Skip to content
2000
image of The Role of Immunosenescence and Inflammaging in the Susceptibility of Older Adults to SARS-CoV-2 Infection

Abstract

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that is one of the most significant challenges to public health over the past few years. Most people are vulnerable to SARS-CoV-2, but older adults are more vulnerable. Aging is one of the major risk factors for the detrimental consequences of COVID-19, likely due to chronic inflammation and immunosenescence, both of which are the characteristics of old age. Immunosenescence refers to the weakening of the immune system with age while inflammaging describes the low-grade chronic inflammation seen in older individuals. One key aspect of human aging is immune deficiency. During aging, our body’s defense system weakens, resulting in decreased responses to infection by novel pathogens and a reduced ability to become immunized. The presence of chronic inflammation and viral infection in old age may cause several adverse unpredictable outcomes increasing the propensity and severity of the disease and requires to be considered, enabling people to better prepare for the potential consequences of this ongoing pandemic. This requires consideration so that individuals can better be prepared to address the potential consequences of this ongoing pandemic. In this review, we discuss the clinical characteristics of elderly COVID-19 patients and survey the associated molecular pathways that are pivotal for the interactions of the coronavirus and host cellular responses, including immunosenescence, inflammation, telomere attrition, impaired autophagy, mitochondrial dysfunction and alterations in major aging signaling pathways, which are crucial for the discovery of new therapeutic and preventive methods in the ongoing pandemic.

Loading

Article metrics loading...

/content/journals/cpb/10.2174/0113892010328697250210065420
2025-02-13
2025-03-26
Loading full text...

Full text loading...

References

  1. Gasmi A. Noor S. Tippairote T. Dadar M. Menzel A. Bjørklund G. Individual risk management strategy and potential therapeutic options for the COVID-19 pandemic. Clin. Immunol. 2020 215 108409 10.1016/j.clim.2020.108409 32276137
    [Google Scholar]
  2. Wu J. Li W. Shi X. Chen Z. Jiang B. Liu J. Li L. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19). J Intern Med. 2020 288 1 128 138 10.1111/joim.13063 32220033
    [Google Scholar]
  3. World Health Organization. (2021). Coronavirus disease (‎‎COVID-19): Situation reports.
  4. Grasselli G. Tonetti T. Protti A. Langer T. Girardis M. Bellani G. Laffey J. Carrafiello G. Carsana L. Rizzuto C. Zanella A. Scaravilli V. Pizzilli G. Grieco D.L. Di Meglio L. de Pascale G. Lanza E. Monteduro F. Zompatori M. Filippini C. Locatelli F. Cecconi M. Fumagalli R. Nava S. Vincent J.L. Antonelli M. Slutsky A.S. Pesenti A. Ranieri V.M. Lissoni A. Rossi N. Guzzardella A. Valsecchi C. Madotto F. Bevilacqua F. Di Laudo M. Querci L. Seccafico C. collaborators Pathophysiology of COVID-19-associated acute respiratory distress syndrome: A multicentre prospective observational study. Lancet Respir. Med. 2020 8 12 1201 1208 10.1016/S2213‑2600(20)30370‑2 32861276
    [Google Scholar]
  5. Merrill J.T. Erkan D. Winakur J. James J.A. Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications. Nat. Rev. Rheumatol. 2020 16 10 581 589 10.1038/s41584‑020‑0474‑5 32733003
    [Google Scholar]
  6. Pan F. Yang L. Li Y. Liang B. Li L. Ye T. Li L. Liu D. Gui S. Hu Y. Zheng C. Factors associated with death outcome in patients with severe coronavirus disease-19 (COVID-19): A case-control study. Int. J. Med. Sci. 2020 17 9 1281 1292 10.7150/ijms.46614 32547323
    [Google Scholar]
  7. Li K. Wu J. Wu F. Guo D. Chen L. Fang Z. Li C. The clinical and chest CT features associated with severe and critical COVID-19 pneumonia. Invest. Radiol. 2020 55 6 327 331 10.1097/RLI.0000000000000672 32118615
    [Google Scholar]
  8. Zhang K. Liu X. Shen J. Li Z. Sang Y. Wu X. Zha Y. Liang W. Wang C. Wang K. Ye L. Gao M. Zhou Z. Li L. Wang J. Yang Z. Cai H. Xu J. Yang L. Cai W. Xu W. Wu S. Zhang W. Jiang S. Zheng L. Zhang X. Wang L. Lu L. Li J. Yin H. Wang W. Li O. Zhang C. Liang L. Wu T. Deng R. Wei K. Zhou Y. Chen T. Yiu-Nam Lau J. Fok M. He J. Lin T. Li W. Wang G. Clinically applicable AI system for accurate diagnosis, quantitative measurements, and prognosis of covid-19 pneumonia using computed tomography. Cell 2020 182 5 1360 10.1016/j.cell.2020.08.029
    [Google Scholar]
  9. Laxminarayan R. Wahl B. Dudala S.R. Gopal K. Mohan B C. Neelima S. Jawahar Reddy K.S. Radhakrishnan J. Lewnard J.A. Epidemiology and transmission dynamics of COVID-19 in two Indian states. Science 2020 370 6517 691 697 10.1126/science.abd7672 33154136
    [Google Scholar]
  10. Ruan Q. Yang K. Wang W. Jiang L. Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 46 5 846 848 10.1007/s00134‑020‑05991‑x 32125452
    [Google Scholar]
  11. Lauder L. Mahfoud F. Azizi M. Bhatt D.L. Ewen S. Kario K. Parati G. Rossignol P. Schlaich M.P. Teo K.K. Townsend R.R. Tsioufis C. Weber M.A. Weber T. Böhm M. Hypertension management in patients with cardiovascular comorbidities. Eur. Heart J. 2023 44 23 2066 2077 10.1093/eurheartj/ehac395 36342266
    [Google Scholar]
  12. Madjid M. Safavi-Naeini P. Solomon S.D. Vardeny O. Potential effects of coronaviruses on the cardiovascular system: A review. JAMA Cardiol. 2020 5 7 831 840 10.1001/jamacardio.2020.1286 32219363
    [Google Scholar]
  13. Sanyaolu A. Okorie C. Marinkovic A. Patidar R. Younis K. Desai P. Hosein Z. Padda I. Mangat J. Altaf M. Comorbidity and its impact on patients with COVID-19. SN Compr. Clin. Med. 2020 2 8 1069 1076 10.1007/s42399‑020‑00363‑4 32838147
    [Google Scholar]
  14. Verity R. Okell L. C. Dorigatti I. Winskill P. Whittaker C. Imai N. Ferguson N. M. Estimates of the severity of coronavirus disease 2019: A model-based analysis. Lancet Infect Dis. 2020 20 6 669 677 10.1016/S1473‑3099(20)30243‑7 32240634
    [Google Scholar]
  15. Santesmasses D. Castro J.P. Zenin A.A. Shindyapina A.V. Gerashchenko M.V. Zhang B. COVID-19 is an emergent disease of aging. MedRxiv 2020 10.1101/2020.04.15.20060095
    [Google Scholar]
  16. Elo I.T. Luck A. Stokes A.C. Hempstead K. Xie W. Preston S.H. Evaluation of age patterns of COVID-19 mortality by race and ethnicity from March 2020 to October 2021 in the US. JAMA Netw. Open 2022 5 5 e2212686 e2212686 10.1001/jamanetworkopen.2022.12686 35579900
    [Google Scholar]
  17. Kalantari H. Tabrizi A.H.H. Foroohi F. Determination of COVID-19 prevalence with regards to age range of patients referring to the hospitals located in western Tehran, Iran. Gene Rep. 2020 21 100910 10.1016/j.genrep.2020.100910 33047096
    [Google Scholar]
  18. Romero Starke K. Reissig D. Petereit-Haack G. Schmauder S. Nienhaus A. Seidler A. The isolated effect of age on the risk of COVID-19 severe outcomes: A systematic review with meta-analysis. BMJ Glob. Health 2021 6 12 e006434 10.1136/bmjgh‑2021‑006434 34916273
    [Google Scholar]
  19. Roy J. Heath S.M. Wang S. Ramkrishna D. Modeling COVID-19 transmission between age groups in the United States considering virus mutations, vaccinations, and reinfection. Sci. Rep. 2022 12 1 20098 10.1038/s41598‑022‑21559‑9 36418377
    [Google Scholar]
  20. Vega-Piris L. Carretero S.G. Mayordomo J.L. Zarzuelo M.B.R. Río V.Á. García V.G. Vázquez M.G. Rodríguez M.C.G. Basile L. González-Coviella N.L. Boada M.I.B. Pérez-Martínez O. Azevedo A.L. Rubio C.Q. Duran J.G. Ibáñez A.F. Rivera M.V.G. Marín V.R. Castrillejo D. Raymundo L.J.V. Larrauri A. Monge S. SARI Sentinel Surveillance Group Severity of respiratory syncytial virus compared with SARS-CoV-2 and influenza among hospitalised adults ≥65 years. J. Infect. 2024 89 5 106292 10.1016/j.jinf.2024.106292 39341402
    [Google Scholar]
  21. Grangier B. Vacheron C.H. De Marignan D. Casalegno J.S. Couray-Targe S. Bestion A. Ader F. Richard J.C. Frobert E. Argaud L. Rimmele T. Lukaszewicz A.C. Aubrun F. Dailler F. Fellahi J.L. Bohe J. Piriou V. Allaouchiche B. Friggeri A. Wallet F. Thiolliere F. Joffredo E. Jay L. Darien M. David J-S. Cerruti C. Lecocq M. Izaute G. Collenot T. Vassal O. Lyon Sud COVID-19 ICU Comparison of mortality and outcomes of four respiratory viruses in the intensive care unit: A multicenter retrospective study. Sci. Rep. 2024 14 1 6690 10.1038/s41598‑024‑55378‑x 38509095
    [Google Scholar]
  22. Surie D. Yuengling K.A. DeCuir J. Zhu Y. Lauring A.S. Gaglani M. Ghamande S. Peltan I.D. Brown S.M. Ginde A.A. Martinez A. Mohr N.M. Gibbs K.W. Hager D.N. Ali H. Prekker M.E. Gong M.N. Mohamed A. Johnson N.J. Srinivasan V. Steingrub J.S. Leis A.M. Khan A. Hough C.L. Bender W.S. Duggal A. Bendall E.E. Wilson J.G. Qadir N. Chang S.Y. Mallow C. Kwon J.H. Exline M.C. Shapiro N.I. Columbus C. Vaughn I.A. Ramesh M. Mosier J.M. Safdar B. Casey J.D. Talbot H.K. Rice T.W. Halasa N. Chappell J.D. Grijalva C.G. Baughman A. Womack K.N. Swan S.A. Johnson C.A. Lwin C.T. Lewis N.M. Ellington S. McMorrow M.L. Martin E.T. Self W.H. Investigating Respiratory Viruses in the Acutely Ill (IVY) Network Severity of respiratory syncytial virus vs. COVID-19 and influenza among hospitalized US adults. JAMA Netw. Open 2024 7 4 e244954 e244954 10.1001/jamanetworkopen.2024.4954 38573635
    [Google Scholar]
  23. Kwon J.H. Paek S.H. Park S.H. Kim M.J. Byun Y.H. Song H.Y. COVID-19, influenza, and RSV in children and adults: A clinical comparative study of 12,000 cases. J. Clin. Med. 2024 13 6 1702 10.3390/jcm13061702 38541927
    [Google Scholar]
  24. Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Guan L. Wei Y. Li H. Wu X. Xu J. Tu S. Zhang Y. Chen H. Cao B. 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 1062 10.1016/S0140‑6736(20)30566‑3 32171076
    [Google Scholar]
  25. Florindo H.F. Kleiner R. Vaskovich-Koubi D. Acúrcio R.C. Carreira B. Yeini E. Tiram G. Liubomirski Y. Satchi-Fainaro R. Immune-mediated approaches against COVID-19. Nat. Nanotechnol. 2020 15 8 630 645 10.1038/s41565‑020‑0732‑3 32661375
    [Google Scholar]
  26. Bai C. Zhong Q. Gao G.F. Overview of SARS-CoV-2 genome-encoded proteins. Sci. China Life Sci. 2022 65 2 280 294 10.1007/s11427‑021‑1964‑4 34387838
    [Google Scholar]
  27. Woo P.C.Y. de Groot R.J. Haagmans B. Lau S.K.P. Neuman B.W. Perlman S. Sola I. van der Hoek L. Wong A.C.P. Yeh S.H. ICTV virus taxonomy profile: Coronaviridae 2023. J. Gen. Virol. 2023 104 4 10.1099/jgv.0.001843 37097842
    [Google Scholar]
  28. Ye Z.W. Yuan S. Yuen K.S. Fung S.Y. Chan C.P. Jin D.Y. Zoonotic origins of human coronaviruses. Int. J. Biol. Sci. 2020 16 10 1686 1697 10.7150/ijbs.45472 32226286
    [Google Scholar]
  29. Liu D.X. Liang J.Q. Fung T.S. Human Coronavirus-229E, -OC43, -NL63, and -HKU1. Reference Module in Life Sciences 2020 10.1016/B978‑0‑12‑809633‑8.21501‑X
    [Google Scholar]
  30. Pal M. Berhanu G. Desalegn C. Kandi V. Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2): An update. Cureus 2020 12 3 e7423 10.7759/cureus.7423 32337143
    [Google Scholar]
  31. Zhang H. Penninger J.M. Li Y. Zhong N. Slutsky A.S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 46 4 586 590 10.1007/s00134‑020‑05985‑9 32125455
    [Google Scholar]
  32. Bestle D. Heindl M.R. Limburg H. Pilgram O. Moulton H. Stein D.A. Hardes K. TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets. bioRxiv 2020 10.1101/2020.04.15.042085
    [Google Scholar]
  33. Zhou L. Niu Z. Jiang X. Zhang Z. Zheng Y. Wang Z. Sun Q. Systemic analysis of tissue cells potentially vulnerable to SARS-CoV-2 infection by the protein-proofed single-cell RNA profiling of ACE2, TMPRSS2 and Furin proteases. bioRxiv preprint 2020 10.1101/2020.04.06.028522
    [Google Scholar]
  34. Bassendine M.F. Bridge S.H. McCaughan G.W. Gorrell M.D. Covid-19 and comorbidities: A role for Dipeptidyl Peptidase 4 (DPP4) in disease severity? J Diabetes 2020 12 9 649 658 10.1111/1753‑0407.13052 32394639
    [Google Scholar]
  35. Vankadari N. Wilce J.A. Emerging COVID-19 coronavirus: Glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg. Microbes Infect. 2020 9 1 601 604 10.1080/22221751.2020.1739565 32178593
    [Google Scholar]
  36. Robson F. Khan K.S. Le T.K. Paris C. Demirbag S. Barfuss P. Rocchi P. Ng W.L. Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting. Mol. Cell 2020 79 5 710 727 10.1016/j.molcel.2020.07.027 32853546
    [Google Scholar]
  37. Li Q. Wu J. Nie J. Zhang L. Hao H. Liu S. Zhao C. Zhang Q. Liu H. Nie L. Qin H. Wang M. Lu Q. Li X. Sun Q. Liu J. Zhang L. Li X. Huang W. Wang Y. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell 2020 182 5 1284 1294.e9 10.1016/j.cell.2020.07.012 32730807
    [Google Scholar]
  38. Huang Y. Yang C. Xu X. Xu W. Liu S. Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19. Acta Pharmacol. Sin. 2020 41 9 1141 1149 10.1038/s41401‑020‑0485‑4 32747721
    [Google Scholar]
  39. Yurkovetskiy L. Wang X. Pascal K.E. Tomkins-Tinch C. Nyalile T.P. Wang Y. Baum A. Diehl W.E. Dauphin A. Carbone C. Veinotte K. Egri S.B. Schaffner S.F. Lemieux J.E. Munro J.B. Rafique A. Barve A. Sabeti P.C. Kyratsous C.A. Dudkina N.V. Shen K. Luban J. Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Cell 2020 183 3 739 751.e8 10.1016/j.cell.2020.09.032 32991842
    [Google Scholar]
  40. Korber B. Fischer W.M. Gnanakaran S. Yoon H. Theiler J. Abfalterer W. Hengartner N. Giorgi E.E. Bhattacharya T. Foley B. Hastie K.M. Parker M.D. Partridge D.G. Evans C.M. Freeman T.M. de Silva T.I. McDanal C. Perez L.G. Tang H. Moon-Walker A. Whelan S.P. LaBranche C.C. Saphire E.O. Montefiori D.C. Angyal A. Brown R.L. Carrilero L. Green L.R. Groves D.C. Johnson K.J. Keeley A.J. Lindsey B.B. Parsons P.J. Raza M. Rowland-Jones S. Smith N. Tucker R.M. Wang D. Wyles M.D. Sheffield COVID-19 Genomics Group Tracking changes in SARS-CoV-2 Spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell 2020 182 4 812 827.e19 10.1016/j.cell.2020.06.043 32697968
    [Google Scholar]
  41. Leung K. Shum M.H.H. Leung G.M. Lam T.T.Y. Wu J.T. Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill. 2021 26 1 2002106 10.2807/1560‑7917.ES.2020.26.1.2002106 33413740
    [Google Scholar]
  42. Rambaut A. Loman N. Pybus O. Preliminary genomic characterisation of an emergent SARSCoV-2 lineage in the UK defined by a novel set of spike mutations. 2020 Available from: https://virological.org/t/preliminarygenomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-ofspike-mutations/563 Accessed 22 December, 2020.
  43. WHO SARS-CoV-2 variant—United Kingdom of Great Britain and Northern Ireland. 2020 Available from: https://www.who.int/csr/don/21-december-2020-sars-cov2-variant-united-kingdom/en
  44. Srivastava P.K. Klomhaus A.M. Tehrani D.M. Fonarow G.C. Ziaeian B. Desai P.S. Rafique A. de Lemos J. Parikh R.V. Yang E.H. Impact of Age and Variant Time Period on Clinical Presentation and Outcomes of Hospitalized Coronavirus Disease 2019 Patients. Mayo Clin. Proc. Innov. Qual. Outcomes 2023 7 5 411 429 10.1016/j.mayocpiqo.2023.07.004 37731677
    [Google Scholar]
  45. Yao Z. Zhang L. Duan Y. Tang X. Lu J. Molecular insights into the adaptive evolution of SARS-CoV-2 spike protein. J. Infect. 2024 88 3 106121 10.1016/j.jinf.2024.106121 38367704
    [Google Scholar]
  46. Akkiz H. Implications of the novel mutations in the SARS-CoV-2 genome for transmission, disease severity, and the vaccine development. Front. Med. (Lausanne) 2021 8 636532 10.3389/fmed.2021.636532 34026780
    [Google Scholar]
  47. Cui L. Wang J. Orlando F. Giacconi R. Malavolta M. Bartozzi B. Galeazzi R. Giorgini G. Pesce L. Cardarelli F. Quagliarini E. Renzi S. Xiao S. Pozzi D. Provinciali M. Caracciolo G. Marchini C. Amici A. Enhancing Immune Responses against SARS-CoV-2 Variants in Aged Mice with INDUK: A Chimeric DNA Vaccine Encoding the Spike S1-TM Subunits. ACS Omega 2024 9 32 34624 34635 10.1021/acsomega.4c03285 39157118
    [Google Scholar]
  48. Thakur S. Sasi S. Pillai S.G. Nag A. Shukla D. Singhal R. Phalke S. Velu G.S.K. SARS-CoV-2 mutations and their impact on diagnostics, therapeutics and vaccines. Front. Med. (Lausanne) 2022 9 815389 10.3389/fmed.2022.815389 35273977
    [Google Scholar]
  49. Huang H. Zhu Y. Niu Z. Zhou L. Sun Q. SARS-CoV-2 N501Y variants of concern and their potential transmission by mouse. Cell Death Differ. 2021 28 10 2840 2842 10.1038/s41418‑021‑00846‑4 34389814
    [Google Scholar]
  50. Rathnasinghe R. Jangra S. Ye C. Cupic A. Singh G. Martínez-Romero C. Mulder L.C.F. Kehrer T. Yildiz S. Choi A. Yeung S.T. Mena I. Gillespie V. De Vrieze J. Aslam S. Stadlbauer D. Meekins D.A. McDowell C.D. Balaraman V. Corley M.J. Richt J.A. De Geest B.G. Miorin L. Kleiner G. Saksena M. Srivastava K. Gleason C.R. Bermúdez-González M.C. Beach K.F. Russo K.T. Sominsky L.A. Ferreri E.D. Chernet R.L. Eaker L.Q. Salimbangon A-B.T. Jurczyszak D. Alshammary H. Mendez W.A. Amoako A.A. Fabre S. Awawda M.H. Shin A.S. Krammer F. Martinez-Sobrido L. Simon V. García-Sastre A. Schotsaert M. PVI study group Characterization of SARS-CoV-2 Spike mutations important for infection of mice and escape from human immune sera. Nat. Commun. 2022 13 1 3921 10.1038/s41467‑022‑30763‑0 35798721
    [Google Scholar]
  51. Komurcu S.Z.M. Artik Y. Cesur N.P. Tanriverdi A. Erdogan D.C. Celik S. Gulec E.Y. The evaluation of potential global impact of the N501Y mutation in SARS‐COV‐2 positive patients. J. Med. Virol. 2022 94 3 1009 1019 10.1002/jmv.27413 34676574
    [Google Scholar]
  52. He X. He C. Hong W. Yang J. Wei X. Research progress in spike mutations of SARS‐CoV‐2 variants and vaccine development. Med. Res. Rev. 2023 43 4 932 971 10.1002/med.21941 36929527
    [Google Scholar]
  53. Islam M.A. Marzan A.A. Arman M.S. Shahi S. Sakif T.I. Hossain M. Islam T. Hoque M.N. Some common deleterious mutations are shared in SARS-CoV-2 genomes from deceased COVID-19 patients across continents. Sci. Rep. 2023 13 1 18644 10.1038/s41598‑023‑45517‑1 37903828
    [Google Scholar]
  54. Marques A.D. Graham-Wooten J. Fitzgerald A.S. Sobel Leonard A. Cook E.J. Everett J.K. Rodino K.G. Moncla L.H. Kelly B.J. Collman R.G. Bushman F.D. SARS-CoV-2 evolution during prolonged infection in immunocompromised patients. MBio 2024 15 3 e00110-24 10.1128/mbio.00110‑24 38364100
    [Google Scholar]
  55. Manuto L. Bado M. Cola M. Vanzo E. Antonello M. Mazzotti G. Pacenti M. Cordioli G. Sasset L. Cattelan A.M. Toppo S. Lavezzo E. Immune System Deficiencies Do Not Alter SARS-CoV-2 Evolutionary Rate but Favour the Emergence of Mutations by Extending Viral Persistence. Viruses 2024 16 3 447 10.3390/v16030447 38543811
    [Google Scholar]
  56. Raglow Z. Surie D. Chappell J.D. Zhu Y. Martin E.T. Kwon J.H. Frosch A.E. Mohamed A. Gilbert J. Bendall E.E. Bahr A. Halasa N. Talbot H.K. Grijalva C.G. Baughman A. Womack K.N. Johnson C. Swan S.A. Koumans E. McMorrow M.L. Harcourt J.L. Atherton L.J. Burroughs A. Thornburg N.J. Self W.H. Lauring A.S. Investigating Respiratory Viruses in the Acutely Ill (IVY) Network SARS-CoV-2 shedding and evolution in patients who were immunocompromised during the omicron period: A multicentre, prospective analysis. Lancet Microbe 2024 5 3 e235 e246 10.1016/S2666‑5247(23)00336‑1 38286131
    [Google Scholar]
  57. Sievers B.L. Cheng M.T.K. Csiba K. Meng B. Gupta R.K. SARS-CoV-2 and innate immunity: The good, the bad, and the “goldilocks”. Cell. Mol. Immunol. 2023 21 2 171 183 10.1038/s41423‑023‑01104‑y 37985854
    [Google Scholar]
  58. Feng S. Reid G.E. Clark N.M. Harrington A. Uprichard S.L. Baker S.C. Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies. Virol. J. 2024 21 1 105 10.1186/s12985‑024‑02378‑y 38715113
    [Google Scholar]
  59. Mengist H.M. Kombe Kombe A.J. Mekonnen D. Abebaw A. Getachew M. Jin T. Mutations of SARS-CoV-2 spike protein: Implications on immune evasion and vaccine-induced immunity. Semin. Immunol. 2021 55 101533 10.1016/j.smim.2021.101533 34836774
    [Google Scholar]
  60. Li Y. Choudhary M.C. Regan J. Boucau J. Nathan A. Speidel T. Li J.Z. SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency. Sci Transl Med. 2024 16 731 eadk1599 10.1126/scitranslmed.adk1599 38266109
    [Google Scholar]
  61. Zabidi N.Z. Liew H.L. Farouk I.A. Puniyamurti A. Yip A.J.W. Wijesinghe V.N. Low Z.Y. Tang J.W. Chow V.T.K. Lal S.K. Evolution of SARS-CoV-2 variants: Implications on immune escape, vaccination, therapeutic and diagnostic strategies. Viruses 2023 15 4 944 10.3390/v15040944 37112923
    [Google Scholar]
  62. Quarleri J. Delpino M.V. Galvan V. Anticipating the future of the COVID-19 pandemic: Insights into the emergence of SARS-CoV-2 variant JN.1 and its projected impact on older adults. Geroscience 2024 46 3 2879 2883 10.1007/s11357‑024‑01066‑7 38198026
    [Google Scholar]
  63. Liu W. Huang Z. Xiao J. Wu Y. Xia N. Yuan Q. Evolution of the SARS-CoV-2 Omicron Variants: Genetic Impact on Viral Fitness. Viruses 2024 16 2 184 10.3390/v16020184 38399960
    [Google Scholar]
  64. Lord J.M. Veenith T. Sullivan J. Sharma-Oates A. Richter A.G. Greening N.J. McAuley H.J.C. Evans R.A. Moss P. Moore S.C. Turtle L. Gautam N. Gilani A. Bajaj M. Wain L.V. Brightling C. Raman B. Marks M. Singapuri A. Elneima O. Openshaw P.J.M. Duggal N.A. Abel K. Adamali H. Adeloye D. Adeyemi O. Adrego R. AguilarJimenez L.A. Ahmad S. Ahmad Haider N. Ahmed R. Ahwireng N. Ainsworth M. Al-Sheklly B. Alamoudi A. Ali M. Aljaroof M. All A.M. Allan L. Allen R.J. Allerton L. Allsop L. Almeida P. Altmann D. Alvarez Corral M. Amoils S. Anderson D. Antoniades C. Arbane G. Arias A. Armour C. Armstrong L. Armstrong N. Arnold D. Arnold H. Ashish A. Ashworth A. Ashworth M. Aslani S. Assefa-Kebede H. Atkin C. Atkin P. Aul R. Aung H. Austin L. Avram C. Ayoub A. Babores M. Baggott R. Bagshaw J. Baguley D. Bailey L. Baillie J.K. Bain S. Bakali M. Bakau M. Baldry E. Baldwin D. Baldwin M. Ballard C. Banerjee A. Bang B. Barker R.E. Barman L. Barratt S. Barrett F. Basire D. Basu N. Bates M. Bates A. Batterham R. Baxendale H. Bayes H. Beadsworth M. Beckett P. Beggs M. Begum M. Beirne P. Bell D. Bell R. Bennett K. Beranova E. Bermperi A. Berridge A. Berry C. Betts S. Bevan E. Bhui K. Bingham M. Birchall K. Bishop L. Bisnauthsing K. Blaikely J. Bloss A. Bolger A. Bolton C.E. Bonnington J. Botkai A. Bourne C. Bourne M. Bramham K. Brear L. Breen G. Breeze J. Briggs A. Bright E. Brill S. Brindle K. Broad L. Broadley A. Brookes C. Broome M. Brown A. Brown A. Brown J. Brown J. Brown J.S. Brown M. Brown M. Brown V. Brugha T. Brunskill N. Buch M. Buckley P. Bularga A. Bullmore E. Burden L. Burdett T. Burn D. Burns G. Burns A. Busby J. Butcher R. Butt A. Byrne S. Cairns P. Calder P.C. Calvelo E. Carborn H. Card B. Carr C. Carr L. Carson G. Carter P. Casey A. Cassar M. Cavanagh J. Chablani M. Chalder T. Chalmers J.D. CHambers R.C. Chan F. Channon K.M. Chapman K. Charalambou A. Chaudhuri N. Checkley A. Chen J. Cheng Y. Chetham L. Childs C. Chilvers E.R. Chinoy H. Chiribiri A. Chong-James K. Choudhury G. Choudhury N. Chowienczyk P. Christie C. Chrystal M. Clark D. Clark C. Clarke J. Clohisey S. Coakley G. Coburn Z. Coetzee S. Cole J. Coleman C. Conneh F. Connell D. Connolly B. Connor L. Cook A. Cooper B. Cooper J. Cooper S. Copeland D. Cosier T. Coulding M. Coupland C. Cox E. Craig T. Crisp P. Cristiano D. Crooks M.G. Cross A. Cruz I. Cullinan P. Cuthbertson D. Daines L. Dalton M. Daly P. Daniels A. Dark P. Dasgin J. David A. David C. Davies E. Davies F. Davies G. Davies G.A. Davies K. Davies M.J. Dawson J. Daynes E. De Soyza A. Deakin B. Deans A. Deas C. Deery J. Defres S. Dell A. Dempsey K. Denneny E. Dennis J. Dewar A. Dharmagunawardena R. Diar-Bakerly N. Dickens C. Dipper A. Diver S. Diwanji S.N. Dixon M. Djukanovic R. Dobson H. Dobson S.L. Docherty A.B. Donaldson A. Dong T. Dormand N. Dougherty A. Dowling R. Drain S. Draxlbauer K. Drury K. Dulawan P. Dunleavy A. Dunn S. Dupont C. Earley J. Easom N. Echevarria C. Edwards S. Edwardson C. El-Taweel H. Elliott A. Elliott K. Ellis Y. Elmer A. Evans D. Evans H. Evans J. Evans R. Evans R.I. Evans T. Evenden C. Evison L. Fabbri L. Fairbairn S. Fairman A. Fallon K. Faluyi D. Favager C. Fayzan T. Featherstone J. Felton T. Finch J. Finney S. Finnigan J. Finnigan L. Fisher H. Fletcher S. Flockton R. Flynn M. Foot H. Foote D. Ford A. Forton D. Fraile E. Francis C. Francis R. Francis S. Frankel A. Fraser E. Free R. French N. Fu X. Fuld J. Furniss J. Garner L. Geddes J.R. George J. George P. Gibbons M. Gill M. Gilmour L. Gleeson F. Glossop J. Glover S. Goodman N. Goodwin C. Gooptu B. Gordon H. Gorsuch T. Greatorex M. Greenhaff P.L. Greenhalf W. Greenhalgh A. Greenwood J. Gregory H. Gregory R. Grieve D. Griffin D. Griffiths L. Guerdette A-M. Guillen Guio B. Gummadi M. Gupta A. Gurram S. Guthrie E. Guy Z. Henson H. Hadley K. Haggar A. Hainey K. Hairsine B. Haldar P. Hall I. Hall L. Halling-Brown M. Hamil R. Hancock A. Hancock K. Hanley N.A. Haq S. Hardwick H.E. Hardy E. Hardy T. Hargadon B. Harrington K. Harris E. Harris V.C. Harrison E.M. Harrison P. Hart N. Harvey A. Harvey M. Harvie M. Haslam L. Havinden-Williams M. Hawkes J. Hawkings N. Haworth J. Hayday A. Haynes M. Hazeldine J. Hazelton T. Heaney L.G. Heeley C. Heeney J.L. Heightman M. Heller S. Henderson M. Hesselden L. Hewitt M. Highett V. Hillman T. Hiwot T. Ho L.P. Hoare A. Hoare M. Hockridge J. Hogarth P. Holbourn A. Holden S. Holdsworth L. Holgate D. Holland M. Holloway L. Holmes K. Holmes M. Holroyd-Hind B. Holt L. Hormis A. Horsley A. Hosseini A. Hotopf M. Houchen-Wolloff L. Howard K. Howard L.S. Howell A. Hufton E. Hughes A.D. Hughes J. Hughes R. Humphries A. Huneke N. Hurditch E. Hurst J. Husain M. Hussell T. Hutchinson J. Ibrahim W. Ilyas F. Ingham J. Ingram L. Ionita D. Isaacs K. Ismail K. Jackson T. Jacob J. James W.Y. Jang W. Jarman C. Jarrold I. Jarvis H. Jastrub R. Jayaraman B. Jenkins R.G. Jezzard P. Jiwa K. Johnson C. Johnson S. Johnston D. Jolley C.J. Jones D. Jones G. Jones H. Jones H. Jones I. Jones L. Jones M.G. Jones S. Jose S. Kabir T. Kaltsakas G. Kamwa V. Kanellakis N. Kaprowska S. Kausar Z. Keenan N. Kelly S. Kemp G. Kerr S. Kerslake H. Key A.L. Khan F. Khunti K. Kilroy S. King B. King C. Kingham L. Kirk J. Kitterick P. Klenerman P. Knibbs L. Knight S. Knighton A. Kon O. Kon S. Kon S.S. Koprowska S. Korszun A. Koychev I. Kurasz C. Kurupati P. Laing C. Lamlum H. Landers G. Langenberg C. Lasserson D. Lavelle-Langham L. Lawrie A. Lawson C. Lawson C. Layton A. Lea A. Leavy O.C. Lee D. Lee J-H. Lee E. Leitch K. Lenagh R. Lewis D. Lewis J. Lewis K.E. Lewis V. Lewis-Burke N. Li X. Light T. Lightstone L. Lilaonitkul W. Lim L. Linford S. Lingford-Hughes A. Lipman M. Liyanage K. Lloyd A. Logan S. Lomas D. Lone N.I. Loosley R. Lota H. Lovegrove W. Lucey A. Lukaschuk E. Lye A. Lynch C. MacDonald S. MacGowan G. Macharia I. Mackie J. Macliver L. Madathil S. Madzamba G. Magee N. Magtoto M.M. Mairs N. Majeed N. Major E. Malein F. Malim M. Mallison G. Man W.D-C. Mandal S. Mangion K. Manisty C. Manley R. March K. Marciniak S. Marino P. Mariveles M. Marouzet E. Marsh S. Marshall B. Marshall M. Martin J. Martineau A. Martinez L.M. Maskell N. Matila D. Matimba-Mupaya W. Matthews L. Mbuyisa A. McAdoo S. McAllister-Williams H. McArdle A. McArdle P. McAulay D. McCann G.P. McCormick J. McCormick W. McCourt P. Mcgarvey L. McGhee C. Mcgee K. McGinness J. McGlynn K. McGovern A. McGuinness H. McInnes I.B. McIntosh J. McIvor E. McIvor K. McLeavey L. McMahon A. McMahon M.J. McMorrow L. Mcnally T. McNarry M. McNeill J. McQueen A. McShane H. Mears C. Megson C. Megson S. Mehta P. Meiring J. Melling L. Mencias M. Menzies D. Merida Morillas M. Michael A. Miller C. Milligan L. Mills C. Mills G. Mills N.L. Milner L. Misra S. Mitchell J. Mohamed A. Mohamed N. Mohammed S. Molyneaux P.L. Monteiro W. Moriera S. Morley A. Morrison L. Morriss R. Morrow A. Moss A.J. Motohashi K. Msimanga N. Mukaetova-Ladinska E. Munawar U. Murira J. Nanda U. Nassa H. Nasseri M. Neal A. Needham R. Neill P. Neubauer S. Newby D.E. Newell H. Newman T. Newman J. Newton-Cox A. Nicholson T. Nicoll D. Nikolaidis A. Nolan C.M. Noonan M.J. Norman C. Novotny P. Nunag J. Nwafor L. Nwanguma U. Nyaboko J. O’Brien C. O’Donnell K. O’Regan D. O’Brien L. Odell N. Ogg G. Olaosebikan O. Oliver C. Omar Z. Orriss-Dib L. Osborne L. Osbourne R. Ostermann M. Overton C. Owen J. Oxton J. Pack J. Pacpaco E. Paddick S. Painter S. Pakzad A. Palmer S. Papineni P. Paques K. Paradowski K. Pareek M. Parekh D. Parfrey H. Pariante C. Parker S. Parmar J. Patale S. Patel B. Patel M. Patel S. Pattenadk D. Pavlides M. Payne S. Pearce L. Pearl J.E. Peckham D. Pendlebury J. Peng Y. Pennington C. Peralta I. Perkins E. Peterkin Z. Peto T. Petousi N. Petrie J. Pfeffer P. Phipps J. Pimm J. Piper Hanley K. Pius R. Plant H. Plein S. Plekhanova T. Plowright M. Poinasamy K. Polgar O. Poll L. Porter J.C. Porter J. Portukhay S. Powell N. Prabhu A. Pratt J. Price A. Price C. Price C. Price D. Price L. Price L. Prickett A. Propescu J. Prosper S. Pugmire S. Quaid S. Quigley J. Quint J. Qureshi H. Qureshi I.N. Radhakrishnan K. Rahman N.M. Ralser M. Ramos A. Ramos H. Rangeley J. Rangelov B. Ratcliffe L. Ravencroft P. Reddington A. Reddy R. Reddy A. Redfearn H. Redwood D. Reed A. Rees M. Rees T. Regan K. Reynolds W. Ribeiro C. Richards A. Richardson E. Richardson M. Rivera-Ortega P. Roberts K. Robertson E. Robinson E. Robinson L. Roche L. Roddis C. Rodger J. Ross A. Ross G. Rossdale J. Rostron A. Rowe A. Rowland A. Rowland J. Rowland M.J. Rowland-Jones S.L. Roy K. Roy M. Rudan I. Russell R. Russell E. Saalmink G. Sabit R. Sage E.K. Samakomva T. Samani N. Sampson C. Samuel K. Samuel R. Sanderson A. Sapey E. Saralaya D. Sargent J. Sarginson C. Sass T. Sattar N. Saunders K. Saunders R.M. Saunders P. Saunders L.C. Savill H. Saxon W. Sayer A. Schronce J. Schwaeble W. Scott J.T. Scott K. Selby N. Semple M.G. Sereno M. Sewell T.A. Shah A. Shah K. Shah P. Shankar-Hari M. Sharma M. Sharpe C. Sharpe M. Shashaa S. Shaw A. Shaw K. Shaw V. Sheikh A. Shelton S. Shenton L. Shevket K. Shikotra A. Short J. Siddique S. Siddiqui S. Sidebottom J. Sigfrid L. Simons G. Simpson J. Simpson N. Singh C. Singh S. Singh S.J. Sissons D. Skeemer J. Slack K. Smith A. Smith D. Smith S. Smith J. Smith L. Soares M. Solano T.S. Solly R. Solstice A.R. Soulsby T. Southern D. Sowter D. Spears M. Spencer L.G. Speranza F. Stadon L. Stanel S. Steele N. Steiner M. Stensel D. Stephens G. Stephenson L. Stern M. Stewart I. Stimpson R. Stockdale S. Stockley J. Stoker W. Stone R. Storrar W. Storrie A. Storton K. Stringer E. Strong-Sheldrake S. Stroud N. Subbe C. Sudlow C.L. Suleiman Z. Summers C. Summersgill C. Sutherland D. Sykes D.L. Sykes R. Talbot N. Tan A.L. Tarusan L. Tavoukjian V. Taylor A. Taylor C. Taylor J. Te A. Tedd H. Tee C.J. Teixeira J. Tench H. Terry S. Thackray-Nocera S. Thaivalappil F. Thamu B. Thickett D. Thomas C. Thomas D.C. Thomas S. Thomas A.K. Thomas-Woods T. Thompson T. Thompson A.A.R. Thornton T. Thorpe M. Thwaites R.S. Tilley J. Tinker N. Tiongson G.F. Tobin M. Tomlinson J. Tong C. Toshner M. Touyz R. Tripp K.A. Tunnicliffe E. Turnbull A. Turner E. Turner S. Turner V. Turner K. Turney S. Turton H. Ugoji J. Ugwuoke R. Upthegrove R. Valabhji J. Ventura M. Vere J. Vickers C. Vinson B. Wade E. Wade P. Wainwright T. Wajero L.O. Walder S. Walker S. Walker S. Wall E. Wallis T. Walmsley S. Walsh J.A. Walsh S. Warburton L. Ward T.J.C. Warwick K. Wassall H. Waterson S. Watson E. Watson L. Watson J. Weir McCall J. Welch C. Welch H. Welsh B. Wessely S. West S. Weston H. Wheeler H. White S. Whitehead V. Whitney J. Whittaker S. Whittam B. Whitworth V. Wight A. Wild J. Wilkins M. Wilkinson D. Williams B. Williams N. Williams N. Williams J. Williams-Howard S.A. Willicombe M. Willis G. Willoughby J. Wilson A. Wilson D. Wilson I. Window N. Witham M. Wolf-Roberts R. Wood C. Woodhead F. Woods J. Wootton D.G. Wormleighton J. Worsley J. Wraith D. Wrey Brown C. Wright C. Wright L. Wright S. Wyles J. Wynter I. Xu M. Yasmin N. Yasmin S. Yates T. Yip K.P. Young B. Young S. Young A. Yousuf A.J. Zawia A. Zeidan L. Zhao B. Zheng B. Zongo O. PHOSP-COVID Study collaborative group ISARIC4C investigators Accelerated immune ageing is associated with COVID-19 disease severity. Immun. Ageing 2024 21 1 6 10.1186/s12979‑023‑00406‑z 38212801
    [Google Scholar]
  65. Geng M.J. Wang L.P. Ren X. Yu J.X. Chang Z.R. Zheng C.J. Risk factors for developing severe COVID-19 in China: An analysis of disease surveillance data. Infect. Dis. Poverty 2021 10 1 10
    [Google Scholar]
  66. Evangelou K. Veroutis D. Paschalaki K. Foukas P.G. Lagopati N. Dimitriou M. Papaspyropoulos A. Konda B. Hazapis O. Polyzou A. Havaki S. Kotsinas A. Kittas C. Tzioufas A.G. de Leval L. Vassilakos D. Tsiodras S. Stripp B.R. Papantonis A. Blandino G. Karakasiliotis I. Barnes P.J. Gorgoulis V.G. Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: Possible implications for viral mutagenesis. Eur. Respir. J. 2022 60 2 2102951 10.1183/13993003.02951‑2021 35086840
    [Google Scholar]
  67. Tizazu A.M. Mengist H.M. Demeke G. Aging, inflammaging and immunosenescence as risk factors of severe COVID-19. Immun. Ageing 2022 19 1 53 10.1186/s12979‑022‑00309‑5 36369012
    [Google Scholar]
  68. Childs B.G. Durik M. Baker D.J. van Deursen J.M. Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nat. Med. 2015 21 12 1424 1435 10.1038/nm.4000 26646499
    [Google Scholar]
  69. van Deursen J.M. The role of senescent cells in ageing. Nature 2014 509 7501 439 446 10.1038/nature13193 24848057
    [Google Scholar]
  70. Gruver A.L. Hudson L.L. Sempowski G.D. Immunosenescence of ageing. J Pathol. 2007 211 2 144 156 10.1002/path.2104 17200946
    [Google Scholar]
  71. Farkhondeh T. Samarghandian S. Azimin-Nezhad M. Samini F. Effect of chrysin on nociception in formalin test and serum levels of noradrenalin and corticosterone in rats. Int. J. Clin. Exp. Med. 2015 8 2 2465 2470 25932190
    [Google Scholar]
  72. Kohandel Z. Farkhondeh T. Aschner M. Samarghandian S. Nrf2 a molecular therapeutic target for Astaxanthin. Biomed. Pharmacother. 2021 137 111374 10.1016/j.biopha.2021.111374 33761600
    [Google Scholar]
  73. Hao X. Wang C. Zhang R. Chromatin basis of the senescence-associated secretory phenotype. Trends Cell Biol. 2022 32 6 513 526 10.1016/j.tcb.2021.12.003 35012849
    [Google Scholar]
  74. Watanabe S. Kawamoto S. Ohtani N. Hara E. Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases. Cancer Sci. 2017 108 4 563 569 10.1111/cas.13184 28165648
    [Google Scholar]
  75. Zinatizadeh M.R. Zarandi P.K. Ghiasi M. Kooshki H. Mohammadi M. Amani J. Rezaei N. Immunosenescence and inflamm-ageing in COVID-19. Ageing Res. Rev. 2023 84 101818 10.1016/j.arr.2022.101818 36516928
    [Google Scholar]
  76. Chen X. Giles J. Yao Y. Yip W. Meng Q. Berkman L. Chen H. Chen X. Feng J. Feng Z. Glinskaya E. Gong J. Hu P. Kan H. Lei X. Liu X. Steptoe A. Wang G. Wang H. Wang H. Wang X. Wang Y. Yang L. Zhang L. Zhang Q. Wu J. Wu Z. Strauss J. Smith J. Zhao Y. The path to healthy ageing in China: A Peking University–Lancet Commission. Lancet 2022 400 10367 1967 2006 10.1016/S0140‑6736(22)01546‑X 36423650
    [Google Scholar]
  77. Kline K.A. Bowdish D.M.E. Infection in an aging population. Curr. Opin. Microbiol. 2016 29 63 67 10.1016/j.mib.2015.11.003 26673958
    [Google Scholar]
  78. Kim J.A. Seong R.K. Shin O.S. Enhanced viral replication by cellular replicative senescence. Immune Netw. 2016 16 5 286 295 10.4110/in.2016.16.5.286 27799874
    [Google Scholar]
  79. Kelley W.J. Zemans R.L. Goldstein D.R. Cellular senescence: Friend or foe to respiratory viral infections? Eur. Respir. J. 2020 56 6 2002708 10.1183/13993003.02708‑2020 33033152
    [Google Scholar]
  80. Jaiswal S. Ebert B.L. Clonal hematopoiesis in human aging and disease. Science 2019 366 6465 eaan4673 10.1126/science.aan4673 31672865
    [Google Scholar]
  81. Chen Z. John Wherry E. T cell responses in patients with COVID-19. Nat. Rev. Immunol. 2020 20 9 529 536 10.1038/s41577‑020‑0402‑6 32728222
    [Google Scholar]
  82. Salam N. Rane S. Das R. Faulkner M. Gund R. Kandpal U. Lewis V. Mattoo H. Prabhu S. Ranganathan V. Durdik J. George A. Rath S. Bal V. T cell ageing: Effects of age on development, survival & function. Indian J. Med. Res. 2013 138 5 595 608 24434315
    [Google Scholar]
  83. Lefebvre J.S. Masters A.R. Hopkins J.W. Haynes L. Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Sci. Rep. 2016 6 1 25051 10.1038/srep25051 27109638
    [Google Scholar]
  84. Costela-Ruiz V.J. Illescas-Montes R. Puerta-Puerta J.M. Ruiz C. Melguizo-Rodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020 54 62 75 10.1016/j.cytogfr.2020.06.001 32513566
    [Google Scholar]
  85. Mahmudpour M. Roozbeh J. Keshavarz M. Farrokhi S. Nabipour I. COVID-19 cytokine storm: The anger of inflammation. Cytokine 2020 133 155151 10.1016/j.cyto.2020.155151 32544563
    [Google Scholar]
  86. Ye Q. Wang B. Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J. Infect. 2020 80 6 607 613 10.1016/j.jinf.2020.03.037 32283152
    [Google Scholar]
  87. Liu Q. Zhou Y. Yang Z. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol. 2016 13 1 3 10 10.1038/cmi.2015.74 26189369
    [Google Scholar]
  88. Xing Z. Gauldie J. Cox G. Baumann H. Jordana M. Lei X.F. Achong M.K. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J. Clin. Invest. 1998 101 2 311 320 10.1172/JCI1368 9435302
    [Google Scholar]
  89. Yu M. Zheng X. Witschi H. Pinkerton K.E. The role of interleukin-6 in pulmonary inflammation and injury induced by exposure to environmental air pollutants. Toxicol. Sci. 2002 68 2 488 497 10.1093/toxsci/68.2.488 12151646
    [Google Scholar]
  90. Velazquez-Salinas L. Verdugo-Rodriguez A. Rodriguez L.L. Borca M.V. The role of interleukin 6 during viral infections. Front. Microbiol. 2019 10 1057 10.3389/fmicb.2019.01057 31134045
    [Google Scholar]
  91. Fehr A.R. Channappanavar R. Perlman S. Middle East respiratory syndrome: Emergence of a pathogenic human coronavirus. Annu. Rev. Med. 2017 68 1 387 399 10.1146/annurev‑med‑051215‑031152 27576010
    [Google Scholar]
  92. Herold T. Jurinovic V. Arnreich C. Lipworth B.J. Hellmuth J.C. von Bergwelt-Baildon M. Weinberger T. Elevated levels of interleukin-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020 146 1 128 136.e4 10.1016/j.jaci.2020.05.008 32425269
    [Google Scholar]
  93. Aziz M. Fatima R. Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol. 2020 92 11 2283 2285 10.1002/jmv.25948 32343429
    [Google Scholar]
  94. Patel S. Rauf A. Khan H. Abu-Izneid T. Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies. Biomed. Pharmacother. 2017 94 317 325 10.1016/j.biopha.2017.07.091 28772209
    [Google Scholar]
  95. de Wit E. van Doremalen N. Falzarano D. Munster V.J. SARS and MERS: Recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 2016 14 8 523 534 10.1038/nrmicro.2016.81 27344959
    [Google Scholar]
  96. Kuba K. Imai Y. Rao S. Gao H. Guo F. Guan B. Huan Y. Yang P. Zhang Y. Deng W. Bao L. Zhang B. Liu G. Wang Z. Chappell M. Liu Y. Zheng D. Leibbrandt A. Wada T. Slutsky A.S. Liu D. Qin C. Jiang C. Penninger J.M. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat. Med. 2005 11 8 875 879 10.1038/nm1267 16007097
    [Google Scholar]
  97. Satou R. Gonzalez-Villalobos R.A. Miyata K. Ohashi N. Katsurada A. Navar L.G. Kobori H. Costimulation with angiotensin II and interleukin 6 augments angiotensinogen expression in cultured human renal proximal tubular cells. Am. J. Physiol. Renal Physiol. 2008 295 1 F283 F289 10.1152/ajprenal.00047.2008 18463317
    [Google Scholar]
  98. Khemais-Benkhiat S. Idris-Khodja N. Ribeiro T.P. Silva G.C. Abbas M. Kheloufi M. Lee J.O. Toti F. Auger C. Schini-Kerth V.B. The redox-sensitive induction of the local angiotensin system promotes both premature and replicative endothelial senescence: Preventive effect of a standardized Crataegus extract. J. Gerontol. A Biol. Sci. Med. Sci. 2016 71 12 1581 1590 10.1093/gerona/glv213 26672612
    [Google Scholar]
  99. Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. Wang B. Xiang H. Cheng Z. Xiong Y. Zhao Y. Li Y. Wang X. Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020 323 11 1061 1069 10.1001/jama.2020.1585 32031570
    [Google Scholar]
  100. Ziegler C.G.K. Allon S.J. Nyquist S.K. Mbano I.M. Miao V.N. Tzouanas C.N. Cao Y. Yousif A.S. Bals J. Hauser B.M. Feldman J. Muus C. Wadsworth M.H. II Kazer S.W. Hughes T.K. Doran B. Gatter G.J. Vukovic M. Taliaferro F. Mead B.E. Guo Z. Wang J.P. Gras D. Plaisant M. Ansari M. Angelidis I. Adler H. Sucre J.M.S. Taylor C.J. Lin B. Waghray A. Mitsialis V. Dwyer D.F. Buchheit K.M. Boyce J.A. Barrett N.A. Laidlaw T.M. Carroll S.L. Colonna L. Tkachev V. Peterson C.W. Yu A. Zheng H.B. Gideon H.P. Winchell C.G. Lin P.L. Bingle C.D. Snapper S.B. Kropski J.A. Theis F.J. Schiller H.B. Zaragosi L.E. Barbry P. Leslie A. Kiem H.P. Flynn J.L. Fortune S.M. Berger B. Finberg R.W. Kean L.S. Garber M. Schmidt A.G. Lingwood D. Shalek A.K. Ordovas-Montanes J. Banovich N. Barbry P. Brazma A. Desai T. Duong T.E. Eickelberg O. Falk C. Farzan M. Glass I. Haniffa M. Horvath P. Hung D. Kaminski N. Krasnow M. Kropski J.A. Kuhnemund M. Lafyatis R. Lee H. Leroy S. Linnarson S. Lundeberg J. Meyer K. Misharin A. Nawijn M. Nikolic M.Z. Ordovas-Montanes J. Pe’er D. Powell J. Quake S. Rajagopal J. Tata P.R. Rawlins E.L. Regev A. Reyfman P.A. Rojas M. Rosen O. Saeb-Parsy K. Samakovlis C. Schiller H. Schultze J.L. Seibold M.A. Shalek A.K. Shepherd D. Spence J. Spira A. Sun X. Teichmann S. Theis F. Tsankov A. van den Berge M. von Papen M. Whitsett J. Xavier R. Xu Y. Zaragosi L-E. Zhang K. HCA Lung Biological Network. Electronic address: Lung-network@humancellatlas.org HCA Lung Biological Network SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020 181 5 1016 1035.e19 10.1016/j.cell.2020.04.035 32413319
    [Google Scholar]
  101. Smith J.C. Sausville E.L. Girish V. Yuan M.L. Vasudevan A. John K.M. Sheltzer J.M. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev. Cell 2020 53 5 514 529.e3 10.1016/j.devcel.2020.05.012 32425701
    [Google Scholar]
  102. Xudong X. Junzhu C. Xingxiang W. Furong Z. Yanrong L. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006 78 19 2166 2171 10.1016/j.lfs.2005.09.038 16303146
    [Google Scholar]
  103. Imai Y. Kuba K. Rao S. Huan Y. Guo F. Guan B. Yang P. Sarao R. Wada T. Leong-Poi H. Crackower M.A. Fukamizu A. Hui C.C. Hein L. Uhlig S. Slutsky A.S. Jiang C. Penninger J.M. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005 436 7047 112 116 10.1038/nature03712 16001071
    [Google Scholar]
  104. Crackower M.A. Sarao R. Oudit G.Y. Yagil C. Kozieradzki I. Scanga S.E. Oliveira-dos-Santos A.J. da Costa J. Zhang L. Pei Y. Scholey J. Ferrario C.M. Manoukian A.S. Chappell M.C. Backx P.H. Yagil Y. Penninger J.M. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002 417 6891 822 828 10.1038/nature00786 12075344
    [Google Scholar]
  105. Burrell L.M. Risvanis J. Kubota E. Dean R.G. MacDonald P.S. Lu S. Tikellis C. Grant S.L. Lew R.A. Smith A.I. Cooper M.E. Johnston C.I. Myocardial infarction increases ACE2 expression in rat and humans. Eur. Heart J. 2005 26 4 369 375 10.1093/eurheartj/ehi114 15671045
    [Google Scholar]
  106. Chen L. Li X. Chen M. Feng Y. Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc. Res. 2020 116 6 1097 1100 10.1093/cvr/cvaa078 32227090
    [Google Scholar]
  107. Wang B. Li R. Lu Z. Huang Y. Does comorbidity increase the risk of patients with COVID-19: Evidence from meta-analysis. Aging (Albany NY) 2020 12 7 6049 6057 10.18632/aging.103000 32267833
    [Google Scholar]
  108. Abbott C.A. McCaughan G.W. Baker E. Sutherland G.R. Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics 1994 40 5 331 338 10.1007/BF01246674 7927537
    [Google Scholar]
  109. Thoma R. Löffler B. Stihle M. Huber W. Ruf A. Hennig M. Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure 2003 11 8 947 959 10.1016/S0969‑2126(03)00160‑6 12906826
    [Google Scholar]
  110. Kim K.M. Noh J.H. Bodogai M. Martindale J.L. Yang X. Indig F.E. Basu S.K. Ohnuma K. Morimoto C. Johnson P.F. Biragyn A. Abdelmohsen K. Gorospe M. Identification of senescent cell surface targetable protein DPP4. Genes Dev. 2017 31 15 1529 1534 10.1101/gad.302570.117 28877934
    [Google Scholar]
  111. Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020 323 13 1239 1242 10.1001/jama.2020.2648 32091533
    [Google Scholar]
  112. Mubarak A. Alturaiki W. Hemida M.G. Middle East respiratory syndrome coronavirus (MERS-CoV): Infection, immunological response, and vaccine development. J. Immunol. Res. 2019 2019 1 11 10.1155/2019/6491738 31089478
    [Google Scholar]
  113. Raj V.S. Mou H. Smits S.L. Dekkers D.H.W. Müller M.A. Dijkman R. Muth D. Demmers J.A.A. Zaki A. Fouchier R.A.M. Thiel V. Drosten C. Rottier P.J.M. Osterhaus A.D.M.E. Bosch B.J. Haagmans B.L. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013 495 7440 251 254 10.1038/nature12005 23486063
    [Google Scholar]
  114. Nassar M.S. Bakhrebah M.A. Meo S.A. Alsuabeyl M.S. Zaher W.A. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: Epidemiology, pathogenesis and clinical characteristics. Eur. Rev. Med. Pharmacol. Sci. 2018 22 15 4956 4961 30070331
    [Google Scholar]
  115. Gralinski L.E. Baric R.S. Molecular pathology of emerging coronavirus infections. J. Pathol. 2015 235 2 185 195 10.1002/path.4454 25270030
    [Google Scholar]
  116. Ahmed A.E. The predictors of 3- and 30-day mortality in 660 MERS-CoV patients. BMC Infect. Dis. 2017 17 1 615 10.1186/s12879‑017‑2712‑2 28893197
    [Google Scholar]
  117. Klemann C. Wagner L. Stephan M. von Hörsten S. Cut to the chase: A review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system. Clin. Exp. Immunol. 2016 185 1 1 21 10.1111/cei.12781 26919392
    [Google Scholar]
  118. Abbott C.A. McCaughan G.W. Levy M.T. Church W.B. Gorrell M.D. Binding to human dipeptidyl peptidase IV by adenosine deaminase and antibodies that inhibit ligand binding involves overlapping, discontinuous sites on a predicted β propeller domain. Eur. J. Biochem. 1999 266 3 798 810 10.1046/j.1432‑1327.1999.00902.x 10583373
    [Google Scholar]
  119. Yu D.M.T. Slaitini L. Gysbers V. Riekhoff A.G.M. Kähne T. Knott H.M. De Meester I. Abbott C.A. McCaughan G.W. Gorrell M.D. Soluble CD26 / dipeptidyl peptidase IV enhances human lymphocyte proliferation in vitro independent of dipeptidyl peptidase enzyme activity and adenosine deaminase binding. Scand. J. Immunol. 2011 73 2 102 111 10.1111/j.1365‑3083.2010.02488.x 21198750
    [Google Scholar]
  120. Cordero O.J. Salgado F.J. Nogueira M. On the origin of serum CD26 and its altered concentration in cancer patients. Cancer Immunol. Immunother. 2009 58 11 1723 1747 10.1007/s00262‑009‑0728‑1 19557413
    [Google Scholar]
  121. Ikeda T. Kumagai E. Iwata S. Yamakawa A. Soluble CD26/dipeptidyl peptidase IV enhances the transcription of IL-6 and TNF-α in THP-1 cells and monocytes. PLoS One 2013 8 6 e66520 10.1371/journal.pone.0066520 23805228
    [Google Scholar]
  122. Wiciński M. Górski K. Walczak M. Wódkiewicz E. Słupski M. Pawlak-Osińska K. Malinowski B. Neuroprotective properties of linagliptin: Focus on biochemical mechanisms in cerebral ischemia, vascular dysfunction and certain neurodegenerative diseases. Int. J. Mol. Sci. 2019 20 16 4052 10.3390/ijms20164052 31434198
    [Google Scholar]
  123. Agrawal S. Tran M.T. Jennings T.S.K. Soliman M.M.H. Heo S. Sasson B. Rahmatpanah F. Agrawal A. Changes in the innate immune response to SARS-CoV-2 with advancing age in humans. Immun. Ageing 2024 21 1 21 10.1186/s12979‑024‑00426‑3 38515147
    [Google Scholar]
  124. Movsisyan M. Truzyan N. Kasparova I. Chopikyan A. Sawaqed R. Bedross A. Sukiasyan M. Dilbaryan K. Shariff S. Kantawala B. Hakobjanyan G. Petrosyan G. Hakobyan A. Yenkoyan K. Tracking the evolution of anti-SARS-CoV-2 antibodies and long-term humoral immunity within 2 years after COVID-19 infection. Sci. Rep. 2024 14 1 13417 10.1038/s41598‑024‑64414‑9 38862731
    [Google Scholar]
  125. Sher E.K. Ćosović A. Džidić-Krivić A. Farhat E.K. Pinjić E. Sher F. Covid-19 a triggering factor of autoimmune and multi-inflammatory diseases. Life Sci. 2023 319 121531 10.1016/j.lfs.2023.121531 36858313
    [Google Scholar]
  126. Asghari F. Asghary A. Majidi Zolbanin N. Faraji F. Jafari R. Immunosenescence and Inflammaging in COVID-19. Viral Immunol. 2023 36 9 579 592 10.1089/vim.2023.0045 37797216
    [Google Scholar]
  127. Bartleson J.M. Radenkovic D. Covarrubias A.J. Furman D. Winer D.A. Verdin E. SARS-CoV-2, COVID-19 and the ageing immune system. Nat Aging 2021 1 9 769 782 10.1038/s43587‑021‑00114‑7 34746804
    [Google Scholar]
  128. Weatherhead J.E. Clark E. Vogel T.P. Atmar R.L. Kulkarni P.A. Inflammatory syndromes associated with SARS-CoV-2 infection: Dysregulation of the immune response across the age spectrum. J. Clin. Invest. 2020 130 12 6194 6197 10.1172/JCI145301 33108354
    [Google Scholar]
  129. Olovnikov A.M. Telomeres, telomerase, and aging: Origin of the theory. Exp. Gerontol. 1996 31 4 443 448 10.1016/0531‑5565(96)00005‑8 9415101
    [Google Scholar]
  130. Harley C.B. Futcher A.B. Greider C.W. Telomeres shorten during ageing of human fibroblasts. Nature 1990 345 6274 458 460 10.1038/345458a0 2342578
    [Google Scholar]
  131. Hayflick L. Moorhead P.S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 1961 25 3 585 621 10.1016/0014‑4827(61)90192‑6 13905658
    [Google Scholar]
  132. Muraki K. Nyhan K. Han L. Murnane J.P. Mechanisms of telomere loss and their consequences for chromosome instability. Front. Oncol. 2012 2 135 10.3389/fonc.2012.00135 23061048
    [Google Scholar]
  133. Blackburn E.H. Epel E.S. Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 2015 350 6265 1193 1198 10.1126/science.aab3389 26785477
    [Google Scholar]
  134. Ilmonen P. Kotrschal A. Penn D.J. Telomere attrition due to infection. PLoS One 2008 3 5 e2143 10.1371/journal.pone.0002143 18478110
    [Google Scholar]
  135. Kordinas V. Ioannidis A. Chatzipanagiotou S. The telomere/telomerase system in chronic inflammatory diseases. Cause or effect? Genes (Basel) 2016 7 9 60 10.3390/genes7090060 27598205
    [Google Scholar]
  136. Cusanelli E. Chartrand P. Telomeric repeat-containing RNA TERRA: A noncoding RNA connecting telomere biology to genome integrity. Front. Genet. 2015 6 143 10.3389/fgene.2015.00143 25926849
    [Google Scholar]
  137. Montero J.J. López de Silanes I. Graña O. Blasco M.A. Telomeric RNAs are essential to maintain telomeres. Nat. Commun. 2016 7 1 12534 10.1038/ncomms12534 27531349
    [Google Scholar]
  138. Wang Z. Deng Z. Dahmane N. Tsai K. Wang P. Williams D.R. Kossenkov A.V. Showe L.C. Zhang R. Huang Q. Conejo-Garcia J.R. Lieberman P.M. Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes. Proc. Natl. Acad. Sci. USA 2015 112 46 E6293 E6300 10.1073/pnas.1505962112 26578789
    [Google Scholar]
  139. Ryan E. Hollingworth R. Grand R. Activation of the DNA damage response by RNA viruses. Biomolecules 2016 6 1 2 10.3390/biom6010002 26751489
    [Google Scholar]
  140. Lamarche B.J. Orazio N.I. Weitzman M.D. The MRN complex in double‐strand break repair and telomere maintenance. FEBS Lett. 2010 584 17 3682 3695 10.1016/j.febslet.2010.07.029 20655309
    [Google Scholar]
  141. Porro A. Feuerhahn S. Delafontaine J. Riethman H. Rougemont J. Lingner J. Functional characterization of the TERRA transcriptome at damaged telomeres. Nat. Commun. 2014 5 1 5379 10.1038/ncomms6379 25359189
    [Google Scholar]
  142. Weng N. Telomeres and immune competency. Curr. Opin. Immunol. 2012 24 4 470 475 10.1016/j.coi.2012.05.001 22626625
    [Google Scholar]
  143. Helby J. Nordestgaard B.G. Benfield T. Bojesen S.E. Shorter leukocyte telomere length is associated with higher risk of infections: A prospective study of 75,309 individuals from the general population. Haematologica 2017 102 8 1457 1465 10.3324/haematol.2016.161943 28522577
    [Google Scholar]
  144. Jose S.S. Bendickova K. Kepak T. Krenova Z. Fric J. Chronic inflammation in immune aging: role of pattern recognition receptor crosstalk with the telomere complex? Front. Immunol. 2017 8 1078 10.3389/fimmu.2017.01078 28928745
    [Google Scholar]
  145. Dock J.N. Effros R.B. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis. 2011 2 5 382 397 22308228
    [Google Scholar]
  146. Najarro K. Nguyen H. Chen G. Xu M. Alcorta S. Yao X. Zukley L. Metter E.J. Truong T. Lin Y. Li H. Oelke M. Xu X. Ling S.M. Longo D.L. Schneck J. Leng S. Ferrucci L. Weng N. Telomere length as an indicator of the robustness of B-and T-cell response to influenza in older adults. J. Infect. Dis. 2015 212 8 1261 1269 10.1093/infdis/jiv202 25828247
    [Google Scholar]
  147. Liu S. Wang C. Green G. Zhuo H. Liu K.D. Kangelaris K.N. Gomez A. Jauregui A. Vessel K. Ke S. Hendrickson C. Matthay M.A. Calfee C.S. Ware L.B. Wolters P.J. Peripheral blood leukocyte telomere length is associated with survival of sepsis patients. Eur. Respir. J. 2020 55 1 1901044 10.1183/13993003.01044‑2019 31619475
    [Google Scholar]
  148. O’Donovan A. Pantell M.S. Puterman E. Dhabhar F.S. Blackburn E.H. Yaffe K. Cawthon R.M. Opresko P.L. Hsueh W.C. Satterfield S. Newman A.B. Ayonayon H.N. Rubin S.M. Harris T.B. Epel E.S. Health Aging and Body Composition Study Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study. PLoS One 2011 6 5 e19687 10.1371/journal.pone.0019687 21602933
    [Google Scholar]
  149. Wong J.Y.Y. De Vivo I. Lin X. Fang S.C. Christiani D.C. The relationship between inflammatory biomarkers and telomere length in an occupational prospective cohort study. PLoS One 2014 9 1 e87348 10.1371/journal.pone.0087348 24475279
    [Google Scholar]
  150. Atal S. Fatima Z. IL-6 inhibitors in the treatment of serious COVID-19: A promising therapy? Pharmaceut. Med. 2020 34 4 223 231 10.1007/s40290‑020‑00342‑z 32535732
    [Google Scholar]
  151. Arsenis N.C. You T. Ogawa E.F. Tinsley G.M. Zuo L. Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget 2017 8 27 45008 45019 10.18632/oncotarget.16726 28410238
    [Google Scholar]
  152. Sellami M. Gasmi M. Denham J. Hayes L.D. Stratton D. Padulo J. Bragazzi N. Effects of acute and chronic exercise on immunological parameters in the elderly aged: Can physical activity counteract the effects of aging? Front. Immunol. 2018 9 2187 10.3389/fimmu.2018.02187 30364079
    [Google Scholar]
  153. Nieman D.C. Wentz L.M. The compelling link between physical activity and the body’s defense system. J. Sport Health Sci. 2019 8 3 201 217 10.1016/j.jshs.2018.09.009 31193280
    [Google Scholar]
  154. de Duve C. Wattiaux R. Functions of Lysosomes. Annu. Rev. Physiol. 1966 28 1 435 492 10.1146/annurev.ph.28.030166.002251 5322983
    [Google Scholar]
  155. Rabinowitz J.D. White E. Autophagy and Metabolism. Science 2010 330 6009 1344 1348 10.1126/science.1193497 21127245
    [Google Scholar]
  156. Russell R.C. Yuan H.X. Guan K.L. Autophagy regulation by nutrient signaling. Cell Res. 2014 24 1 42 57 10.1038/cr.2013.166 24343578
    [Google Scholar]
  157. Sridharan S. Jain K. Basu A. Regulation of autophagy by kinases. Cancers (Basel) 2011 3 2 2630 2654 10.3390/cancers3022630 24212825
    [Google Scholar]
  158. Jung C.H. Ro S.H. Cao J. Otto N.M. Kim D.H. mTOR regulation of autophagy. FEBS Lett. 2010 584 7 1287 1295 10.1016/j.febslet.2010.01.017 20083114
    [Google Scholar]
  159. Alers S. Löffler A.S. Wesselborg S. Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: Cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 2012 32 1 2 11 10.1128/MCB.06159‑11 22025673
    [Google Scholar]
  160. Xiang H. Zhang J. Lin C. Zhang L. Liu B. Ouyang L. Targeting autophagy-related protein kinases for potential therapeutic purpose. Acta Pharm. Sin. B 2020 10 4 569 581 10.1016/j.apsb.2019.10.003 32322463
    [Google Scholar]
  161. Kudchodkar S.B. Levine B. Viruses and autophagy. Rev. Med. Virol. 2009 19 6 359 378 10.1002/rmv.630 19750559
    [Google Scholar]
  162. Choi Y. Bowman J.W. Jung J.U. Autophagy during viral infection — a double-edged sword. Nat. Rev. Microbiol. 2018 16 6 341 354 10.1038/s41579‑018‑0003‑6 29556036
    [Google Scholar]
  163. Rubinsztein D.C. Codogno P. Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 2012 11 9 709 730 10.1038/nrd3802 22935804
    [Google Scholar]
  164. Jackson W.T. Viruses and the autophagy pathway. Virology 2015 479-480 450 456 10.1016/j.virol.2015.03.042 25858140
    [Google Scholar]
  165. Crotzer V.L. Blum J.S. Autophagy and its role in MHC-mediated antigen presentation. J. Immunol. 2009 182 6 3335 3341 10.4049/jimmunol.0803458 19265109
    [Google Scholar]
  166. Jiang G.M. Tan Y. Wang H. Peng L. Chen H.T. Meng X.J. Li L.L. Liu Y. Li W.F. Shan H. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol. Cancer 2019 18 1 17 10.1186/s12943‑019‑0944‑z 30678689
    [Google Scholar]
  167. Gannagé M. Dormann D. Albrecht R. Dengjel J. Torossi T. Rämer P.C. Lee M. Strowig T. Arrey F. Conenello G. Pypaert M. Andersen J. García-Sastre A. Münz C. Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. Cell Host Microbe 2009 6 4 367 380 10.1016/j.chom.2009.09.005 19837376
    [Google Scholar]
  168. Zhang R. Chi X. Wang S. Qi B. Yu X. Chen J.L. The regulation of autophagy by influenza A virus. BioMed Res. Int. 2014 2014 1 7 10.1155/2014/498083 24779013
    [Google Scholar]
  169. Comber J.D. Robinson T.M. Siciliano N.A. Snook A.E. Eisenlohr L.C. Functional macroautophagy induction by influenza A virus without a contribution to major histocompatibility complex class II-restricted presentation. J. Virol. 2011 85 13 6453 6463 10.1128/JVI.02122‑10 21525345
    [Google Scholar]
  170. Ahmad L. Mostowy S. Sancho-Shimizu V. Autophagy-virus interplay: From cell biology to human disease. Front. Cell Dev. Biol. 2018 6 155 10.3389/fcell.2018.00155 30510929
    [Google Scholar]
  171. Fung T.S. Liu D.X. Human coronavirus: Host-pathogen interaction. Annu. Rev. Microbiol. 2019 73 1 529 557 10.1146/annurev‑micro‑020518‑115759 31226023
    [Google Scholar]
  172. Shojaei S. Suresh M. Klionsky D. J. Labouta H. I. Ghavami S. Autophagy and SARS-CoV-2 infection: A possible smart targeting of the autophagy pathway. Virulence 2020 11 1 805 810 10.1080/21505594.2020.1780088 32567972
    [Google Scholar]
  173. Chen X. Wang K. Xing Y. Tu J. Yang X. Zhao Q. Li K. Chen Z. Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity. Protein Cell 2014 5 12 912 927 10.1007/s13238‑014‑0104‑6 25311841
    [Google Scholar]
  174. Cottam E.M. Whelband M.C. Wileman T. Coronavirus NSP6 restricts autophagosome expansion. Autophagy 2014 10 8 1426 1441 10.4161/auto.29309 24991833
    [Google Scholar]
  175. Benvenuto D. Angeletti S. Giovanetti M. Bianchi M. Pascarella S. Cauda R. Ciccozzi M. Cassone A. Evolutionary analysis of SARS-CoV-2: How mutation of Non-Structural Protein 6 (NSP6) could affect viral autophagy. J. Infect. 2020 81 1 e24 e27 10.1016/j.jinf.2020.03.058 32283146
    [Google Scholar]
  176. Siekevitz P. Powerhouse of the Cell. Sci. Am. 1957 197 1 131 144 10.1038/scientificamerican0757‑131
    [Google Scholar]
  177. Harman D. The biologic clock: The mitochondria? J. Am. Geriatr. Soc. 1972 20 4 145 147 10.1111/j.1532‑5415.1972.tb00787.x 5016631
    [Google Scholar]
  178. Scialò F. Sriram A. Fernández-Ayala D. Gubina N. Lõhmus M. Nelson G. Logan A. Cooper H.M. Navas P. Enríquez J.A. Murphy M.P. Sanz A. Mitochondrial ROS produced via reverse electron transport extend animal lifespan. Cell Metab. 2016 23 4 725 734 10.1016/j.cmet.2016.03.009 27076081
    [Google Scholar]
  179. Nunnari J. Suomalainen A. Mitochondria: In sickness and in health. Cell 2012 148 6 1145 1159 10.1016/j.cell.2012.02.035 22424226
    [Google Scholar]
  180. Held N.M. Houtkooper R.H. Mitochondrial quality control pathways as determinants of metabolic health. BioEssays 2015 37 8 867 876 10.1002/bies.201500013 26010263
    [Google Scholar]
  181. Gonzalez-Freire M. de Cabo R. Bernier M. Sollott S.J. Fabbri E. Navas P. Ferrucci L. Reconsidering the role of mitochondria in aging. J. Gerontol. A Biol. Sci. Med. Sci. 2015 70 11 1334 1342 10.1093/gerona/glv070 25995290
    [Google Scholar]
  182. Friedman J.R. Nunnari J. Mitochondrial form and function. Nature 2014 505 7483 335 343 10.1038/nature12985 24429632
    [Google Scholar]
  183. Fang E.F. Scheibye-Knudsen M. Chua K.F. Mattson M.P. Croteau D.L. Bohr V.A. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 2016 17 5 308 321 10.1038/nrm.2016.14 26956196
    [Google Scholar]
  184. Gomes A.P. Price N.L. Ling A.J.Y. Moslehi J.J. Montgomery M.K. Rajman L. White J.P. Teodoro J.S. Wrann C.D. Hubbard B.P. Mercken E.M. Palmeira C.M. de Cabo R. Rolo A.P. Turner N. Bell E.L. Sinclair D.A. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013 155 7 1624 1638 10.1016/j.cell.2013.11.037 24360282
    [Google Scholar]
  185. Lee S.J. Hwang A.B. Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr. Biol. 2010 20 23 2131 2136 10.1016/j.cub.2010.10.057 21093262
    [Google Scholar]
  186. Weinberg S.E. Sena L.A. Chandel N.S. Mitochondria in the regulation of innate and adaptive immunity. Immunity 2015 42 3 406 417 10.1016/j.immuni.2015.02.002 25786173
    [Google Scholar]
  187. Angajala A. Lim S. Phillips J.B. Kim J.H. Yates C. You Z. Tan M. Diverse roles of mitochondria in immune responses: Novel insights into immuno-metabolism. Front. Immunol. 2018 9 1605 10.3389/fimmu.2018.01605 30050539
    [Google Scholar]
  188. Walker M.A. Volpi S. Sims K.B. Walter J.E. Traggiai E. Powering the immune system: Mitochondria in immune function and deficiency. J. Immunol. Res. 2014 2014 1 8 10.1155/2014/164309 25309931
    [Google Scholar]
  189. Kruk S.K. Pacheco S.E. Koenig M.K. Bergerson J.R.E. Gordon-Lipkin E. McGuire P.J. Vulnerability of pediatric patients with mitochondrial disease to vaccine-preventable diseases. J. Allergy Clin. Immunol. Pract. 2019 7 7 2415 2418.e3 10.1016/j.jaip.2019.03.046 30954647
    [Google Scholar]
  190. Kapnick S.M. Pacheco S.E. McGuire P.J. The emerging role of immune dysfunction in mitochondrial diseases as a paradigm for understanding immunometabolism. Metabolism 2018 81 97 112 10.1016/j.metabol.2017.11.010 29162500
    [Google Scholar]
  191. Cheng M.H. Zhang S. Porritt R.A. Noval Rivas M. Paschold L. Willscher E. Binder M. Arditi M. Bahar I. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc. Natl. Acad. Sci. USA 2020 117 41 25254 25262 10.1073/pnas.2010722117 32989130
    [Google Scholar]
  192. Jiang S. Mitochondrial oxidative phosphorylation is linked to T-cell exhaustion. Aging (Albany NY) 2020 12 17 16665 16666 10.18632/aging.103995 32897246
    [Google Scholar]
  193. Thompson E.A. Cascino K. Ordonez A.A. Zhou W. Vaghasia A. Hamacher-Brady A. Brady N.R. Mitochondrial induced T cell apoptosis and aberrant myeloid metabolic programs define distinct immune cell subsets during acute and recovered SARS-CoV-2 infection. medRxiv 2020 10.1101/2020.09.10.20186064
    [Google Scholar]
  194. Picca A. Lezza A. Leeuwenburgh C. Pesce V. Calvani R. Landi F. Bernabei R. Marzetti E. Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. Int. J. Mol. Sci. 2017 18 5 933 10.3390/ijms18050933 28452964
    [Google Scholar]
  195. Callender L.A. Carroll E.C. Bober E.A. Akbar A.N. Solito E. Henson S.M. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell 2020 19 2 e13067 10.1111/acel.13067 31788930
    [Google Scholar]
  196. Stephenson L.M. Miller B.C. Ng A. Eisenberg J. Zhao Z. Cadwell K. Graham D.B. Mizushima N.N. Xavier R. Virgin H.W. Swat W. Identification of Atg5 -dependent transcriptional changes and increases in mitochondrial mass in Atg5 -deficient T lymphocytes. Autophagy 2009 5 5 625 635 10.4161/auto.5.5.8133 19276668
    [Google Scholar]
  197. Desdín-Micó G. Soto-Heredero G. Aranda J.F. Oller J. Carrasco E. Gabandé-Rodríguez E. Blanco E.M. Alfranca A. Cussó L. Desco M. Ibañez B. Gortazar A.R. Fernández-Marcos P. Navarro M.N. Hernaez B. Alcamí A. Baixauli F. Mittelbrunn M. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 2020 368 6497 1371 1376 10.1126/science.aax0860 32439659
    [Google Scholar]
  198. Shi C.S. Qi H.Y. Boularan C. Huang N.N. Abu-Asab M. Shelhamer J.H. Kehrl J.H. SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J. Immunol. 2014 193 6 3080 3089 10.4049/jimmunol.1303196 25135833
    [Google Scholar]
  199. Hwang M.S. Boulanger J. Howe J.D. Albecka A. Pasche M. Mureşan L. Modis Y. MAVS polymers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling. FEBS J. 2019 286 8 1543 1560 10.1111/febs.14772 30715798
    [Google Scholar]
  200. Brisse M. Ly H. Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5. Front. Immunol. 2019 10 1586 10.3389/fimmu.2019.01586 31379819
    [Google Scholar]
  201. Subramanian N. Natarajan K. Clatworthy M.R. Wang Z. Germain R.N. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 2013 153 2 348 361 10.1016/j.cell.2013.02.054 23582325
    [Google Scholar]
  202. Kelley N. Jeltema D. Duan Y. He Y. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 2019 20 13 3328 10.3390/ijms20133328 31284572
    [Google Scholar]
  203. Zhao C. Zhao W. NLRP3 inflammasome—a key player in antiviral responses. Front. Immunol. 2020 11 211 10.3389/fimmu.2020.00211 32133002
    [Google Scholar]
  204. Freeman T.L. Swartz T.H. Targeting the NLRP3 inflammasome in severe COVID-19. Front. Immunol. 2020 11 1518 10.3389/fimmu.2020.01518 32655582
    [Google Scholar]
  205. Pourbagher-Shahri A.M. Farkhondeh T. Talebi M. Kopustinskiene D.M. Samarghandian S. Bernatoniene J. An Overview of NO Signaling Pathways in Aging. Molecules 2021 26 15 4533 10.3390/molecules26154533 34361685
    [Google Scholar]
  206. Ashrafizadeh M. Ahmadi Z. Farkhondeh T. Samarghandian S. Autophagy regulation using luteolin: new insight into its anti-tumor activity. Cancer Cell Int. 2020 20 1 537 10.1186/s12935‑020‑01634‑9 33292250
    [Google Scholar]
  207. Zia A. Farkhondeh T. Pourbagher-Shahri A.M. Samarghandian S. The Roles of Mitochondrial Dysfunction and Reactive Oxygen Species in Aging and Senescence. Curr. Mol. Med. 2021 22 1 37 49 10.2174/18755666MTE0jMzMc0 33602082
    [Google Scholar]
  208. Ashrafizadeh M. Ahmadi Z. Farkhondeh T. Samarghandian S. Autophagy as a molecular target of quercetin underlying its protective effects in human diseases. Arch. Physiol. Biochem. 2022 128 1 200 208 10.1080/13813455.2019.1671458 31564166
    [Google Scholar]
  209. Zia A. Farkhondeh T. Pourbagher-Shahri A.M. Samarghandian S. The role of curcumin in aging and senescence: Molecular mechanisms. Biomed. Pharmacother. 2021 134 111119 10.1016/j.biopha.2020.111119 33360051
    [Google Scholar]
  210. Kensler T. W. Wakabayashi N. Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007 47 89 116 10.1146/annurev.pharmtox.46.120604.141046 16968214
    [Google Scholar]
  211. Gorrini C. Harris I.S. Mak T.W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 2013 12 12 931 947 10.1038/nrd4002 24287781
    [Google Scholar]
  212. Samini M. Farkhondeh T. Azimi-Nezhad M. Samarghandian S. Chrysin Impact on Oxidative and Inflammation Damages in the Liver of Aged Male Rats. Endocr. Metab. Immune Disord. Drug Targets 2020 32679027
    [Google Scholar]
  213. Nabel G. Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 1987 326 6114 711 713 10.1038/326711a0 3031512
    [Google Scholar]
  214. Schwarz K.B. Oxidative stress during viral infection: A review. Free Radic. Biol. Med. 1996 21 5 641 649 10.1016/0891‑5849(96)00131‑1 8891667
    [Google Scholar]
  215. Delgado-Roche L. Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch. Med. Res. 2020 51 5 384 387 10.1016/j.arcmed.2020.04.019 32402576
    [Google Scholar]
  216. Cecchini R. Cecchini A.L. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med. Hypotheses 2020 143 110102 10.1016/j.mehy.2020.110102 32721799
    [Google Scholar]
  217. Cipolla-Neto J. Amaral F.G. Melatonin as a hormone: new physiological and clinical insights. Endocr. Rev. 2018 39 6 990 1028 10.1210/er.2018‑00084 30215696
    [Google Scholar]
  218. Konturek S.J. Konturek P.C. Brzozowska I. Pawlik M. Sliwowski Z. Cześnikiewicz-Guzik M. Kwiecień S. Brzozowski T. Bubenik G.A. Pawlik W.W. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J. Physiol. Pharmacol. 2007 58 3 381 405 17928638
    [Google Scholar]
  219. Carrillo-Vico A. Lardone P. Álvarez-Sánchez N. Rodríguez-Rodríguez A. Guerrero J. Melatonin: buffering the immune system. Int. J. Mol. Sci. 2013 14 4 8638 8683 10.3390/ijms14048638 23609496
    [Google Scholar]
  220. Hardeland R. Pandi-Perumal S.R. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr. Metab. (Lond.) 2005 2 1 22 10.1186/1743‑7075‑2‑22 16153306
    [Google Scholar]
  221. Huang S.H. Liao C.L. Chen S.J. Shi L.G. Lin L. Chen Y.W. Cheng C-P. Sytwu H-K. Shang S-T. Lin G-J. Melatonin possesses an anti-influenza potential through its immune modulatory effect. J. Funct. Foods 2019 58 189 198 10.1016/j.jff.2019.04.062
    [Google Scholar]
  222. Zhang R. Wang X. Ni L. Di X. Ma B. Niu S. Liu C. Reiter R.J. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 2020 250 117583 10.1016/j.lfs.2020.117583 32217117
    [Google Scholar]
  223. Mousavi S.A. Heydari K. Mehravaran H. Saeedi M. Alizadeh-Navaei R. Hedayatizadeh-Omran A. Shamshirian A. Melatonin effects on sleep quality and outcomes of COVID‐19 patients: An open‐label, randomized, controlled trial. J. Med. Virol. 2022 94 1 263 271 10.1002/jmv.27312 34460132
    [Google Scholar]
  224. Alizadeh Z. Keyhanian N. Ghaderkhani S. Dashti-Khavidaki S. Shoormasti R. S. Pourpak Z. A pilot study on controlling coronavirus disease 2019 (COVID-19) inflammation using melatonin supplement. Iran J Allergy Asthma Immunol. 2021 20 4 494 499 34418903
    [Google Scholar]
  225. Farnoosh G. Akbariqomi M. Badri T. Bagheri M. Izadi M. Saeedi-Boroujeni A. Rezaie E. Ghaleh H.E.G. Aghamollaei H. Fasihi-ramandi M. Hassanpour K. Alishiri G. Efficacy of a low dose of melatonin as an adjunctive therapy in hospitalized patients with COVID-19: a randomized, double-blind clinical trial. Arch. Med. Res. 2022 53 1 79 85 10.1016/j.arcmed.2021.06.006 34229896
    [Google Scholar]
  226. Hou W.C. Chen H.J. Lin Y.H. Antioxidant peptides with Angiotensin converting enzyme inhibitory activities and applications for Angiotensin converting enzyme purification. J. Agric. Food Chem. 2003 51 6 1706 1709 10.1021/jf0260242 12617609
    [Google Scholar]
  227. José HC Emilio LS Patricia FS Gustavo CF Carnosine and related peptides: therapeutic potential in age-related disorders. Aging Dis. 2015 6 5 369 379 10.14336/AD.2015.0616 26425391
    [Google Scholar]
  228. Wiczk A. Hofman D. Konopa G. Herman-Antosiewicz A. Sulforaphane, a cruciferous vegetable-derived isothiocyanate, inhibits protein synthesis in human prostate cancer cells. Biochim. Biophys. Acta Mol. Cell Res. 2012 1823 8 1295 1305 10.1016/j.bbamcr.2012.05.020 22640870
    [Google Scholar]
  229. Houghton C.A. Fassett R.G. Coombes J.S. Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician’s expectation be matched by the reality? Oxid. Med. Cell. Longev. 2016 2016 1 7857186 10.1155/2016/7857186 26881038
    [Google Scholar]
  230. Cuadrado A. Pajares M. Benito C. Jiménez-Villegas J. Escoll M. Fernández-Ginés R. Dinkova-Kostova A. T. Can activation of NRF2 be a strategy against COVID-19? Trends Pharmacol Sci. 2020 41 9 598 610 10.1016/j.tips.2020.07.003 32711925
    [Google Scholar]
  231. Markus M.A. Morris B.J. Resveratrol in prevention and treatment of common clinical conditions of aging. Clin. Interv. Aging 2008 3 2 331 339 18686754
    [Google Scholar]
  232. Bhullar K.S. Hubbard B.P. Lifespan and healthspan extension by resveratrol. Biochim. Biophys. Acta Mol. Basis Dis. 2015 1852 6 1209 1218 10.1016/j.bbadis.2015.01.012
    [Google Scholar]
  233. Ungvari Z. Bagi Z. Feher A. Recchia F.A. Sonntag W.E. Pearson K. de Cabo R. Csiszar A. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am. J. Physiol. Heart Circ. Physiol. 2010 299 1 H18 H24 10.1152/ajpheart.00260.2010 20418481
    [Google Scholar]
  234. Ghanim H. Sia C.L. Korzeniewski K. Lohano T. Abuaysheh S. Marumganti A. Chaudhuri A. Dandona P. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J. Clin. Endocrinol. Metab. 2011 96 5 1409 1414 10.1210/jc.2010‑1812 21289251
    [Google Scholar]
  235. Kode A. Rajendrasozhan S. Caito S. Yang S.R. Megson I.L. Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2008 294 3 L478 L488 10.1152/ajplung.00361.2007 18162601
    [Google Scholar]
  236. Floyd S. Favre C. Lasorsa F.M. Leahy M. Trigiante G. Stroebel P. Marx A. Loughran G. O’Callaghan K. Marobbio C.M.T. Slotboom D.J. Kunji E.R.S. Palmieri F. O’Connor R. The insulin-like growth factor-I-mTOR signaling pathway induces the mitochondrial pyrimidine nucleotide carrier to promote cell growth. Mol. Biol. Cell 2007 18 9 3545 3555 10.1091/mbc.e06‑12‑1109 17596519
    [Google Scholar]
  237. Tsang C.K. Qi H. Liu L.F. Zheng X.F.S. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov. Today 2007 12 3-4 112 124 10.1016/j.drudis.2006.12.008 17275731
    [Google Scholar]
  238. Sharp Z.D. Bartke A. Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J. Gerontol. A Biol. Sci. Med. Sci. 2005 60 3 293 300 10.1093/gerona/60.3.293 15860463
    [Google Scholar]
  239. Li J. Kim S.G. Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014 19 3 373 379 10.1016/j.cmet.2014.01.001 24508508
    [Google Scholar]
  240. Lamming D.W. Ye L. Sabatini D.M. Baur J.A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 2013 123 3 980 989 10.1172/JCI64099 23454761
    [Google Scholar]
  241. Longo V.D. Antebi A. Bartke A. Barzilai N. Brown-Borg H.M. Caruso C. Curiel T.J. Cabo R. Franceschi C. Gems D. Ingram D.K. Johnson T.E. Kennedy B.K. Kenyon C. Klein S. Kopchick J.J. Lepperdinger G. Madeo F. Mirisola M.G. Mitchell J.R. Passarino G. Rudolph K.L. Sedivy J.M. Shadel G.S. Sinclair D.A. Spindler S.R. Suh Y. Vijg J. Vinciguerra M. Fontana L. Interventions to slow aging in humans: are we ready? Aging Cell 2015 14 4 497 510 10.1111/acel.12338 25902704
    [Google Scholar]
  242. Coquillard C. Vilchez V. Marti F. Gedaly R. mTOR signaling in regulatory T cell differentiation and expansion. SOJ Immunol 2015 3 1 1 10
    [Google Scholar]
  243. Huang N. Perl A. Metabolism as a target for modulation in autoimmune diseases. Trends Immunol. 2018 39 7 562 576 10.1016/j.it.2018.04.006 29739666
    [Google Scholar]
  244. Wang R. Yu Z. Sunchu B. Shoaf J. Dang I. Zhao S. Caples K. Bradley L. Beaver L.M. Ho E. Löhr C.V. Perez V.I. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell 2017 16 3 564 574 10.1111/acel.12587 28371119
    [Google Scholar]
  245. Conti P. Ronconi G. Caraffa A. Gallenga C.E. Ross R. Frydas I. Kritas S.K. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J. Biol. Regul. Homeost. Agents 2020 34 2 327 331 32171193
    [Google Scholar]
  246. Jia X. Liu B. Bao L. Lv Q. Li F. Li H. An Y. Zhang X. Cao B. Wang C. Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration. PLoS Pathog. 2018 14 11 e1007428 10.1371/journal.ppat.1007428 30422993
    [Google Scholar]
  247. Wang C.H. Chung F.T. Lin S.M. Huang S.Y. Chou C.L. Lee K.Y. Lin T.Y. Kuo H.P. Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit. Care Med. 2014 42 2 313 321 10.1097/CCM.0b013e3182a2727d 24105455
    [Google Scholar]
  248. Yang M. Cell pyroptosis, a potential pathogenic mechanism of 2019-nCoV infection. SSRN 2020 10.2139/ssrn.3527420
    [Google Scholar]
  249. Zhou Y. Hou Y. Shen J. Huang Y. Martin W. Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020 6 1 14 10.1038/s41421‑020‑0153‑3 32194980
    [Google Scholar]
  250. Eisenberg T. Knauer H. Schauer A. Büttner S. Ruckenstuhl C. Carmona-Gutierrez D. Ring J. Schroeder S. Magnes C. Antonacci L. Fussi H. Deszcz L. Hartl R. Schraml E. Criollo A. Megalou E. Weiskopf D. Laun P. Heeren G. Breitenbach M. Grubeck-Loebenstein B. Herker E. Fahrenkrog B. Fröhlich K.U. Sinner F. Tavernarakis N. Minois N. Kroemer G. Madeo F. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 2009 11 11 1305 1314 10.1038/ncb1975 19801973
    [Google Scholar]
  251. Yang Y. Chen S. Zhang Y. Lin X. Song Y. Xue Z. Qian H. Wang S. Wan G. Zheng X. Zhang L. Induction of autophagy by spermidine is neuroprotective via inhibition of caspase 3-mediated Beclin 1 cleavage. Cell Death Dis. 2017 8 4 e2738 e2738 10.1038/cddis.2017.161 28383560
    [Google Scholar]
  252. Ha J. Kim J. Novel pharmacological modulators of autophagy: an updated patent review (2012-2015). Expert Opin. Ther. Pat. 2016 26 11 1273 1289 10.1080/13543776.2016.1217996 27476990
    [Google Scholar]
  253. Puleston D.J. Zhang H. Powell T.J. Lipina E. Sims S. Panse I. Watson A.S. Cerundolo V. Townsend A.R.M. Klenerman P. Simon A.K. Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 2014 3 e03706 10.7554/eLife.03706 25385531
    [Google Scholar]
  254. Sacitharan P.K. Lwin S. Gharios G.B. Edwards J.R. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300. Exp. Mol. Med. 2018 50 9 1 10 10.1038/s12276‑018‑0149‑3 30232322
    [Google Scholar]
  255. Shackelford D.B. Shaw R.J. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 2009 9 8 563 575 10.1038/nrc2676 19629071
    [Google Scholar]
  256. Stephenne X. Foretz M. Taleux N. van der Zon G.C. Sokal E. Hue L. Viollet B. Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 2011 54 12 3101 3110 10.1007/s00125‑011‑2311‑5 21947382
    [Google Scholar]
  257. Kalender A. Selvaraj A. Kim S.Y. Gulati P. Brûlé S. Viollet B. Kemp B.E. Bardeesy N. Dennis P. Schlager J.J. Marette A. Kozma S.C. Thomas G. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010 11 5 390 401 10.1016/j.cmet.2010.03.014 20444419
    [Google Scholar]
  258. Schultze S.M. Hemmings B.A. Niessen M. Tschopp O. PI3K/AKT, MAPK and AMPK signalling: protein kinases in glucose homeostasis. Expert Rev. Mol. Med. 2012 14 e1 10.1017/S1462399411002109 22233681
    [Google Scholar]
  259. Mannick J.B. Teo G. Bernardo P. Quinn D. Russell K. Klickstein L. Marshall W. Shergill S. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2021 2 5 e250 e262 10.1016/S2666‑7568(21)00062‑3 33977284
    [Google Scholar]
  260. Ventura-López C. Cervantes-Luevano K. Aguirre-Sánchez J.S. Flores-Caballero J.C. Alvarez-Delgado C. Bernaldez-Sarabia J. Sánchez-Campos N. Lugo-Sánchez L.A. Rodríguez-Vázquez I.C. Sander-Padilla J.G. Romero-Antonio Y. Arguedas-Núñez M.M. González-Canudas J. Licea-Navarro A.F. Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial. Biomed. Pharmacother. 2022 152 113223 10.1016/j.biopha.2022.113223 35709650
    [Google Scholar]
  261. Michan S. Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem. J. 2007 404 1 1 13 10.1042/BJ20070140 17447894
    [Google Scholar]
  262. Haigis M.C. Sinclair D.A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 2010 5 1 253 295 10.1146/annurev.pathol.4.110807.092250 20078221
    [Google Scholar]
  263. North B.J. Verdin E. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 2004 5 5 224 10.1186/gb‑2004‑5‑5‑224 15128440
    [Google Scholar]
  264. Alarcón de la Lastra C. Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. Mol. Nutr. Food Res. 2005 49 5 405 430 10.1002/mnfr.200500022 15832402
    [Google Scholar]
  265. Taguchi A. Wada-Hiraike O. Kawana K. Koga K. Yamashita A. Shirane A. Urata Y. Kozuma S. Osuga Y. Fujii T. Resveratrol suppresses inflammatory responses in endometrial stromal cells derived from endometriosis: A possible role of the sirtuin 1 pathway. J. Obstet. Gynaecol. Res. 2014 40 3 770 778 10.1111/jog.12252 24320086
    [Google Scholar]
  266. Milne J.C. Denu J.M. The Sirtuin family: therapeutic targets to treat diseases of aging. Curr. Opin. Chem. Biol. 2008 12 1 11 17 10.1016/j.cbpa.2008.01.019 18282481
    [Google Scholar]
  267. Alano C.C. Garnier P. Ying W. Higashi Y. Kauppinen T.M. Swanson R.A. NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J. Neurosci. 2010 30 8 2967 2978 10.1523/JNEUROSCI.5552‑09.2010 20181594
    [Google Scholar]
  268. Mao Z. Hine C. Tian X. Van Meter M. Au M. Vaidya A. Seluanov A. Gorbunova V. SIRT6 promotes DNA repair under stress by activating PARP1. Science 2011 332 6036 1443 1446 10.1126/science.1202723 21680843
    [Google Scholar]
  269. Giblin W. Skinner M.E. Lombard D.B. Sirtuins: guardians of mammalian healthspan. Trends Genet. 2014 30 7 271 286 10.1016/j.tig.2014.04.007 24877878
    [Google Scholar]
  270. Fatokun A.A. Dawson V.L. Dawson T.M. Parthanatos: mitochondrial‐linked mechanisms and therapeutic opportunities. Br. J. Pharmacol. 2014 171 8 2000 2016 10.1111/bph.12416 24684389
    [Google Scholar]
  271. Cantó C. Houtkooper R.H. Pirinen E. Youn D.Y. Oosterveer M.H. Cen Y. Fernandez-Marcos P.J. Yamamoto H. Andreux P.A. Cettour-Rose P. Gademann K. Rinsch C. Schoonjans K. Sauve A.A. Auwerx J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 15 6 838 847 10.1016/j.cmet.2012.04.022 22682224
    [Google Scholar]
  272. Trammell S.A.J. Schmidt M.S. Weidemann B.J. Redpath P. Jaksch F. Dellinger R.W. Li Z. Abel E.D. Migaud M.E. Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun. 2016 7 1 12948 10.1038/ncomms12948 27721479
    [Google Scholar]
  273. Curtin N. Bányai K. Thaventhiran J. Le Quesne J. Helyes Z. Bai P. Repositioning PARP inhibitors for SARS‐CoV‐2 infection(COVID‐19); a new multi‐pronged therapy for acute respiratory distress syndrome? Br. J. Pharmacol. 2020 177 16 3635 3645 10.1111/bph.15137 32441764
    [Google Scholar]
  274. Ge Y. Tian T. Huang S. Wan F. Li J. Li S. A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19. BioRxiv 2020 10.1101/2020.03.11.986836
    [Google Scholar]
  275. Wheaton W. W. Weinberg S. E. Hamanaka R. B. Soberanes S. Sullivan L. B. Anso E. Chandel N. S. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 2014 3 e02242 10.7554/eLife.02242 24843020
    [Google Scholar]
  276. An H. He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol. 2016 228 3 R97 R106 10.1530/JOE‑15‑0447 26743209
    [Google Scholar]
  277. Sharma S. Ray A. Sadasivam B. Metformin in COVID-19: A possible role beyond diabetes. Diabetes Res. Clin. Pract. 2020 164 108183 10.1016/j.diabres.2020.108183 32360697
    [Google Scholar]
  278. Elhassan Y.S. Philp A.A. Lavery G.G. Targeting NAD+ in metabolic disease: new insights into an old molecule. J. Endocr. Soc. 2017 1 7 816 835 10.1210/js.2017‑00092 29264533
    [Google Scholar]
  279. Cuyàs E. Verdura S. Llorach-Parés L. Fernández-Arroyo S. Joven J. Martin-Castillo B. Bosch-Barrera J. Brunet J. Nonell-Canals A. Sanchez-Martinez M. Menendez J.A. Metformin is a direct SIRT1-activating compound: computational modeling and experimental validation. Front. Endocrinol. (Lausanne) 2018 9 657 10.3389/fendo.2018.00657 30459716
    [Google Scholar]
  280. Zilfou J.T. Lowe S.W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol. 2009 1 5 a001883 10.1101/cshperspect.a001883 20066118
    [Google Scholar]
  281. Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med. 2016 6 3 a026104 10.1101/cshperspect.a026104 26931810
    [Google Scholar]
  282. Puzio-Kuter A.M. The role of p53 in metabolic regulation. Genes Cancer 2011 2 4 385 391 10.1177/1947601911409738 21779507
    [Google Scholar]
  283. Zia A. Pourbagher-Shahri A.M. Farkhondeh T. Samarghandian S. Molecular and cellular pathways contributing to brain aging. Behav. Brain Funct. 2021 17 1 6 10.1186/s12993‑021‑00179‑9 34118939
    [Google Scholar]
  284. Freund A. Patil C.K. Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011 30 8 1536 1548 10.1038/emboj.2011.69 21399611
    [Google Scholar]
  285. Luftig M.A. Viruses and the DNA damage response: activation and antagonism. Annu. Rev. Virol. 2014 1 1 605 625 10.1146/annurev‑virology‑031413‑085548 26958736
    [Google Scholar]
  286. Lindner H.A. Fotouhi-Ardakani N. Lytvyn V. Lachance P. Sulea T. Ménard R. The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J. Virol. 2005 79 24 15199 15208 10.1128/JVI.79.24.15199‑15208.2005 16306591
    [Google Scholar]
  287. Yuan L. Chen Z. Song S. Wang S. Tian C. Xing G. Chen X. Xiao Z.X. He F. Zhang L. p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling. J. Biol. Chem. 2015 290 5 3172 3182 10.1074/jbc.M114.619890 25505178
