COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?

Camillo Sargiacomo, Federica Sotgia, Michael P Lisanti, Camillo Sargiacomo, Federica Sotgia, Michael P Lisanti

Abstract

COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.

Keywords: Azithromycin; COVID-19; Doxycycline; Hydroxy-chloroquine; Quercetin; Rapamycin; aging; antibiotic; corona virus; drug repurposing; prevention; senescence; senolytic drug therapy; viral replication.

Conflict of interest statement

CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
What is the relationship between COVID-19 and advanced chronological age? Here, we suggest that the COVID-19 corona virus preferentially targets senescent lung cells, resulting in increased morbidity and mortality in the aging population. One possible solution for prevention/treatment would be the use of senolytics or other anti-aging drugs. Testing this hypothesis will require the necessary clinical trials, with a focus on drug repurposing.

References

    1. 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, et al.. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395:1054–62. 10.1016/S0140-6736(20)30566-3
    1. Severe Outcomes Among Patients with Coronavirus Disease. 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020; 369:343–46. 10.15585/mmwr.mm6912e2
    1. Vankadari N, Wilce JA. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect. 2020; 9:601–04. 10.1080/22221751.2020.1739565
    1. Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, Zhou Y, Du L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020. [Epub ahead of print]. 10.1038/s41423-020-0400-4
    1. Song J, Hu B, Qu H, Wang L, Huang X, Li M, Zhang M. Upregulation of angiotensin converting enzyme 2 by shear stress reduced inflammation and proliferation in vascular endothelial cells. Biochem Biophys Res Commun. 2020. Epub ahead of print. 10.1016/j.bbrc.2020.02.151
    1. Khemais-Benkhiat S, Idris-Khodja N, Ribeiro TP, Silva GC, Abbas M, Kheloufi M, Lee JO, Toti F, Auger C, Schini-Kerth VB, Gerontol A. 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; 71:1581–90. 10.1093/gerona/glv213
    1. Kim KM, Noh JH, Bodogai M, Martindale JL, Yang X, Indig FE, Basu SK, Ohnuma K, Morimoto C, Johnson PF, Biragyn A, Abdelmohsen K, Gorospe M. Identification of senescent cell surface targetable protein DPP4. Genes Dev. 2017; 31:1529–34. 10.1101/gad.302570.117
    1. Guy JL, Lambert DW, Turner AJ, Porter KE. Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts. Exp Physiol. 2008; 93:579–88. 10.1113/expphysiol.2007.040139
    1. Mah W, Jiang G, Olver D, Gallant-Behm C, Wiebe C, Hart DA, Koivisto L, Larjava H, Häkkinen L. Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts. Am J Pathol. 2017; 187:1717–35. 10.1016/j.ajpath.2017.04.017
    1. Kleine-Weber H, Schroeder S, Krüger N, Prokscha A, Naim HY, Müller MA, Drosten C, Pöhlmann S, Hoffmann M. Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus. Emerg Microbes Infect. 2020; 9:155–68. 10.1080/22221751.2020.1713705
    1. Kim J, Yang YL, Jeong Y, Jang YS. Middle East respiratory syndrome-coronavirus infection into established hDDP4-transgenic mice accelerates lung damage via activation of the pro-inflammatory response and pulmonary fibrosis. J Microbiol Biotechnol. 2020; 30:427–38. 10.4014/jmb.1910.10055
    1. van Doremalen N, Miazgowicz KL, Milne-Price S, Bushmaker T, Robertson S, Scott D, Kinne J, McLellan JS, Zhu J, Munster VJ. Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J Virol. 2014; 88:9220–32. 10.1128/JVI.00676-14
    1. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, et al.. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. [Epub ahead of print]. 10.1016/j.ijantimicag.2020.105949
    1. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000; 113:3613–22.
    1. Tishler M, Yaron I, Shirazi I, Yaron M. Hydroxychloroquine treatment for primary Sjögren’s syndrome: its effect on salivary and serum inflammatory markers. Ann Rheum Dis. 1999; 58:253–56. 10.1136/ard.58.4.253
    1. Ozsvari B, Nuttall JR, Sotgia F, Lisanti MP. Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY). 2018; 10:3294–307. 10.18632/aging.101633
    1. Mosquera RA, De Jesus-Rojas W, Stark JM, Yadav A, Jon CK, Atkins CL, Samuels CL, Gonzales TR, McBeth KE, Hashmi SS, Garolalo R, Colasurdo GN. Role of prophylactic azithromycin to reduce airway inflammation and mortality in a RSV mouse infection model. Pediatr Pulmonol. 2018; 53:567–74. 10.1002/ppul.23956
    1. Tang F, Li R, Xue J, Lan J, Xu H, Liu Y, Zhou L, Lu Y. Azithromycin attenuates acute radiation-induced lung injury in mice. Oncol Lett. 2017; 14:5211–20. 10.3892/ol.2017.6813
    1. Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, Mancia Leon WR, Krencik R, Ullian EM, Spatazza J, Pollen AA, Mandel-Brehm C, Nowakowski TJ, et al.. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci USA. 2016; 113:14408–13. 10.1073/pnas.1618029113
    1. Bosseboeuf E, Aubry M, Nhan T, de Pina JJ, Rolain JM, Raoult D, Musso D. Azithromycin Inhibits the Replication of Zika Virus. J Antivir Antiretrovir. 2018; 10:6–11. 10.4172/1948-5964.1000173
    1. Madrid PB, Panchal RG, Warren TK, Shurtleff AC, Endsley AN, Green CE, Kolokoltsov A, Davey R, Manger ID, Gilfillan L, Bavari S, Tanga MJ. Evaluation of Ebola Virus Inhibitors for Drug Repurposing. ACS Infect Dis. 2015; 1:317–26. 10.1021/acsinfecdis.5b00030
    1. Roy J, Paquette JS, Fortin JF, Tremblay MJ. The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 2002; 46:3447–55. 10.1128/AAC.46.11.3447-3455.2002
    1. Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY). 2019; 11:8048–67. 10.18632/aging.102355
    1. Blagosklonny MV. Rapamycin, proliferation and geroconversion to senescence. Cell Cycle. 2018; 17:2655–65. 10.1080/15384101.2018.1554781
    1. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009; 8:1888–95. 10.4161/cc.8.12.8606
    1. Peiris-Pagès M, Ozsvári B, Sotgia F, Lisanti MP. Mitochondrial and ribosomal biogenesis are new hallmarks of stemness, oncometabolism and biomass accumulation in cancer: mito-stemness and ribo-stemness features. Aging (Albany NY). 2019; 11:4801–35. 10.18632/aging.102054
    1. Rothan HA, Mohamed Z, Paydar M, Rahman NA, Yusof R. Inhibitory effect of doxycycline against dengue virus replication in vitro. Arch Virol. 2014; 159:711–18. 10.1007/s00705-013-1880-7
    1. Fredeking TM, Zavala-Castro JE, González-Martínez P, Moguel-Rodríguez W, Sanchez EC, Foster MJ, Diaz-Quijano FA. Dengue Patients Treated with Doxycycline Showed Lower Mortality Associated to a Reduction in IL-6 and TNF Levels. Recent Pat Antiinfect Drug Discov. 2015; 10:51–58. 10.2174/1574891X10666150410153839
    1. Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013; 497:451–57. 10.1038/nature12188
    1. Smith M, Smith JC. Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface. 2020. ChemRxiv. 10.26434/chemrxiv.11871402.v4
    1. Cavalcante MB, Saccon TD, Nunes AD, Kirkland JL, Tchkonia T, Schneider A, Masternak MM. Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice. Aging (Albany NY). 2020; 12:2711–22. 10.18632/aging.102772
    1. Baas T, Roberts A, Teal TH, Vogel L, Chen J, Tumpey TM, Katze MG, Subbarao K. Genomic analysis reveals age-dependent innate immune responses to severe acute respiratory syndrome coronavirus. J Virol. 2008; 82:9465–76. 10.1128/JVI.00489-08
    1. Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, Subbarao K. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol. 2010; 84:1289–301. 10.1128/JVI.01281-09

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel