. 42. 
    Husebye E, Hellstrom PM, Midtvedt T. 1994. Intestinal microflora stimulates myoelectric activity of rat small intestine by promoting cyclic initiation and aboral propagation of migrating myoelectric complex. Dig. Dis. Sci. 39:946–56
    [Google Scholar]
  43. 43. 
    Xu J, Bjursell MK, Himrod J, Deng S, Carmichael LK et al. 2003. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science 299:2074–76
    [Google Scholar]
  44. 44. 
    Macfarlane S, Macfarlane GT. 2003. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62:67–72
    [Google Scholar]
  45. 45. 
    Yoshii K, Hosomi K, Sawane K, Kunisawa J. 2019. Metabolism of dietary and microbial vitamin B family in the regulation of host immunity. Front. Nutr. 6:48
    [Google Scholar]
  46. 46. 
    Marin L, Miguelez EM, Villar CJ, Lombo F. 2015. Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed. Res. Int. 2015 905215
    [Google Scholar]
  47. 47. 
    Zheng D, Liwinski T, Elinav E. 2020. Interaction between microbiota and immunity in health and disease. Cell Res 30:492–506
    [Google Scholar]
  48. 48. 
    Macpherson AJ, Harris NL. 2004. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4:478–85
    [Google Scholar]
  49. 49. 
    Round JL, Mazmanian SK. 2009. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9:313–23
    [Google Scholar]
  50. 50. 
    Bouskra D, Brezillon C, Berard M, Werts C, Varona R et al. 2008. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456:507–10
    [Google Scholar]
  51. 51. 
    Suzuki K, Maruya M, Kawamoto S, Sitnik K, Kitamura H et al. 2010. The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut. Immunity 33:71–83
    [Google Scholar]
  52. 52. 
    Cario E, Gerken G, Podolsky DK. 2007. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132:1359–74
    [Google Scholar]
  53. 53. 
    Cools N, Petrizzo A, Smits E, Buonaguro FM, Tornesello ML et al. 2011. Dendritic cells in the pathogenesis and treatment of human diseases: a Janus Bifrons?. Immunotherapy 3:1203–22
    [Google Scholar]
  54. 54. 
    Shen C, He Y, Cheng K, Zhang D, Miao S et al. 2011. Killer artificial antigen-presenting cells deplete alloantigen-specific T cells in a murine model of alloskin transplantation. Immunol. Lett. 138:144–55
    [Google Scholar]
  55. 55. 
    Kelsall BL, Leon F. 2005. Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol. Rev. 206:132–48
    [Google Scholar]
  56. 56. 
    Iwasaki A, Kelsall BL. 1999. Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J. Exp. Med. 190:229–39
    [Google Scholar]
  57. 57. 
    Pickard JM, Zeng MY, Caruso R, Núñez G. 2017. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol. Rev. 279:70–89
    [Google Scholar]
  58. 58. 
    Kho ZY, Lal SK. 2018. The human gut microbiome—a potential controller of wellness and disease. Front. Microbiol. 9:1835
    [Google Scholar]
  59. 59. 
    Kamada N, Chen GY, Inohara N, Nunez G. 2013. Control of pathogens and pathobionts by the gut microbiota. Nat. Immunol. 14:685–90
    [Google Scholar]
  60. 60. 
    Schamberger GP, Diez-Gonzalez F. 2002. Selection of recently isolated colicinogenic Escherichia coli strains inhibitory to Escherichia coli O157:H7. J. Food Prot. 65:1381–87
    [Google Scholar]
  61. 61. 
    Hammami R, Fernandez B, Lacroix C, Fliss I. 2013. Anti-infective properties of bacteriocins: an update. Cell Mol. Life Sci. 70:2947–67
    [Google Scholar]
  62. 62. 
    Momose Y, Hirayama K, Itoh K. 2008. Competition for proline between indigenous Escherichia coli and E. coli O157:H7 in gnotobiotic mice associated with infant intestinal microbiota and its contribution to the colonization resistance against E. coli O157:H7. Antonie Van Leeuwenhoek 94:165–71
    [Google Scholar]
  63. 63. 
    Gantois I, Ducatelle R, Pasmans F, Haesebrouck F, Hautefort I et al. 2006. Butyrate specifically down-regulates Salmonella pathogenicity island 1 gene expression. Appl. Environ. Microbiol. 72:946–49
    [Google Scholar]
  64. 64. 
    Bartlett JG. 2002. Antibiotic-associated diarrhea. N. Engl. J. Med. 346:334–39
    [Google Scholar]
  65. 65. 
    Sorg JA, Sonenshein AL. 2008. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190:2505–12
    [Google Scholar]
  66. 66. 
    Van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG et al. 2013. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368:407–15
    [Google Scholar]
  67. 67. 
    Konturek PC, Koziel J, Dieterich W, Haziri D, Wirtz S et al. 2016. Successful therapy of Clostridium difficile infection with fecal microbiota transplantation. J. Physiol. Pharmacol. 67:859–66
    [Google Scholar]
  68. 68. 
    Fabbrizzi A, Amedei A, Lavorini F, Renda T, Fontana G 2019. The lung microbiome: clinical and therapeutic implications. Intern. Emerg. Med. 14:1241–50
    [Google Scholar]
  69. 69. 
    Motta J-P, Wallace JL, Buret AG, Deraison C, Vergnolle N 2021. Gastrointestinal biofilms in health and disease. Nat. Rev. Gastroenterol. Hepatol. 18:314–34
    [Google Scholar]
  70. 70. 
    Belizário JE, Faintuch J 2018. Microbiome and gut dysbiosis. Metabolic Interaction in Infection R Silvestre, E Torrado 459–76 Cham, Switz: Springer
    [Google Scholar]
  71. 71. 
    De Palma G, Nadal I, Medina M, Donat E, Ribes-Koninckx C et al. 2010. Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol 10:63
    [Google Scholar]
  72. 72. 
    Shen XJ, Rawls JF, Randall T, Burcal L, Mpande CN et al. 2010. Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes 1:138–47
    [Google Scholar]
  73. 73. 
    Maruvada P, Leone V, Kaplan LM, Chang EB. 2017. The human microbiome and obesity: moving beyond associations. Cell Host Microbe 22:589–99
    [Google Scholar]
  74. 74. 
    Wei B, Wang Y, Xiang S, Jiang Y, Chen R, Hu N 2020. Alterations of gut microbiome in patients with type 2 diabetes mellitus who had undergone cholecystectomy. Am. J. Physiol. Endocrinol. Metab. 320:E113–21
    [Google Scholar]
  75. 75. 
    Sedighi M, Razavi S, Navab-Moghadam F, Khamseh ME, Alaei-Shahmiri F et al. 2017. Comparison of gut microbiota in adult patients with type 2 diabetes and healthy individuals. Microbial. Pathog. 111:362–69
    [Google Scholar]
  76. 76. 
    Tilg H, Moschen AR. 2014. Microbiota and diabetes: an evolving relationship. Gut 63:1513–21
    [Google Scholar]
  77. 77. 
    Bryrup T, Thomsen CW, Kern T, Allin KH, Brandslund I et al. 2019. Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study. Diabetologia 62:1024–35
    [Google Scholar]
  78. 78. 
    Foster JA, McVey Neufeld KA. 2013. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36:305–12
    [Google Scholar]
  79. 79. 
    Mussell M, Kroenke K, Spitzer RL, Williams JB, Herzog W, Lowe B. 2008. Gastrointestinal symptoms in primary care: prevalence and association with depression and anxiety. J. Psychosom. Res. 64:605–12
    [Google Scholar]
  80. 80. 
    De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A et al. 2013. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLOS ONE 8:e76993
    [Google Scholar]
  81. 81. 
    Castro-Nallar E, Bendall ML, Perez-Losada M, Sabuncyan S, Severance EG et al. 2015. Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls. PeerJ 3:e1140
    [Google Scholar]
  82. 82. 
    De Luca F, Shoenfeld Y. 2019. The microbiome in autoimmune diseases. Clin. Exp. Immunol. 195:74–85
    [Google Scholar]
  83. 83. 
    Şafak B, Altunan B, Topçu B, Eren Topkaya A 2020. The gut microbiome in epilepsy. Microbial. Pathog. 139:103853
    [Google Scholar]
  84. 84. 
    Haran JP, McCormick BA. 2021. Aging, frailty, and the microbiome—how dysbiosis influences human aging and disease. Gastroenterology 160:507–23
    [Google Scholar]
  85. 85. 
    Ragonnaud E, Biragyn A 2021. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immunity Ageing 18:2
    [Google Scholar]
  86. 86. 
    Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL 2019. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 570:462–67
    [Google Scholar]
  87. 87. 
    Wilson ID, Nicholson JK 2017. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl. Res. 179:204–22
    [Google Scholar]
  88. 88. 
    Freedberg DE, Toussaint NC, Chen SP, Ratner AJ, Whittier S et al. 2015. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology 149:883–85.e9
    [Google Scholar]
  89. 89. 
    Sun C, Chen L, Shen Z 2019. Mechanisms of gastrointestinal microflora on drug metabolism in clinical practice. Saudi. Pharm. J. 27:1146–56
    [Google Scholar]
  90. 90. 
    Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK 2009. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. PNAS 106:14728–33
    [Google Scholar]
  91. 91. 
    Wallace BD, Wang H, Lane KT, Scott JE, Orans J et al. 2010. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330:831–35
    [Google Scholar]
  92. 92. 
    Uejima M, Kinouchi T, Kataoka K, Hiraoka I, Ohnishi Y 1996. Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug. Microbiol. Immunol. 40:553–60
    [Google Scholar]
  93. 93. 
    Robert A, Asano T 1977. Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins 14:333–41
    [Google Scholar]
  94. 94. 
    Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM et al. 2011. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLOS ONE 6:e25482
    [Google Scholar]
  95. 95. 
    Jackson MA, Verdi S, Maxan ME, Shin CM, Zierer J et al. 2018. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat. Commun. 9:2655
    [Google Scholar]
  96. 96. 
    Maurice CF, Haiser HJ, Turnbaugh PJ. 2013. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152:39–50
    [Google Scholar]
  97. 97. 
    Vich Vila A, Collij V, Sanna S, Sinha T, Imhann F et al. 2020. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11:362
    [Google Scholar]
  98. 98. 
    Hill DA, Hoffmann C, Abt MC, Du Y, Kobuley D et al. 2010. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol 3:148–58
    [Google Scholar]
  99. 99. 
    Ianiro G, Tilg H, Gasbarrini A. 2016. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut 65:1906–15
    [Google Scholar]
  100. 100. 
    Jernberg C, Lofmark S, Edlund C, Jansson JK. 2007. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J 1:56–66
    [Google Scholar]
  101. 101. 
    Hansen CH, Krych L, Nielsen DS, Vogensen FK, Hansen LH et al. 2012. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 55:2285–94
    [Google Scholar]
  102. 102. 
    Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L 2010. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLOS ONE 5:e9836
    [Google Scholar]
  103. 103. 
    Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z et al. 2016. Proton pump inhibitors affect the gut microbiome. Gut 65:740–48
    [Google Scholar]
  104. 104. 
    Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A et al. 2018. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555:623–28
    [Google Scholar]
  105. 105. 
    Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. 2012. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am. J. Gastroenterol. 107:1001–10
    [Google Scholar]
  106. 106. 
    Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R et al. 2017. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23:850–58
    [Google Scholar]
  107. 107. 
    Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E et al. 2015. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–66
    [Google Scholar]
  108. 108. 
    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G et al. 2010. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. PNAS 107:11971–75
    [Google Scholar]
  109. 109. 
    Huang S, Haiminen N, Carrieri A-P, Hu R, Jiang L et al. 2020. Human skin, oral, and gut microbiomes predict chronological age. mSystems 5:e00630-19
    [Google Scholar]
  110. 110. 
    Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG et al. 2012. Human gut microbiome viewed across age and geography. Nature 486:222–27
    [Google Scholar]
  111. 111. 
    Maynard C, Weinkove D 2018. The gut microbiota and ageing. Biochemistry and Cell Biology of Ageing: Part I Biomedical Science JR Harris, VI Korolchuk 351–71 Singapore: Springer
    [Google Scholar]
  112. 112. 
    Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM et al. 2014. Geroscience: linking aging to chronic disease. Cell 159:709–13
    [Google Scholar]
  113. 113. 
    Elyahu Y, Hekselman I, Eizenberg-Magar I, Berner O, Strominger I et al. 2019. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci. Adv. 5:eaaw8330
    [Google Scholar]
  114. 114. 
    Fessler J, Ficjan A, Duftner C, Dejaco C. 2013. The impact of aging on regulatory T-cells. Front. Immunol. 4:231
    [Google Scholar]
  115. 115. 
    Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. 2015. Naive T cell maintenance and function in human aging. J. Immunol. 194:4073–80
    [Google Scholar]
  116. 116. 
