REVIEW published: 12 January 2021 doi: 10.3389/fphys.2020.612268 The Impact of Polyphenols-Based Diet on the Inflammatory Profile in COVID-19 Elderly and Obese Patients Juliana Carvalho Santos 1, Marcelo Lima Ribeiro 2* and Alessandra Gambero 3* 1 Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain, 2 Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University, Bragança Paulista, Brazil, 3 Life Science Center, Pontifical Catholic University of Campinas (PUCCAMP), Campinas, Brazil 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 Edited by: already kills more than 1.5 million of people worldwide. Since aged and obese COVID-19 Georges Leftheriotis, Université Côte d’Azur, France patients exhibit an enhanced inflammatory status, they represent a high-risk cluster for Reviewed by: rapidly progressive clinical deterioration. These individuals present comorbid disorders Alessandro Tonacci, and immunosenescence that may promote viral-induced cytokine storm and expression Italian National Research Council, Italy of molecules acting as virus receptor as angiotensin I converting enzyme 2 (ACE2) and Gautham Yepuri, CD26 (dipeptidyl-peptidase 4), resulting in respiratory failure and increased morbidity and New York University, United States mortality. A better knowledge of SARS-CoV-2 infection in inflammatory-associated high- *Correspondence: risk population is essential in order to develop the therapies needed to combat or prevent Marcelo Lima Ribeiro marcelo.ribeiro@usf.edu.br severe COVID-19. Here, we review the pathogenesis and clinical implications of Alessandra Gambero inflammatory disorders and disease markers associated to senescence in COVID-19 alessandra.gambero@puc-campinas. edu.br; patients and the emerging evidence to argue that a high intake of polyphenols may have alegambero@gmail.com a protective effect on SARS-CoV-2 illness severity. Specialty section: Keywords: COVID-19, cytokine storm, inflammation, senescence, polyphenols This article was submitted to Integrative Physiology, a section of the journal INTRODUCTION Frontiers in Physiology Received: 01 October 2020 According to the World Health Organization, as of December 1st coronavirus disease 2019 Accepted: 16 December 2020 (COVID-19) had been confirmed in almost 63 million of people worldwide, carrying a mortality Published: 12 January 2021 of approximately 2.5%, with the vast majority of them (74%) being in people over 65 years Citation: (Webmeter, 2020; World Health Organization, 2020). Indeed, age is undoubtedly the most important Santos JC, Ribeiro ML and risk factor for death in COVID-19 patients (Williamson et al., 2020). In addition, it has been Gambero A (2021) The Impact of reported that the severity of COVID-19 is associated with several comorbidities (i.e., respiratory Polyphenols-Based Diet on the Inflammatory Profile in COVID-19 system diseases, hypertension, diabetes, obesity, and cardiovascular disease; Webmeter, 2020). Elderly and Obese Patients. Although around 80% of confirmed severe acute respiratory syndrome coronavirus-2 (SARS- Front. Physiol. 11:612268. CoV-2) positive cases exhibit mild symptoms or are asymptomatic, the remaining 20% of patients doi: 10.3389/fphys.2020.612268 may develop serious symptoms, potentially leading to death (Lai et al., 2020). These patients do Frontiers in Physiology | www.frontiersin.org 1 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation not develop severe clinical manifestations in the early stages population most affected by COVID-19 by modifying these of the disease; however, an acute respiratory distress syndrome senescence markers (Zhou et al., 2020). (ARDS) and multiple-organ failure can occur at later stages. Remarkably, it has been reported that respiratory failure is responsible for 86% of death associated to SARS-CoV-2 PATHOGENESIS OF SARS-CoV-2 IN infection (Ruan et al., 2020). INFLAMMATORY COMORBIDITIES The so-called cytokine storm has been pointed out as one of the major player in the process of disease aggravation In early February 2020, the Chinese Center for Disease Control (Chousterman et al., 2017; Shimabukuro-Vornhagen et al., and Prevention (CDC) reported a large viewpoint (including 2018). Accordingly, in vitro data showed that a delayed release 72,314 cases) summarizing that the case fatality was 8.0% (312 of cytokines and chemokines occurs in respiratory epithelial of 3,918) in patients 70–79 years old and 14.8% in patients cells, dendritic cells, and macrophages at the early stage of aged ≥80 years (208 of 1,408; Wu and McGoogan, 2020). SARS-CoV-2 infection. These cells secrete low levels of interferons With the expansion of the pandemic throughout the world, (IFNs) and high levels of pro-inflammatory cytokines and it has been widely reported that elderly and geriatric adults chemokines (Cheung et al., 2005; Law et al., 2005; Lau et al., are among the highest risk population for death among 2013) which attracts inflammatory cells, such as neutrophils COVID-19 patients (Covino et al., 2020; Imam et al., 2020; and monocytes, resulting in excessive infiltration of the Nguyen et al., 2020; Wang et al., 2020). Indeed, several meta- inflammatory cells into lung tissue, an consequent lung injury. analysis confirmed that SARS-CoV-2 infection causes the Cellular senescence is a conserved mechanism characterized highest morbidity and mortality in patients aged >60 years by cell cycle arrest in response to both, extrinsic and intrinsic (Hu et al., 2020; Huang et al., 2020; Wang et al., 2020; Wu stimulation. Although senescent cells no longer replicate, they et al., 2020; Zheng et al., 2020). The reason for worsening remain metabolically active and become bigger than the disease severity may be attributed to the immunosenescence non-senescent cells, secrete high levels of inflammatory proteins and inflammageing (Chung et al., 2019; Rabi et al., 2020). as part of the senescence associated secretory phenotype Moreover, some comorbidities associated with age as hypertension, (SASP), and acquire cell metabolism changes (van Deursen, diabetes, chronic respiratory diseases, dysregulation of immune 2014). It has been shown that senescent cells may contribute response, and obesity have been associated with severe to cell proliferation, inflammation (Freund et al., 2010), COVID-19 (Chen et al., 2020b). angiogenesis (Coppe et al., 2006), epithelial-to-mesenchymal Obesity has previously been associated with hospitalization transition (EMT; Laberge et al., 2012), and wound healing due to viruses infection, such as influenza and coronavirus (Jun and Lau, 2010). Importantly, cellular senescence is also (van Kerkhove et al., 2011; Moser et al., 2019). In addition, associated to age-related organ dysfunction and various chronic severe obesity is a risk factor associated with fatalities in age-related diseases, such as Alzheimer, atherosclerosis, hospitalized patients (Louie et al., 2011; Cocoros et al., 2014). osteoarthritis, and pulmonary fibrosis (Naylor et al., 2013). In this sense, growing evidences indicate that obesity is also Additionally, aging and most of age-related diseases are also an important risk factor for worst prognosis among COVID-19 related to a chronic systemic condition of inflammation, known patients. The driving hypothesis point out to the axis excess as inflammageing (Michaud et al., 2013; Sanada et al., 2018). of adipose tissue and inflammation, which exacerbate the The activation of immune system is another important source cytokine storm associated with virus infection, as described of chronic inflammation in virus-infected patients. Patients below. Accordingly, several meta-analysis were able to show with COVID-19 harbor high levels of inflammatory cytokines, that comparing with non-obese patients, obese COVID-19 which may activate the T-helper type 1 (Th1) cell response patients have higher risk to die (Santos et al., 2018; Halvatsiotis (Huang et al., 2020). The host inflammatory response is driven et al., 2020; Smith et al., 2020; Zheng et al., 2020). In addition, by binding to toll-like receptors (TLRs), which recognize it has been reported that obese aged patients are more likely structural components belonging to viruses, a process known to be admitted at UCI for ARDS, and have also higher risk as “pathogen-associated molecular patterns” (PAMPs; Janeway for fatality (Caussy et al., 2020; Lighter et al., 2020). and Medzhitov, 2002). Moreover, neutrophil infiltration in the A better understanding of the pathogenesis of SARS-CoV-2 lungs of individuals infected by SARS-CoV-2 may result in is supported by data generated from previous studies with the secretion of damage-associated molecular patterns (DAMPs), SARS-CoV and MERS-CoV; however, it is still under as a cell death signal following the viral invasion (Tang et al., 2012; construction. Mechanistically, the SARS-CoV-2 virus initially Cicco et al., 2020). binds to the angiotensin I converting enzyme (ACE)-2 receptor Thus, it has been suggested that the disturbance of via the spike glycoprotein envelope (S-protein) to enter into inflammatory homeostasis in elderly COVID-19 patients may the target cells (Wan et al., 2020b), a mechanism shared with play a pivotal role in the risk of a cytokine storm and subsequently SARS-CoV (Hofmann et al., 2005) but not by MERS-CoV, ARDS, enhancing the mortality risk (Koelman et al., 2019; that employs dipeptidyl-peptidase 4 (DPP4 or CD26) as a cell Williamson et al., 2020). In this review, we discuss the relationship entry receptor (Raj et al., 2013). After binding to ACE-2, the between senescence markers, present in elderly and obese virus envelope fuses with membrane