Cellular senescence is caused by repeated cell divisions and cellular stressors (Kelley et al., 2020). Replicative senescence results from repeated cellular divisions and has been confirmed to be related to the gradual shortening of telomeres during cell division (Shay, 2016; Lynch et al., 2021). Stress-induced senescence arises from cellular stressors, such as oncogene activation, DNA damage, reactive oxygen species (ROS), mitochondrial dysfunction and epigenetic stress (Hernandez-Segura et al., 2018), which may result from irradiation, chemotherapeutic drugs, pathogen infections, long-term exposure to pollutants (cigarette smoke) and certain aging syndromes such as progeria (Nyunoya et al., 2006; Nyunoya et al., 2009; Wheaton et al., 2017; Kelley et al., 2020; Di Micco et al., 2021) ( Figure 1 ). Therefore, cells from both young and aged hosts may exhibit senescent properties (Kelley et al., 2020).

Activation of DNA damage response (DDR) signaling cascades initiated by nucleus DNA double-strand breaks (DSBs) is considered to be a common factor to induce cellular senescence (Di Micco et al., 2021). Specifically, there are two kinases upstream of DDR, known as ataxia telangiectasia mutated (ATM) and ATM- and Rad3-Related (ATR) protein kinases, they are respectively activated by the MRE11-RAD50-NBS1 (MRN) complex at DSBs and the TopBP1 or ETAA1 at replication protein A coated ssDNA (RPA-ssDNA). Activated ATR and ATM can further phosphorylate the downstream kinases CHK1 and CHK2, respectively, which in turn activate the p53 pathway, leading to cell cycle arrest (Blackford and Jackson, 2017; Di Micco et al., 2021). Importantly, factors that can cause DNA damage, such as telomere shortening, oncogene activation and ROS, would ultimately be involved in activating the DDR pathway(van Deursen, 2014). If DNA damage from various causes persists, prolonged DDR signaling and proliferation arrest can invoke the onset of cellular senescence (Fumagalli et al., 2014). In addition, studies have reported that IFN-β secreted by senescent cells can stimulate DDR through ROS and generate senescence-like cell cycle arrest in human fibroblasts, which can trigger positive feedback activation of DDR and further amplify the senescence phenotype (Yu et al., 2015).

Senescent cells have various characteristics (Hernandez-Segura et al., 2018) ( Figure 1 ): (1) Morphologically, senescent cells are abnormally enlarged and flattened, with a disproportionate increase in the cytoplasm and nuclei (Bent et al., 2016; Druelle et al., 2016; Cormenier et al., 2018; Di Micco et al., 2021); changes in the composition of the plasma membrane, such as caveolin-1 protein upregulation (Dasari et al., 2006; Chrétien et al., 2008; Althubiti et al., 2014); increased lysosome content and some proteins (Cho and Hwang, 2012); accumulated mitochondria and decreased membrane potential (MMP) (Passos et al., 2007; Korolchuk et al., 2017; Tai et al., 2017); nuclear membrane structural protein loss, such as the downregulation of LaminB1 protein and presence of nuclear senescence-associated heterochromatin foci (SAHFs) with detectable dense 4’,6-diamidino-2-phenylindole (DAPI)-positive nuclear structural features (Di Micco et al., 2011; Sadaie et al., 2013); (2) Elevated senescence-associated β-galactosidase (SA-β-gal) activity: SA-β-gal is a lysosomal-derived enzyme that is regarded as a surrogate marker for increased lysosomal content in senescent cells and is one of the most common markers of senescence (Dimri et al., 1995; Kurz et al., 2000; Lee et al., 2006); (3) Accumulation of cyclin-dependent kinase inhibitors (CDKis): Senescence-related cell cycle arrest is primarily driven by CDKis encoded at CDKN2A (p16^INK4a or p16), CDKN2B (p15^INK4b or p15) and CDKN1A (p21^CIP1 or p21) loci. p21 and p16 maintain the tumor suppressor protein pRb in an inactive hypophosphorylated state, thereby preventing the transcription factor E2F from transcribing genes that promote cell cycle progression, and both are often used as unique senescence hallmarks to identify senescent cells in tissues and cultured cells (Narita et al., 2003; Baker et al., 2011; Di Micco et al., 2021); (4) Senescence-associated secretory phenotype (SASP): SASP consists of various cytokines, chemokines and some enzymes involved in extracellular matrix remodeling, mainly including IL-1α/β, IL-6, IL-8, TNF-α, TGF-β, monocyte chemotactic protein 1 (MCP1, also known as CCL-2) and matrix metalloproteinases (MMPs). SASP is thought to be the main mechanism by which senescent cells exert their pleiotropic biological functions and can also induce paracrine senescence (Freund et al., 2010; Acosta et al., 2013; Tchkonia et al., 2013; Gorgoulis et al., 2019); (5) Enhanced apoptosis resistance: Senescent cells stimulate a wide range of pro-survival factors, such as BCL-2 family members, particularly Bcl-xL and Bcl-w, which can be resistant to apoptosis and favor the survival of senescent cells (Childs et al., 2014; Yosef et al., 2016).

Defects associated with aging of the immune system are another feature of aging, termed “immunosenescence” (Kelley et al., 2020). It is characterized by decreased proliferation of hematopoietic stem cells, dysfunction of innate immunity, degeneration of the thymus and reduced numbers of naïve T and B cells, as well as accumulation of memory T and B cells, and decline in T and B cell functions (Kelley et al., 2020; Xu et al., 2020). Immunosenescence is associated with increased susceptibility to various diseases, such as infections, cancer, cardiovascular diseases, hypertension, diabetes, neurological dysfunction, and autoimmune diseases (Xu et al., 2020).

As aging occurs, cumulative senescent cells accelerate chronic inflammation through senescence-associated secretory phenotype (SASP), whereby SASP demonstrates a double-edged sword role (Hernandez-Segura et al., 2017). On the one hand, short-term SASP secretion promotes tissue repair and wound healing (Jun and Lau, 2010; Demaria et al., 2014) and enhances immune surveillance to inhibit tumor progression and pathological fibrosis (Xue et al., 2007; Krizhanovsky et al., 2008; Kang et al., 2011; Sagiv et al., 2016), while on the other hand, prolonged SASP secretion contributes to the development of age-related chronic inflammatory diseases by triggering over-recruitment of immune cells (Muñoz-Espín and Serrano, 2014; Childs et al., 2015; He and Sharpless, 2017). Excessive SASP can also recruit immature myeloid cells to favor tumorigenesis and tumor progression in a paracrine manner and affect tissue regeneration by limiting the proliferative potential of stem and progenitor cells (Yoshimoto et al., 2013; Di Mitri et al., 2014; Eggert et al., 2016; Gonzalez-Meljem et al., 2017; Di Micco et al., 2021). The mechanisms of excessive inflammation and tissue damage caused by aging may involve the abnormal activation of the mtDNA/CCFs-cGAS-STING pathway and NLRP3 inflammasome, the role of pre-activated macrophages and over-recruited immune cells and the accumulation of innate immune cells with trained immunity ( Figure 2 ).

The effects of viral infections on the organism often involve multiple systems and organs. For example, SARS-CoV-2, a respiratory virus, in addition to causing lung infection, the virus can also replicate in cells of the intestine, liver and kidney, thus causing a variety of clinical symptoms other than the respiratory tract, such as gastrointestinal disorders, liver and kidney dysfunction (Chu et al., 2020) and even multi-organ failure (Chen et al., 2020). However, there is growing evidence supporting the role of aging in multi-organ dysfunction caused by viral infections ( Figure 2 ).

Coagulation abnormalities and thrombosis can occur in the late stages in patients with viral infections and are often associated with poor prognosis (Nehme et al., 2020). Several factors, however, including aging, have been shown to be risk factors for vascular dysfunction (Nehme et al., 2020). On the one hand, senescent cells can secrete large amounts of SASP pro-inflammatory mediators that may trigger endothelial injury and favor thrombosis. On the other hand, together with inflammatory factors, senescent endothelial cells can shift the balance between pro- and anticoagulant pathways towards an elevated risk for thrombosis via the upregulation of factors that induce platelet aggregation such as plasminogen activator inhibitor-1 (PAI-1), thromboxane A2 (TXA2) and von Willebrand factor (vWF), while downregulating factors that inhibit platelet aggregation such as endothelial NO synthase (eNOS), prostacyclin and thrombomodulin (Bochenek et al., 2016; Wiley et al., 2019; Nehme et al., 2020). Therefore, the elderly may develop more severe coagulation disorders if infected by SARS-CoV, MERS-CoV, H1N1, HIV or other viruses (Obi et al., 2019; Ackermann et al., 2020; de Magalhães et al., 2020; Giannis et al., 2020). It was found that compared with young controls, aged hamsters exhibited prolongation of PT, intravascular clotting and acute kidney damage upon SARS-CoV-2 infection (Ohno et al., 2021). These changes are often present in patients with COVID-19 and strongly associated with disease severity and higher mortality (Helms et al., 2020; Porfidia et al., 2020; Loo et al., 2021). In addition, H1N1 acute respiratory distress syndrome (ARDS) patients possessed a 23.3-fold higher risk for pulmonary embolism and a 17.9-fold increased risk for venous thromboembolism (Obi et al., 2019). Simultaneously, in HIV-infected patients, endothelial dysfunction caused by HIV replication may also lead to a hypercoagulable state (Kuller et al., 2008; Armah et al., 2012), while aging-related inflammation and cellular changes may further contribute to coagulation dysfunction (de Magalhães et al., 2020).

Additionally, due to abnormal immune responses and excessive inflammation associated with aging, the elderly are more prone to complications such as liver and kidney dysfunction, myocardial injury, and neurological symptoms in the event of viral infections such as SARS-CoV-2. In particular, the massive secretion of SASP may generate fibrosis or cause injuries in organs other than the lungs, such as the liver, kidney and cardiovascular system (Cai et al., 2020; George et al., 2020; Napoli et al., 2020; Sharma et al., 2020; D'Agnillo et al., 2021). A decline in the blood-brain barrier function with aging may also cause infection of the central nervous system, leading to neurological symptoms (Yamazaki et al., 2016; Mao et al., 2020; Propson et al., 2021).

Presently, it is believed that aging may cause dual effects during antiviral infection. Primarily, SASP cytokines and chemokines from senescent cells and accordingly recruited innate immune cells such as PMNs may predispose virus-induced senescence to become a part of the antiviral immune response (Baz-Martínez et al., 2016). This antiviral mechanism may enable the secretion of SASP factors by virus-induced senescent cells to restrict virus replication in neighboring cells and avoid its spread (Kelley et al., 2020). Moreover, the human papillomavirus (HPV), HBV, EBV and KSHV have evolved various mechanisms that can specifically combat cellular senescence (Yang et al., 2000; Oishi et al., 2007; Leidal et al., 2012; Zhi et al., 2015; Estêvão et al., 2019), indirectly suggesting that senescence may lead to antiviral defense in certain circumstances (Kelley et al., 2020).

Conversely, it was documented that senescence is conducive to the pathophysiology of viral infections and may promote viral replication and mutagenesis (Kelley et al., 2020; Evangelou et al., 2022). For instance, RSV infection can alter human airway epithelial differentiation and trigger the senescence of lung epithelial cells both in vivo and in vitro by generating ROS and causing DNA damage, thereby contributing to airway tissue remodeling and the severity and long-term consequences of RSV infections (Persson et al., 2014; Martínez et al., 2016). The influenza and varicella-zoster viruses can replicate more efficiently in senescent human bronchial epithelial cells and senescent human dermal fibroblasts, respectively, compared with non-senescent cells (Kim et al., 2016). The possible reasons for this phenomenon are the downregulation of type I interferon induction upon senescence and the defective mitochondrial dynamics of senescent cells, which consequently inhibit interferon expression and early interferon responses, thus favoring viral replication (Kim et al., 2016; Kelley et al., 2020). However, Baz-Martínez M et al. found that primary or chemotherapy-induced senescence reduces VSV replication (Baz-Martínez et al., 2016), suggesting that senescence plays a different role in response to diverse viral infections under distinguishing conditions. Remarkably, recent studies revealed that infected senescent cells might be a source of apolipoprotein B mRNA-editing (APOBEC) enzyme-mediated SARS-CoV-2 mutations (Evangelou et al., 2022).

Taken together, the effects of senescence on the body’s antiviral immune response are multifaceted ( Figure 3 ). In this regard, it has been hypothesized from the perspective of acute respiratory viral infections that aging may play different roles in viral infections depending on host resilience (Kelley et al., 2020). In young hosts, VIS may enhance antiviral immunity by recruiting PMNs and other immune cells via SASP, thereby promoting viral clearance and tissue repair. However, in old or vulnerable hosts, VIS coupled with an existing senescence condition may lead to excessive immune responses with high levels of SASP cytokines and chemokines, resulting in secondary senescence and over-recruitment of immune cells, eliciting severe tissue damage and multi-organ failure (Kelley et al., 2020; Camell et al., 2021).

The most widely studied therapeutic strategy for the targeted elimination of senescent cells by senolytics is the combination therapy of dasatinib (D) with quercetin (Q). “D+Q” treatment was shown to reduce the cellular stress of aged mice, lessen vascular sclerosis, strengthen vasodilatory functions and impel lung function in mice with pulmonary fibrosis, thus improving the health status and lifespan of elderly mice (Roos et al., 2016; Lehmann et al., 2017; Xu et al., 2018). Likewise, preliminary clinical trials have demonstrated that “D+Q” therapy significantly improved the physical function of elderly patients with pulmonary fibrosis, reduced the burden of senescent cells in diabetic patients with chronic kidney disease, decreased the levels of major circulating SASP factors, and slowed disease progression (Hickson et al., 2019; Justice et al., 2019).

In terms of viral infectious diseases, Camell et al. discovered that human endothelial senescent cells initiated excessive inflammation upon exposure to SARS-CoV-2, which was accompanied by enhanced SASP expression and a pronounced increase in cellular senescence, inflammation and mortality among aged mice with similar β-coronavirus infection (Camell et al., 2021). However, the use of fisetin or the “D+Q” therapy with senescence-targeted ability selectively combated senescent cells, substantially reduced the signs of senescence and the levels of inflammatory markers and decreased viral infections-related mortality (Camell et al., 2021). In a recent study (Lee et al., 2021), SARS-CoV-2 virus infection and the subsequent VIS were determined to be driving factors in modulating COVID-19-related cytokine storm and tissue damage. However, the targeted removal of senescent cells with senescence-targeted drugs such as navitoclax, D+Q and fisetin lead to a significant reduction in senescent cells and a marked attenuation of senescence-related traits, both in vitro and in the respiratory epithelium of hamster models. Further, COVID-19-related lung diseases, inflammation, tissue damage and coagulation disorders significantly subsided (Lee et al., 2021). Additionally, in senescent macrophages exposed to IAV or SARS-CoV-2 (Lv et al., 2022), fisetin prominently suppressed the aberrant activation of the cGAS-STING pathway, NLRP3 inflammasome and the resultant excessive inflammatory responses in senescent macrophages via the induction of apoptosis and reduction of dysfunctional mitochondrial load. In the Tere^-/- aged mice model, fisetin was also found to dampen pathogenic inflammation mediated by the cGAS-STING pathway and NLRP3 inflammasome by lowering senescent cells-related burden and improving mitochondrial integrity, thus providing a considerable improvement in the survival rate of Tere^-/- mice infected with IAV. Comparable results were obtained upon validation using the “D+Q” combination treatment (Lv et al., 2022).

In prospective randomized controlled clinical trials among patients with COVID-19, quercetin appeared to be effective in decreasing viral load and relieving clinical symptoms during the early application of viral infection in combination with standardized care, which offered protection against serious complications and conferred a high safety profile (Di Pierro et al., 2021a; Di Pierro et al., 2021b). Correspondingly, a systematic review of quercetin revealed that quercetin and its derivatives were associated with significantly reduced mean viral load and generation of pro-inflammatory cytokines, chemokines, reactive oxygen species, mucus and airway resistance in animals infected with respiratory viruses such as influenza virus and human rhinovirus. These observations were associated with a significant reduction in infected animal fatality and were considered a potential strategy for treating lower respiratory tract viral diseases (Brito et al., 2021).

The mammalian target of rapamycin (mTOR) pathway has been demonstrated to facilitate SASP production in recent years by regulating the translation of mRNA subsets, including those encoding IL-1α (Herranz et al., 2015; Laberge et al., 2015). Rapamycin can target the mTOR pathway to inhibit the activity of the mTORC1 complex, which is known to regulate mRNA translation, leading to reduced mRNA levels of cytokines such as IL-6 and IL-10 and selective inhibition of the translation of IL-1α. This creates a drop in SASP production and reduces the risk of age-related cognitive decline and cardiac or hepatic dysfunction, eventually extending the lifespan of mice and improving immune functions in the elderly (Majumder et al., 2012; Wilkinson et al., 2012; Flynn et al., 2013; Mannick et al., 2014; Laberge et al., 2015). More importantly, the application of rapamycin can potentiate antiviral activity in the event of SARS-CoV-2, MERS-CoV, H1N1 and other viral infections, which can be conducive to attenuating the severity of diseases (Wang et al., 2014; Kindrachuk et al., 2015; Husain and Byrareddy, 2020). Currently, ongoing clinical trials are assessing the safety and efficacy of rapamycin in the treatment or prevention of COVID-19 (Geier and Perl, 2021).

In addition, metformin, a biguanide that combats age-related diseases to extend health span, is the first drug for age-targeted effects in a large clinical trial (Kulkarni et al., 2020). Available evidence supports that metformin can dampen aging-related features directly or indirectly through multiple pathways, such as improving nutrient perception, inhibiting the NF-κB pathway and pro-inflammatory factors production, enhancing cellular autophagy and intercellular communication, regulating mitochondrial function, modulating gut microbiota, delaying stem cell aging, curtailing telomere attrition, and attenuating cellular senescence (Kulkarni et al., 2020). It was reported that metformin could extend the lifespan of mice by inhibiting the production of pro-inflammatory factors and diminishing DNA damage (Martin-Montalvo et al., 2013; Moiseeva et al., 2013; Valencia et al., 2017). It could also decrease age-related chronic inflammation and the risk of cardiovascular diseases, cancer, neurodegenerative diseases and cognitive dysfunction, ultimately exerting a constructive effect on improving the overall health status and prolonging the lifespan of aged persons (Barzilai et al., 2016; Campbell et al., 2017; Markowicz-Piasecka et al., 2017; Campbell et al., 2018; Tizazu et al., 2019).

Data from China revealed that the metformin treatment was associated with lower mortality in hospital patients with COVID-19 (Li et al., 2020; Luo et al., 2020) and fewer COVID-19-related heart failure and inflammation compared with other anti-diabetic agents (Cheng et al., 2020). Similarly, metformin could also cause an almost 11-fold reduction in the odds ratio of death among COVID-19 African-American patients with T2DM (Crouse et al., 2020). A recent study confirmed that metformin inhibited mtDNA synthesis and cytoplasmic Ox-mtDNA production in macrophages, thereby suppressing NLRP3 inflammasome activation, IL-1β generation and IL-6 secretion and relieving lung inflammation in human ACE2 transgenic mice infected with SARS-CoV-2 (Xian et al., 2021). Such protective effects were independent of glycemic control and correlated with the anti-inflammatory properties of metformin (Valencia et al., 2017; Marcucci et al., 2020). Nevertheless, it should also be noted that metformin use is linked to a high incidence of acidosis, especially in severe COVID-19 cases (Cheng et al., 2020), and careful consideration should be made on tackling the complications during clinical administration.

Anakinra, an IL-1 receptor antagonist, was shown to cause a rapid decrease in inflammatory and febrile symptoms, lower oxygen requirements, increase the duration of non-invasive mechanical ventilation and improve various clinical conditions when administered early in COVID-19 patients (Cauchois et al., 2020). In parallel, another cohort study also concluded that therapy with Anakinra was associated with fewer needs for invasive mechanical ventilation, lowered the mortality of patients with severe COVID-19, and, importantly, did not cause serious side effects (Huet et al., 2020). Moreover, a multicenter cohort study enrolling 3924 COVID-19 patients suggested that treatment with a monoclonal antibody of the IL-6 receptor (Tocilizumab) during the first 2 days of patient admission to the ICU could significantly reduce the risk of in-hospital mortality (Gupta et al., 2021). A randomized controlled clinical trial from the United Kingdom also demonstrated that Tocilizumab lowered the probability of invasive mechanical ventilation needs and 28-day mortality in patients with COVID-19 (Group, 2021). Further, a Bruton tyrosine kinase (BTK) inhibitor was also found to reduce BTK-dependent activation of NF-κB and NLRP3 inflammasome, which suppressed pro-inflammatory factors production and COVID-19 cytokine storm, thereby improving the prognosis of COVID-19 patients (Roschewski et al., 2020).

Altogether, these findings not only further illustrate the critical role of SASP components in the development of viral infectious diseases such as COVID-19 but also demonstrate the high interest in targeting SASP components or the inflammatory pathways involved in their synthesis for the treatment of aging-related viral infectious diseases.