    Haynes L, Maue AC. 2009. Effects of aging on T cell function. Curr. Opin. Immunol. 21:414–17
    [Google Scholar]
  117. 117. 
    Lee N, Kim W-U. 2017. Microbiota in T-cell homeostasis and inflammatory diseases. Exp. Mol. Med. 49:e340
    [Google Scholar]
  118. 118. 
    Toor D, Wasson MK, Kumar P, Karthikeyan G, Kaushik NK et al. 2019. Dysbiosis disrupts gut immune homeostasis and promotes gastric diseases. Int. J. Mol. Sci. 20:2432
    [Google Scholar]
  119. 119. 
    Megias J, Yanez A, Moriano S, O'Connor JE, Gozalbo D, Gil ML 2012. Direct Toll-like receptor-mediated stimulation of hematopoietic stem and progenitor cells occurs in vivo and promotes differentiation toward macrophages. Stem Cells 30:1486–95
    [Google Scholar]
  120. 120. 
    Mitroulis I, Kalafati L, Hajishengallis G, Chavakis T. 2018. Myelopoiesis in the context of innate immunity. J. Innate Immun. 10:365–72
    [Google Scholar]
  121. 121. 
    Yanez A, Goodridge HS, Gozalbo D, Gil ML 2013. TLRs control hematopoiesis during infection. Eur. J. Immunol. 43:2526–33
    [Google Scholar]
  122. 122. 
    Shintouo CM, Mets T, Beckwee D, Bautmans I, Ghogomu SM et al. 2020. Is inflammageing influenced by the microbiota in the aged gut? A systematic review. Exp. Gerontol. 141:111079
    [Google Scholar]
  123. 123. 
    Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM et al. 2012. Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178–84
    [Google Scholar]
  124. 124. 
    Kumar A, Wu H, Collier-Hyams LS, Hansen JM, Li T et al. 2007. Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species. EMBO J 26:4457–66
    [Google Scholar]
  125. 125. 
    Pamer EG. 2007. Immune responses to commensal and environmental microbes. Nat. Immunol. 8:1173–78
    [Google Scholar]
  126. 126. 
    Kelly CP, Pothoulakis C, Lamont JT 1994. Clostridium difficile colitis. N. Engl. J. Med. 330:257–62
    [Google Scholar]
  127. 127. 
    Toward R, Montandon S, Walton G, Gibson GR 2012. Effect of prebiotics on the human gut microbiota of elderly persons. Gut Microbes 3:57–60
    [Google Scholar]
  128. 128. 
    Weaver LK, Minichino D, Biswas C, Chu N, Lee J-J et al. 2019. Microbiota-dependent signals are required to sustain TLR-mediated immune responses. JCI Insight 4:e124370
    [Google Scholar]
  129. 129. 
    Gorjifard S, Goldszmid RS. 2016. Microbiota–myeloid cell crosstalk beyond the gut. J. Leukoc. Biol. 100:865–79
    [Google Scholar]
  130. 130. 
    Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. 2016. Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment. Front. Immunol. 7:502
    [Google Scholar]
  131. 131. 
    Clements SJ, Carding SR. 2018. Diet, the intestinal microbiota, and immune health in aging. Crit. Rev. Food Sci. Nutr. 58:651–61
    [Google Scholar]
  132. 132. 
    Durand A, Audemard-Verger A, Guichard V, Mattiuz R, Delpoux A et al. 2018. Profiling the lymphoid-resident T cell pool reveals modulation by age and microbiota. Nat. Commun. 9:68
    [Google Scholar]
  133. 133. 
    Gadecka A, Bielak-Zmijewska A. 2019. Slowing down ageing: the role of nutrients and microbiota in modulation of the epigenome. Nutrients 11:1251
    [Google Scholar]
  134. 134. 
    Kim S, Jazwinski SM 2018. The gut microbiota and healthy aging: a mini-review. Gerontology 64:513–20
    [Google Scholar]
  135. 135. 
    Macaulay R, Akbar AN, Henson SM. 2013. The role of the T cell in age-related inflammation. Age 35:563–72
    [Google Scholar]
  136. 136. 
    Peniche AG, Spinler JK, Boonma P, Savidge TC, Dann SM. 2018. Aging impairs protective host defenses against Clostridioides (Clostridium) difficile infection in mice by suppressing neutrophil and IL-22 mediated immunity. Anaerobe 54:83–91
    [Google Scholar]
  137. 137. 
    Smith CK, Trinchieri G. 2018. The interplay between neutrophils and microbiota in cancer. J. Leukoc. Biol. 104:701–15
    [Google Scholar]
  138. 138. 
    Stavropoulou E, Bezirtzoglou E. 2019. Human microbiota in aging and infection: a review. Crit. Rev. Food Sci. Nutr. 59:537–45
    [Google Scholar]
  139. 139. 
    Bailey CJ. 2017. Metformin: historical overview. Diabetologia 60:1566–76
    [Google Scholar]
  140. 140. 
    Bailey C, Day C. 2004. Metformin: its botanical background. Pract. Diabetes Int. 21:115–17
    [Google Scholar]
  141. 141. 
    Wang YW, He SJ, Feng X, Cheng J, Luo YT et al. 2017. Metformin: a review of its potential indications. Drug Des. Devel. Ther. 11:2421–29
    [Google Scholar]
  142. 142. 
    Moon MK, Hur KY, Ko SH, Park SO, Lee BW et al. 2017. Combination therapy of oral hypoglycemic agents in patients with type 2 diabetes mellitus. Diabetes Metab. J. 41:357–66
    [Google Scholar]
  143. 143. 
    Wagstaff AJ, Figgitt DP. 2004. Extended-release metformin hydrochloride: single-composition osmotic tablet formulation. Treat. Endocrinol. 3:327–32
    [Google Scholar]
  144. 144. 
    Wang GS, Hoyte C. 2019. Review of biguanide (metformin) toxicity. J. Intensive Care Med. 34:863–76
    [Google Scholar]
  145. 145. 
    Johnson HK, Waterhouse C 1968. Lactic acidosis and phenformin: report of two successfully treated patients. Arch. Intern. Med. 122:367–70
    [Google Scholar]
  146. 146. 
    Ball S, Woods HF, Alberti KGMM. 1974. Lacticacidosis, ketoacidosis, and hyperalaninaemia in a phenformin-treated diabetic patient. Br. Med. J. 4:699–700
    [Google Scholar]
  147. 147. 
    Kruse JA. 2001. Metformin-associated lactic acidosis. J. Emerg. Med. 20:267–72
    [Google Scholar]
  148. 148. 
    Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A et al. 2014. Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin. Toxicol. 52:129–35
    [Google Scholar]
  149. 149. 
    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F 2012. Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. 122:253–70
    [Google Scholar]
  150. 150. 
    Duong JK, Kumar SS, Kirkpatrick CM, Greenup LC, Arora M et al. 2013. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin. Pharmacokinet. 52:373–84
    [Google Scholar]
  151. 151. 
    Kajbaf F, Lalau JD. 2013. The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis. BMC Pharmacol. Toxicol. 14:22
    [Google Scholar]
  152. 152. 
    Pasquel FJ, Klein R, Adigweme A, Hinedi Z, Coralli R et al. 2015. Metformin-associated lactic acidosis. Am. J. Med. Sci. 349:263–67
    [Google Scholar]
  153. 153. 
    Bell S, Farran B, McGurnaghan S, McCrimmon RJ, Leese GP et al. 2017. Risk of acute kidney injury and survival in patients treated with metformin: an observational cohort study. BMC Nephrol. 18:163
    [Google Scholar]
  154. 154. 
    Corchia A, Wynckel A, Journet J, Moussi Frances J, Skandrani N et al. 2020. Metformin-related lactic acidosis with acute kidney injury: results of a French observational multicenter study. Clin. Toxicol. 58:375–82
    [Google Scholar]
  155. 155. 
    Dunn CJ, Peters DH. 1995. Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs 49:721–49
    [Google Scholar]
  156. 156. 
    Svare A. 2009. A patient presenting with symptomatic hypomagnesemia caused by metformin-induced diarrhoea: a case report. Cases J 2:156
    [Google Scholar]
  157. 157. 
    Babich MM, Pike I, Shiffman ML. 1998. Metformin-induced acute hepatitis. Am. J. Med. 104:490–92
    [Google Scholar]
  158. 158. 
    Nammour FE, Fayad NF, Peikin SR. 2003. Metformin-induced cholestatic hepatitis. Endocr. Pract. 9:307–9
    [Google Scholar]
  159. 159. 
    Cone CJ, Bachyrycz AM, Murata GH. 2010. Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease. Ann. Pharmacother. 44:1655–59
    [Google Scholar]
  160. 160. 
    Miralles-Linares F, Puerta-Fernandez S, Bernal-Lopez MR, Tinahones FJ, Andrade RJ, Gomez-Huelgas R. 2012. Metformin-induced hepatotoxicity. Diabetes Care 35:e21
    [Google Scholar]
  161. 161. 
    Callaghan TS, Hadden DR, Tomkin GH. 1980. Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment. Br. Med. J. 280:1214–15
    [Google Scholar]
  162. 162. 
    Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V 2000. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23:1227–31
    [Google Scholar]
  163. 163. 
    Mazokopakis EE, Starakis IK. 2012. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res. Clin. Pract. 97:359–67
    [Google Scholar]
  164. 164. 
    Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. 2013. The hallmarks of aging. Cell 153:1194–217
    [Google Scholar]
  165. 165. 
    Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A et al. 2013. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res. Rev. 12:661–84
    [Google Scholar]
  166. 166. 
    Dogan Turacli I, Candar T, Yuksel BE, Demirtas S 2018. Role of metformin on base excision repair pathway in p53 wild-type H2009 and HepG2 cancer cells. Hum. Exp. Toxicol. 37:909–19
    [Google Scholar]
  167. 167. 
    Szewczuk M, Boguszewska K, Kazmierczak-Baranska J, Karwowski BT. 2020. The role of AMPK in metabolism and its influence on DNA damage repair. Mol. Biol. Rep. 47:9075–86
    [Google Scholar]
  168. 168. 
    Dogan Turacli I, Candar T, Yuksel EB, Kalay S, Oguz AK, Demirtas S 2018. Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes. Biochimie 154:62–68
    [Google Scholar]
  169. 169. 
    Jin C, Li J, Green CD, Yu X, Tang X et al. 2011. Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab 14:161–72
    [Google Scholar]
  170. 170. 
    Bridgeman SC, Ellison GC, Melton PE, Newsholme P, Mamotte CDS 2018. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes. Metab. 20:1553–62
    [Google Scholar]
  171. 171. 
    Cuyàs E, Verdura S, Llorach-Pares L, Fernández-Arroyo S, Luciano-Mateo F et al. 2018. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging Cell 17:e12772
    [Google Scholar]
  172. 172. 
    Yu T, Wang C, Yang J, Guo Y, Wu Y, Li X 2017. Metformin inhibits SUV39H1-mediated migration of prostate cancer cells. Oncogenesis 6:e324
    [Google Scholar]
  173. 173. 
    Chen J, Ou Y, Li Y, Hu S, Shao LW, Liu Y 2017. Metformin extends C. elegans lifespan through lysosomal pathway. eLife 6:e31268
    [Google Scholar]
  174. 174. 
    Crawley D, Chandra A, Loda M, Gillett C, Cathcart P et al. 2017. Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer. BMC Cancer 17:494
    [Google Scholar]
  175. 175. 
    Csaba G. 2019. Immunity and longevity. Acta Microbiol. Immunol. Hung. 66:1–17
    [Google Scholar]
  176. 176. 
    Fang J, Yang J, Wu X, Zhang G, Li T et al. 2018. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 17:e12765
    [Google Scholar]
  177. 177. 
    Garg G, Singh S, Singh AK, Rizvi SI. 2017. Metformin alleviates altered erythrocyte redox status during aging in rats. Rejuvenation Res 20:15–24
    [Google Scholar]
  178. 178. 
    Sica A, Guarneri V, Gennari A. 2019. Myelopoiesis, metabolism and therapy: a crucial crossroads in cancer progression. Cell Stress 3:284–94
    [Google Scholar]
  179. 179. 
    Cai H, Han B, Hu Y, Zhao X, He Z et al. 2020. Metformin attenuates the D‑galactose‑induced aging process via the UPR through the AMPK/ERK1/2 signaling pathways. Int. J. Mol. Med. 45:715–30
    [Google Scholar]
  180. 180. 
    Fontana L, Partridge L, Longo VD. 2010. Extending healthy life span—from yeast to humans. Science 328:321–26
    [Google Scholar]
  181. 181. 
    Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T, Robinson AR et al. 2008. Delayed and accelerated aging share common longevity assurance mechanisms. PLOS Genet 4:e1000161
    [Google Scholar]
  182. 182. 
    Garinis GA, van der Horst GT, Vijg J, Hoeijmakers JH. 2008. DNA damage and ageing: new-age ideas for an age-old problem. Nat. Cell Biol. 10:1241–47
    [Google Scholar]
  183. 183. 
