The Impact of Polyphenols-Based Diet on the Inflammatory Profile in COVID-19 Elderly and Obese Patients

Juliana Carvalho Santos, Marcelo Lima Ribeiro, Alessandra Gambero, Juliana Carvalho Santos, Marcelo Lima Ribeiro, Alessandra Gambero

Abstract

The World Health Organization declared the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated disease (coronavirus disease 2019 - COVID-19) as a pandemic in March 2020. COVID-19 is characterized by cytokine storm, acute respiratory distress syndrome (ARDS), and systemic inflammation-related pathology and already kills more than 1.5 million of people worldwide. Since aged and obese COVID-19 patients exhibit an enhanced inflammatory status, they represent a high-risk cluster for rapidly progressive clinical deterioration. These individuals present comorbid disorders and immunosenescence that may promote viral-induced cytokine storm and expression of molecules acting as virus receptor as angiotensin I converting enzyme 2 (ACE2) and CD26 (dipeptidyl-peptidase 4), resulting in respiratory failure and increased morbidity and mortality. A better knowledge of SARS-CoV-2 infection in inflammatory-associated high-risk population is essential in order to develop the therapies needed to combat or prevent severe COVID-19. Here, we review the pathogenesis and clinical implications of inflammatory disorders and disease markers associated to senescence in COVID-19 patients and the emerging evidence to argue that a high intake of polyphenols may have a protective effect on SARS-CoV-2 illness severity.

Keywords: COVID-19; cytokine storm; inflammation; polyphenols; senescence.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Santos, Ribeiro and Gambero.

Figures

Figure 1
Figure 1
Infection of pulmonary epithelial cells occurs through the interaction of the spike glycoprotein envelope (S-protein) with the angiotensin I converting enzyme (ACE)-2 receptor that allows viral replication and triggers mechanisms to combat infection by the host cells thought toll-like receptors (TLRs) and mitochondrial antiviral-signaling protein (MAVS). Cytokines pro-inflammatory are produced by nuclear factor kappa -B (NF-kB) and interferon-regulatory factors (IRFs) signaling pathways recruiting more immune cells (dendritic cell and T-cell) to lungs. Recruited immune cells increased cytokine production resulting in a cytokine storm that is associated with a worse prognosis of infected patients. During aging and obesity, the production of pro-inflammatory cytokines and the establishment of low-grade systemic inflammation are also observed. The expression of components of the renin-angiotensin-aldosterone system, such as ACE2, is also modified by aging and obesity, which could explain why elderly and obese patients are affected and headed the death statistics by COVID-19. Dietary bioactive substances such as polyphenols are able to block the production of cytokines by senescent cells (senescence-associated secretory phenotype; SASP) and adipocytes, as well as modify the ACE-1/ACE-2 ratio, which can potentially result in beneficial effects in COVID-19.

References

    1. Acosta J. C., Banito A., Wuestefeld T., Georgilis A., Janich P., Morton J. P., et al. . (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990. 10.1038/ncb2784, PMID:
    1. Ahmadian E., Hosseiniyan Khatibi S. M., Razi Soofiyani S., Abediazar S., Shoja M. M., Ardalan M., et al. (2020). Covid-19 and kidney injury: pathophysiology and molecular mechanisms. Rev. Med. Virol. e2176. 10.1002/rmv.2176 [Epub ahead of print]
    1. Beauséjour C. M., Krtolica A., Galimi F., Narita M., Lowe S. W., Yaswen P., et al. . (2003). Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222. 10.1093/emboj/cdg417, PMID:
    1. Behrens E. M., Koretzky G. A. (2017). Review: cytokine storm syndrome: looking toward the precision medicine era. Arthritis Rheum. 69, 1135–1143. 10.1002/art.40071
    1. Ben Othman N., Roblain D., Thonart P., Hamdi M. (2008). Tunisian table olive phenolic compounds and their antioxidant capacity. J. Food Sci. 73, C235–C240. 10.1111/j.1750-3841.2008.00711.x, PMID:
    1. Bian X., Griffin T. P., Zhu X., Islam M. N., Conley S. M., Eirin A., et al. . (2019). Senescence marker activin a is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy. BMJ Open Diabetes Res. Care 7:e000720. 10.1136/bmjdrc-2019-000720, PMID:
    1. Bigagli E., Luceri C., Scartabelli T., Dolara P., Casamenti F., Pellegrini-Giampietro D. E., et al. . (2016). Long-term neuroglial cocultures as a brain aging model: hallmarks of senescence, microRNA expression profiles, and comparison with in vivo models. J. Gerontol. A Biol. Sci. Med. Sci. 71, 50–60. 10.1093/gerona/glu231, PMID:
    1. Biswas S. K. (2016). Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxidative Med. Cell. Longev. 2016:5698931. 10.1155/2016/5698931, PMID:
    1. Burns J., Yokota T., Ashihara H., Lean M. E. J., Crozier A. (2002). Plant foods and herbal sources of resveratrol. J. Agric. Food Chem. 50, 3337–3340. 10.1021/jf0112973, PMID:
    1. Burrell L. M., Risvanis J., Kubota E., Dean R. G., MacDonald P. S., Lu S., et al. . (2005). Myocardial infarction increases ACE2 expression in rat and humans. Eur. Heart J. 26, 369–375. 10.1093/eurheartj/ehi114, PMID:
    1. Cao X. (2020). COVID-19: immunopathology and its implications for therapy. Nat. Rev. Immunol. 20, 269–270. 10.1038/s41577-020-0308-3, PMID:
    1. Carr A. C. (2020). A new clinical trial to test high-dose vitamin C in patients with COVID-19. Crit. Care 24:133. 10.1186/s13054-020-02851-4, PMID:
    1. Caussy C., Pattou F., Wallet F., Simon C., Chalopin S., Telliam C., et al. . (2020). Prevalence of obesity among adult inpatients with COVID-19 in France. Lancet Diabetes Endocrinol. 8, 562–564. 10.1016/S2213-8587(20)30160-1, PMID:
    1. Centers for Disease Control and Prevention (2020). People who are at higher risk for severe illness|CDC. Centers Dis. Control Prev. 68:703. 10.4103/ijo.IJO_843_20
    1. Channappanavar R., Perlman S. (2017). Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39, 529–539. 10.1007/s00281-017-0629-x, PMID:
    1. Chen J., Jiang Q., Xia X., Liu K., Yu Z., Tao W., et al. . (2020a). Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 19:e13168. 10.1111/acel.13168, PMID:
    1. Chen J., Kelley W. J., Goldstein D. R. (2020b). Role of aging and the immune response to respiratory viral infections: potential implications for COVID-19. J. Immunol. 205, 313–320. 10.4049/jimmunol.2000380, PMID:
    1. Chen L., Liu H. G., Liu W., Liu J., Liu K., Shang J., et al. . (2020c). Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 43:E005. 10.3760/cma.j.issn.1001-0939.2020.0005, PMID:
    1. Chen I. Y., Moriyama M., Chang M. F., Ichinohe T. (2019). Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front. Microbiol. 10:50. 10.3389/fmicb.2019.00050, PMID:
    1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., et al. . (2020d). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395, 507–513. 10.1016/S0140-6736(20)30211-7, PMID:
    1. Cheung C. Y., Poon L. L. M., Ng I. H. Y., Luk W., Sia S. -F., Wu M. H. S., et al. . (2005). Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol. 79, 7819–7826. 10.1128/jvi.79.12.7819-7826.2005, PMID:
    1. Chousterman B. G., Swirski F. K., Weber G. F. (2017). Cytokine storm and sepsis disease pathogenesis. Semin. Immunopathol. 39, 517–528. 10.1007/s00281-017-0639-8, PMID:
    1. Chung H. Y., Kim D. H., Lee E. K., Chung K. W., Chung S., Lee B., et al. . (2019). Redefining chronic inflammation in aging and age-related diseases: proposal of the senoinflammation concept. Aging Dis. 10, 367–382. 10.14336/AD.2018.0324, PMID:
    1. Cicco S., Cicco G., Racanelli V., Vacca A. (2020). Neutrophil extracellular traps (NETs) and damage-associated molecular patterns (DAMPs): two potential targets for COVID-19 treatment. Mediat. Inflamm. 2020:7527953. 10.1155/2020/7527953, PMID:
    1. Cocoros N. M., Lash T. L., Demaria A., Klompas M. (2014). Obesity as a risk factor for severe influenza-like illness. Influenza Other Respir. Viruses 8, 25–32. 10.1111/irv.12156, PMID:
    1. Coppe J. P., Kauser K., Campisi J., Beauséjour C. M. (2006). Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281, 29568–29574. 10.1074/jbc.M603307200, PMID:
    1. Covarrubias A. J., Kale A., Perrone R., Lopez-Dominguez J. A., Pisco A. O., Kasler H. G., et al. . (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, 1265–1283. 10.1038/s42255-020-00305-3, PMID:
    1. Covino M., De Matteis G., Santoro M., Sabia L., Simeoni B., Candelli M., et al. . (2020). Clinical characteristics and prognostic factors in COVID-19 patients aged ≥80 years. Geriatr Gerontol Int 20, 704–708. 10.1111/ggi.13960, PMID:
    1. Crayne C. B., Albeituni S., Nichols K. E., Cron R. Q. (2019). The immunology of macrophage activation syndrome. Front. Immunol. 10:119. 10.3389/fimmu.2019.00119, PMID:
    1. Cristiani L., Mancino E., Matera L., Nenna R., Pierangeli A., Scagnolari C., et al. . (2020). Will children reveal their secret? The coronavirus dilemma. Eur. Respir. J. 55:2000749. 10.1183/13993003.00749-2020, PMID:
    1. Csiszar A., Sosnowska D., Wang M., Lakatta E. G., Sonntag W. E., Ungvari Z. (2012). Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J. Gerontol. A Biol. Sci. Med. Sci. 67, 811–820. 10.1093/gerona/glr228, PMID:
    1. D’Errico S., Zanon M., Montanaro M., Radaelli D., Sessa F., Di Mizio G., et al. . (2020). More than pneumonia: distinctive features of SARS-CoV-2 infection. From autopsy findings to clinical implications: a systematic review. Microorganisms 8:1642. 10.3390/microorganisms8111642, PMID:
    1. Dalan R., Bornstein S. R., El-Armouche A., Rodionov R. N., Markov A., Wielockx B., et al. . (2020). The ACE-2 in COVID-19: foe or friend? Horm. Metab. Res. 52, 257–263. 10.1055/a-1155-0501, PMID:
    1. Daneshkhah A., Agrawal V., Eshein A., Subramanian H., Roy H. K., Backman V. (2020). The possible role of Vitamin D in suppressing cytokine storm and associated mortality in COVID-19 patients. MedRxiv [Preprint]. 10.1101/2020.04.08.20058578
    1. Di Paola R., Mazzon E., Muià C., Crisafulli C., Genovese T., Di Bella P., et al. . (2006). Green tea polyphenol extract attenuates zymosan-induced non-septic shock in mice. Shock 26, 402–409. 10.1097/01.shk.0000191379.62897.1d, PMID:
    1. Donoghue M., Hsieh F., Baronas E., Godbout K., Gosselin M., Stagliano N., et al. . (2000). A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res. 87, E1–E9. 10.1161/01.res.87.5.e1, PMID:
    1. Eguchi S., Kawai T., Scalia R., Rizzo V. (2018). Understanding angiotensin II type 1 receptor signaling in vascular pathophysiology. Hypertension 71, 804–810. 10.1161/HYPERTENSIONAHA.118.10266, PMID:
    1. Fischer-Posovszky P., Kukulus V., Tews D., Unterkircher T., Debatin K. M., Fulda S., et al. . (2010). Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am. J. Clin. Nutr. 92, 5–15. 10.3945/ajcn.2009.28435, PMID:
    1. Freund A., Orjalo A. V., Desprez P. Y., Campisi J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246. 10.1016/j.molmed.2010.03.003, PMID:
    1. Gambero A., Ribeiro M. L. (2015). The positive effects of yerba maté (Ilex paraguariensis) in obesity. Nutrients 7, 730–750. 10.3390/nu7020730, PMID:
    1. Gao Y. -M., Xu G., Wang B., Liu B. -C. (2020). Cytokine storm syndrome in coronavirus disease 2019: a narrative review. J. Intern. Med. 10.1111/joim.13144 [Epub ahead of print]
    1. Garrido A., Cruces J., Ceprián N., Vara E., de la Fuente M. (2019). Oxidative-inflammatory stress in immune cells from adult mice with premature aging. Int. J. Mol. Sci. 20:769. 10.3390/ijms20030769, PMID:
    1. Goronzy J. J., Fulbright J. W., Crowson C. S., Poland G. A., O’Fallon W. M., Weyand C. M. (2001). Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J. Virol. 75, 12182–12187. 10.1128/jvi.75.24.12182-12187.2001, PMID:
    1. Grant W. B., Lahore H., McDonnell S. L., Baggerly C. A., French C. B., Aliano J. L., et al. . (2020). Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients 12:988. 10.3390/nu12040988, PMID:
    1. Gruver A. L., Hudson L. L., Sempowski G. D. (2007). Immunosenescence of ageing. J. Pathol. 211, 144–156. 10.1002/path.2104
    1. Halvatsiotis P., Kotanidou A., Tzannis K., Jahaj E., Magira E., Theodorakopoulou M., et al. . (2020). Demographic and clinical features of critically ill patients with COVID-19 in Greece: the burden of diabetes and obesity. Diabetes Res. Clin. Pract. 166:108331. 10.1016/j.diabres.2020.108331, PMID:
    1. Hamming I., Timens W., Bulthuis M. L. C., Lely A. T., Navis G. J., van Goor H. (2004). Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 203, 631–637. 10.1002/path.1570, PMID:
    1. Hayflick L., Moorhead P. S. (1961). The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621. 10.1016/0014-4827(61)90192-6, PMID:
    1. He M., Chiang H. H., Luo H., Zheng Z., Qiao Q., Wang L., et al. . (2020). An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance. Cell Metab. 31:580.e5–591.e5. 10.1016/j.cmet.2020.01.009, PMID:
    1. He L., Ding Y., Zhang Q., Che X., He Y., Shen H., et al. . (2006). Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J. Pathol. 210, 288–297. 10.1002/path.2067, PMID:
    1. Hickson L. T. J., Langhi Prata L. G. P., Bobart S. A., Evans T. K., Giorgadze N., Hashmi S. K., et al. . (2019). Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456. 10.1016/j.ebiom.2019.08.069, PMID:
    1. Hofmann H., Pyrc K., van der Hoek L., Geier M., Berkhout B., Pöhlmann S. (2005). Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl. Acad. Sci. U. S. A. 102, 7988–7993. 10.1073/pnas.0409465102, PMID:
    1. Honce R., Schultz-Cherry S. (2019). Impact of obesity on influenza a virus pathogenesis, immune response, and evolution. Front. Immunol. 10:1071. 10.3389/fimmu.2019.01071, PMID:
    1. Hu H., Du H., Li J., Wang Y., Wu X., Wang C., et al. . (2020). Early prediction and identification for severe patients during the pandemic of COVID-19: a severe COVID-19 risk model constructed by multivariate logistic regression analysis. J. Glob. Health 10:020510. 10.7189/jogh.10.020510, PMID:
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. . (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506. 10.1016/S0140-6736(20)30183-5, PMID:
    1. Imam Z., Odish F., Gill I., O’Connor D., Armstrong J., Vanood A., et al. . (2020). Older age and comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States. J. Intern. Med. 288, 469–476. 10.1111/joim.13119, PMID:
    1. Janeway C. A., Medzhitov R. (2002). Innate immune recognition. Annu. Rev. Immunol. 20, 197–216. 10.1146/annurev.immunol.20.083001.084359, PMID:
    1. Jang I. A., Kim E. N., Lim J. H., Kim M. Y., Ban T. H., Yoon H. E., et al. . (2018). Effects of resveratrol on the renin-angiotensin system in the aging kidney. Nutrients 10:1741. 10.3390/nu10111741, PMID:
    1. Jimenez-Gomez Y., Mattison J. A., Pearson K. J., Martin-Montalvo A., Palacios H. H., Sossong A. M., et al. . (2013). Resveratrol improves adipose insulin signaling and reducestheinflammatoryresponsein adiposetissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 18, 533–545. 10.1016/j.cmet.2013.09.004, PMID:
    1. Jun J. -I., Lau L. F. (2010). The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685. 10.1038/ncb2070, PMID:
    1. Justice J. N., Nambiar A. M., Tchkonia T., LeBrasseur N. K., Pascual R., Hashmi S. K., et al. . (2019). Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563. 10.1016/j.ebiom.2018.12.052, PMID:
    1. Khan N., Syed D. N., Ahmad N., Mukhtar H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxid. Redox Signal. 19, 151–162. 10.1089/ars.2012.4901, PMID:
    1. Kim E. N., Kim M. Y., Lim J. H., Kim Y., Shin S. J., Park C. W., et al. . (2018). The protective effect of resveratrol on vascular aging by modulation of the renin–angiotensin system. Atherosclerosis 270, 123–131. 10.1016/j.atherosclerosis.2018.01.043, PMID:
    1. Kirkland J. L. (1992). The biochemistry of mammalian senescence. Clin. Biochem. 25, 61–75. 10.1016/0009-9120(92)80047-K, PMID:
    1. Kirkland J. L. (2013). Inflammation and cellular senescence: potential contribution to chronic diseases and disabilities with aging. Public Policy Aging Rep. 23, 12–15. 10.1093/ppar/23.4.12
    1. Kirkland J. L., Tchkonia T. (2020). Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536. 10.1111/joim.13141, PMID:
    1. Koelman L., Pivovarova-Ramich O., Pfeiffer A. F. H., Grune T., Aleksandrova K. (2019). Cytokines for evaluation of chronic inflammatory status in ageing research: reliability and phenotypic characterisation. Immun. Ageing 16:11. 10.1186/s12979-019-0151-1, PMID:
    1. Kogelmann K., Jarczak D., Scheller M., Drüner M. (2017). Hemoadsorption by CytoSorb in septic patients: a case series. Crit. Care 21:74. 10.1186/s13054-017-1662-9, PMID:
    1. Laberge R. M., Awad P., Campisi J., Desprez P. Y. (2012). Epithelial-mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron. 5, 39–44. 10.1007/s12307-011-0069-4, PMID:
    1. Lai C. C., Shih T. P., Ko W. C., Tang H. J., Hsueh P. R. (2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int. J. Antimicrob. Agents 55:105924. 10.1016/j.ijantimicag.2020.105924, PMID:
    1. Lara P. C., Macías-Verde D., Burgos-Burgos J. (2020). Age-induced NLRP3 inflammasome over-activation increases lethality of SARS-CoV-2 pneumonia in elderly patients. Aging Dis. 11, 756–762. 10.14336/ad.2020.0601, PMID:
    1. Lau S. K. P., Lau C. C. Y., Chan K. H., Li C. P. Y., Chen H., Jin D. Y., et al. . (2013). Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J. Gen. Virol. 94, 2679–2690. 10.1099/vir.0.055533-0, PMID:
    1. Law H. K. W., Chung Y. C., Hoi Y. N., Sin F. S., Yuk O. C., Luk W., et al. . (2005). Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood 106, 2366–2374. 10.1182/blood-2004-10-4166, PMID:
    1. Li G., Fan Y., Lai Y., Han T., Li Z., Zhou P., et al. . (2020). Coronavirus infections and immune responses. J. Med. Virol. 92, 424–432. 10.1002/jmv.25685, PMID:
    1. Lighter J., Phillips M., Hochman S., Sterling S., Johnson D., Francois F., et al. . (2020). Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Clin. Infect. Dis. 71, 896–897. 10.1093/cid/ciaa415, PMID:
    1. Lim H., Park H., Kim H. P. (2015). Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem. Pharmacol. 96, 337–348. 10.1016/j.bcp.2015.06.013, PMID:
    1. Liu R. M., Liu G. (2020). Cell senescence and fibrotic lung diseases. Exp. Gerontol. 132:110836. 10.1016/j.exger.2020.110836, PMID:
    1. Liu S., Zhang J., Pang Q., Song S., Miao R., Chen W., et al. . (2016). The protective role of curcumin in zymosan-induced multiple organ dysfunction syndrome in mice. Shock 45, 209–219. 10.1097/SHK.0000000000000502, PMID:
    1. Louie J. K., Acosta M., Samuel M. C., Schechter R., Vugia D. J., Harriman K., et al. . (2011). A novel risk factor for a novel virus: obesity and 2009 pandemic influenza a (H1N1). Clin. Infect. Dis. 52, 301–312. 10.1093/cid/ciq152, PMID:
    1. Lu L., Zhang H., Dauphars D. J., He Y. -W. (2020). A potential role of interleukin-10 in COVID-19 pathogenesis. Trends Immunol. 10.1016/j.it.2020.10.012 [Epub ahead of print]
    1. Mahallawi W. H., Khabour O. F., Zhang Q., Makhdoum H. M., Suliman B. A. (2018). MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 104, 8–13. 10.1016/j.cyto.2018.01.025, PMID:
    1. Marik P. E., Kory P., Varon J. (2020). Does vitamin D status impact mortality from SARS-CoV-2 infection? Med. Drug Discov. 6:100041. 10.1016/j.medidd.2020.100041, PMID:
    1. Marinella M. A. (2020). Indomethacin and resveratrol as potential treatment adjuncts for SARS-CoV-2/COVID-19. Int. J. Clin. Pract. 74:e13535. 10.1111/ijcp.13535, PMID:
    1. Massudi H., Grant R., Braidy N., Guest J., Farnsworth B., Guillemin G. J. (2012). Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7:e42357. 10.1371/journal.pone.0042357, PMID:
    1. Michaud M., Balardy L., Moulis G., Gaudin C., Peyrot C., Vellas B., et al. . (2013). Proinflammatory cytokines, aging, and age-related diseases. J. Am. Med. Dir. Assoc. 14, 877–882. 10.1016/j.jamda.2013.05.009, PMID:
    1. Moser J. A. S., Galindo-Fraga A., Ortiz-Hernández A. A., Gu W., Hunsberger S., Galán-Herrera J. F., et al. . (2019). Underweight, overweight, and obesity as independent risk factors for hospitalization in adults and children from influenza and other respiratory viruses. Influenza Other Respir. Viruses 13, 3–9. 10.1111/irv.12618, PMID:
    1. Mousavizadeh L., Ghasemi S. (2020). Genotype and phenotype of COVID-19: their roles in pathogenesis. J. Microbiol. Immunol. Infect. 10.1016/j.jmii.2020.03.022 [Epub ahead of print]
    1. Müller T., Kirsch M., Petrat F. (2017). Attenuation of multiple organ damage by continuous low-dose solvent-free infusions of resveratrol after severe hemorrhagic shock in rats. Nutrients 9:889. 10.3390/nu9080889, PMID:
    1. Murakami M., Kamimura D., Hirano T. (2019). Pleiotropy and specificity: insights from the interleukin 6 family of cytokines. Immunity 50, 812–831. 10.1016/j.immuni.2019.03.027, PMID:
    1. Murthy H., Iqbal M., Chavez J. C., Kharfan-Dabaja M. A. (2019). Cytokine release syndrome: current perspectives. Immunotargets Ther. 8, 43–52. 10.2147/ITT.S202015, PMID:
    1. Musi N., Valentine J. M., Sickora K. R., Baeuerle E., Thompson C. S., Shen Q., et al. . (2018). Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17:e12840. 10.1111/acel.12840, PMID:
    1. Nagai A., Matsumiya H., Hayashi M., Yasui S., Okamoto H., Konno K. (1994). Effects of nicotinamide and niacin on bleomycin-induced acute injury and subsequent fibrosis in hamster lungs. Exp. Lung Res. 20, 263–281. 10.3109/01902149409064387, PMID:
    1. Naylor R. M., Baker D. J., van Deursen J. M. (2013). Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin. Pharmacol. Ther. 93, 105–116. 10.1038/clpt.2012.193, PMID:
    1. Nguyen S., Major K., Cochet C., Bizzozzero T., Barbarossa L., Bosshard W., et al. (2020). COVID-19 infection in the elderly in French-speaking Switzerland: an inventory of beliefs, convictions and certainties. Rev. Med. Suisse 16, 835–838.