    [Google Scholar]
  288. Yuan X. Yao Z. Wu J. Zhou Y. Shan Y. Dong B. Zhao Z. Hua P. Chen J. Cong Y. G1 phase cell cycle arrest induced by SARS-CoV 3a protein via the cyclin D3/pRb pathway. Am. J. Respir. Cell Mol. Biol. 2007 37 1 9 19 10.1165/rcmb.2005‑0345RC 17413032
    [Google Scholar]
  289. Surjit M. Liu B. Chow V.T.K. Lal S.K. The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells. J. Biol. Chem. 2006 281 16 10669 10681 10.1074/jbc.M509233200 16431923
    [Google Scholar]
  290. Tan Y.X. Tan T.H.P. Lee M.J.R. Tham P.Y. Gunalan V. Druce J. Birch C. Catton M. Fu N.Y. Yu V.C. Tan Y.J. Induction of apoptosis by the severe acute respiratory syndrome coronavirus 7a protein is dependent on its interaction with the Bcl-XL protein. J. Virol. 2007 81 12 6346 6355 10.1128/JVI.00090‑07 17428862
    [Google Scholar]
  291. Tan Y.J. Lim S.G. Hong W. Regulation of cell death during infection by the severe acute respiratory syndrome coronavirus and other coronaviruses. Cell. Microbiol. 2007 9 11 2552 2561 10.1111/j.1462‑5822.2007.01034.x 17714515
    [Google Scholar]
  292. Lim Y. Ng Y. Tam J. Liu D. Human coronaviruses: a review of virus–host interactions. Diseases 2016 4 3 26 10.3390/diseases4030026 28933406
    [Google Scholar]
  293. Chen J. Jiang Q. Xia X. Liu K. Yu Z. Tao W. Gong W. Han J.D.J. Individual variation of the SARS‐CoV‐2 receptor ACE2 gene expression and regulation. Aging Cell 2020 19 7 e13168 10.1111/acel.13168 32558150
    [Google Scholar]
  294. Gheblawi M. Wang K. Viveiros A. Nguyen Q. Zhong J.C. Turner A.J. Raizada M.K. Grant M.B. Oudit G.Y. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ. Res. 2020 126 10 1456 1474 10.1161/CIRCRESAHA.120.317015 32264791
    [Google Scholar]
  295. South A.M. Brady T.M. Flynn J.T. ACE2 (angiotensin-converting enzyme 2), COVID-19, and ACE inhibitor and Ang II (Angiotensin II) receptor blocker use during the pandemic: the pediatric perspective. Hypertension 2020 76 1 16 22 10.1161/HYPERTENSIONAHA.120.15291 32367746
    [Google Scholar]
  296. Patel A.B. Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA 2020 323 18 1769 1770 10.1001/jama.2020.4812 32208485
    [Google Scholar]
  297. Xiang Z. Liu J. Shi D. Chen W. Li J. Yan R. Bi Y. Hu W. Zhu Z. Yu Y. Yang Z. Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels. Int. J. Biol. Sci. 2020 16 13 2382 2391 10.7150/ijbs.47652 32760206
    [Google Scholar]
  298. da Silva Oliveira G.L. de Freitas R.M. Diminazene aceturate—An antiparasitic drug of antiquity: Advances in pharmacology & therapeutics. Pharmacol. Res. 2015 102 138 157 10.1016/j.phrs.2015.10.005 26470648
    [Google Scholar]
  299. Velkoska E. Patel S.K. Burrell L.M. Angiotensin converting enzyme 2 and diminazene. Curr. Opin. Nephrol. Hypertens. 2016 25 5 384 395 10.1097/MNH.0000000000000254 27367913
    [Google Scholar]
  300. Prata L.O. Rodrigues C.R. Martins J.M. Vasconcelos P.C. Oliveira F.M.S. Ferreira A.J. Rodrigues-Machado M.G. Caliari M.V. Original Research: ACE2 activator associated with physical exercise potentiates the reduction of pulmonary fibrosis. Exp. Biol. Med. (Maywood) 2017 242 1 8 21 10.1177/1535370216665174 27550926
    [Google Scholar]
  301. Qaradakhi T. Gadanec L.K. McSweeney K.R. Tacey A. Apostolopoulos V. Levinger I. Rimarova K. Egom E.E. Rodrigo L. Kruzliak P. Kubatka P. Zulli A. The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases. Clin. Exp. Pharmacol. Physiol. 2020 47 5 751 758 10.1111/1440‑1681.13251 31901211
    [Google Scholar]
  302. de Simone G. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. Eur Soc Cardiol. 2020 13
    [Google Scholar]
  303. Bozkurt B. Kovacs R. Harrington B. Joint HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. J. Card. Fail. 2020 26 5 370 10.1016/j.cardfail.2020.04.013 32439095
    [Google Scholar]
  304. Trifirò G. Crisafulli S. Andò G. Racagni G. Drago F. Should patients receiving ACE Inhibitors or angiotensin receptor blockers be switched to other antihypertensive drugs to prevent or improve prognosis of novel coronavirus disease 2019 (COVID-19)? Drug Saf 2020 43 6 507 509 10.1007/s40264‑020‑00935‑2 32303915
    [Google Scholar]
  305. Khan A. Benthin C. Zeno B. Albertson T.E. Boyd J. Christie J.D. Hall R. Poirier G. Ronco J.J. Tidswell M. Hardes K. Powley W.M. Wright T.J. Siederer S.K. Fairman D.A. Lipson D.A. Bayliffe A.I. Lazaar A.L. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit. Care 2017 21 1 234 10.1186/s13054‑017‑1823‑x 28877748
    [Google Scholar]
  306. Alexandre J. Cracowski J.L. Richard V. Bouhanick B. ‘Drugs, COVID-19’ working group of the French Society of Pharmacology, Therapeutics Renin-angiotensin-aldosterone system and COVID-19 infection. Ann. Endocrinol. (Paris) 2020 81 2-3 63 67 10.1016/j.ando.2020.04.005 32370986
    [Google Scholar]
  307. Monteil V. Kwon H. Prado P. Hagelkrüys A. Wimmer R.A. Stahl M. Leopoldi A. Garreta E. Hurtado del Pozo C. Prosper F. Romero J.P. Wirnsberger G. Zhang H. Slutsky A.S. Conder R. Montserrat N. Mirazimi A. Penninger J.M. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020 181 4 905 913.e7 10.1016/j.cell.2020.04.004 32333836
    [Google Scholar]
  308. Imbert I. Snijder E.J. Dimitrova M. Guillemot J.C. Lécine P. Canard B. The SARS-Coronavirus PLnc domain of nsp3 as a replication/transcription scaffolding protein. Virus Res. 2008 133 2 136 148 10.1016/j.virusres.2007.11.017 18255185
    [Google Scholar]
  309. van Hemert M.J. van den Worm S.H.E. Knoops K. Mommaas A.M. Gorbalenya A.E. Snijder E.J. SARS-coronavirus replication/transcription complexes are membrane-protected and need a host factor for activity in vitro. PLoS Pathog. 2008 4 5 e1000054 10.1371/journal.ppat.1000054 18451981
    [Google Scholar]
  310. Hillen H.S. Kokic G. Farnung L. Dienemann C. Tegunov D. Cramer P. Structure of replicating SARS-CoV-2 polymerase. Nature 2020 584 7819 154 156 10.1038/s41586‑020‑2368‑8 32438371
    [Google Scholar]
  311. Gao Y. Yan L. Huang Y. Liu F. Zhao Y. Cao L. Wang T. Sun Q. Ming Z. Zhang L. Ge J. Zheng L. Zhang Y. Wang H. Zhu Y. Zhu C. Hu T. Hua T. Zhang B. Yang X. Li J. Yang H. Liu Z. Xu W. Guddat L.W. Wang Q. Lou Z. Rao Z. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 2020 368 6492 779 782 10.1126/science.abb7498 32277040
    [Google Scholar]
  312. Kuzuhara T. Iwai Y. Takahashi H. Hatakeyama D. Echigo N. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase. PLoS Curr. 2009 1 RRN1052 10.1371/currents.RRN1052 20025206
    [Google Scholar]
  313. Chacko S.M. Thambi P.T. Kuttan R. Nishigaki I. Beneficial effects of green tea: A literature review. Chin. Med. 2010 5 1 13 10.1186/1749‑8546‑5‑13 20370896
    [Google Scholar]
  314. Lin Y.T. Wu Y.H. Tseng C.K. Lin C.K. Chen W.C. Hsu Y.C. Lee J.C. Green tea phenolic epicatechins inhibit hepatitis C virus replication via cycloxygenase-2 and attenuate virus-induced inflammation. PLoS One 2013 8 1 e54466 10.1371/journal.pone.0054466 23365670
    [Google Scholar]
  315. Cantatore A. Randall S.D. Traum D. Adams S.D. Effect of black tea extract on herpes simplex virus-1 infection of cultured cells. BMC Complement. Altern. Med. 2013 13 1 139 10.1186/1472‑6882‑13‑139 23777309
    [Google Scholar]
  316. Chowdhury P. Sahuc M.E. Rouillé Y. Rivière C. Bonneau N. Vandeputte A. Brodin P. Goswami M. Bandyopadhyay T. Dubuisson J. Séron K. Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus in cell culture. PLoS One 2018 13 11 e0198226 10.1371/journal.pone.0198226 30485282
    [Google Scholar]
  317. Jeon S. Ko M. Lee J. Choi I. Byun S.Y. Park S. Shum D. Kim S. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob. Agents Chemother. 2020 64 7 e00819-20 10.1128/AAC.00819‑20 32366720
    [Google Scholar]
  318. Şi̇mşek Yavuz S. Ünal S. Antiviral treatment of COVID-19. Turk. J. Med. Sci. 2020 50 SI-1 611 619 10.3906/sag‑2004‑145 32293834
    [Google Scholar]
  319. Mauthe M. Orhon I. Rocchi C. Zhou X. Luhr M. Hijlkema K.J. Coppes R.P. Engedal N. Mari M. Reggiori F. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 2018 14 8 1435 1455 10.1080/15548627.2018.1474314 29940786
    [Google Scholar]
  320. Al-Bari M.A.A. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 2017 5 1 e00293 10.1002/prp2.293 28596841
    [Google Scholar]
  321. García L.F. Immune response, inflammation, and the clinical spectrum of COVID-19. Front. Immunol. 2020 11 1441 10.3389/fimmu.2020.01441 32612615
    [Google Scholar]
  322. Shi Y. Wang Y. Shao C. Huang J. Gan J. Huang X. Melino G. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020 27 5 1451 1454 10.1038/s41418‑020‑0530‑3 32205856
    [Google Scholar]
  323. Chen C.F. Chien C.H. Yang Y.P. Chou S.J. Wang M.L. Huo T.I. Lin C.C. Role of dipeptidyl peptidase-4 inhibitors in patients with diabetes infected with coronavirus-19. J. Chin. Med. Assoc. 2020 83 8 710 711 10.1097/JCMA.0000000000000338 32349031
    [Google Scholar]
  324. Kawasaki T. Chen W. Htwe Y.M. Tatsumi K. Dudek S.M. DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 2018 315 5 L834 L845 10.1152/ajplung.00031.2018 30188745
    [Google Scholar]
  325. Birnbaum Y. Bajaj M. Qian J. Ye Y. Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome. BMJ Open Diabetes Res. Care 2016 4 1 e000227 10.1136/bmjdrc‑2016‑000227 27547413
    [Google Scholar]
  326. Berger J.P. SinhaRoy R. Pocai A. Kelly T.M. Scapin G. Gao Y.D. Pryor K.A.D. Wu J.K. Eiermann G.J. Xu S.S. Zhang X. Tatosian D.A. Weber A.E. Thornberry N.A. Carr R.D. A comparative study of the binding properties, dipeptidyl peptidase‐4 ( DPP ‐4) inhibitory activity and glucose‐lowering efficacy of the DPP ‐4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice. Endocrinol. Diabetes Metab. 2018 1 1 e00002 10.1002/edm2.2 30815539
    [Google Scholar]
  327. Tang S. Ma W. Bai P. A novel dynamic model describing the spread of the MERS-CoV and the expression of dipeptidyl peptidase 4. Comput. Math. Methods Med. 2017 2017 1 6 10.1155/2017/5285810 28894474
    [Google Scholar]
  328. Iacobellis G. COVID-19 and diabetes: Can DPP4 inhibition play a role? Diabetes Res. Clin. Pract. 2020 162 108125 10.1016/j.diabres.2020.108125 32224164
    [Google Scholar]
  329. Lurie N. Sharfstein J.M. Goodman J.L. The development of COVID-19 vaccines: safeguards needed. JAMA 2020 324 5 439 440 10.1001/jama.2020.12461 32749496
    [Google Scholar]
  330. Thanh Le T. Andreadakis Z. Kumar A. Gómez Román R. Tollefsen S. Saville M. Mayhew S. The COVID-19 vaccine development landscape. Nat. Rev. Drug Discov. 2020 19 5 305 306 10.1038/d41573‑020‑00073‑5 32273591
    [Google Scholar]
  331. Ulmer J.B. Valley U. Rappuoli R. Vaccine manufacturing: challenges and solutions. Nat. Biotechnol. 2006 24 11 1377 1383 10.1038/nbt1261 17093488
    [Google Scholar]
  332. Nascimento I.P. Leite L.C.C. Recombinant vaccines and the development of new vaccine strategies. Braz. J. Med. Biol. Res. 2012 45 12 1102 1111 10.1590/S0100‑879X2012007500142 22948379
    [Google Scholar]
  333. Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Li P. Koury K. Kalina W. Cooper D. Fontes-Garfias C. Shi P.Y. Türeci Ö. Tompkins K.R. Walsh E.E. Frenck R. Falsey A.R. Dormitzer P.R. Gruber W.C. Şahin U. Jansen K.U. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020 586 7830 589 593 10.1038/s41586‑020‑2639‑4 32785213
    [Google Scholar]
  334. Dooling K. McClung N. Chamberland M. Marin M. Wallace M. Bell B.P. Lee G.M. Talbot H.K. Romero J.R. Oliver S.E. The Advisory Committee on Immunization Practices’ Interim Recommendation for Allocating Initial Supplies of COVID-19 Vaccine — United States, 2020. MMWR Morb. Mortal. Wkly. Rep. 2020 69 49 1857 1859 10.15585/mmwr.mm6949e1 33301429
    [Google Scholar]
  335. Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Pérez Marc G. Moreira E.D. Zerbini C. Bailey R. Swanson K.A. Roychoudhury S. Koury K. Li P. Kalina W.V. Cooper D. Frenck R.W. Jr Hammitt L.L. Türeci Ö. Nell H. Schaefer A. Ünal S. Tresnan D.B. Mather S. Dormitzer P.R. Şahin U. Jansen K.U. Gruber W.C. C4591001 Clinical Trial Group Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 2020 383 27 2603 2615 10.1056/NEJMoa2034577 33301246
    [Google Scholar]
  336. Walsh E.E. Frenck R.W. Jr Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Swanson K.A. Li P. Koury K. Kalina W. Cooper D. Fontes-Garfias C. Shi P.Y. Türeci Ö. Tompkins K.R. Lyke K.E. Raabe V. Dormitzer P.R. Jansen K.U. Şahin U. Gruber W.C. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N. Engl. J. Med. 2020 383 25 2439 2450 10.1056/NEJMoa2027906 33053279
    [Google Scholar]
  337. Pfizer-BioNTech COVID-19 Vaccine Emergency Use Authorization. Silver Spring, MD: US Department of Health and Human Services. Food and Drug Administration 2020
    [Google Scholar]
  338. Jackson L. A. Anderson E. J. Rouphael N. G. Roberts P. C. Makhene M. Coler R. N. Beigel J. H. An mRNA vaccine against SARS-CoV-2 — preliminary report. N Engl J Med 2020 383 20 1920 1931 10.1056/NEJMoa2022483
    [Google Scholar]
  339. Oliver S.E. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Moderna COVID-19 Vaccine—United States, December 2020. MMWR Morb. Mortal. Wkly. Rep. 2020 ••• 69 33382675
    [Google Scholar]
  340. Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2020 33378609
    [Google Scholar]
  341. Folegatti P.M. Ewer K.J. Aley P.K. Angus B. Becker S. Belij-Rammerstorfer S. Bellamy D. Bibi S. Bittaye M. Clutterbuck E.A. Dold C. Faust S.N. Finn A. Flaxman A.L. Hallis B. Heath P. Jenkin D. Lazarus R. Makinson R. Minassian A.M. Pollock K.M. Ramasamy M. Robinson H. Snape M. Tarrant R. Voysey M. Green C. Douglas A.D. Hill A.V.S. Lambe T. Gilbert S.C. Pollard A.J. Aboagye J. Adams K. Ali A. Allen E. Allison J.L. Anslow R. Arbe-Barnes E.H. Babbage G. Baillie K. Baker M. Baker N. Baker P. Baleanu I. Ballaminut J. Barnes E. Barrett J. Bates L. Batten A. Beadon K. Beckley R. Berrie E. Berry L. Beveridge A. Bewley K.R. Bijker E.M. Bingham T. Blackwell L. Blundell C.L. Bolam E. Boland E. Borthwick N. Bower T. Boyd A. Brenner T. Bright P.D. Brown-O’Sullivan C. Brunt E. Burbage J. Burge S. Buttigieg K.R. Byard N. Cabera Puig I. Calvert A. Camara S. Cao M. Cappuccini F. Carr M. Carroll M.W. Carter V. Cathie K. Challis R.J. Charlton S. Chelysheva I. Cho J-S. Cicconi P. Cifuentes L. Clark H. Clark E. Cole T. Colin-Jones R. Conlon C.P. Cook A. Coombes N.S. Cooper R. Cosgrove C.A. Coy K. Crocker W.E.M. Cunningham C.J. Damratoski B.E. Dando L. Datoo M.S. Davies H. De Graaf H. Demissie T. Di Maso C. Dietrich I. Dong T. Donnellan F.R. Douglas N. Downing C. Drake J. Drake-Brockman R. Drury R.E. Dunachie S.J. Edwards N.J. Edwards F.D.L. Edwards C.J. Elias S.C. Elmore M.J. Emary K.R.W. English M.R. Fagerbrink S. Felle S. Feng S. Field S. Fixmer C. Fletcher C. Ford K.J. Fowler J. Fox P. Francis E. Frater J. Furze J. Fuskova M. Galiza E. Gbesemete D. Gilbride C. Godwin K. Gorini G. Goulston L. Grabau C. Gracie L. Gray Z. Guthrie L.B. Hackett M. Halwe S. Hamilton E. Hamlyn J. Hanumunthadu B. Harding I. Harris S.A. Harris A. Harrison D. Harrison C. Hart T.C. Haskell L. Hawkins S. Head I. Henry J.A. Hill J. Hodgson S.H.C. Hou M.M. Howe E. Howell N. Hutlin C. Ikram S. Isitt C. Iveson P. Jackson S. Jackson F. James S.W. Jenkins M. Jones E. Jones K. Jones C.E. Jones B. Kailath R. Karampatsas K. Keen J. Kelly S. Kelly D. Kerr D. Kerridge S. Khan L. Khan U. Killen A. Kinch J. King T.B. King L. King J. Kingham-Page L. Klenerman P. Knapper F. Knight J.C. Knott D. Koleva S. Kupke A. Larkworthy C.W. Larwood J.P.J. Laskey A. Lawrie A.M. Lee A. Ngan Lee K.Y. Lees E.A. Legge H. Lelliott A. Lemm N-M. Lias A.M. Linder A. Lipworth S. Liu X. Liu S. Lopez Ramon R. Lwin M. Mabesa F. Madhavan M. Mallett G. Mansatta K. Marcal I. Marinou S. Marlow E. Marshall J.L. Martin J. McEwan J. McInroy L. Meddaugh G. Mentzer A.J. Mirtorabi N. Moore M. Moran E. Morey E. Morgan V. Morris S.J. Morrison H. Morshead G. Morter R. Mujadidi Y.F. Muller J. Munera-Huertas T. Munro C. Munro A. Murphy S. Munster V.J. Mweu P. Noé A. Nugent F.L. Nuthall E. O’Brien K. O’Connor D. Oguti B. Oliver J.L. Oliveira C. O’Reilly P.J. Osborn M. Osborne P. Owen C. Owens D. Owino N. Pacurar M. Parker K. Parracho H. Patrick-Smith M. Payne V. Pearce J. Peng Y. Peralta Alvarez M.P. Perring J. Pfafferott K. Pipini D. Plested E. Pluess-Hall H. Pollock K. Poulton I. Presland L. Provstgaard-Morys S. Pulido D. Radia K. Ramos Lopez F. Rand J. Ratcliffe H. Rawlinson T. Rhead S. Riddell A. Ritchie A.J. Roberts H. Robson J. Roche S. Rohde C. Rollier C.S. Romani R. Rudiansyah I. Saich S. Sajjad S. Salvador S. Sanchez Riera L. Sanders H. Sanders K. Sapaun S. Sayce C. Schofield E. Screaton G. Selby B. Semple C. Sharpe H.R. Shaik I. Shea A. Shelton H. Silk S. Silva-Reyes L. Skelly D.T. Smee H. Smith C.C. Smith D.J. Song R. Spencer A.J. Stafford E. Steele A. Stefanova E. Stockdale L. Szigeti A. Tahiri-Alaoui A. Tait M. Talbot H. Tanner R. Taylor I.J. Taylor V. Te Water Naude R. Thakur N. Themistocleous Y. Themistocleous A. Thomas M. Thomas T.M. Thompson A. Thomson-Hill S. Tomlins J. Tonks S. Towner J. Tran N. Tree J.A. Truby A. Turkentine K. Turner C. Turner N. Turner S. Tuthill T. Ulaszewska M. Varughese R. Van Doremalen N. Veighey K. Verheul M.K. Vichos I. Vitale E. Walker L. Watson M.E.E. Welham B. Wheat J. White C. White R. Worth A.T. Wright D. Wright S. Yao X.L. Yau Y. Oxford COVID Vaccine Trial Group Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020 396 10249 467 478 10.1016/S0140‑6736(20)31604‑4 32702298
    [Google Scholar]
  342. Voysey M. Clemens S.A.C. Madhi S.A. Weckx L.Y. Folegatti P.M. Aley P.K. Angus B. Baillie V.L. Barnabas S.L. Bhorat Q.E. Bibi S. Briner C. Cicconi P. Collins A.M. Colin-Jones R. Cutland C.L. Darton T.C. Dheda K. Duncan C.J.A. Emary K.R.W. Ewer K.J. Fairlie L. Faust S.N. Feng S. Ferreira D.M. Finn A. Goodman A.L. Green C.M. Green C.A. Heath P.T. Hill C. Hill H. Hirsch I. Hodgson S.H.C. Izu A. Jackson S. Jenkin D. Joe C.C.D. Kerridge S. Koen A. Kwatra G. Lazarus R. Lawrie A.M. Lelliott A. Libri V. Lillie P.J. Mallory R. Mendes A.V.A. Milan E.P. Minassian A.M. McGregor A. Morrison H. Mujadidi Y.F. Nana A. O’Reilly P.J. Padayachee S.D. Pittella A. Plested E. Pollock K.M. Ramasamy M.N. Rhead S. Schwarzbold A.V. Singh N. Smith A. Song R. Snape M.D. Sprinz E. Sutherland R.K. Tarrant R. Thomson E.C. Török M.E. Toshner M. Turner D.P.J. Vekemans J. Villafana T.L. Watson M.E.E. Williams C.J. Douglas A.D. Hill A.V.S. Lambe T. Gilbert S.C. Pollard A.J. Aban M. Abayomi F. Abeyskera K. Aboagye J. Adam M. Adams K. Adamson J. Adelaja Y.A. Adewetan G. Adlou S. Ahmed K. Akhalwaya Y. Akhalwaya S. Alcock A. Ali A. Allen E.R. Allen L. Almeida T.C.D.S.C. Alves M.P.S. Amorim F. Andritsou F. Anslow R. Appleby M. Arbe-Barnes E.H. Ariaans M.P. Arns B. Arruda L. Azi P. Azi L. Babbage G. Bailey C. Baker K.F. Baker M. Baker N. Baker P. Baldwin L. Baleanu I. Bandeira D. Bara A. Barbosa M.A.S. Barker D. Barlow G.D. Barnes E. Barr A.S. Barrett J.R. Barrett J. Bates L. Batten A. Beadon K. Beales E. Beckley R. Belij-Rammerstorfer S. Bell J. Bellamy D. Bellei N. Belton S. Berg A. Bermejo L. Berrie E. Berry L. Berzenyi D. Beveridge A. Bewley K.R. Bexhell H. Bhikha S. Bhorat A.E. Bhorat Z.E. Bijker E. Birch G. Birch S. Bird A. Bird O. Bisnauthsing K. Bittaye M. Blackstone K. Blackwell L. Bletchly H. Blundell C.L. Blundell S.R. Bodalia P. Boettger B.C. Bolam E. Boland E. Bormans D. Borthwick N. Bowring F. Boyd A. Bradley P. Brenner T. Brown P. Brown C. Brown-O’Sullivan C. Bruce S. Brunt E. Buchan R. Budd W. Bulbulia Y.A. Bull M. Burbage J. Burhan H. Burn A. Buttigieg K.R. Byard N. Cabera Puig I. Calderon G. Calvert A. Camara S. Cao M. Cappuccini F. Cardoso J.R. Carr M. Carroll M.W. Carson-Stevens A. Carvalho Y.M. Carvalho J.A.M. Casey H.R. Cashen P. Castro T. Castro L.C. Cathie K. Cavey A. Cerbino-Neto J. Chadwick J. Chapman D. Charlton S. Chelysheva I. Chester O. Chita S. Cho J-S. Cifuentes L. Clark E. Clark M. Clarke A. Clutterbuck E.A. Collins S.L.K. Conlon C.P. Connarty S. Coombes N. Cooper C. Cooper R. Cornelissen L. Corrah T. Cosgrove C. Cox T. Crocker W.E.M. Crosbie S. Cullen L. Cullen D. Cunha D.R.M.F. Cunningham C. Cuthbertson F.C. Da Guarda S.N.F. da Silva L.P. Damratoski B.E. Danos Z. Dantas M.T.D.C. Darroch P. Datoo M.S. Datta C. Davids M. Davies S.L. Davies H. Davis E. Davis J. Davis J. De Nobrega M.M.D. De Oliveira Kalid L.M. Dearlove D. Demissie T. Desai A. Di Marco S. Di Maso C. Dinelli M.I.S. Dinesh T. Docksey C. Dold C. Dong T. Donnellan F.R. Dos Santos T. dos Santos T.G. Dos Santos E.P. Douglas N. Downing C. Drake J. Drake-Brockman R. Driver K. Drury R. Dunachie S.J. Durham B.S. Dutra L. Easom N.J.W. van Eck S. Edwards M. Edwards N.J. El Muhanna O.M. Elias S.C. Elmore M. English M. Esmail A. Essack Y.M. Farmer E. Farooq M. Farrar M. Farrugia L. Faulkner B. Fedosyuk S. Felle S. Feng S. Ferreira Da Silva C. Field S. Fisher R. Flaxman A. Fletcher J. Fofie H. Fok H. Ford K.J. Fowler J. Fraiman P.H.A. Francis E. Franco M.M. Frater J. Freire M.S.M. Fry S.H. Fudge S. Furze J. Fuskova M. Galian-Rubio P. Galiza E. Garlant H. Gavrila M. Geddes A. Gibbons K.A. Gilbride C. Gill H. Glynn S. Godwin K. Gokani K. Goldoni U.C. Goncalves M. Gonzalez I.G.S. Goodwin J. Goondiwala A. Gordon-Quayle K. Gorini G. Grab J. Gracie L. Greenland M. Greenwood N. Greffrath J. Groenewald M.M. Grossi L. Gupta G. Hackett M. Hallis B. Hamaluba M. Hamilton E. Hamlyn J. Hammersley D. Hanrath A.T. Hanumunthadu B. Harris S.A. Harris C. Harris T. Harrison T.D. Harrison D. Hart T.C. Hartnell B. Hassan S. Haughney J. Hawkins S. Hay J. Head I. Henry J. Hermosin Herrera M. Hettle D.B. Hill J. Hodges G. Horne E. Hou M.M. Houlihan C. Howe E. Howell N. Humphreys J. Humphries H.E. Hurley K. Huson C. Hyder-Wright A. Hyams C. Ikram S. Ishwarbhai A. Ivan M. Iveson P. Iyer V. Jackson F. De Jager J. Jaumdally S. Jeffers H. Jesudason N. Jones B. Jones K. Jones E. Jones C. Jorge M.R. Jose A. Joshi A. Júnior E.A.M.S. Kadziola J. Kailath R. Kana F. Karampatsas K. Kasanyinga M. Keen J. Kelly E.J. Kelly D.M. Kelly D. Kelly S. Kerr D. Kfouri R.Á. Khan L. Khozoee B. Kidd S. Killen A. Kinch J. Kinch P. King L.D.W. King T.B. Kingham L. Klenerman P. Knapper F. Knight J.C. Knott D. Koleva S. Lang M. Lang G. Larkworthy C.W. Larwood J.P.J. Law R. Lazarus E.M. Leach A. Lees E.A. Lemm N-M. Lessa A. Leung S. Li Y. Lias A.M. Liatsikos K. Linder A. Lipworth S. Liu S. Liu X. Lloyd A. Lloyd S. Loew L. Lopez Ramon R. Lora L. Lowthorpe V. Luz K. MacDonald J.C. MacGregor G. Madhavan M. Mainwaring D.O. Makambwa E. Makinson R. Malahleha M. Malamatsho R. Mallett G. Mansatta K. Maoko T. Mapetla K. Marchevsky N.G. Marinou S. Marlow E. Marques G.N. Marriott P. Marshall R.P. Marshall J.L. Martins F.J. Masenya M. Masilela M. Masters S.K. Mathew M. Matlebjane H. Matshidiso K. Mazur O. Mazzella A. McCaughan H. McEwan J. McGlashan J. McInroy L. McIntyre Z. McLenaghan D. McRobert N. McSwiggan S. Megson C. Mehdipour S. Meijs W. Mendonça R.N.Á. Mentzer A.J. Mirtorabi N. Mitton C. Mnyakeni S. Moghaddas F. Molapo K. Moloi M. Moore M. Moraes-Pinto M.I. Moran M. Morey E. Morgans R. Morris S. Morris S. Morris H.C. Morselli F. Morshead G. Morter R. Mottal L. Moultrie A. Moya N. Mpelembue M. Msomi S. Mugodi Y. Mukhopadhyay E. Muller J. Munro A. Munro C. Murphy S. Mweu P. Myasaki C.H. Naik G. Naker K. Nastouli E. Nazir A. Ndlovu B. Neffa F. Njenga C. Noal H. Noé A. Novaes G. Nugent F.L. Nunes G. O’Brien K. O’Connor D. Odam M. Oelofse S. Oguti B. Olchawski V. Oldfield N.J. Oliveira M.G. Oliveira C. Oosthuizen A. O’Reilly P. Osborne P. Owen D.R.J. Owen L. Owens D. Owino N. Pacurar M. Paiva B.V.B. Palhares E.M.F. Palmer S. Parkinson S. Parracho H.M.R.T. Parsons K. Patel D. Patel B. Patel F. Patel K. Patrick-Smith M. Payne R.O. Peng Y. Penn E.J. Pennington A. Peralta Alvarez M.P. Perring J. Perry N. Perumal R. Petkar S. Philip T. Phillips D.J. Phillips J. Phohu M.K. Pickup L. Pieterse S. Piper J. Pipini D. Plank M. Du Plessis J. Pollard S. Pooley J. Pooran A. Poulton I. Powers C. Presa F.B. Price D.A. Price V. Primeira M. Proud P.C. Provstgaard-Morys S. Pueschel S. Pulido D. Quaid S. Rabara R. Radford A. Radia K. Rajapaska D. Rajeswaran T. Ramos A.S.F. Ramos Lopez F. Rampling T. Rand J. Ratcliffe H. Rawlinson T. Rea D. Rees B. Reiné J. Resuello-Dauti M. Reyes Pabon E. Ribiero C.M. Ricamara M. Richter A. Ritchie N. Ritchie A.J. Robbins A.J. Roberts H. Robinson R.E. Robinson H. Rocchetti T.T. Rocha B.P. Roche S. Rollier C. Rose L. Ross Russell A.L. Rossouw L. Royal S. Rudiansyah I. Ruiz S. Saich S. Sala C. Sale J. Salman A.M. Salvador N. Salvador S. Sampaio M. Samson A.D. Sanchez-Gonzalez A. Sanders H. Sanders K. Santos E. Santos Guerra M.F.S. Satti I. Saunders J.E. Saunders C. Sayed A. Schim van der Loeff I. Schmid A.B. Schofield E. Screaton G. Seddiqi S. Segireddy R.R. Senger R. Serrano S. Shah R. Shaik I. Sharpe H.E. Sharrocks K. Shaw R. Shea A. Shepherd A. Shepherd J.G. Shiham F. Sidhom E. Silk S.E. da Silva Moraes A.C. Silva-Junior G. Silva-Reyes L. Silveira A.D. Silveira M.B.V. Sinha J. Skelly D.T. Smith D.C. Smith N. Smith H.E. Smith D.J. Smith C.C. Soares A. Soares T. Solórzano C. Sorio G.L. Sorley K. Sosa-Rodriguez T. Souza C.M.C.D.L. Souza B.S.D.F. Souza A.R. Spencer A.J. Spina F. Spoors L. Stafford L. Stamford I. Starinskij I. Stein R. Steven J. Stockdale L. Stockwell L.V. Strickland L.H. Stuart A.C. Sturdy A. Sutton N. Szigeti A. Tahiri-Alaoui A. Tanner R. Taoushanis C. Tarr A.W. Taylor K. Taylor U. Taylor I.J. Taylor J. te Water Naude R. Themistocleous Y. Themistocleous A. Thomas M. Thomas K. Thomas T.M. Thombrayil A. Thompson F. Thompson A. Thompson K. Thompson A. Thomson J. Thornton-Jones V. Tighe P.J. Tinoco L.A. Tiongson G. Tladinyane B. Tomasicchio M. Tomic A. Tonks S. Towner J. Tran N. Tree J. Trillana G. Trinham C. Trivett R. Truby A. Tsheko B.L. Turabi A. Turner R. Turner C. Ulaszewska M. Underwood B.R. Varughese R. Verbart D. Verheul M. Vichos I. Vieira T. Waddington C.S. Walker L. Wallis E. Wand M. Warbick D. Wardell T. Warimwe G. Warren S.C. Watkins B. Watson E. Webb S. Webb-Bridges A. Webster A. Welch J. Wells J. West A. White C. White R. Williams P. Williams R.L. Winslow R. Woodyer M. Worth A.T. Wright D. Wroblewska M. Yao A. Zimmer R. Zizi D. Zuidewind P. Oxford COVID Vaccine Trial Group Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021 397 10269 99 111 10.1016/S0140‑6736(20)32661‑1 33306989
    [Google Scholar]
  343. Knoll M.D. Wonodi C. Oxford–AstraZeneca COVID-19 vaccine efficacy. Lancet 2021 397 10269 72 74 10.1016/S0140‑6736(20)32623‑4 33306990
    [Google Scholar]
  344. Wong S.S. Webby R.J. Traditional and new influenza vaccines. Clin. Microbiol. Rev. 2013 26 3 476 492 10.1128/CMR.00097‑12 23824369
    [Google Scholar]
  345. Petrova V.N. Russell C.A. The evolution of seasonal influenza viruses. Nat. Rev. Microbiol. 2018 16 1 47 60 10.1038/nrmicro.2017.118 29081496
    [Google Scholar]
  346. European Centre for Disease Prevention and Control. Risk related to spread of new SARS-CoV-2 variants of concern in the EU/EEA, first update – 21 January 2021 ECDC Stockholm 2021
    [Google Scholar]
  347. Callaway E. Ledford H. How to redesign COVID vaccines so they protect against variants. Nature 2021 590 7844 15 16 10.1038/d41586‑021‑00241‑6 33514888
    [Google Scholar]
  348. Callaway E. Could new COVID variants undermine vaccines? Labs scramble to find out. Nature 2021 589 7841 177 178 10.1038/d41586‑021‑00031‑0 33432212
    [Google Scholar]
/content/journals/cpb/10.2174/0113892010328697250210065420
Loading
/content/journals/cpb/10.2174/0113892010328697250210065420
Loading

Data & Media loading...


  • Article Type:
    Review Article
Keywords: COVID-19 ; Immunosenescence ; Aging ; Inflammaging ; SARS-CoV-2 infection
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
Please enter a valid_number test