    Xie Y, Wang JL, Ji M, Yuan ZF, Peng Z et al. 2014. Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells. Oncol. Lett. 8:1993–99
    [Google Scholar]
  184. 184. 
    Klement RJ, Fink MK 2016. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer. Oncogenesis 5:e193
    [Google Scholar]
  185. 185. 
    Amin S, Lux A, O'Callaghan F. 2019. The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth. Br. J. Clin. Pharmacol. 85:37–46
    [Google Scholar]
  186. 186. 
    Cuyas E, Verdura S, Llorach L, Fernández Arroyo S, Joven J et al. 2018. Metformin is a direct SIRT1-activating compound: computational modeling and experimental validation. Front. Endocrinol. 9:657
    [Google Scholar]
  187. 187. 
    Adeyemo MA, McDuffie JR, Kozlosky M, Krakoff J, Calis KA et al. 2015. Effects of metformin on energy intake and satiety in obese children. Diabetes Obes. Metab. 17:363–70
    [Google Scholar]
  188. 188. 
    Mair W, Dillin A 2008. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77:727–54
    [Google Scholar]
  189. 189. 
    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]
  190. 190. 
    Bridges HR, Jones AJ, Pollak MN, Hirst J. 2014. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 462:475–87
    [Google Scholar]
  191. 191. 
    El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X 2000. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275:223–28
    [Google Scholar]
  192. 192. 
    Hardie DG, Ross FA, Hawley SA 2012. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13:251–62
    [Google Scholar]
  193. 193. 
    Zhou G, Myers R, Li Y, Chen Y, Shen X et al. 2001. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Investig. 108:1167–74
    [Google Scholar]
  194. 194. 
    Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT et al. 2014. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–46
    [Google Scholar]
  195. 195. 
    Li X, Guo Y, Yan W, Snyder MP, Li X 2015. Metformin improves diabetic bone health by re-balancing catabolism and nitrogen disposal. PLOS ONE 10:e0146152
    [Google Scholar]
  196. 196. 
    Guo Y, Cho SW, Saxena D, Li X. 2020. Multifaceted actions of succinate as a signaling transmitter vary with its cellular locations. Endocrinol. Metab. 35:36–43
    [Google Scholar]
  197. 197. 
    Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. 2010. The essence of senescence. Genes Dev 24:2463–79
    [Google Scholar]
  198. 198. 
    Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G et al. 2013. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 12:489–98
    [Google Scholar]
  199. 199. 
    Noren Hooten N, Martin-Montalvo A, Dluzen DF, Zhang Y, Bernier M et al. 2016. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15:572–81
    [Google Scholar]
  200. 200. 
    Kuang Y, Hu B, Feng G, Xiang M, Deng Y et al. 2020. Metformin prevents against oxidative stress-induced senescence in human periodontal ligament cells. Biogerontology 21:13–27
    [Google Scholar]
  201. 201. 
    Hu Q, Peng J, Jiang L, Li W, Su Q et al. 2020. Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma. Cell Death Dis 11:925
    [Google Scholar]
  202. 202. 
    Yi G, He Z, Zhou X, Xian L, Yuan T et al. 2013. Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int. J. Oncol. 43:1503–10
    [Google Scholar]
  203. 203. 
    Na HJ, Pyo JH, Jeon HJ, Park JS, Chung HY, Yoo MA 2018. Deficiency of Atg6 impairs beneficial effect of metformin on intestinal stem cell aging in Drosophila. Biochem. Biophys. Res. Commun. 498:18–24
    [Google Scholar]
  204. 204. 
    Fatt M, Hsu K, He L, Wondisford F, Miller FD et al. 2015. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Rep 5:988–95
    [Google Scholar]
  205. 205. 
    Neumann B, Baror R, Zhao C, Segel M, Dietmann S et al. 2019. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 25:473–85.e8
    [Google Scholar]
  206. 206. 
    Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M et al. 2000. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908:244–54
    [Google Scholar]
  207. 207. 
    Franceschi C, Campisi J. 2014. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69:Suppl. 1S4–9
    [Google Scholar]
  208. 208. 
    Bauer PV, Duca FA, Waise TMZ, Rasmussen BA, Abraham MA et al. 2018. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab 27:101–17.e5
    [Google Scholar]
  209. 209. 
    Sun L, Xie C, Wang G, Wu Y, Wu Q et al. 2018. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat. Med. 24:1919–29
    [Google Scholar]
  210. 210. 
    Armanios M, Blackburn EH. 2012. The telomere syndromes. Nat. Rev. Genet. 13:693–704
    [Google Scholar]
  211. 211. 
    Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A et al. 2008. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135:609–22
    [Google Scholar]
  212. 212. 
    Kulkarni AS, Gubbi S, Barzilai N 2020. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab 32:15–30
    [Google Scholar]
  213. 213. 
    Liu J, Ge Y, Wu S, Ma D, Xu W et al. 2019. Association between antidiabetic agents use and leukocyte telomere shortening rates in patients with type 2 diabetes. Aging 11:741–55
    [Google Scholar]
  214. 214. 
    Shin NR, Lee JC, Lee HY, Kim MS, Whon TW et al. 2014. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63:727–35
    [Google Scholar]
  215. 215. 
    Vallianou NG, Stratigou T, Tsagarakis S. 2019. Metformin and gut microbiota: their interactions and their impact on diabetes. Hormones 18:141–44
    [Google Scholar]
  216. 216. 
    Check Hayden E 2015. Anti-ageing pill pushed as bona fide drug. Nature 522:265–66
    [Google Scholar]
  217. 217. 
    Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL et al. 2016. Strategies and challenges in clinical trials targeting human aging. J. Gerontol. A Biol. Sci. Med. Sci. 71:1424–34
    [Google Scholar]
  218. 218. 
    Soukas AA, Hao H, Wu L. 2019. Metformin as anti-aging therapy: Is it for everyone?. Trends Endocrinol. Metab. 30:745–55
    [Google Scholar]
  219. 219. 
    Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T et al. 2016. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535:376–81
    [Google Scholar]
  220. 220. 
    Perry RJ, Peng L, Barry NA, Cline GW, Zhang D et al. 2016. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 534:213–17
    [Google Scholar]
  221. 221. 
    Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E et al. 2015. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–66
    [Google Scholar]
  222. 222. 
    de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velasquez-Mejia EP, Carmona JA et al. 2017. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care 40:54–62
    [Google Scholar]
  223. 223. 
    Geerlings SY, Kostopoulos I, de Vos WM, Belzer C 2018. Akkermansia muciniphila in the human gastrointestinal tract: when, where, and how?. Microorganisms 6:75
    [Google Scholar]
  224. 224. 
    Lee H, Ko G. 2014. Effect of metformin on metabolic improvement and gut microbiota. Appl. Environ. Microbiol. 80:5935–43
    [Google Scholar]
  225. 225. 
    Montandon SA, Jornayvaz FR. 2017. Effects of antidiabetic drugs on gut microbiota composition. Genes 8:250
    [Google Scholar]
  226. 226. 
    Zhou ZY, Ren LW, Zhan P, Yang HY, Chai DD, Yu ZW. 2016. Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling. Acta Pharmacol. Sin. 37:1063–75
    [Google Scholar]
  227. 227. 
    Fernandes A, Vaz AR, Falcao AS, Silva RF, Brito MA, Brites D. 2007. Glycoursodeoxycholic acid and interleukin-10 modulate the reactivity of rat cortical astrocytes to unconjugated bilirubin. J. Neuropathol. Exp. Neurol. 66:789–98
    [Google Scholar]
  228. 228. 
    Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM et al. 2013. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–39
    [Google Scholar]
  229. 229. 
    Nijhout HF, Reed MC, Budu P, Ulrich CM. 2004. A mathematical model of the folate cycle: new insights into folate homeostasis. J. Biol. Chem. 279:55008–16
    [Google Scholar]
  230. 230. 
    Garigan D, Hsu AL, Fraser AG, Kamath RS, Ahringer J, Kenyon C 2002. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161:1101–12
    [Google Scholar]
  231. 231. 
    Pryor R, Norvaisas P, Marinos G, Best L, Thingholm LB et al. 2019. Host-microbe-drug-nutrient screen identifies bacterial effectors of metformin therapy. Cell 178:1299–312.e29
    [Google Scholar]
  232. 232. 
    Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. 2016. Metformin as a tool to target aging. Cell Metab 23:1060–65
    [Google Scholar]
  233. 233. 
    Barzilai N, Huffman DM, Muzumdar RH, Bartke A. 2012. The critical role of metabolic pathways in aging. Diabetes 61:1315–22
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-051920-093829
Loading
/content/journals/10.1146/annurev-pharmtox-051920-093829
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error