    1. Norelli M., Camisa B., Barbiera G., Falcone L., Purevdorj A., Genua M., et al. . (2018). Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748. 10.1038/s41591-018-0036-4, PMID:
    1. Ohtani N. (2019). Deciphering the mechanism for induction of senescence-associated secretory phenotype (SASP) and its role in ageing and cancer development. J. Infect. Dis. 10.1093/jb/mvz055 [Epub ahead of print]
    1. Petrakis D., Margină D., Tsarouhas K., Tekos F., Stan M., Nikitovic D., et al. . (2020). Obesity—a risk factor for increased COVID-19 prevalence, severity and lethality (review). Mol. Med. Rep. 22, 9–19. 10.3892/mmr.2020.11127, PMID:
    1. Pitozzi V., Mocali A., Laurenzana A., Giannoni E., Cifola I., Battaglia C., et al. . (2013). Chronic resveratrol treatment ameliorates cell adhesion and mitigates the inflammatory phenotype in senescent human fibroblasts. J. Gerontol. A Biol. Sci. Med. Sci. 68, 371–381. 10.1093/gerona/gls183, PMID:
    1. Qin C., Zhou L., Hu Z., Zhang S., Yang S., Tao Y., et al. . (2020). Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. 71, 762–768. 10.1093/cid/ciaa248, PMID:
    1. Qiu P., Cui X., Sun J., Welsh J., Natanson C., Eichacker P. Q. (2013). Antitumor necrosis factor therapy is associated with improvedsurvival in clinical sepsis trials: a meta-analysis. Crit. Care Med. 41, 2419–2429. 10.1097/CCM.0b013e3182982add, PMID:
    1. Rabi F. A., Al Zoubi M. S., Al-Nasser A. D., Kasasbeh G. A., Salameh D. M. (2020). Sars-cov-2 and coronavirus disease 2019: what we know so far. Pathogens 9:231. 10.3390/pathogens9030231, PMID:
    1. Raj V. S., Mou H., Smits S. L., Dekkers D. H. W., Müller M. A., Dijkman R., et al. . (2013). Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495, 251–254. 10.1038/nature12005, PMID:
    1. Rhodes J. M., Subramanian S., Laird E., Kenny R. A. (2020). Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees north supports vitamin D as a factor determining severity. Aliment. Pharmacol. Ther. 51, 1434–1437. 10.1111/apt.15777, PMID:
    1. Rodrigues Prestes T. R., Rocha N. P., Miranda A. S., Teixeira A. L., Simoes-e-Silva A. C. (2017). The anti-inflammatory potential of ACE2/angiotensin-(1-7)/mas receptor axis: evidence from basic and clinical research. Curr. Drug Targets 18, 1301–1313. 10.2174/1389450117666160727142401, PMID:
    1. Ros U., Pedrera L., Garcia-Saez A. J. (2020). Partners in crime: the interplay of proteins and membranes in regulated necrosis. Int. J. Mol. Sci. 21:2412. 10.3390/ijms21072412, PMID:
    1. Ruan Q., Yang K., Wang W., Jiang L., Song J. (2020). Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 46, 846–848. 10.1007/s00134-020-05991-x
    1. Rutkowska-Zapała M., Suski M., Szatanek R., Lenart M., Weglarczyk K., Olszanecki R., et al. . (2015). Human monocyte subsets exhibit divergent angiotensin I-converting activity. Clin. Exp. Immunol. 181, 126–132. 10.1111/cei.12612, PMID:
    1. Sanada F., Taniyama Y., Muratsu J., Otsu R., Shimizu H., Rakugi H., et al. . (2018). Source of chronic inflammation in aging. Front. Cardiovasc. Med. 5:12. 10.3389/fcvm.2018.00012, PMID:
    1. Santos I. B., de Bem G. F., da Costa C. A., de Carvalho L. C. R. M., de Medeiros A. F., Silva D. L. B., et al. . (2020). Açaí seed extract prevents the renin-angiotensin system activation, oxidative stress and inflammation in white adipose tissue of high-fat diet–fed mice. Nutr. Res. 79, 35–49. 10.1016/j.nutres.2020.05.006, PMID:
    1. Santos J. C., Gambeloni R. Z., Roque A. T., Oeck S., Ribeiro M. L. (2018). Epigenetic mechanisms of ATM activation after helicobacter pylori infection. Am. J. Pathol. 188, 329–335. 10.1016/j.ajpath.2017.10.005, PMID:
    1. Schafer M. J., White T. A., Iijima K., Haak A. J., Ligresti G., Atkinson E. J., et al. . (2017). Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8:14532. 10.1038/ncomms14532, PMID:
    1. Scheller J., Rose-John S. (2006). Interleukin-6 and its receptor: from bench to bedside. Med. Microbiol. Immunol. 195, 173–183. 10.1007/s00430-006-0019-9, PMID:
