A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin.
Aging
COVID-19
Geroscience
Immunity
Metformin
Journal
GeroScience
ISSN: 2509-2723
Titre abrégé: Geroscience
Pays: Switzerland
ID NLM: 101686284
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
01
07
2020
accepted:
27
08
2020
pubmed:
10
9
2020
medline:
16
6
2021
entrez:
9
9
2020
Statut:
ppublish
Résumé
We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.
Identifiants
pubmed: 32902818
doi: 10.1007/s11357-020-00261-6
pii: 10.1007/s11357-020-00261-6
pmc: PMC7479299
doi:
Substances chimiques
RNA, Viral
0
Metformin
9100L32L2N
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1093-1112Subventions
Organisme : NIAID NIH HHS
ID : R01 AI142086
Pays : United States
Organisme : NIA NIH HHS
ID : P30AG038072
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG058814
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG060746
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI124297
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK020541
Pays : United States
Organisme : NIA NIH HHS
ID : UH3 AG056925
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG059837
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG063528
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124922
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG038072
Pays : United States
Organisme : American Federation for Aging Research
ID : N/A
Organisme : NIA NIH HHS
ID : R21 AG060018
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG021332
Pays : United States
Organisme : NIA NIH HHS
ID : R33 AG061456
Pays : United States
Références
Statistics, C.N.C.f.H. COVID-19 Death Data and Resources. 2020; Available from: https://www.cdc.gov/nchs/covid19/ .
The OpenSAFELY Collaborative, et al., OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. MedRxiv, 2020. 2020.05.06.20092999.
Zhou F, Yu T, du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.
pubmed: 7270627
pmcid: 7270627
Wang, D., et al., Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA, 2020.
Ben-Yehuda A, Weksler ME. Host resistance and the immune system. Clin Geriatr Med. 1992;8(4):701–11.
pubmed: 1423129
Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis. 2000;30(6):931–3.
pubmed: 10880303
Promislow, D.E.L., A geroscience perspective on COVID-19 mortality. J Gerontol A Biol Sci Med Sci, 2020.
DuGoff EH, Canudas-Romo V, Buttorff C, Leff B, Anderson GF. Multiple chronic conditions and life expectancy: a life table analysis. Med Care. 2014;52(8):688–94.
pubmed: 25023914
Kato M, Natarajan R. Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Nat Rev Nephrol. 2019;15(6):327–45.
pubmed: 30894700
pmcid: 6889804
Sato Y, Yanagita M. Immunology of the ageing kidney. Nat Rev Nephrol. 2019;15(10):625–40.
pubmed: 31477915
Li H, Hastings MH, Rhee J, Trager LE, Roh JD, Rosenzweig A. Targeting age-related pathways in heart failure. Circ Res. 2020;126(4):533–51.
pubmed: 32078451
pmcid: 7041880
Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:2052.
pubmed: 32320003
pmcid: 32320003
Ajaimy M, Melamed ML. COVID-19 in patients with kidney disease. Clin J Am Soc Nephrol. 2020;15(8):1087–9.
pubmed: 32636199
Wu J, Li J, Zhu G, Zhang Y, Bi Z, Yu Y, et al. Clinical features of maintenance hemodialysis patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. Clin J Am Soc Nephrol. 2020;15(8):1139–45.
pubmed: 32444393
Guo, T., et al., Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol, 2020.
Lindner, D., et al., Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol, 2020.
Sierra F. Geroscience and the coronavirus pandemic: the whack-a-mole approach is not enough. J Am Geriatr Soc. 2020;68(5):951–2.
pubmed: 32293024
pmcid: 7262305
Yew WW, et al. Metformin as a host-directed therapeutic in tuberculosis: is there a promise? Tuberculosis (Edinb). 2019;115:76–80.
Zumla A, Wang FS, Ippolito G, Petrosillo N, Agrati C, Azhar EI, et al. Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of mesenchymal stromal (stem) cell (MSC) therapy - achieving global consensus and visibility for cellular host-directed therapies. Int J Infect Dis. 2020;96:431–9.
pubmed: 32425638
pmcid: 7231497
Mitchell SJ, Bernier M, Mattison JA, Aon MA, Kaiser TA, Anson RM, et al. Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metab. 2019;29(1):221–8 e3.
pubmed: 30197301
Hwangbo DS, et al. Mechanisms of lifespan regulation by calorie restriction and intermittent fasting in model organisms. Nutrients. 2020;12(4):1194.
pmcid: 7230387
Bartley JM, Zhou X, Kuchel GA, Weinstock GM, Haynes L. Impact of age, caloric restriction, and influenza infection on mouse gut microbiome: an exploratory study of the role of age-related microbiome changes on influenza responses. Front Immunol. 2017;8:1164.
pubmed: 28979265
pmcid: 5611400
Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28.
pubmed: 30279143
pmcid: 6197652
Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–45.
pubmed: 23325216
pmcid: 3687363
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290(4):486–94.
pubmed: 12876091
Mannick JB, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018;10(449):eaaq1564.
pubmed: 29997249
Chen C, et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2(98):ra75.
pubmed: 19934433
pmcid: 4020596
Mannick JB, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179.
pubmed: 25540326
Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.
pubmed: 23900241
pmcid: 3736576
Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060–5.
pubmed: 27304507
pmcid: 5943638
Justice JN, Niedernhofer L, Robbins PD, Aroda VR, Espeland MA, Kritchevsky SB, et al. Development of clinical trials to extend healthy lifespan. Cardiovasc Endocrinol Metab. 2018;7(4):80–3.
pubmed: 30906924
pmcid: 6428447
EY G. Flumamine, a new synthetic analgesic and antiflu drug. J Philippine Med Assoc. 1950;26:287–93.
Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–76.
pubmed: 28776081
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131): p. 854–65.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
pubmed: 11832527
Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32:15–30.
pubmed: 32333835
pmcid: 7347426
Zhang CS, Li M, Ma T, Zong Y, Cui J, Feng JW, et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab. 2016;24(4):521–2.
Pollak M. The effects of metformin on gut microbiota and the immune system as research frontiers. Diabetologia. 2017;60(9):1662–7.
pubmed: 28770326
Soukas AA, Hao H, Wu L. Metformin as anti-aging therapy: is it for everyone? Trends Endocrinol Metab. 2019;30(10):745–55.
pubmed: 31405774
pmcid: 6779524
Bridgeman SC, Ellison GC, Melton PE, Newsholme P, Mamotte CDS. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab. 2018;20(7):1553–62.
pubmed: 29457866
Marcucci F, Romeo E, Caserta CA, Rumio C, Lefoulon F. Context-dependent pharmacological effects of metformin on the immune system. Trends Pharmacol Sci. 2020;41(3):162–71.
pubmed: 32033771
Ding L, Liang G, Yao Z, Zhang J, Liu R, Chen H, et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget. 2015;6(34):36441–55.
pubmed: 26497364
pmcid: 4742188
Uehara T, Eikawa S, Nishida M, Kunisada Y, Yoshida A, Fujiwara T, et al. Metformin induces CD11b+−cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects. Int Immunol. 2019;31(4):187–98.
pubmed: 30508092
Pereira FV, Melo ACL, Low JS, de Castro ÍA, Braga TT, Almeida DC, et al. Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response. Oncotarget. 2018;9(40):25808–25.
pubmed: 29899823
pmcid: 5995253
Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112(6):1809–14.
pubmed: 25624476
pmcid: 4330733
Qing L, Fu J, Wu P, Zhou Z, Yu F, Tang J. Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway. Am J Transl Res. 2019;11(2):655–68.
pubmed: 30899369
pmcid: 6413292
Sun Y, Tian T, Gao J, Liu X, Hou H, Cao R, et al. Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice. J Neuroimmunol. 2016;292:58–67.
pubmed: 26943960
Park MJ, Lee SY, Moon SJ, Son HJ, Lee SH, Kim EK, et al. Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs. Transl Res. 2016;173:115–30.
pubmed: 27126953
Lee SY, Moon SJ, Kim EK, Seo HB, Yang EJ, Son HJ, et al. Metformin suppresses systemic autoimmunity in Roquin(san/san) mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK/mTOR/STAT3. J Immunol. 2017;198(7):2661–70.
pubmed: 28242651
pmcid: 5357783
Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vázquez G, Yurchenko E, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015;42(1):41–54.
pubmed: 25607458
Singhal A, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014;6(263):263ra159.
pubmed: 25411472
Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest. 2019;129(9):3625–39.
pubmed: 31355779
pmcid: 6715373
Nikolich-Zugich J, Knox KS, Rios CT, Natt B, Bhattacharya D, Fain MJ. SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. Geroscience. 2020;42(2):505–14.
pubmed: 32274617
pmcid: 7145538
Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11.
pubmed: 32169119
pmcid: 7068984
Meftahi GH, Jangravi Z, Sahraei H, Bahari Z. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging". Inflamm Res. 2020;69:825–39.
pubmed: 32529477
Schuiveling M, Vazirpanah N, Radstake TRDJ, Zimmermann M, Broen JCA. Metformin, a new era for an old drug in the treatment of immune mediated disease? Curr Drug Targets. 2018;19(8):945–59.
pubmed: 28606032
Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64(6):2028–41.
pubmed: 25552600
Ba W, Xu Y, Yin G, Yang J, Wang R, Chi S, et al. Metformin inhibits pro-inflammatory responses via targeting nuclear factor-kappaB in HaCaT cells. Cell Biochem Funct. 2019;37(1):4–10.
pubmed: 30520054
Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–65.
pubmed: 27418629
pmcid: 4990459
Tizazu AM, Nyunt MSZ, Cexus O, Suku K, Mok E, Xian CH, et al. Metformin monotherapy downregulates diabetes-associated inflammatory status and impacts on mortality. Front Physiol. 2019;10:572.
pubmed: 31178745
pmcid: 6537753
Zmijewski JW, Lorne E, Zhao X, Tsuruta Y, Sha Y, Liu G, et al. Mitochondrial respiratory complex I regulates neutrophil activation and severity of lung injury. Am J Respir Crit Care Med. 2008;178(2):168–79.
pubmed: 18436790
pmcid: 2453511
Ouyang J, Isnard S, Lin J, Fombuena B, Marette A, Routy B, et al. Metformin effect on gut microbiota: insights for HIV-related inflammation. AIDS Res Ther. 2020;17(1):10.
pubmed: 32156291
pmcid: 7063824
Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23(7):850–8.
pubmed: 28530702
Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X, et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015;5:14405.
pubmed: 26396057
pmcid: 4585776
Forslund K, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–6.
pubmed: 26633628
pmcid: 4681099
Ma W, Chen J, Meng Y, Yang J, Cui Q, Zhou Y. Metformin alters gut microbiota of healthy mice: implication for its potential role in gut microbiota homeostasis. Front Microbiol. 2018;9:1336.
pubmed: 29988362
pmcid: 6023991
Ahmadi S, Razazan A, Nagpal R, Jain S, Wang B, Mishra SP, et al. Metformin reduces aging-related leaky gut and improves cognitive function by beneficially modulating gut microbiome/goblet cell/mucin axis. J Gerontol A Biol Sci Med Sci. 2020;75(7):e9–e21.
pubmed: 32129462
pmcid: 7302182
Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63(5):727–35.
pubmed: 23804561
Velavan TP, Meyer CG. The COVID-19 epidemic. Tropical Med Int Health. 2020;25(3):278–80.
Chen Y, Liu Q, Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol. 2020;92(4):418–23.
pubmed: 31967327
pmcid: 31967327
Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest. 2020;130(5):2202–5.
pubmed: 32217834
pmcid: 7190904
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433.
pubmed: 32113704
pmcid: 7127067
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Inf Secur. 2020;80(6):607–13.
Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181(5):1036–45 e9.
pubmed: 7227586
pmcid: 7227586
Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763.
pubmed: 32361250
pmcid: 7165294
Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473–4.
pubmed: 32303591
Luo P, Qiu L, Liu Y, Liu XL, Zheng JL, Xue HY, et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis. Am J Trop Med Hyg. 2020;103:69–72.
pubmed: 7356425
pmcid: 7356425
Bramante, C., et al., Observational study of metformin and risk of mortality in patients hospitalized with Covid-19. MedRxiv, 2020.
Naicker N, Sigal A, Naidoo K. Metformin as host-directed therapy for TB treatment: scoping review. Front Microbiol. 2020;11:435.
pubmed: 32411100
pmcid: 7201016
Degner NR, Wang JY, Golub JE, Karakousis PC. Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment. Clin Infect Dis. 2018;66(2):198–205.
pubmed: 29325084
Malik F, Mehdi SF, Ali H, Patel P, Basharat A, Kumar A, et al. Is metformin poised for a second career as an antimicrobial? Diabetes Metab Res Rev. 2018;34(4):e2975.
pubmed: 29271563
Brima W, Eden DJ, Mehdi SF, Bravo M, Wiese MM, Stein J, et al. The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice. Diabetes Metab Res Rev. 2015;31(4):346–59.
pubmed: 25613819
pmcid: 4427523
Mallia P, Webber J, Gill SK, Trujillo-Torralbo MB, Calderazzo MA, Finney L, et al. Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2018;142(3):815–23 e6.
pubmed: 29310905
pmcid: 6127032
Patkee WR, et al. Metformin prevents the effects of Pseudomonas aeruginosa on airway epithelial tight junctions and restricts hyperglycaemia-induced bacterial growth. J Cell Mol Med. 2016;20(4):758–64.
pubmed: 26837005
pmcid: 4864950
Kalsi KK, Garnett JP, Patkee W, Weekes A, Dockrell ME, Baker EH, et al. Metformin attenuates the effect of Staphylococcus aureus on airway tight junctions by increasing PKCzeta-mediated phosphorylation of occludin. J Cell Mol Med. 2019;23(1):317–27.
pubmed: 30450773
Kajiwara C, Kusaka Y, Kimura S, Yamaguchi T, Nanjo Y, Ishii Y, et al. Metformin mediates protection against Legionella pneumonia through activation of AMPK and mitochondrial reactive oxygen species. J Immunol. 2018;200(2):623–31.
pubmed: 29246951
Mortensen E, Anzueto A. Association of metformin and mortality for patients with diabetes who are hospitalized with pneumonia. Eur Respir J. 2018;52:PA2639.
Yen FS, Wei JCC, Yang YC, Hsu CC, Hwu CM. Respiratory outcomes of metformin use in patients with type 2 diabetes and chronic obstructive pulmonary disease. Sci Rep. 2020;10(1):10298.
pubmed: 32581289
pmcid: 7314747
Xun YH, Zhang YJ, Pan QC, Mao RC, Qin YL, Liu HY, et al. Metformin inhibits hepatitis B virus protein production and replication in human hepatoma cells. J Viral Hepat. 2014;21(8):597–603.
pubmed: 24164660
Chen CI, Kuan CF, Fang YA, Liu SH, Liu JC, Wu LL, et al. Cancer risk in HBV patients with statin and metformin use: a population-based cohort study. Medicine (Baltimore). 2015;94(6):e462.
Hofmeister MG, Rosenthal EM, Barker LK, Rosenberg ES, Barranco MA, Hall EW, et al. Estimating prevalence of hepatitis C virus infection in the United States, 2013-2016. Hepatology. 2019;69(3):1020–31.
pubmed: 30398671
Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother. 2013;47(10):1348–52.
pubmed: 24259699
Sheth SH, Larson RJ. The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of randomized trials. BMC Infect Dis. 2010;10:183.
pubmed: 20573187
pmcid: 2906460
Lamarca K, García Sarasola A, Vidal F, Domingo P. Drug therapies for HIV-related metabolic disorders. Expert Opin Pharmacother. 2016;17(10):1327–38.
pubmed: 27192322
Dagenais-Lussier X, Mouna A, Routy JP, Tremblay C, Sekaly RP, el-Far M, et al. Current topics in HIV-1 pathogenesis: the emergence of deregulated immuno-metabolism in HIV-infected subjects. Cytokine Growth Factor Rev. 2015;26(6):603–13.
pubmed: 26409789
Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol. 2012;107(1):46–52.
pubmed: 22085817
Chen X, Chen H, Zhang Z, Fu Y, Han X, Zhang Y, et al. Elevated CD54 expression renders CD4+ T cells susceptible to natural killer cell-mediated killing. J Infect Dis. 2019;220(12):1892–903.
pubmed: 31433832
Shikuma CM, Chew GM, Kohorn L, Souza SA, Chow D, SahBandar IN, et al. Short communication: metformin reduces CD4 T cell exhaustion in HIV-infected adults on suppressive antiretroviral therapy. AIDS Res Hum Retrovir. 2020;36(4):303–5.
pubmed: 31731885
Routy JP, Isnard S, Mehraj V, Ostrowski M, Chomont N, Ancuta P, et al. Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol. BMJ Open. 2019;9(4):e028444.
pubmed: 31005944
pmcid: 6500211
Doyle MA, Singer J, Lee T, Muir M, Cooper C. Improving treatment and liver fibrosis outcomes with metformin in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance: study protocol for a randomized controlled trial. Trials. 2016;17(1):331.
pubmed: 27439433
pmcid: 4955144
Hammerstad SS, et al. Diabetes and hepatitis C: a two-way association. Front Endocrinol (Lausanne). 2015;6:134.
Dillon SM, Kibbie J, Lee EJ, Guo K, Santiago ML, Austin GL, et al. Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation. AIDS. 2017;31(4):511–21.
pubmed: 28002063
pmcid: 5263163
Gonzalez-Hernandez LA, et al. Alterations in bacterial communities, SCFA and biomarkers in an elderly HIV-positive and HIV-negative population in western Mexico. BMC Infect Dis. 2019;19(1):234.
pubmed: 30845929
pmcid: 6407185
Diaz A, Romero M, Vazquez T, Lechner S, Blomberg BB, Frasca D. Metformin improves in vivo and in vitro B cell function in individuals with obesity and type-2 diabetes. Vaccine. 2017;35(20):2694–700.
pubmed: 28392139
pmcid: 5560851
Agarwal D, Schmader KE, Kossenkov AV, Doyle S, Kurupati R, Ertl HCJ. Immune response to influenza vaccination in the elderly is altered by chronic medication use. Immun Ageing. 2018;15:19.
pubmed: 30186359
pmcid: 6119322
Campbell JM, Bellman SM, Stephenson MD, Lisy K. 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. 2017;40:31–44.
pubmed: 28802803
Wang CP, Lorenzo C, Habib SL, Jo B, Espinoza SE. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complicat. 2017;31(4):679–86.
Espinoza SE, Musi N, Wang CP, Michalek J, Orsak B, Romo T, et al. Rationale and study design of a randomized clinical trial of metformin to prevent frailty in older adults with prediabetes. J Gerontol A Biol Sci Med Sci. 2020;75(1):102–9.
pubmed: 30888034
Cawthon, P., et al., Assessing the impact of the covid-19 pandemic and accompanying mitigation efforts on older adults. J Gerontol A Biol Sci Med Sci, 2020.
Kivi, M., I. Hansson, and P. Bjalkebring, Up and about: older adults’ wellbeing during the COVID-19 pandemic in a Swedish longitudinal study. J Gerontol B Psychol Sci Soc Sci, 2020.
Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell. 2013;12(3):489–98.
pubmed: 23521863
Bauer PV, Duca FA, Waise TMZ, Rasmussen BA, Abraham MA, Dranse HJ, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27(1):101–17 e5.
pubmed: 29056513
Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80(19):5935–43.
pubmed: 25038099
pmcid: 4178684
Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–39.
pubmed: 23540700
pmcid: 3898468
Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes. 2002;51(8):2420–5.
pubmed: 12145153
Onken B, Driscoll M. 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. 2010;5(1):e8758.
pubmed: 20090912
pmcid: 2807458
Cuyas E, et al. Metformin is a direct SIRT1-activating compound: computational modeling and experimental validation. Front Endocrinol (Lausanne). 2018;9:657.
Canto C, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458(7241):1056–60.
pubmed: 19262508
pmcid: 3616311
Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390–401.
pubmed: 20444419
pmcid: 3081779
Dowling RJ, et al. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67(22):10804–12.
pubmed: 18006825
Ben Sahra I, Regazzetti C, Robert G, Laurent K, le Marchand-Brustel Y, Auberger P, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71(13):4366–72.
pubmed: 21540236
Howell JJ, Hellberg K, Turner M, Talbott G, Kolar MJ, Ross DS, et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 2017;25(2):463–71.
pubmed: 28089566
pmcid: 5299044
Sarfstein R, Friedman Y, Attias-Geva Z, Fishman A, Bruchim I, Werner H. Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. PLoS One. 2013;8(4):e61537.
pubmed: 23620761
pmcid: 3631250
Na HJ, Park JS, Pyo JH, Lee SH, Jeon HJ, Kim YS, et al. Mechanism of metformin: inhibition of DNA damage and proliferative activity in Drosophila midgut stem cell. Mech Ageing Dev. 2013;134(9):381–90.
pubmed: 23891756
Lee YS, et al. Combined metformin and resveratrol confers protection against UVC-induced DNA damage in A549 lung cancer cells via modulation of cell cycle checkpoints and DNA repair. Oncol Rep. 2016;35(6):3735–41.
pubmed: 27109601
Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Martin-Castillo B, Menendez JA. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle. 2011;10(9):1499–501.
pubmed: 21566461
Wang GY, Bi YG, Liu XD, Zhao Y, Han JF, Wei M, et al. Autophagy was involved in the protective effect of metformin on hyperglycemia-induced cardiomyocyte apoptosis and Connexin43 downregulation in H9c2 cells. Int J Med Sci. 2017;14(7):698–704.
pubmed: 28824303
pmcid: 5562122
Wang Y, Xu W, Yan Z, Zhao W, Mi J, Li J, et al. Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res. 2018;37(1):63.
pubmed: 29554968
pmcid: 5859411
Tsai HH, Lai HY, Chen YC, Li CF, Huang HS, Liu HS, et al. Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway. Oncotarget. 2017;8(8):13832–45.
pubmed: 28099155
pmcid: 5355142
El-Mir MY, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–8.
pubmed: 10617608
De Haes W, et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci U S A. 2014;111(24):E2501–9.
pubmed: 24889636
pmcid: 4066537
Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;3:e02242.
pubmed: 24843020
pmcid: 4017650
Algire C, Moiseeva O, Deschenes-Simard X, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012;5(4):536–43.
Aatsinki SM, Buler M, Salomäki H, Koulu M, Pavek P, Hakkola J. Metformin induces PGC-1alpha expression and selectively affects hepatic PGC-1alpha functions. Br J Pharmacol. 2014;171(9):2351–63.
pubmed: 24428821
pmcid: 3997275
Fang J, Yang J, Wu X, Zhang G, Li T, Wang X', et al. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell. 2018;17(4):e12765.
pubmed: 29659168
pmcid: 6052468
Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, et al. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell. 2019;25(4):473–85 e8.
pubmed: 31585093
pmcid: 6863391
Fatt M, Hsu K, He L, Wondisford F, Miller FD, Kaplan DR, et al. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Reports. 2015;5(6):988–95.
pubmed: 26677765
pmcid: 4682208
Na HJ, Pyo JH, Jeon HJ, Park JS, Chung HY, Yoo MA. Deficiency of Atg6 impairs beneficial effect of metformin on intestinal stem cell aging in Drosophila. Biochem Biophys Res Commun. 2018;498(1):18–24.
pubmed: 29496445
Noren Hooten N, Martin-Montalvo A, Dluzen DF, Zhang Y, Bernier M, Zonderman AB, et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell. 2016;15(3):572–81.
pubmed: 26990999
pmcid: 4854919
Diman A, Boros J, Poulain F, Rodriguez J, Purnelle M, Episkopou H, et al. Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription. Sci Adv. 2016;2(7):e1600031.
pubmed: 27819056
pmcid: 5087959
Smieszek A, et al. 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).
Jiang X, et al. Metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway. Oxidative Med Cell Longev. 2020;2020:8708236.
Yu LL, Zhu M, Huang Y, Zhao YM, Wen JJ, Yang XJ, et al. Metformin relieves acute respiratory distress syndrome by reducing miR-138 expression. Eur Rev Med Pharmacol Sci. 2018;22(16):5355–63.
pubmed: 30178862
Wang G, Song Y, Feng W, Liu L, Zhu Y, Xie X, et al. Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1alpha and SOD1. Exp Ther Med. 2016;12(3):1551–5.
pubmed: 27602077
pmcid: 4998213
Gregoire M, et al. Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS. Eur Respir J. 2018;52(2):1702590.
pubmed: 29946009
Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24(8):1121–7.
pubmed: 6081262
pmcid: 6081262
Lachmandas E, Eckold C, Böhme J, Koeken VACM, Marzuki MB, Blok B, et al. Metformin alters human host responses to mycobacterium tuberculosis in healthy subjects. J Infect Dis. 2019;220(1):139–50.
pubmed: 30753544
pmcid: 6548897
Rodriguez-Carlos A, Valdez-Miramontes C, Marin-Luevano P, González-Curiel I, Enciso-Moreno JA, Rivas-Santiago B. Metformin promotes mycobacterium tuberculosis killing and increases the production of human beta-defensins in lung epithelial cells and macrophages. Microbes Infect. 2020;22(3):111–8.
pubmed: 31689532
Dutta NK, Pinn ML, Karakousis PC. Metformin adjunctive therapy does not improve the sterilizing activity of the first-line antitubercular regimen in mice. Antimicrob Agents Chemother. 2017;61(8):e00652.
pubmed: 28559262
pmcid: 5527622
Gill SK, Hui K, Farne H, Garnett JP, Baines DL, Moore LSP, et al. Increased airway glucose increases airway bacterial load in hyperglycaemia. Sci Rep. 2016;6:27636.
pubmed: 27273266
pmcid: 4897689
Xiao Y, Liu F, Li S, Jiang N, Yu C, Zhu X, et al. Metformin promotes innate immunity through a conserved PMK-1/p38 MAPK pathway. Virulence. 2020;11(1):39–48.
pubmed: 31851866
Garnett JP, Braun D, McCarthy AJ, Farrant MR, Baker EH, Lindsay JA, et al. Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid. Cell Mol Life Sci. 2014;71(23):4665–73.
pubmed: 24810961
pmcid: 4232747
Garnett JP, Baker EH, Naik S, Lindsay JA, Knight GM, Gill S, et al. Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose. Thorax. 2013;68(9):835–45.
pubmed: 23709760
pmcid: 3756442
Ruivo MTG, Vera IM, Sales-Dias J, Meireles P, Gural N, Bhatia SN, et al. Host AMPK is a modulator of plasmodium liver infection. Cell Rep. 2016;16(10):2539–45.
pubmed: 27568570
pmcid: 5014760
Vera IM, et al. Targeting liver stage malaria with metformin. JCI Insight. 2019;4(24):e127441.
Miyakoda M, Bayarsaikhan G, Kimura D, Akbari M, Udono H, Yui K. Metformin promotes the protection of mice infected with Plasmodium yoelii independently of gammadelta T cell expansion. Front Immunol. 2018;9:2942.
pubmed: 30619302
pmcid: 6300485
Del Campo JA, et al. Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy. PLoS One. 2018;13(1):e0191805.
pubmed: 29385181
pmcid: 5791999
Nakashima K, Takeuchi K, Chihara K, Hotta H, Sada K. Inhibition of hepatitis C virus replication through adenosine monophosphate-activated protein kinase-dependent and -independent pathways. Microbiol Immunol. 2011;55(11):774–82.
pubmed: 21895746
Romero-Gomez M, et al. Treatment of insulin resistance with metformin in naive genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin. Hepatology. 2009;50(6):1702–8.
pubmed: 19845037
Yu JW, Sun LJ, Zhao YH, Kang P, Yan BZ. The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. Int J Infect Dis. 2012;16(6):e436–41.
pubmed: 22486858
Sharifi AH, Mohammadi M, Fakharzadeh E, Zamini H, Zaer-Rezaee H, Jabbari H, et al. Efficacy of adding metformin to pegylated interferon and ribavirin in treatment naive patients with chronic hepatitis C: a randomized double-blind controlled trial. Middle East J Dig Dis. 2014;6(1):13–7.
pubmed: 24829699
pmcid: 4005479
Shen C, Peng C, Shen B, Zhu Z, Xu N, Li T, et al. Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation. Oncotarget. 2016;7(38):62647–56.
pubmed: 27577068
pmcid: 5308754
Kim JH, Alam MM, Park DB, Cho M, Lee SH, Jeon YJ, et al. The effect of metformin treatment on CRBP-I level and cancer development in the liver of HBx transgenic mice. Korean J Physiol Pharmacol. 2013;17(5):455–61.
pubmed: 24227948
pmcid: 3823960
Jiang Z, Liu H. Metformin inhibits tumorigenesis in HBV-induced hepatocellular carcinoma by suppressing HULC overexpression caused by HBX. J Cell Biochem. 2018;119(6):4482–95.
pubmed: 29231260
Mehla R, Bivalkar-Mehla S, Zhang R, Handy I, Albrecht H, Giri S, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One. 2010;5(6):e11160.
pubmed: 20585398
pmcid: 2886842
Moseley CE, Webster RG, Aldridge JR. Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza Other Respir Viruses. 2010;4(5):307–11.
pubmed: 20716159
pmcid: 3584640
Chen TM, Lin CC, Huang PT, Wen CF. Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. J Gastroenterol Hepatol. 2011;26(5):858–65.
pubmed: 21251068
Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96(8):2601–8.
pubmed: 21752887