epithelial cell, and the individuals, and the severity of COVID-19. We also highlight RNA strand is released into the cytoplasm of the host cell, the possibility that dietary polyphenols could be beneficial for initiating viral replication (Figure 1). Frontiers in Physiology | www.frontiersin.org 2 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation The ACE-2 receptor is broad and constitutively expressed injury was induced with LPS in rats of different ages, there in various tissues, such as heart and vascular endothelium was an imbalance of ACE/ACE2 ratio correlated with strong (Hamming et al., 2004; Burrell et al., 2005), kidneys (Donoghue inflammation, which lead to acute respiratory failure in the et al., 2000), gastrointestinal tract (Hamming et al., 2004), age-dependent way (Schouten et al., 2016). A clinical study lungs, mainly type II alveolar epithelial cells, and immune with patients of different age groups with ARDS demonstrated cells, including monocytes (mainly in the classical subset of that the activity of ACE1, ACE2, and the ACE2/ACE1 ratio CD14++ CD16− cells; Rutkowska-Zapała et al., 2015) and in bronchoalveolar lavage fluid was no different between macrophages (mainly in the M1 phenotype; He et al., 2006). groups of neonates, children, adults, or elderly (> 65 years; ACE-2 is the key enzyme in the balance between the production Schouten et al., 2019). These data indicate that we still need of angiotensin II (AngII) by the classical pathway of the renin to understand the role of alterations in the ACE2/ angiotensin system (RAS) and production of angiotensin 1–7 Angiotensin-(1–7)/MasR axis in the lung of elderly individuals. (Ang 1–7) that binds to the orphan MAS receptor (MasR) In the SARS-CoV-2 pandemic’s context, age-dependent decline triggering vasodilator, anti-inflammatory and antifibrotic events, of ACE2 expression have been associated with COVID-19 characterizing the “anti-RAS” pathway (Rodrigues Prestes et al., fatality (Chen et al., 2020a; Cristiani et al., 2020). 2017). After entering into the cell, SARS-CoV-2 virus represses ACE-2 expression, which results in an increase of AngII, and exacerbation of inflammation and pulmonary fibrosis (Dalan CYTOKINE STORM IN COVID-19 et al., 2020). The infection of lung epithelial cells and resident immune cells, such as macrophages and dendritic cells results Cytokine storm syndrome (CSS) is a systemic inflammatory in an important production of pro-inflammatory cytokines that response induced by a wide range of cytokines, resulting in contribute to the worsening of the disease. clinical manifestations, such as high fever, lymphadenopathy, In an experimental aging model, it was observed that the hepatosplenomegaly, hyperferritinaemia, and cytopaenia and, expression of pulmonary ACE2 was lower in old- versus if untreated, may progress to multiple organ failure and death young-rats (Xudong et al., 2006). However, when the lung (Behrens and Koretzky, 2017; Murthy et al., 2019). The formation of 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. Frontiers in Physiology | www.frontiersin.org 3 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation cytokine storm is characterized by a feedforward activation and was already found to be significantly elevated in severe of host immune that causes an uncontrollable release of a COVID-19 patients (Chen et al., 2020c; Wan et al., 2020a). several cytokines, such as IFN-gamma, tumor necrosis factor Similarly, the cytokine storm caused by unbalanced AngII/ (TNF)-α, interleukin (IL)-1, IL-6, and IL-18 resulting in immune Ang1–7 may also explain the direct cardiovascular system regulation disorder (Chousterman et al., 2017; Shimabukuro- injury of SARS-CoV-2 infected patients. Endothelial dysfunction Vornhagen et al., 2018). The continuous release of these cytokines can increase prothrombotic blood activity and myocarditis, triggers a loop reaction characterized by hyperactivation of which contributes to the high mortality rate observed in immune cells, including T cells, macrophages, dendritic, and COVID-19 patients (Shi et al., 2020a). Moreover, the virus- endothelial cells with further excessive cytokine releasing, which induced CSS associated with an unbalanced AngII/Ang1–7 in in turn, leads to a self-amplifying hyperinflammatory state kidney tubules and podocytes is pointed as responsible for known as cytokine storm (Crayne et al., 2019). acute kidney injury (Ahmadian et al., 2020). The multiple Immune response to SARS-CoV-2 infections initially consists organ injuries characterized by a high incidence of liver in an adaptive immune response necessary to control virus dysfunction, gastrointestinal, and neurological injuries, endocrine propagation and to prevent disease progression. Once the alterations, and cutaneous manifestation have also been observed virus gets to the lung tissue, it will initiate an inflammatory in non-surviving patients (D’Errico et al., 2020). response as part of its immunity to combat the infection The cytokine storm landscape of COVID-19 patients was (Li et al., 2020). There are strong evidences showing that further demonstrated in a retrospective study showing higher cytokine storms may participate in the pathogenesis of concentrations of IL-2, IL-7, IL-10, G-CSF, C-X-C motif COVID-19 (Chen et al., 2020d; Huang et al., 2020), similar chemokine ligand (CXCL)-10, C-C motif chemokine ligand to prior epidemics such as those caused by SARS and MERS (CCL)-2, CCL-3, and TNF-α in the plasma of severe COVID-19 (Channappanavar and Perlman, 2017; Mahallawi et al., 2018). patients (Huang et al., 2020; Lu et al., 2020). Similarly, previous Like many other pathogenic microorganisms, SARS-CoV-2 studies also showed higher levels of some cytokines, such as also evolves mechanisms in order to evade the host immune IFN-γ, TGF-β, IL-1, IL-6, IL-8, and IL-12 in the serum of system. The CSS caused by SARS-CoV-2 enhances the invasion SARS and MERS patients, highlighting the cytokine storm role and dissemination of the virus by recruiting different immune in the pathogenesis of severe coronaviruses infection cells to the lungs, resulting in an aggressive inflammatory (Channappanavar and Perlman, 2017). Thus, the severity and response (Figure 1). The rapid onset of spread inflammation pathogenicity of the viral infection could be directly correlated in the lungs of patients infected with SARS-CoV-2 could to the CSS, which implies that the management of lead to life-threatening respiratory disorders and subsequent hyperinflammation, the major cause of COVID-19 deaths, would death at the severe stage (Xu et al., 2020). Indeed, Wan significantly avoid fatal complications. Although there is no et al. (2020a) showed a reduction of 47.62% of natural killer standard diagnosis recognition of CSS in COVID-19, it has (NK) cells in severe COVID-19 patients. Remarkably, the been proposed that a sudden or rapid disease progression with autopsy findings revealed spleen and lymph node atrophy in multiple organ involvement, a significant decline of peripheral COVID-19 patients as well as diffused alveolar damage, and blood lymphocyte counts, and an increase of multiple cytokines, macrophages infiltration indicating that macrophages may such as IL-1β, IL-2R, IL-6, IFN-c, CXCL-10, CCL-2, CCL-3, also play an important role in CSS induced by SARS-CoV-2 and TNF-α are the main biomarkers of CSS in COVID-19 (Wei et al., 2020; Yao et al., 2020). patients (Gao et al., 2020). As previously mentioned, mechanistically the binding of Additionally, it has been proposed that overactivation the SARS-CoV-2 spike protein to ACE2 host receptor leads of NOD-, LRR-, and pyrin domain-containing protein 3 to the downregulation of ACE2, which in turn results in (NLRP3) inflammasome also has a central as a trigger of excessive secretion of AngII and reduced secretion of vasodilator cytokine storm. Mechanistically, the multiprotein complexes angiotensins. AngII plays an important role in proinflammatory form in the cytosol and drive caspase-1 cleavage and the response through angiotensin receptor 1 (AT1R). This activated secretion of the pro-inflammatory cytokines IL-1β and IL-18 pathway further activates nuclear factor kappa B (NF-kB), and other DAMPs (Ros et al., 2020). Moreover, it was which stimulates the overexpression of epidermal growth factor recently demonstrated that sirtuin 2 (SIRT2) directly represses receptor (EGFR) ligands and TNF-α (Eguchi et al., 2018). the NLRP3 inflammasome activity (He et al., 2020). Indeed, higher levels of ACE2 receptors in lung epithelial Accordingly, the well reported age-related decline in the cells in children and young adults may have a protective effect activity of the sirtuins (Massudi et al., 2012) might explain on severe COVID-19 clinical manifestations. On the other age-dependent increases in NLRP3 inflammasome activation hand, downregulation of ACE2 and unbalanced Ang II/Ang1–7 (Stout-Delgado et al., 2016). level during aging can enhance the cytokine storm (Cristiani It has been demonstrated that a viral protein, called viroporin et al., 2020). In addition, the hyperactivation of both NF-kB protein 3a leads to a direct activation of NLRP3 in SARS-CoV and activator of transcription (STAT)3, leads to a (Chen et al., 2019). Similarly, the presence of this protein in hyperinflammatory state mediated by amplification of IL-6, SARS-CoV-2 genome also suggest a direct activation of NLRP3 resulting in increased pulmonary vascular permeability (Mousavizadeh and Ghasemi, 2020). Indeed, patients with a (Murakami et al., 2019). The IL-6 is one of the major cytokines reduced immune capacity demonstrated a dysregulated NLRP3 involved in acute inflammation (Scheller and Rose-John, 2006) inflammasome activity, which results in severe COVID-19 with Frontiers in Physiology | www.frontiersin.org 4 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation tissue damage and a cytokine storm (van den Berg and te SENESCENCE AND COVID-19 Velde, 2020). Considering that NLRP3 is frequently over-activated in elderly individuals, it is believed that the NLRP3 inflammasome Cellular senescence was first reported by Hayflick and Moorehead plays a central role in the increased lethality observed in aged in 1961 (Hayflick and Moorhead, 1961) as a cellular state COVID-19 patients (Lara et al., 2020). characterized by replicative arrest and resistance to apoptosis Taking into account that COVID-19 is increasingly being (Kirkland, 1992). Several intra and extracellular signals can recognized as a syndrome of host inflammatory response, the activate molecular pathways, such as cyclin dependent kinase discovery of effective therapy approaches is urgently needed, inhibitor 2A (CDKN2A aka p16INK4a)-Rb, p53, and CDKN 1A especially in certain patients with prior inflammatory-related (CDKN1A akap21CIP1) to induce senescent cell fate (Beauséjour comorbidities, such as older age, specific genetic background, et al., 2003). Besides of the high level of these key regulators, or obesity, where the CSS promotes the progression to severe senescent cells can also present increased lysosomal β-galactosidase organ damage (Shi et al., 2020b). Although glucocorticoid, activity, high DNA damage detected by an accumulation of blood purification therapy, and biological agents, such as ƴH2AX, and telomere-associated foci and are usually larger than interleukins inhibitors may be beneficial to improve the outcome non-senescent cells (Kirkland and Tchkonia, 2020). Moreover, of patients with CSS-induced injury, the efficacy and safety terminal telomeric repeats shortening after each cell division of these approaches still needs to be elucidated in further during the lifespan is also a hallmark of cellular senescence. COVID-19 clinical trials (Qiu et al., 2013; Behrens and Koretzky, Senescent cells accumulate in different tissues during lifespan 2017; Chousterman et al., 2017; Kogelmann et al., 2017; e.g., in adipose tissue in conditions like diabetes and obesity, Norelli et al., 2018; Wang et al., 2020). in the hippocampi and frontal cortex in Alzheimer’s disease, As COVID-19 still lacks a specific effective-proven therapy, in the lungs of idiopathic pulmonary fibrosis individuals, in preventive measures could help to fighting off SARS-CoV-2 the liver of patients with cirrhosis, and in the kidneys of infection. It is well known that the decrease of fat mass diabetic kidney disease patients (Kirkland, 2013; Musi et al., normalizes the systemic inflammatory status of the body by 2018; Bian et al., 2019; Justice et al., 2019; Suvakov et al., reducing proinflammatory cytokines. Thus, a diet enriched in 2019; Liu and Liu, 2020). Thus, senescence is considered as functional ingredients that have anti-inflammatory, antioxidant, natural aging process that affects all cell types. and immunomodulatory properties should be incorporated in Some senescent cells may also have an hyperinflammatory the dietary routine, in particular of those individuals with state caused by secretion of cytokines, chemokines, growth factors, preexisting hyperinflammatory conditions as obesity or elderly. and matrix metalloproteinases, a phenomenon called SASP In this sense, there are some speculative studies about the (Ohtani, 2019). Importantly, cells in SASP can also induce potential association between vitamin D and the survival of senescence of surrounding cells, and may confer deleterious COVID-19 patients, which could be ascribe to its anti- effects in the tissue microenvironment (Acosta et al., 2013). inflammatory properties (Daneshkhah et al., 2020; Grant et al., The aging itself is also associated to the continual production 2020). It has also been shown that vitamin D has of pro-inflammatory factors, known as “inflammaging” (Sanada immunomodulatory properties and its deficiency is a risk factor et al., 2018; Koelman et al., 2019), which may lead to a chronic for persistent inflammation and the severe course of COVID- inflammation and organ dysfunction. Additionally, other studies 19, which might partly explain the geographic variations of suggest that the excess of reactive oxygen species (ROS) production COVID-19 mortality rate (Marik et al., 2020; Rhodes et al., during aging may favor an inflammatory landscape through the 2020). Another vitamin with potential beneficial role in increased secretion of pro-inflammatory cytokines, such as TNF-α, COVID-19 care management is ascorbic acid. Based on a new IL-1β, IL-2, and IL-6 (Garrido et al., 2019). Interestingly, the clinical trial in Wuhan, China, Carr et al. (Carr, 2020) suggested excess of pro-inflammatory cytokines can also increase the ROS the potential role of high-dose of ascorbic acid for the treatment production, sustaining the inflammaging phenotype (Biswas, 2016). and prevention of severe COVID-19. Additionally, several studies A key process in immunological aging, also known as have shown that vitamin B3 is highly effective in preventing immunosenescence, is the decrease of thymic activity in about lung tissue damage (Nagai et al., 1994). 99% in elderly people compared to newborns (Gruver et al., Moreover, it has been suggested that the anti-inflammatory 2007), declining the competency of the immune system to combat effects of polyphenols may help to overcome COVID-19 pathogen infections, such as SARS-CoV-2. Although severity. Considering the global emergency of this pandemic immunosenescence is described as the progressive loss of all with regard to the cost and availability of treatment especially immune effectors, Goronzy et al. (2001) have found a correlation in poor countries, it would be also interesting to know how specifically between CD8+CD28null T cells and the defective antibody effective polyphenols supplementation is in attenuating cytokine responses to influenza vaccine in elderly adults due to thymic storm in comparison to other agents. It is also important to involution. Indeed, the increase in these cells’ population has know at which stage of the COVID-19 the polyphenols been consistently observed and is currently used as a biomarker supplementation would be the most beneficial. Could they of immunosenescence in older individuals (Zanni et al., 2003). be used in the dietary routine as a prophylactic therapy to Accordantly, lymphopenia, decrease in CD4+ and CD8+ T cells prevent cytokine storm at early stages of the disease or would population, decrease of B cells and NK cells, monocytes, eosinophils, their anti-inflammatory and anti-oxidant properties delay and basophils are common feature in patients with severe COVID-19. viral dissemination? Currently, the available data suggest that the accumulation of Frontiers in Physiology | www.frontiersin.org 5 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation senescent T-cells negatively impact the prognosis of COVID-19, compounds, such as polyphenols, have been shown to effectively as the patients have an ineffective CD8+ response, as well as inhibit RNA viruses. Likewise, Zhang et al. (2020) selected an excessive cytokine secretion from the senescent cells biologically proven anti-SARS or MERS coronavirus natural (Cao, 2020; Huang et al., 2020; Qin et al., 2020). compounds and undertook molecular docking analysis to Adipose tissue is a key player in metabolism and inflammation predict the possible SARS-CoV-2 therapeutic effects of these modulation. The adipose tissue dysfunction during aging is herbal extracts. They observed that the polyphenols, such as likely associated with chronic inflammation (Stout et al., 2017). kaempferol, lignan, and quercetin among the 13 anti- As age advances, CD38+ macrophages and senescent cells inflammatory and anti-oxidant natural compounds potentially accumulate in visceral white adipose tissue producing high suitable for anti-viral usage. Similarly, the results of Singh levels of inflammatory cytokines in the microenvironment et al. (2020) suggested that the polyphenols epigallocatechin (Covarrubias et al., 2019). Indeed, a recent study reported gallate (EGCG), theaflavin-3-gallate (TF2a), theaflavin-3'-gallate that obese elderly adults have higher susceptibility to more (TF2b), and theaflavin-3,3'-digallate (TF3) can inhibit viral serious complications of COVID-19 as compared to younger RNA polymerase and may represent an effective therapy for patients. The authors have shown that the mortality rate for COVID-19. these COVID-19 patients was approximately 14% (Petrakis Even if the consumption of polyphenols is not enough to et al., 2020). One possible explanation for this observation guarantee a consistent anti-viral effect, many polyphenols have could be that the increased secretion of pro-inflammatory been identified as senolytic agents, which cause the selective cytokines by senescent adipocytes could lead to the cytokine death of senescent cells or regulate inflammmageing and storm in poor prognosis COVID-19 patients. immunosenencence. A panel that includes numerous Although the exact mechanisms of SARS-CoV-2 morbidity polyphenols in human and murine senescent fibroblasts and mortality in high risk patients still require extensive research, demonstrated that fisetin (a flavonoid present in fruits and we may speculate some hypothesis based on the previous vegetables, such as strawberry, apple, persimmon, grape, onion, SARS-CoV infection understanding, given the high (80%) genetic and cucumber) and curcumin, were those with the greatest similarity between both viruses (Yan et al., 2020). The strong senolitic activity (Khan et al., 2013). Fisetin treatment in correlation between obesity and the disease severity was previously mice with progeroid syndrome revealed a reduction in IL-6 reported in SARS-CoV infected patients. Furthermore, it has levels, which is mainly produced by adipose tissue (Yousefzadeh been reported that obese patients exhibit delayed and blunted et al., 2018). Moreover, it has been shown that quercetin, antiviral responses to influenza virus infection, and have poor apigenin, wogonin, and kaempferol inhibited the expression prognosis (Honce and Schultz-Cherry, 2019). Thus, it has been of several SASPs markers, including IL-1α, IL-1β, IL-6, IL-8, proposed that obesity may also be an important condition that GM-CSF, CXCL1, monocyte chemoattractant protein-2 increases the mortality risk of the SARS-CoV-2 infected patients (MCP-2), and MMP-3 in senescent fibroblasts model. (Petrakis et al., 2020). Indeed, the Centers for CDC advised Considering that apigenin was the most powerful to inhibit that people of any age who have serious underlying medical IL-6, the in vivo approach confirmed that this flavone, found conditions, including severe obesity [body mass index (BMI) > 40], mainly in aromatics as parsley, chamomile, celery, and oregano might be at higher risk for COVID-19 complications and severe (Shukla and Gupta, 2010), was able to significantly reduces illness (Centers for Disease Control and Prevention, 2020). SASP in the kidneys of aged rats (Lim et al., 2015). These findings highlight the importance to look for Chronic treatment with resveratrol, found abundantly in interventions that remove senescent cells as a preventive treatment the skins of red grapes, wine, peanuts, cocoa, and berries strategy against SARS-CoV-2 infection. In this sense, some (Burns et al., 2002), in senescent lung fibroblasts (MRC5 polyphenols (as quercetin and fisetin) and tyrosine kinase fibroblasts) reduced the production of IL-6, IL-8, GROα, and inhibitors (as dasatinib) have been used as senolytic therapy VEGF (Pitozzi et al., 2013). Additionally, it has been (Yousefzadeh et al., 2018; Hickson et al., 2019). Interestingly, demonstrated that senescence markers (e.g., IL-6 production) polyphenol-based senolytics alleviate dysfunction in murine was counteracted by resveratrol in neuroglial cells (Bigagli models of chronic lung diseases (Schafer et al., 2017), and et al., 2016), vascular smooth muscle cells (Csiszar et al., reduced the mortality of mice infected with mouse β-coronavirus 2012). Lastly, olive-derived polyphenols including oleuropein, and SARS-CoV-2 viral antigens (Kirkland and Tchkonia, 2020). found at very low level in edible table oil olive (Ben Othman These findings lead to health regulatory agencies around the et al., 2008), significantly reduced the senescence in world to approve a clinical trial to test flavonoids for elderly chondrocytes, synovial, and bone cells from osteoarthritic hospitalized COVID-19 patients to prevent progression to patients, an event that was accompanied by reduced activity cytokine storm and ARDS (Table 1). of the NF-kB transcription factor and reduced SASP markers, as IL-6, IL-1β, and COX-2 (Varela-Eirín et al., 2020). To date, there are data showing that mice treated for POLYPHENOLS AS A PROTECTIVE 18 months with resveratrol presented a significant reduction APPROACH in the expression of ACE1 and an increase in the expression of ACE2 in the aorta, which translated into an increase in Polyphenols are key dietary components in preventing serum levels of Ang (1–7) in parallel with the reduction inflammatory comorbidities. Interestingly, several plant-derived of AngII (Kim et al., 2018). Similar profile was observed Frontiers in Physiology | www.frontiersin.org 6 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation TABLE 1 | Clinical trials evaluating polyphenols in coronavirus disease 2019 (COVID-19) patients. Identifier Study title Intervention Status Primary Phase purpose study NCT04400890 Randomized proof-of-concept trial to evaluate the Plant Polyphenol and Vitamin D3 Recruiting Treatment Phase 2 safety and explore the effectiveness of a plant polyphenol for COVID-19 NCT04377789 Quercetin on prophylaxis and treatment of COVID-19 Quercetin 500 mg (Prophylaxis) Recruiting Prevention n.a. Quercetin 1,000 mg (Treatment) NCT04578158 Trial to study the adjuvant benefits of quercetin Quercetin 500 mg Recruiting Treatment Phase 2 phytosome in patients with COVID-19 NCT04468139 The Study of quadruple therapy zinc, quercetin, Quercetin (500 mg), bromelain (500 mg), zinc Recruiting Treatment Phase 4 bromelain, and vitamin C on the clinical outcomes of (50 mg), and vitamin c (1,000 mg) patients infected with COVID-19 NCT04622865 Masitinib combined with Isoquercetin and best Masitinib, Isoquercetin, and best supportive care Recruiting Treatment Phase 2 supportive care in hospitalized patients with moderate and severe COVID-19 NCT04536090 Study of Isoquercetin (IQC-950AN) plus standard of Isoquercetin (IQC-950AN) Not yet Treatment Phase 2 care vs. standard of care only for the treatment of recruiting COVID-19 NCT04404218 The Açaí Berry COVID-19 anti-inflammation trial (ACAI) 1,560 mg/day of Açaí Berry extract Recruiting Treatment Phase 2 NCT04392141 Colchicine plus phenolic monoterpenes to treat Oral administration of Colchicine plus Herbal Treatment Phase 2 COVID-19 Phenolic Monoterpene Fractions NCT04542993 Can SARS-CoV-2 viral load and COVID-19 disease Zinc Picolinate (50 mg) and Resveratrol (2 g) Recruiting Supportive Phase 2 severity be reduced by resveratrol-assisted zinc Care therapy (Reszinate) NCT04507867 Effect of a Nss to reduce complications in patients with NSS-1 (Spirulina Maxima 2.5 g), folic acid 5 mg, Not yet Supportive n.a. COVID-19 and comorbidities in stage III (type 2 DM, Glutamine 5 g, Cyanomax Ultra (10 g of powder), recruiting Care SAH, and overweight/obesity with BMI <35) ascorbic acid 1 g, zinc 20 mg, selenium 100 mcg, cholecalciferol 2000 IU, resveratrol 200 mg, concentrated omega 3 fatty acids (10 grams of powder), L-Arginine 1.5 g, and magnesium 400 mg NCT04382040 A Phase II, controlled clinical study designed to ArtemiC is a medical spray comprised of Artemisinin Recruiting Treatment Phase 2 evaluate the effect of ArtemiC in patients diagnosed (6 mg/ml), Curcumin (20 mg/ml), Frankincense with COVID-19 (=Boswellia; 15 mg/ml), and vitamin C (60 mg/ml) NCT04403646 Tannin specific natural extract for COVID-19 infection ARBOX [dry extract of polyphenols (tannins) form Not yet Treatment n.d. (TaCOVID) quebracho and chestnut 240 mg, B12 vitamin recruiting 0.72 μg] NCT04410510 P2Et extract in the symptomatic treatment of subjects P2Et (Caesalpinia spinosa extract) Recruiting Treatment Phase 2/3 with COVID-19 NCT04446065 Protection of health workers against COVID-19 Previfenon® (patent pending) provides 250 mg Not yet Prevention Phase 2/3 (HERD) EGCG recruiting n.a., not applicable; n.d., not described. in aged kidneys and was associated with improvement in restriction, which delay age-related diseases and to extend oxidative stress, inflammation, and renal fibrosis (Jang et al., life span in mammals (Fischer-Posovszky et al., 2010). 2018), suggesting that polyphenols could increase ACE2 Resveratrol also inhibited the activation of NLRP3 expression in aged subjects and that these alterations in inflammasome in liver of diet-induced obesity mice, reducing the ACE2/Angiotensin- (1–7)/MasR axis have beneficial IL-1, IL-6, and TNF-α production (Yang and Lim, 2014), results. Experimental data also demonstrated that resveratrol as well as, reduced NF-kb signaling and IL-6 expression in has an organ-protection function, protecting myocardium adipose tissue of monkeys fed with high caloric diet (Jimenez- in peritonitis/sepsis model (Shang et al., 2019), intestine, Gomez et al., 2013). Consumption of yerba mate, rich in liver, kidney, and lung injuries in a hemorrhagic shock model flavonoids like quercetin and rutin, and phenolic acids like (Müller et al., 2017). It has also been shown a protective chlorogenic and caffeic acid can control inflammation in role of curcumin and green tea polyphenols in a multiple obesity models (for review, see Gambero and Ribeiro, 2015). organ dysfunction syndrome model (Di Paola et al., 2006; Quercetin monotherapy or combined with resveratrol also Liu et al., 2016). showed anti-inflammatory activity in adipose tissue, reducing Furthermore, the consumption of a diet rich in polyphenols the IL-6 release (Zhao et al., 2017). Açai seeds extract, has often been claimed as a powerful aid in the control of which is rich in proanthocyanidins, in addition to controlling inflammatory response associated with obesity. The use of the production of inflammatory mediators, also reduced the resveratrol has been proven to be protective in obesity models expression of AT1 in the adipose tissue of obese mice (Santos through the activation of sirtuin-1, mimicking the caloric et al., 2020). Altogether, these data highlight the hypothesis Frontiers in Physiology | www.frontiersin.org 7 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation that these important bioactive dietary components might CONCLUSION AND PERSPECTIVES have modulatory effects on inflammatory pathways present in aging and obesity, as well as, on markers that are been The COVID-19 pandemic brought to light that changes in the associated with SARS-Cov-2 infection (Figure 1). cell physiology determined by senescence and inflammation Based on the literature evidence showing that polyphenols increase substantially the vulnerability of the elderly population might be helpful in protecting the body from the negative effects and those with comorbidities such as obesity. Indeed, “inflammaged of the disease, several clinical trials are ongoing to test such patients” are particularly susceptible to adverse clinical outcomes hypothesis. Indeed, a Phase 2 randomized double-blind placebo- during SARS-CoV-2 infection and the treatment is challenging. controlled study aims to explore the effectiveness of a commercial It has been shown that the changes in the expression of the plant polyphenols supplemented with vitamin D3 in a set of ACE-2 receptor, the imbalance in the angiotensin 1–7/AngII 200 mild COVID-19 patients (NCT04400890). Moreover, it has production which increases cardiovascular risk, as well as the been suggested that quercetin, a well-characterized antioxidant, increased production of pro-inflammatory cytokines observed anti-inflammatory and immunomodulatory compound would in aging and obesity models, can be reversed or controlled by be a good option in COVID-19 therapeutics (Solnier and Fladerer, bioactive substances from dietary sources, such as polyphenols. 2020). Currently, there are five clinical trials evaluating the Thus, the data presented here reinforce the hypothesis that adjuvant benefits of quercetin (alone or in combination) in polyphenols could have the potential for their use for senescence patients with COVID-19 (Table 1) The antiviral properties of and inflammation prevention and, therefore for the treatment/ resveratrol have also been shown both in vitro and in vivo management of patients with viral infections such as SARS- (Marinella, 2020). Thus, a Phase 2 study aiming to evaluate the CoV-2. It is hoped that the clinical studies under development effects of resveratrol as a means to minimize viral load and can add valuable information about this hypothesis and help severity of resulting COVID-19 disease (NCT04542993) is currently reduce suffering and mortality imposed by SARS-CoV-2 infection. ongoing. In addition, a resveratrol-containing nutritional support system is also under investigation to evaluate its effect in reducing complications and comorbidities in the evolution of patients AUTHOR CONTRIBUTIONS with COVID-19 (NCT04507867). Considering the protective anti-inflammatory and anti-viral effects of tannins (Ueda et al., The authors contributed equally to the writing and the revision 2013), a double-blind, randomized trial will be conducted in of this article. All authors contributed to the article and approved 140 COVID-19 patients to study the effect of the treatment the submitted version. with dry extract of tannins + B12 vitamin (NCT04403646). Based on promising unpublished in vitro and in vivo data, the Caesalpinia spinosa standardized polyphenol-rich P2Et extract FUNDING is currently in a Phase2/3 clinical trial (NCT04410510). The study aims to evaluate the efficacy of the supplement in reducing This study was supported by Conselho Nacional de the hospital stay of COVID-19 patients. A brief summary from Desenvolvimento Científico e Tecnológico (CNPq 303625/2019-8 the clinical trials including polyphenols is shown in Table 1. and 305402/2019-6). REFERENCES as a brain aging model: hallmarks of senescence, microRNA expression profiles, and comparison with in vivo models. J. Gerontol. A Biol. Sci. Med. Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Sci. 71, 50–60. doi: 10.1093/gerona/glu231 et al. (2013). A complex secretory program orchestrated by the inflammasome Biswas, S. K. (2016). Does the interdependence between oxidative stress and controls paracrine senescence. Nat. Cell Biol. 15, 978–990. doi: 10.1038/ncb2784 inflammation explain the antioxidant paradox? Oxidative Med. Cell. Longev. Ahmadian, E., Hosseiniyan Khatibi, S. M., Razi Soofiyani, S., Abediazar, S., 2016:5698931. doi: 10.1155/2016/5698931 Shoja, M. M., Ardalan, M., et al. (2020). Covid-19 and kidney injury: Burns, J., Yokota, T., Ashihara, H., Lean, M. E. J., and Crozier, A. (2002). pathophysiology and molecular mechanisms. Rev. Med. Virol. e2176. Plant foods and herbal sources of resveratrol. J. Agric. Food Chem. 50, doi:10.1002/rmv.2176 [Epub ahead of print] 3337–3340. doi: 10.1021/jf0112973 Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., Burrell, L. M., Risvanis, J., Kubota, E., Dean, R. G., MacDonald, P. S., Lu, S., et al. (2003). Reversal of human cellular senescence: roles of the p53 and et al. (2005). Myocardial infarction increases ACE2 expression in rat and p16 pathways. EMBO J. 22, 4212–4222. doi: 10.1093/emboj/cdg417 humans. Eur. Heart J. 26, 369–375. doi: 10.1093/eurheartj/ehi114 Behrens, E. M., and Koretzky, G. A. (2017). Review: cytokine storm syndrome: Cao, X. (2020). COVID-19: immunopathology and its implications for therapy. looking toward the precision medicine era. Arthritis Rheum. 69, 1135–1143. Nat. Rev. Immunol. 20, 269–270. doi: 10.1038/s41577-020-0308-3 doi: 10.1002/art.40071 Carr, A. C. (2020). A new clinical trial to test high-dose vitamin C in patients Ben Othman, N., Roblain, D., Thonart, P., and Hamdi, M. (2008). Tunisian with COVID-19. Crit. Care 24:133. doi: 10.1186/s13054-020-02851-4 table olive phenolic compounds and their antioxidant capacity. J. Food Sci. Caussy, C., Pattou, F., Wallet, F., Simon, C., Chalopin, S., Telliam, C., et al. 73, C235–C240. doi: 10.1111/j.1750-3841.2008.00711.x (2020). Prevalence of obesity among adult inpatients with COVID-19 in France. Bian, X., Griffin, T. P., Zhu, X., Islam, M. N., Conley, S. M., Eirin, A., et al. Lancet Diabetes Endocrinol. 8, 562–564. doi: 10.1016/S2213-8587(20)30160-1 (2019). Senescence marker activin a is increased in human diabetic kidney Centers for Disease Control and Prevention (2020). People who are at higher risk disease: association with kidney function and potential implications for therapy. for severe illness|CDC. Centers Dis. Control Prev. 68:703. doi: 10.4103/ijo.IJO_843_20 BMJ Open Diabetes Res. Care 7:e000720. doi: 10.1136/bmjdrc-2019-000720 Channappanavar, R., and Perlman, S. (2017). Pathogenic human coronavirus Bigagli, E., Luceri, C., Scartabelli, T., Dolara, P., Casamenti, F., infections: causes and consequences of cytokine storm and immunopathology. Pellegrini-Giampietro, D. E., et al. (2016). Long-term neuroglial cocultures Semin. Immunopathol. 39, 529–539. doi: 10.1007/s00281-017-0629-x Frontiers in Physiology | www.frontiersin.org 8 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation Chen, J., Jiang, Q., Xia, X., Liu, K., Yu, Z., Tao, W., et al. (2020a). Individual Di Paola, R., Mazzon, E., Muià, C., Crisafulli, C., Genovese, T., Di Bella, P., et al. variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. (2006). Green tea polyphenol extract attenuates zymosan-induced non-septic Aging Cell 19:e13168. doi: 10.1111/acel.13168 shock in mice. Shock 26, 402–409. doi: 10.1097/01.shk.0000191379.62897.1d Chen, J., Kelley, W. J., and Goldstein, D. R. (2020b). Role of aging and the Donoghue, M., Hsieh, F., Baronas, E., Godbout, K., Gosselin, M., Stagliano, N., immune response to respiratory viral infections: potential implications for et al. (2000). A novel angiotensin-converting enzyme-related carboxypeptidase COVID-19. J. Immunol. 205, 313–320. doi: 10.4049/jimmunol.2000380 (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res. 87, E1–E9. Chen, L., Liu, H. G., Liu, W., Liu, J., Liu, K., Shang, J., et al. (2020c). Analysis doi: 10.1161/01.res.87.5.e1 of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Eguchi, S., Kawai, T., Scalia, R., and Rizzo, V. (2018). Understanding angiotensin Zhonghua Jie He He Hu Xi Za Zhi 43:E005. doi: 10.3760/cma.j.issn. II type 1 receptor signaling in vascular pathophysiology. Hypertension 71, 1001-0939.2020.0005 804–810. doi: 10.1161/HYPERTENSIONAHA.118.10266 Chen, I. Y., Moriyama, M., Chang, M. F., and Ichinohe, T. (2019). Severe acute Fischer-Posovszky, P., Kukulus, V., Tews, D., Unterkircher, T., Debatin, K. M., respiratory syndrome coronavirus viroporin 3a activates the NLRP3 Fulda, S., et al. (2010). Resveratrol regulates human adipocyte number and inflammasome. Front. Microbiol. 10:50. doi: 10.3389/fmicb.2019.00050 function in a Sirt1-dependent manner. Am. J. Clin. Nutr. 92, 5–15. doi: Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., et al. (2020d). 10.3945/ajcn.2009.28435 Epidemiological and clinical characteristics of 99 cases of 2019 novel Freund, A., Orjalo, A. V., Desprez, P. Y., and Campisi, J. (2010). Inflammatory coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395, networks during cellular senescence: causes and consequences. Trends Mol. 507–513. doi: 10.1016/S0140-6736(20)30211-7 Med. 16, 238–246. doi: 10.1016/j.molmed.2010.03.003 Cheung, C. Y., Poon, L. L. M., Ng, I. H. Y., Luk, W., Sia, S. -F., Wu, M. H. S., Gambero, A., and Ribeiro, M. L. (2015). The positive effects of yerba maté et al. (2005). Cytokine responses in severe acute respiratory syndrome (Ilex paraguariensis) in obesity. Nutrients 7, 730–750. doi: 10.3390/nu7 coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. 020730 J. Virol. 79, 7819–7826. doi: 10.1128/jvi.79.12.7819-7826.2005 Gao, Y. -M., Xu, G., Wang, B., and Liu, B. -C. (2020). Cytokine storm syndrome Chousterman, B. G., Swirski, F. K., and Weber, G. F. (2017). Cytokine storm in coronavirus disease 2019: a narrative review. J. Intern. Med. doi:10.1111/ and sepsis disease pathogenesis. Semin. Immunopathol. 39, 517–528. doi: joim.13144 [Epub ahead of print] 10.1007/s00281-017-0639-8 Garrido, A., Cruces, J., Ceprián, N., Vara, E., and de la Fuente, M. (2019). Chung, H. Y., Kim, D. H., Lee, E. K., Chung, K. W., Chung, S., Lee, B., et al. Oxidative-inflammatory stress in immune cells from adult mice with premature (2019). Redefining chronic inflammation in aging and age-related diseases: aging. Int. J. Mol. Sci. 20:769. doi: 10.3390/ijms20030769 proposal of the senoinflammation concept. Aging Dis. 10, 367–382. doi: Goronzy, J. J., Fulbright, J. W., Crowson, C. S., Poland, G. A., O’Fallon, W. M., 10.14336/AD.2018.0324 and Weyand, C. M. (2001). Value of immunological markers in predicting Cicco, S., Cicco, G., Racanelli, V., and Vacca, A. (2020). Neutrophil extracellular responsiveness to influenza vaccination in elderly individuals. J. Virol. 75, traps (NETs) and damage-associated molecular patterns (DAMPs): two 12182–12187. doi: 10.1128/jvi.75.24.12182-12187.2001 potential targets for COVID-19 treatment. Mediat. Inflamm. 2020:7527953. Grant, W. B., Lahore, H., McDonnell, S. L., Baggerly, C. A., French, C. B., doi: 10.1155/2020/7527953 Aliano, J. L., et al. (2020). Evidence that vitamin d supplementation could Cocoros, N. M., Lash, T. L., Demaria, A., and Klompas, M. (2014). Obesity reduce risk of influenza and covid-19 infections and deaths. Nutrients 12:988. as a risk factor for severe influenza-like illness. Influenza Other Respir. Viruses doi: 10.3390/nu12040988 8, 25–32. doi: 10.1111/irv.12156 Gruver, A. L., Hudson, L. L., and Sempowski, G. D. (2007). Immunosenescence Coppe, J. P., Kauser, K., Campisi, J., and Beauséjour, C. M. (2006). Secretion of ageing. J. Pathol. 211, 144–156. doi: 10.1002/path.2104 of vascular endothelial growth factor by primary human fibroblasts at Halvatsiotis, P., Kotanidou, A., Tzannis, K., Jahaj, E., Magira, E., senescence. J. Biol. Chem. 281, 29568–29574. doi: 10.1074/jbc.M6033 Theodorakopoulou, M., et al. (2020). Demographic and clinical features of 07200 critically ill patients with COVID-19 in Greece: the burden of diabetes and Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., obesity. Diabetes Res. Clin. Pract. 166:108331. doi: 10.1016/j.diabres.2020.108331 Kasler, H. G., et al. (2020). Senescent cells promote tissue NAD+ decline Hamming, I., Timens, W., Bulthuis, M. L. C., Lely, A. T., Navis, G. J., and during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, van Goor, H. (2004). Tissue distribution of ACE2 protein, the functional 1265–1283. doi: 10.1038/s42255-020-00305-3 receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. Covino, M., De Matteis, G., Santoro, M., Sabia, L., Simeoni, B., Candelli, M., J. Pathol. 203, 631–637. doi: 10.1002/path.1570 et al. (2020). Clinical characteristics and prognostic factors in COVID-19 Hayflick, L., and Moorhead, P. S. (1961). The serial cultivation of human patients aged ≥80 years. Geriatr Gerontol Int 20, 704–708. doi: 10.1111/ diploid cell strains. Exp. Cell Res. 25, 585–621. doi: 10.1016/0014- ggi.13960 4827(61)90192-6 Crayne, C. B., Albeituni, S., Nichols, K. E., and Cron, R. Q. (2019). The He, M., Chiang, H. H., Luo, H., Zheng, Z., Qiao, Q., Wang, L., et al. (2020). immunology of macrophage activation syndrome. Front. Immunol. 10:119. An acetylation switch of the NLRP3 inflammasome regulates aging-associated doi: 10.3389/fimmu.2019.00119 chronic inflammation and insulin resistance. Cell Metab. 31:580.e5–591.e5. Cristiani, L., Mancino, E., Matera, L., Nenna, R., Pierangeli, A., Scagnolari, C., doi: 10.1016/j.cmet.2020.01.009 et al. (2020). Will children reveal their secret? The coronavirus dilemma. He, L., Ding, Y., Zhang, Q., Che, X., He, Y., Shen, H., et al. (2006). Expression Eur. Respir. J. 55:2000749. doi: 10.1183/13993003.00749-2020 of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected Csiszar, A., Sosnowska, D., Wang, M., Lakatta, E. G., Sonntag, W. E., and ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis Ungvari, Z. (2012). Age-associated proinflammatory secretory phenotype in of SARS. J. Pathol. 210, 288–297. doi: 10.1002/path.2067 vascular smooth muscle cells from the non-human primate Macaca mulatta: Hickson, L. T. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., reversal by resveratrol treatment. J. Gerontol. A Biol. Sci. Med. Sci. 67, Hashmi, S. K., et al. (2019). Senolytics decrease senescent cells in humans: 811–820. doi: 10.1093/gerona/glr228 preliminary report from a clinical trial of Dasatinib plus Quercetin in D’Errico, S., Zanon, M., Montanaro, M., Radaelli, D., Sessa, F., Di Mizio, G., individuals with diabetic kidney disease. EBioMedicine 47, 446–456. doi: et al. (2020). More than pneumonia: distinctive features of SARS-CoV-2 10.1016/j.ebiom.2019.08.069 infection. From autopsy findings to clinical implications: a systematic review. Hofmann, H., Pyrc, K., van der Hoek, L., Geier, M., Berkhout, B., and Microorganisms 8:1642. doi: 10.3390/microorganisms8111642 Pöhlmann, S. (2005). Human coronavirus NL63 employs the severe acute Dalan, R., Bornstein, S. R., El-Armouche, A., Rodionov, R. N., Markov, A., respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl. Wielockx, B., et al. (2020). The ACE-2 in COVID-19: foe or friend? Horm. Acad. Sci. U. S. A. 102, 7988–7993. doi: 10.1073/pnas.0409465102 Metab. Res. 52, 257–263. doi: 10.1055/a-1155-0501 Honce, R., and Schultz-Cherry, S. (2019). Impact of obesity on influenza a Daneshkhah, A., Agrawal, V., Eshein, A., Subramanian, H., Roy, H. K., and virus pathogenesis, immune response, and evolution. Front. Immunol. 10:1071. Backman, V. (2020). The possible role of Vitamin D in suppressing cytokine doi: 10.3389/fimmu.2019.01071 storm and associated mortality in COVID-19 patients. MedRxiv [Preprint]. Hu, H., Du, H., Li, J., Wang, Y., Wu, X., Wang, C., et al. (2020). Early prediction doi: 10.1101/2020.04.08.20058578 and identification for severe patients during the pandemic of COVID-19: Frontiers in Physiology | www.frontiersin.org 9 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation a severe COVID-19 risk model constructed by multivariate logistic regression Lighter, J., Phillips, M., Hochman, S., Sterling, S., Johnson, D., Francois, F., analysis. J. Glob. Health 10:020510. doi: 10.7189/jogh.10.020510 et al. (2020). Obesity in patients younger than 60 years is a risk factor for Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical COVID-19 hospital admission. Clin. Infect. Dis. 71, 896–897. doi: 10.1093/ features of patients infected with 2019 novel coronavirus in Wuhan, China. cid/ciaa415 Lancet 395, 497–506. doi: 10.1016/S0140-6736(20)30183-5 Lim, H., Park, H., and Kim, H. P. (2015). Effects of flavonoids on senescence- Imam, Z., Odish, F., Gill, I., O’Connor, D., Armstrong, J., Vanood, A., et al. associated secretory phenotype formation from bleomycin-induced senescence (2020). Older age and comorbidity are independent mortality predictors in in BJ fibroblasts. Biochem. Pharmacol. 96, 337–348. doi: 10.1016/j. a large cohort of 1305 COVID-19 patients in Michigan, United States. J. bcp.2015.06.013 Intern. Med. 288, 469–476. doi: 10.1111/joim.13119 Liu, R. M., and Liu, G. (2020). Cell senescence and fibrotic lung diseases. Janeway, C. A., and Medzhitov, R. (2002). Innate immune recognition. Annu. Exp. Gerontol. 132:110836. doi: 10.1016/j.exger.2020.110836 Rev. Immunol. 20, 197–216. doi: 10.1146/annurev.immunol.20.083001.084359 Liu, S., Zhang, J., Pang, Q., Song, S., Miao, R., Chen, W., et al. (2016). The Jang, I. A., Kim, E. N., Lim, J. H., Kim, M. Y., Ban, T. H., Yoon, H. E., et al. protective role of curcumin in zymosan-induced multiple organ dysfunction (2018). Effects of resveratrol on the renin-angiotensin system in the aging syndrome in mice. Shock 45, 209–219. doi: 10.1097/SHK.0000000000000502 kidney. Nutrients 10:1741. doi: 10.3390/nu10111741 Louie, J. K., Acosta, M., Samuel, M. C., Schechter, R., Vugia, D. J., Harriman, K., Jimenez-Gomez, Y., Mattison, J. A., Pearson, K. J., Martin-Montalvo, A., et al. (2011). A novel risk factor for a novel virus: obesity and 2009 pandemic Palacios, H. H., Sossong, A. M., et al. (2013). Resveratrol improves adipose influenza a (H1N1). Clin. Infect. Dis. 52, 301–312. doi: 10.1093/cid/ciq152 insulin signaling and reducestheinflammatoryresponsein adiposetissue of Lu, L., Zhang, H., Dauphars, D. J., and He, Y. -W. (2020). A potential role rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 18, 533–545. doi: of interleukin-10 in COVID-19 pathogenesis. Trends Immunol. doi:10.1016/j. 10.1016/j.cmet.2013.09.004 it.2020.10.012 [Epub ahead of print] Jun, J. -I., and Lau, L. F. (2010). The matricellular protein CCN1 induces Mahallawi, W. H., Khabour, O. F., Zhang, Q., Makhdoum, H. M., and Suliman, B. A. fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. (2018). MERS-CoV infection in humans is associated with a pro-inflammatory Cell Biol. 12, 676–685. doi: 10.1038/ncb2070 Th1 and Th17 cytokine profile. Cytokine 104, 8–13. doi: 10.1016/j.cyto.2018.01.025 Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Marik, P. E., Kory, P., and Varon, J. (2020). Does vitamin D status impact Hashmi, S. K., et al. (2019). Senolytics in idiopathic pulmonary fibrosis: mortality from SARS-CoV-2 infection? Med. Drug Discov. 6:100041. doi: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 10.1016/j.medidd.2020.100041 554–563. doi: 10.1016/j.ebiom.2018.12.052 Marinella, M. A. (2020). Indomethacin and resveratrol as potential treatment Khan, N., Syed, D. N., Ahmad, N., and Mukhtar, H. (2013). Fisetin: a dietary adjuncts for SARS-CoV-2/COVID-19. Int. J. Clin. Pract. 74:e13535. doi: antioxidant for health promotion. Antioxid. Redox Signal. 19, 151–162. doi: 10.1111/ijcp.13535 10.1089/ars.2012.4901 Massudi, H., Grant, R., Braidy, N., Guest, J., Farnsworth, B., and Guillemin, G. J. Kim, E. N., Kim, M. Y., Lim, J. H., Kim, Y., Shin, S. J., Park, C. W., et al. (2012). Age-associated changes in oxidative stress and NAD+ metabolism (2018). The protective effect of resveratrol on vascular aging by modulation in human tissue. PLoS One 7:e42357. doi: 10.1371/journal.pone.0042357 of the renin–angiotensin system. Atherosclerosis 270, 123–131. doi: 10.1016/j. Michaud, M., Balardy, L., Moulis, G., Gaudin, C., Peyrot, C., Vellas, B., et al. atherosclerosis.2018.01.043 (2013). Proinflammatory cytokines, aging, and age-related diseases. J. Am. Kirkland, J. L. (1992). The biochemistry of mammalian senescence. Clin. Biochem. Med. Dir. Assoc. 14, 877–882. doi: 10.1016/j.jamda.2013.05.009 25, 61–75. doi: 10.1016/0009-9120(92)80047-K Moser, J. A. S., Galindo-Fraga, A., Ortiz-Hernández, A. A., Gu, W., Hunsberger, S., Kirkland, J. L. (2013). Inflammation and cellular senescence: potential contribution Galán-Herrera, J. F., et al. (2019). Underweight, overweight, and obesity as to chronic diseases and disabilities with aging. Public Policy Aging Rep. 23, independent risk factors for hospitalization in adults and children from 12–15. doi: 10.1093/ppar/23.4.12 influenza and other respiratory viruses. Influenza Other Respir. Viruses 13, Kirkland, J. L., and Tchkonia, T. (2020). Senolytic drugs: from discovery to 3–9. doi: 10.1111/irv.12618 translation. J. Intern. Med. 288, 518–536. doi: 10.1111/joim.13141 Mousavizadeh, L., and Ghasemi, S. (2020). Genotype and phenotype of COVID-19: Koelman, L., Pivovarova-Ramich, O., Pfeiffer, A. F. H., Grune, T., and their roles in pathogenesis. J. Microbiol. Immunol. Infect. doi:10.1016/j. Aleksandrova, K. (2019). Cytokines for evaluation of chronic inflammatory jmii.2020.03.022 [Epub ahead of print] status in ageing research: reliability and phenotypic characterisation. Immun. Müller, T., Kirsch, M., and Petrat, F. (2017). Attenuation of multiple organ Ageing 16:11. doi: 10.1186/s12979-019-0151-1 damage by continuous low-dose solvent-free infusions of resveratrol after Kogelmann, K., Jarczak, D., Scheller, M., and Drüner, M. (2017). Hemoadsorption severe hemorrhagic shock in rats. Nutrients 9:889. doi: 10.3390/nu9080889 by CytoSorb in septic patients: a case series. Crit. Care 21:74. doi: 10.1186/ Murakami, M., Kamimura, D., and Hirano, T. (2019). Pleiotropy and specificity: s13054-017-1662-9 insights from the interleukin 6 family of cytokines. Immunity 50, 812–831. Laberge, R. M., Awad, P., Campisi, J., and Desprez, P. Y. (2012). Epithelial- doi: 10.1016/j.immuni.2019.03.027 mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron. Murthy, H., Iqbal, M., Chavez, J. C., and Kharfan-Dabaja, M. A. (2019). Cytokine 5, 39–44. doi: 10.1007/s12307-011-0069-4 release syndrome: current perspectives. Immunotargets Ther. 8, 43–52. doi: Lai, C. C., Shih, T. P., Ko, W. C., Tang, H. J., and Hsueh, P. R. (2020). Severe 10.2147/ITT.S202015 acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus Musi, N., Valentine, J. M., Sickora, K. R., Baeuerle, E., Thompson, C. S., disease-2019 (COVID-19): the epidemic and the challenges. Int. J. Antimicrob. Shen, Q., et al. (2018). Tau protein aggregation is associated with cellular Agents 55:105924. doi: 10.1016/j.ijantimicag.2020.105924 senescence in the brain. Aging Cell 17:e12840. doi: 10.1111/acel.12840 Lara, P. C., Macías-Verde, D., and Burgos-Burgos, J. (2020). Age-induced NLRP3 Nagai, A., Matsumiya, H., Hayashi, M., Yasui, S., Okamoto, H., and Konno, K. inflammasome over-activation increases lethality of SARS-CoV-2 pneumonia (1994). Effects of nicotinamide and niacin on bleomycin-induced acute injury in elderly patients. Aging Dis. 11, 756–762. doi: 10.14336/ad.2020.0601 and subsequent fibrosis in hamster lungs. Exp. Lung Res. 20, 263–281. doi: Lau, S. K. P., Lau, C. C. Y., Chan, K. H., Li, C. P. Y., Chen, H., Jin, D. Y., 10.3109/01902149409064387 et al. (2013). Delayed induction of proinflammatory cytokines and suppression Naylor, R. M., Baker, D. J., and van Deursen, J. M. (2013). Senescent cells: a of innate antiviral response by the novel Middle East respiratory syndrome novel therapeutic target for aging and age-related diseases. Clin. Pharmacol. coronavirus: implications for pathogenesis and treatment. J. Gen. Virol. 94, Ther. 93, 105–116. doi: 10.1038/clpt.2012.193 2679–2690. doi: 10.1099/vir.0.055533-0 Nguyen, S., Major, K., Cochet, C., Bizzozzero, T., Barbarossa, L., Bosshard, W., Law, H. K. W., Chung, Y. C., Hoi, Y. N., Sin, F. S., Yuk, O. C., Luk, W., et al. et al. (2020). COVID-19 infection in the elderly in French-speaking Switzerland: (2005). Chemokine up-regulation in SARS-coronavirus-infected, monocyte- an inventory of beliefs, convictions and certainties. Rev. Med. Suisse 16, derived human dendritic cells. Blood 106, 2366–2374. doi: 10.1182/ 835–838. blood-2004-10-4166 Norelli, M., Camisa, B., Barbiera, G., Falcone, L., Purevdorj, A., Genua, M., Li, G., Fan, Y., Lai, Y., Han, T., Li, Z., Zhou, P., et al. (2020). Coronavirus et al. (2018). Monocyte-derived IL-1 and IL-6 are differentially required infections and immune responses. J. Med. Virol. 92, 424–432. doi: 10.1002/ for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. jmv.25685 Med. 24, 739–748. doi: 10.1038/s41591-018-0036-4 Frontiers in Physiology | www.frontiersin.org 10 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation Ohtani, N. (2019). Deciphering the mechanism for induction of senescence- Shang, X., Lin, K., Yu, R., Zhu, P., Zhang, Y., Wang, L., et al. (2019). Resveratrol associated secretory phenotype (SASP) and its role in ageing and cancer protects the myocardium in sepsis by activating the phosphatidylinositol development. J. Infect. Dis. doi:10.1093/jb/mvz055 [Epub ahead of print] 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and Petrakis, D., Margină, D., Tsarouhas, K., Tekos, F., Stan, M., Nikitovic, D., inhibiting the nuclear factor-κB (NF-κB) signaling pathway. Med. Sci. Monit. et al. (2020). Obesity—a risk factor for increased COVID-19 prevalence, 25, 9290–9298. doi: 10.12659/MSM.918369 severity and lethality (review). Mol. Med. Rep. 22, 9–19. doi: 10.3892/ Shi, S., Qin, M., Shen, B., Cai, Y., Liu, T., Yang, F., et al. (2020a). Association mmr.2020.11127 of Cardiac Injury with mortality in hospitalized patients with COVID-19 in Pitozzi, V., Mocali, A., Laurenzana, A., Giannoni, E., Cifola, I., Battaglia, C., Wuhan, China. JAMA Cardiol. 5, 802–810. doi: 10.1001/jamacardio.2020.0950 et al. (2013). Chronic resveratrol treatment ameliorates cell adhesion and Shi, Y., Wang, Y., Shao, C., Huang, J., Gan, J., Huang, X., et al. (2020b). mitigates the inflammatory phenotype in senescent human fibroblasts. J. COVID-19 infection: the perspectives on immune responses. Cell Death Gerontol. A Biol. Sci. Med. Sci. 68, 371–381. doi: 10.1093/gerona/gls183 Differ. 27, 1451–1454. doi: 10.1038/s41418-020-0530-3 Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., et al. (2020). Dysregulation Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M., Stemmler, H. J., of immune response in patients with COVID-19 in Wuhan, China. Clin. Schlößer, H. A., Schlaak, M., et al. (2018). Cytokine release syndrome. Infect. Dis. 71, 762–768. doi: 10.1093/cid/ciaa248 J. Immunother. Cancer 6:56. doi: 10.1186/s40425-018-0343-9 Qiu, P., Cui, X., Sun, J., Welsh, J., Natanson, C., and Eichacker, P. Q. (2013). Shukla, S., and Gupta, S. (2010). Apigenin: a promising molecule for cancer Antitumor necrosis factor therapy is associated with improvedsurvival in prevention. Pharm. Res. 27, 962–978. doi: 10.1007/s11095-010-0089-7 clinical sepsis trials: a meta-analysis. Crit. Care Med. 41, 2419–2429. doi: Singh, S., Sonawane, A., and Sadhukhan, S. (2020). Plant-derived natural 10.1097/CCM.0b013e3182982add polyphenols as potential antiviral drugs against SARS-CoV-2 via RNA- Rabi, F. A., Al Zoubi, M. S., Al-Nasser, A. D., Kasasbeh, G. A., and Salameh, D. M. dependent RNA Polymerase (RdRp) Inhibition: An In-Silico Analysis. (2020). Sars-cov-2 and coronavirus disease 2019: what we know so far. ChemRxiv [Preprint]. doi:10.26434/CHEMRXIV.12312263.V1 Pathogens 9:231. doi: 10.3390/pathogens9030231 Smith, A. A., Fridling, J., Ibhrahim, D., and Porter, P. S. (2020). Identifying Raj, V. S., Mou, H., Smits, S. L., Dekkers, D. H. W., Müller, M. A., Dijkman, R., patients at greatest risk of mortality due to COVID-19: a New England et al. (2013). Dipeptidyl peptidase 4 is a functional receptor for the emerging perspective. West. J. Emerg. Med. 21, 785–789. doi: 10.5811/westjem.2020.6.47957 human coronavirus-EMC. Nature 495, 251–254. doi: 10.1038/nature12005 Solnier, J., and Fladerer, J. P. (2020). Flavonoids: a complementary approach Rhodes, J. M., Subramanian, S., Laird, E., and Kenny, R. A. (2020). Editorial: to conventional therapy of COVID-19? Phytochem. Rev. doi:10.1007/ low population mortality from COVID-19 in countries south of latitude s11101-020-09720-6 [Epub ahead of print] 35 degrees north supports vitamin D as a factor determining severity. Stout, M. B., Justice, J. N., Nicklas, B. J., and Kirkland, J. L. (2017). Physiological Aliment. Pharmacol. Ther. 51, 1434–1437. doi: 10.1111/apt.15777 aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology Rodrigues Prestes, T. R., Rocha, N. P., Miranda, A. S., Teixeira, A. L., and 32, 9–19. doi: 10.1152/physiol.00012.2016 Simoes-e-Silva, A. C. (2017). The anti-inflammatory potential of ACE2/ Stout-Delgado, H. W., Cho, S. J., Chu, S. G., Mitzel, D. N., Villalba, J., angiotensin-(1-7)/mas receptor axis: evidence from basic and clinical research. El-Chemaly, S., et al. (2016). Age-dependent susceptibility to pulmonary Curr. Drug Targets 18, 1301–1313. doi: 10.2174/1389450117666160727142401 fibrosis is associated with NLRP3 inflammasome activation. Am. J. Respir. Ros, U., Pedrera, L., and Garcia-Saez, A. J. (2020). Partners in crime: the Cell Mol. Biol. 55, 252–263. doi: 10.1165/rcmb.2015-0222OC interplay of proteins and membranes in regulated necrosis. Int. J. Mol. Sci. Suvakov, S., Cubro, H., White, W. M., Butler Tobah, Y. S., Weissgerber, T. L., 21:2412. doi: 10.3390/ijms21072412 Jordan, K. L., et al. (2019). Targeting senescence improves angiogenic potential Ruan, Q., Yang, K., Wang, W., Jiang, L., and Song, J. (2020). Clinical predictors of adipose-derived mesenchymal stem cells in patients with preeclampsia. of mortality due to COVID-19 based on an analysis of data of 150 patients Biol. Sex Differ. 10:49. doi: 10.1186/s13293-019-0263-5 from Wuhan, China. Intensive Care Med. 46, 846–848. doi: 10.1007/ Tang, D., Kang, R., Coyne, C. B., Zeh, H. J., and Lotze, M. T. (2012). PAMPs s00134-020-05991-x and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. Rutkowska-Zapała, M., Suski, M., Szatanek, R., Lenart, M., Weglarczyk, K., 249, 158–175. doi: 10.1111/j.1600-065X.2012.01146.x Olszanecki, R., et al. (2015). Human monocyte subsets exhibit divergent Ueda, K., Kawabata, R., Irie, T., Nakai, Y., Tohya, Y., and Sakaguchi, T. (2013). angiotensin I-converting activity. Clin. Exp. Immunol. 181, 126–132. doi: Inactivation of pathogenic viruses by plant-derived tannins: strong effects 10.1111/cei.12612 of extracts from persimmon (Diospyros kaki) on a broad range of viruses. Sanada, F., Taniyama, Y., Muratsu, J., Otsu, R., Shimizu, H., Rakugi, H., et al. PLoS One 8:e55343. doi: 10.1371/journal.pone.0055343 (2018). Source of chronic inflammation in aging. Front. Cardiovasc. Med. van den Berg, D. F., and te Velde, A. A. (2020). Severe COVID-19: NLRP3 inflammasome 5:12. doi: 10.3389/fcvm.2018.00012 dysregulated. Front. Immunol. 11:1580. doi: 10.3389/fimmu.2020.01580 Santos, I. B., de Bem, G. F., da Costa, C. A., de Carvalho, L. C. R. M., van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature 509, de Medeiros, A. F., Silva, D. L. B., et al. (2020). Açaí seed extract prevents 439–446. doi: 10.1038/nature13193 the renin-angiotensin system activation, oxidative stress and inflammation van Kerkhove, M. D., Vandemaele, K. A. H., Shinde, V., Jaramillo-Gutierrez, G., in white adipose tissue of high-fat diet–fed mice. Nutr. Res. 79, 35–49. doi: Koukounari, A., Donnelly, C. A., et al. (2011). Risk factors for severe 10.1016/j.nutres.2020.05.006 outcomes following 2009 influenza a (H1N1) infection: a global pooled Santos, J. C., Gambeloni, R. Z., Roque, A. T., Oeck, S., and Ribeiro, M. L. analysis. PLoS Med. 8:e1001053. doi: 10.1371/journal.pmed.1001053 (2018). Epigenetic mechanisms of ATM activation after helicobacter pylori Varela-Eirín, M., Carpintero-Fernández, P., Sánchez-Temprano, A., infection. Am. J. Pathol. 188, 329–335. doi: 10.1016/j.ajpath.2017.10.005 Varela-Vázquez, A., Paíno, C. L., Casado-Díaz, A., et al. (2020). Senolytic Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., activity of small molecular polyphenols from olive restores chondrocyte et al. (2017). Cellular senescence mediates fibrotic pulmonary disease. Nat. redifferentiation and promotes a pro-regenerative environment in osteoarthritis. Commun. 8:14532. doi: 10.1038/ncomms14532 Aging 12, 15882–15905. doi: 10.18632/aging.103801 Scheller, J., and Rose-John, S. (2006). Interleukin-6 and its receptor: from Wan, Y., Shang, J., Graham, R., Baric, R. S., and Li, F. (2020b). Receptor bench to bedside. Med. Microbiol. Immunol. 195, 173–183. doi: 10.1007/ recognition by the novel coronavirus from Wuhan: an analysis based on s00430-006-0019-9 decade-long structural studies of SARS coronavirus. J. Virol. 94, e00127–e00120. Schouten, L. R. A., Helmerhorst, H. J. F., Wagenaar, G. T. M., Haltenhof, T., doi: 10.1128/jvi.00127-20 Lutter, R., Roelofs, J. J. T. H., et al. (2016). Age-dependent changes in the Wan, S., Yi, Q., Fan, S., Lv, J., Zhang, X., Guo, L., et al. (2020a). Characteristics pulmonary renin-angiotensin system are associated with severity of lung of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized injury in a model of acute lung injury in rats. Crit. Care Med. 44, patients with 2019 novel coronavirus pneumonia (NCP). medRxiv [Preprint]. e1226–e1235. doi: 10.1097/CCM.0000000000002008 doi: 10.1101/2020.02.10.20021832 Schouten, L. R., van Kaam, A. H., Kohse, F., Veltkamp, F., Bos, L. D., Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., et al. (2020). Clinical de Beer, F. M., et al. (2019). Age-dependent differences in pulmonary host characteristics of 138 hospitalized patients with 2019 novel coronavirus- responses in ARDS: a prospective observational cohort study. Ann. Intensive infected pneumonia in Wuhan, China. JAMA. 323, 1061–1069. doi: 10.1001/ Care 9:55. doi: 10.1186/s13613-019-0529-4 jama.2020.1585 Frontiers in Physiology | www.frontiersin.org 11 January 2021 | Volume 11 | Article 612268 Santos et al. Polyphenols Improving COVID-19 Inflammation Wei, P.-F. (Released by National Health Commission & National Administration Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., of Traditional Chinese Medicine on March 3, 2020) (2020). Diagnosis and Xu, M., et al. (2018). Fisetin is a senotherapeutic that extends health and treatment protocol for novel coronavirus pneumonia (Trial Version 7). Chin. lifespan. EBioMedicine 36, 18–28. doi: 10.1016/j.ebiom.2018.09.015 Med. J. 133, 1087–1095. doi: 10.1097/CM9.0000000000000819 Zanni, F., Vescovini, R., Biasini, C., Fagnoni, F., Zanlari, L., Telera, A., et al. Webmeter (2020). Coronavirus Age, Sex, Demographics (COVID-19)—Worldometer. (2003). Marked increase with age of type 1 cytokines within memory and Available at: www.worldometers.info (Accessed December 01, 2020). effector/cytotoxic CD8+ T cells in humans: a contribution to understand Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., the relationship between inflammation and immunosenescence. Exp. Gerontol. et al. (2020). OpenSAFELY: factors associated with COVID-19 death in 17 38, 981–987. doi: 10.1016/S0531-5565(03)00160-8 million patients. Nature 584, 430–436. doi: 10.1038/s41586-020-2521-4 Zhang, D. -H., Wu, K. -L., Zhang, X., Deng, S. -Q., and Peng, B. (2020). In World Health Organization (2020). WHO coronavirus disease (COVID-19) silico screening of Chinese herbal medicines with the potential to directly Dashboard. World Heal. Organ. inhibit 2019 novel coronavirus. J. Integr. Med. 18, 152–158. doi: 10.1016/j. Wu, J. T., Leung, K., Bushman, M., Kishore, N., Niehus, R., de Salazar, P. M., joim.2020.02.005 et al. (2020). Estimating clinical severity of COVID-19 from the transmission Zhao, L., Cen, F., Tian, F., Li, M. J., Zhang, Q., Shen, H. Y., et al. (2017). dynamics in Wuhan, China. Nat. Med. 26, 506–510. doi: 10.1038/ Combination treatment with quercetin and resveratrol attenuates high fat s41591-020-0822-7 diet-induced obesity and associated inflammation in rats via the AMPKα1/ Wu, Z., and McGoogan, J. M. (2020). Characteristics of and important lessons SIRT1 signaling pathway. Exp. Ther. Med. 14, 5942–5948. doi: 10.3892/ from the coronavirus disease 2019 (COVID-19) outbreak in China. JAMA etm.2017.5331 323, 1239–1242. doi: 10.1001/jama.2020.2648 Zheng, Z., Peng, F., Xu, B., Zhao, J., Liu, H., Peng, J., et al. (2020). Risk factors Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., et al. (2020). of critical & mortal COVID-19 cases: a systematic literature review and Pathological findings of COVID-19 associated with acute respiratory distress meta-analysis. J. Inf. Secur. 81, e16–e25. doi: 10.1016/j.jinf.2020.04.021 syndrome. Lancet Respir. Med. 8, 420–422. doi: 10.1016/S2213-2600(20) Zhou, P., Yang, X. -L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., et al. 30076-X (2020). A pneumonia outbreak associated with a new coronavirus of probable Xudong, X., Junzhu, C., Xingxiang, W., Furong, Z., and Yanrong, L. (2006). bat origin. Nature 579, 270–273. doi: 10.1038/s41586-020-2012-7 Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 78, 2166–2171. doi: 10.1016/j.lfs.2005.09.038 Conflict of Interest: The authors declare that the research was conducted in Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., and Zhou, Q. (2020). Structural the absence of any commercial or financial relationships that could be construed basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science as a potential conflict of interest. 367, 1444–1448. doi: 10.1126/science.abb2762 Yang, S. J., and Lim, Y. (2014). Resveratrol ameliorates hepatic metaflammation Copyright © 2021 Santos, Ribeiro and Gambero. This is an open-access article and inhibits NLRP3 inflammasome activation. Metabolism 63, 693–701. doi: distributed under the terms of the Creative Commons Attribution License (CC BY). 10.1016/j.metabol.2014.02.003 The use, distribution or reproduction in other forums is permitted, provided the Yao, X. H., Li, T. Y., He, Z. C., Ping, Y. F., Liu, H. W., Yu, S. C., et al. (2020). original author(s) and the copyright owner(s) are credited and that the original A pathological report of three COVID-19 cases by minimally invasive publication in this journal is cited, in accordance with accepted academic practice. autopsies. Zhonghua Bing Li Xue Za Zhi 49, 411–417. doi: 10.3760/cma.j. No use, distribution or reproduction is permitted which does not comply with cn112151-20200312-00193 these terms. Frontiers in Physiology | www.frontiersin.org 12 January 2021 | Volume 11 | Article 612268