    1. Schouten L. R. A., Helmerhorst H. J. F., Wagenaar G. T. M., Haltenhof T., Lutter R., Roelofs J. J. T. H., et al. . (2016). Age-dependent changes in the pulmonary renin-angiotensin system are associated with severity of lung injury in a model of acute lung injury in rats. Crit. Care Med. 44, e1226–e1235. 10.1097/CCM.0000000000002008, PMID:
    1. Schouten L. R., van Kaam A. H., Kohse F., Veltkamp F., Bos L. D., de Beer F. M., et al. . (2019). Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study. Ann. Intensive Care 9:55. 10.1186/s13613-019-0529-4, PMID:
    1. Shang X., Lin K., Yu R., Zhu P., Zhang Y., Wang L., et al. . (2019). Resveratrol protects the myocardium in sepsis by activating the phosphatidylinositol 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and inhibiting the nuclear factor-κB (NF-κB) signaling pathway. Med. Sci. Monit. 25, 9290–9298. 10.12659/MSM.918369, PMID:
    1. Shi S., Qin M., Shen B., Cai Y., Liu T., Yang F., et al. . (2020a). Association of Cardiac Injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 5, 802–810. 10.1001/jamacardio.2020.0950, PMID:
    1. Shi Y., Wang Y., Shao C., Huang J., Gan J., Huang X., et al. . (2020b). COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 27, 1451–1454. 10.1038/s41418-020-0530-3, PMID:
    1. Shimabukuro-Vornhagen A., Gödel P., Subklewe M., Stemmler H. J., Schlößer H. A., Schlaak M., et al. . (2018). Cytokine release syndrome. J. Immunother. Cancer 6:56. 10.1186/s40425-018-0343-9, PMID:
    1. Shukla S., Gupta S. (2010). Apigenin: a promising molecule for cancer prevention. Pharm. Res. 27, 962–978. 10.1007/s11095-010-0089-7, PMID:
    1. Singh S., Sonawane A., Sadhukhan S. (2020). Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2 via RNA-dependent RNA Polymerase (RdRp) Inhibition An In-Silico Analysis. ChemRxiv [Preprint]. 10.26434/CHEMRXIV.12312263.V1
    1. Smith A. A., Fridling J., Ibhrahim D., Porter P. S. (2020). Identifying patients at greatest risk of mortality due to COVID-19: a New England perspective. West. J. Emerg. Med. 21, 785–789. 10.5811/westjem.2020.6.47957, PMID:
    1. Solnier J., Fladerer J. P. (2020). Flavonoids: a complementary approach to conventional therapy of COVID-19? Phytochem. Rev. 10.1007/s11101-020-09720-6 [Epub ahead of print]
    1. Stout M. B., Justice J. N., Nicklas B. J., Kirkland J. L. (2017). Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology 32, 9–19. 10.1152/physiol.00012.2016, PMID:
    1. Stout-Delgado H. W., Cho S. J., Chu S. G., Mitzel D. N., Villalba J., El-Chemaly S., et al. . (2016). Age-dependent susceptibility to pulmonary fibrosis is associated with NLRP3 inflammasome activation. Am. J. Respir. Cell Mol. Biol. 55, 252–263. 10.1165/rcmb.2015-0222OC, PMID:
    1. Suvakov S., Cubro H., White W. M., Butler Tobah Y. S., Weissgerber T. L., Jordan K. L., et al. . (2019). Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol. Sex Differ. 10:49. 10.1186/s13293-019-0263-5, PMID:
    1. Tang D., Kang R., Coyne C. B., Zeh H. J., Lotze M. T. (2012). PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158–175. 10.1111/j.1600-065X.2012.01146.x, PMID:
    1. Ueda K., Kawabata R., Irie T., Nakai Y., Tohya Y., Sakaguchi T. (2013). Inactivation of pathogenic viruses by plant-derived tannins: strong effects of extracts from persimmon (Diospyros kaki) on a broad range of viruses. PLoS One 8:e55343. 10.1371/journal.pone.0055343, PMID:
    1. van den Berg D. F., te Velde A. A. (2020). Severe COVID-19: NLRP3 inflammasome dysregulated. Front. Immunol. 11:1580. 10.3389/fimmu.2020.01580, PMID:
    1. van Deursen J. M. (2014). The role of senescent cells in ageing. Nature 509, 439–446. 10.1038/nature13193, PMID:
    1. van Kerkhove M. D., Vandemaele K. A. H., Shinde V., Jaramillo-Gutierrez G., Koukounari A., Donnelly C. A., et al. . (2011). Risk factors for severe outcomes following 2009 influenza a (H1N1) infection: a global pooled analysis. PLoS Med. 8:e1001053. 10.1371/journal.pmed.1001053, PMID:
    1. Varela-Eirín M., Carpintero-Fernández P., Sánchez-Temprano A., Varela-Vázquez A., Paíno C. L., Casado-Díaz A., et al. . (2020). Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and promotes a pro-regenerative environment in osteoarthritis. Aging 12, 15882–15905. 10.18632/aging.103801, PMID:
    1. Wan Y., Shang J., Graham R., Baric R. S., Li F. (2020b). Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J. Virol. 94, e00127–e00120. 10.1128/jvi.00127-20, PMID:
    1. Wan S., Yi Q., Fan S., Lv J., Zhang X., Guo L., et al. (2020a). Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv [Preprint]. 10.1101/2020.02.10.20021832
    1. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., et al. . (2020). Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 323, 1061–1069. 10.1001/jama.2020.1585, PMID:
    1. Wei P.-F., (Released by National Health Commission & National Administration of Traditional Chinese Medicine on March 3, 2020) (2020). Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7). Chin. Med. J. 133, 1087–1095. 10.1097/CM9.0000000000000819, PMID:
    1. Webmeter (2020). Coronavirus Age, Sex, Demographics (COVID-19)—Worldometer. Available at: (Accessed December 01, 2020).
    1. Williamson E. J., Walker A. J., Bhaskaran K., Bacon S., Bates C., Morton C. E., et al. . (2020). OpenSAFELY: factors associated with COVID-19 death in 17 million patients. Nature 584, 430–436. 10.1038/s41586-020-2521-4, PMID:
    1. World Health Organization (2020). WHO coronavirus disease (COVID-19) Dashboard. World Heal. Organ.
    1. Wu J. T., Leung K., Bushman M., Kishore N., Niehus R., de Salazar P. M., et al. . (2020). Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat. Med. 26, 506–510. 10.1038/s41591-020-0822-7, PMID:
    1. Wu Z., McGoogan J. M. (2020). Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China. JAMA 323, 1239–1242. 10.1001/jama.2020.2648, PMID:
    1. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., et al. . (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422. 10.1016/S2213-2600(20)30076-X, PMID:
    1. Xudong X., Junzhu C., Xingxiang W., Furong Z., Yanrong L. (2006). Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 78, 2166–2171. 10.1016/j.lfs.2005.09.038, PMID:
    1. Yan R., Zhang Y., Li Y., Xia L., Guo Y., Zhou Q. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367, 1444–1448. 10.1126/science.abb2762, PMID:
    1. Yang S. J., Lim Y. (2014). Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism 63, 693–701. 10.1016/j.metabol.2014.02.003, PMID:
    1. Yao X. H., Li T. Y., He Z. C., Ping Y. F., Liu H. W., Yu S. C., et al. . (2020). A pathological report of three COVID-19 cases by minimally invasive autopsies. Zhonghua Bing Li Xue Za Zhi 49, 411–417. 10.3760/cma.j.cn112151-20200312-00193, PMID:
    1. Yousefzadeh M. J., Zhu Y., McGowan S. J., Angelini L., Fuhrmann-Stroissnigg H., Xu M., et al. . (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28. 10.1016/j.ebiom.2018.09.015, PMID:
    1. Zanni F., Vescovini R., Biasini C., Fagnoni F., Zanlari L., Telera A., et al. . (2003). Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence. Exp. Gerontol. 38, 981–987. 10.1016/S0531-5565(03)00160-8, PMID:
    1. Zhang D. -H., Wu K. -L., Zhang X., Deng S. -Q., Peng B. (2020). In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J. Integr. Med. 18, 152–158. 10.1016/j.joim.2020.02.005, PMID:
    1. Zhao L., Cen F., Tian F., Li M. J., Zhang Q., Shen H. Y., et al. . (2017). Combination treatment with quercetin and resveratrol attenuates high fat diet-induced obesity and associated inflammation in rats via the AMPKα1/SIRT1 signaling pathway. Exp. Ther. Med. 14, 5942–5948. 10.3892/etm.2017.5331, PMID:
    1. Zheng Z., Peng F., Xu B., Zhao J., Liu H., Peng J., et al. . (2020). Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J. Inf. Secur. 81, e16–e25. 10.1016/j.jinf.2020.04.021, PMID:
    1. Zhou P., Yang X. -L., Wang X. G., Hu B., Zhang L., Zhang W., et al. . (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273. 10.1038/s41586-020-2012-7, PMID:

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe