A biomarker is a biological indicator that may be used alone or in combination with others to identify a particular cell types or biological conditions. These may consist in different types of biomolecules, including proteins, nucleic acids, carbohydrates, and lipids (Matjusaitis et al., 2016). Below, we evoke different biomarkers associated with senescence that help identify these cells. It is important to keep in mind that although some of these hallmark features relate to senescence, they also connect to other cellular processes and cellular states and thus, to date, there is still some difficulty in defining a particular set of markers that allow full recognizing and distinguishing senescent cells from other cell types (Sharpless and Sherr, 2015; Wang and Dreesen, 2018). Indeed, no single biomarker currently provides a reliable and precise representation of a senescent cell phenotype (Matjusaitis et al., 2016).

At present, the most reliable indicators of senescent cells in cell cultures, or tissue samples are those related to the expanded and flattened shape of cells, together with enhanced activity SA-β-Gal, which is considered a gold-standard marker for the identification of these types of cells (Debacq-Chainiaux et al., 2009). The drawback of this method is that it requires assessing the enzymatic activity, which is preferentially preserved in fresh tissues and/or samples, and may be lost in samples that have been subjected to fixation or cold preservation (Severino et al., 2000; Wang and Dreesen, 2018). Another marker related to senescence at the lysosomal level is the accumulation of the “age pigment” lipofuscin, which is a non-degradable aggregate consisting of oxidized proteins, lipids, and metals (Jung et al., 2007; Georgakopoulou et al., 2013). There is evidence that lipofuscin and SA-β-Gal are colocalized in senescent cells both, in vitro and in vivo, which strongly supports the idea that lipofuscin may be a valuable biomarker of cellular senescence (Georgakopoulou et al., 2013) ( Figure 1 ). However, viral infections frequently involve altered dynamics of cellular organelles and compartments, and thus alterations in the localization of host proteins within the cell might occur (Glingston et al., 2019). Other biomarkers include sensors of the unfolded protein response (UPR), such as IRE1α, ATF6 and PERK, which are activated in senescent cells, indicating that senescence may be induced by an imbalance and alterations in cellular proteostasis (Abbadie and Pluquet, 2020). Indeed, the UPR may be a critical process involved in the senescence phenotype; however, there are significant nuances and particularities in how the many complex UPR pathways may be involved (Abbadie and Pluquet, 2020) ( Figure 1 ). Nevertheless, given the relevance of this pathway, cell infection with microorganisms may lead to the activation or inhibition of these pathways as part of the infectious pathogen cycle, as reviewed by Vibhu Prasad et al. (Prasad and Greber, 2021).

During oncogene-induced senescence (OIS) in vitro, there are changes at the chromatin level as heterochromatin is redistributed into senescence-associated heterochromatin foci (SAHF), which co-localize with the heterochromatin protein 1γ (HP-1γ protein) which is related to transcriptional repression of genes associated with cell proliferation (Chen et al., 2007). The gold-standard marker for senescence is the phosphorylation of histone H2A.X at serine139 (γH2A.X), (Saldías et al., 2017; Fernandez et al., 2021). Concurrent with the redistribution of heterochromatin, telomere-associated DNA damage foci (TAF) have also been used as a senescence marker (Rossiello et al., 2022). Interestingly, these senescence biomarkers have been less explored in the context of infections and thus, it will be relevant to determine if they arise during the interaction of microorganisms with target cells.

In addition, the downregulation of Lamin B1 in cells undergoing different sublethal stimuli in vitro has also been reported and used as a biomarker of cellular senescence (Wang and Dreesen, 2018) ( Figure 1 ). This latter biomarker can result particularly challenging considering that some pathogens, namely some types of viruses, alter or disrupt nuclear integrity upon infection as a mechanism to extend their genomes from this compartment onto the cytoplasm on their way out of the cell. This is particularly relevant for pathogens such as retroviruses (De Noronha et al., 2001; Takeshima et al., 2022; Wen et al., 2022).

Finally, senescent cells can develop a which has been used to detect and assess senescence in cultured cells or tissue samples. It comprises inflammatory mediators, growth factors, proteases, soluble surface molecules, and extracellular matrix components, among others (Coppé et al., 2010). However, the drawback of the secretory profile of senescent cells is that it varies depending on the cell type and the stage of senescence and in the context of cell infection will likely be overlapped with profiles of soluble molecules being secreted as a result of infection (Coppé et al., 2008; Campisi et al., 2011; Acosta et al., 2013) ( Figure 1 ). Thus, defining which components of the secreted molecules relate to SASP, and which are inherent to a cellular response to pathogens will be relevant to identify senescence in the context of infections and assess the contribution of this latter process in the host response to harmful microorganisms.

As revised above, senescence relates to numerous cellular markers that overlap with host responses to infection and thus, defining a state of senescence in such cells can be particularly challenging. Undoubtedly, while adaptive immune cells, and to a lesser extent innate immune cells, may experience a process called immunobiography which corresponds to a reduction or a cessation of their defensive functions in cases of prolonged, chronic, or recurrent infections, they may also undergo senescence as a response to these persistent infections. This senescence can serve as a mechanism to signal and enhance the recruitment of immune cells (Franceschi,et al., 2017) or that pathogens are favored by cellular senescence phenotypes in target cells, assuring cell viability, yet at the potential cost of the infected cells being recognized by host immune components. These scenarios remain to be addressed in future studies.

Since late 2019, a considerable amount of attention from the biomedical field has focused on SARS-CoV-2 and the emergence of its related respiratory infectious disease termed coronavirus disease 2019 (COVID-19), which after identified was rapidly considered a somewhat systemic-related disease in an important fraction of individuals together with a respiratory disease (Maldonado et al., 2022). Interestingly, it has been reported that T cells from patients with COVID-19 display a senescent phenotype and exhaustion, which is associated with exacerbated cytokine production (De Biasi et al., 2020). Also, the function of CD4⁺ and CD8⁺ T cells was severely altered in patients with this disease, displaying a senescent phenotype involved in severe disease manifestations (Zuin et al., 2022). Furthermore, a study reported senescent and hyperinflammatory phenotypes in nonimmune cells obtained from patients who died from COVID-19 (Evangelou et al., 2022). Moreover, the same study showed that senescence promoted DNA damage in SARS-CoV-2-infected Vero-E6 cells and increased the expression of the apolipoprotein B mRNA-editing enzyme, which plays a role in virus mutagenesis, likely enhancing viral pathogenicity and persistence (Evangelou et al., 2022).

Lung epithelial and endothelial cells obtained from tissue samples from sick COVID-19 patients evidenced that the spread of a senescent phenotype was related to increased disease susceptibility and severity (D’Agnillo et al., 2021), consistent with an increased risk in older adults or people with underlying diseases (D’Agnillo et al., 2021). Moreover, in an aged mouse model of SARS-CoV-2-induced pneumonia, senescence was also promoted, especially in macrophages, which displayed abnormal activation of the STING/NLRP3 inflammasome pathway, seemingly by mitochondrial DNA leakage and animals predisposed to severe inflammation (Lv et al., 2022). Interestingly, mitochondrial integrity, macrophage-associated burden, and the course of viral infection were improved by using senolytic drugs, that selectively cleared senescent cells, suggesting that exacerbated inflammatory response and increased susceptibility to infection is regulated by senescence in mice deficient in telomerase RNA Terc^-/- mice (Lv et al., 2022).

It has been reported that severe COVID-19 is also characterized by hemostatic alterations that promote thrombotic complications (Meyer et al., 2021). SARS-CoV-2-induced senescence in endothelial cells has been described to be accompanied by an increase in pro-inflammatory cytokines, reactive oxygen species (ROS), as well as endothelial adhesion molecule expression Intercellular Adhesion Molecule 1 (ICAM-1) and Vascular Cell adhesión Molecule 1 (VCAM-1), and enhanced leukocytes attachment (Meyer et al., 2021). Interestingly, those features were also prevented with senolytic agents, pointing out a critical role for senescence, and highlighting its therapeutic potential to attenuate COVID-19-elicited adverse symptoms ( Figure 2 ).

Current evidence indicates that the relationship between senescence and the dysfunctional inflammatory response induced by SARS-CoV-2 is far from being unidirectional. A recent report (Kandhaya-Pillai et al., 2022) suggests positive feedback between the inflammatory cytokines TNF-α and IFN-γ, and the induction of a senescent phenotype, decreasing cellular proliferation capacity in primary endothelial cells and increasing the expression of the SARS-CoV-2 receptors ACE2/DPP4 through the JAK/STAT1 pathway (Kandhaya-Pillai et al., 2022). All these findings support a feedback loop between prolonged infection, hyperinflammatory states, and a senescent status. In addition, Toll-like receptor (TLR) 3 has recently emerged as an uncovered participant involved in initiating and amplifying SARS-CoV-2-induced senescence, increasing the inflammatory burden and worsening the host response in COVID-19 (Tripathi et al., 2021) ( Figure 2 ).

Several other viral infections have also been described to be associated with senescence, for example, hepatitis C virus (HCV) which infects more than 170 million people worldwide and is linked to liver inflammation and diseases, such as diabetes mellitus, cirrhosis, and fatty liver disease (Serfaty and Capeau, 2009; Malnick et al., 2014). Studies with this virus suggest that the progression of liver fibrosis is closely associated with senescence in parenchymal and non-parenchymal liver cells during hepatitis and liver-associated diseases, such as hepatic steatosis and non-alcoholic liver disease elicited by this virus (Marshall et al., 2005; Aravinthan et al., 2013; Wandrer et al., 2018). Interestingly, it has been reported that the expression of CDK inhibitors p21, p27, and p16 is increased in liver tissues obtained from patients with chronic HCV infection, as compared to livers from healthy individuals (Bassiouny et al., 2010; Wandrer et al., 2018). HCV infection is also associated with senescence-related epigenetic alterations recruited at SAHF, such as the phosphorylation of HP-1γ in liver tissue samples and the histone γH2A.X in peripheral blood mononuclear cells (PBMCs), which are known to be markers of senescence (Hoare et al., 2013; Wandrer et al., 2018) ( Figure 2 ). Furthermore, tissue samples obtained from patients at different stages of infection with HCV-related fibrosis showed a higher proportion of p-HP-1γ and γ-H2AX positive cells during chronic HCV than healthy controls (Wandrer et al., 2018) ( Figure 2 ). These senescence markers were more expressed along fibrotic scars, whereas only a few senescent cells were found in the liver parenchyma (Krizhanovsky et al., 2008; Wandrer et al., 2018). Moreover, in vitro analyses with HepG2 cells have shown a direct association between hepatocyte-related senescence and liver fibrosis caused by HCV. This association is related to the senescence markers SA-βgal and IL-1β, which are also highly expressed in non-alcoholic fatty liver disease and alcoholic liver disease (Wijayasiri et al., 2022).

HCV chronic hepatitis has been reported to be capable of accelerating telomere shortening in hepatocytes infected by this virus. This promotes the accumulation of senescent cells, which shows a strong correlation with increased hepatic fibrosis in hepatocellular carcinoma (HCC) and the overexpression of p16 and p21 (Paradis et al., 2001; El-Serag and Rudolph, 2007; Desai et al., 2019) ( Figure 2 ). Additionally, it has been proposed that the number of senescent cells in the liver reflects the progression of fibrosis in patients with chronic hepatitis C, evidenced by the presence of senescence markers in non-parenchymal fibrotic tissue, and to a higher proportion of intrahepatic senescent T cells (Wandrer et al., 2018; Giannakoulis et al., 2021). Noteworthy, these senescent T cells are not functional. Yet, they are abundant during in vivo viral infection (Voehringer et al., 2001). Thus, overall, HCV infection likely elicits an increase in senescent T cells that may predispose the individual to the development of HCC, as these T cells would not able to eliminate premalignant senescent hepatocytes (Kang et al., 2011).

Another scenario that connects virus and senescence is osteoporosis and osteopenia, in which the human immunodeficiency virus (HIV) increases the likelihood of these senescence-related diseases (Ofotokun et al., 2012; Olali et al., 2022). Cellular senescence is considered to be an important factor in this disease, and there is compelling evidence that HIV infection is a risk factor for this pathological condition (Dolan et al., 2006; Stone et al., 2010). There is evidence that HIV may increase bone turnover by itself and that it may be associated to an increase in cytokine expression, such as IL-6 and TNF during infection (Dolan et al., 2006) ( Figure 2 ). However, the mechanisms underlying this phenomenon are yet to be elucidated (Dolan et al., 2006). Interestingly, it has been shown in individuals living with HIV and co-infected with HCV that the spontaneous clearance of the latter corelates with a slightly lower senescence profile (Lara-Aguilar et al., 2023).

Another example is measles virus (MV), which when infecting human lung fibroblast cells (IMR90 cells) is capable of generating cellular senescence as evidenced by reduced cell proliferation, SA-β-Gal activity, increased expression of p53 and p21, or the induction of SASP with interleukin-8 (IL-8) or C-C motif chemokine ligand 5 chemokine ligand 5 (CCL5) expression (Seoane et al., 2020) ( Figure 2 ). In addition, MV infection has also been related to triggering senescence in the A549 adenocarcinoma cell line, in a p53-dependent manner (Seoane et al., 2020).

On the other hand, dengue virus (DENV) when infecting human umbilical vein endothelial cells (HUVEC) has been reported to elicit SA-β-Gal expression, cell cycle arrest and morphological changes are typical of senescent cells ( Figure 2 ). It has been proposed that this process contributes to the pathogenesis of the virus. However, whether DENV-induced senescence occurs through a DNA damage-mediated pathway is unknown at this time (AbuBakar et al., 2014).

Finally, in some strains of influenza A virus (IAV), the non-structural protein NS1 which is related to the evasion of the host antiviral response and interference with the translation and maturation of interferon mRNAs, has been shown to be capable of generating cellular senescence (Yan et al., 2017). In a fast-growing mouse neuroblastoma cell line (Neuro2a cells) and in mouse cortical cells neurons, the NS1 protein of IAV strain H7N9 was described to induce cellular senescence related to an increase in the expression of the nitrous oxide synthase enzyme, which in turn lead to a higher release of nitric oxide (Yan et al., 2017) ( Figure 2 ). Recently, it has been shown, both in an in vitro model of infected human monocyte-derived macrophages on primary lung fibroblasts, and in vivo in 5-week-old female BALB/cJRj-wild-type mice that infections with IAV lead to premature cellular senescence through paracrine induction of TNF-α, and that subsequent infections lead to an increased viral replication (Schulz et al., 2023).

Although vaccines are directly related to increased quality of life and extended living of individuals, it seems that studies evaluating senescence and immunosenescence in the context of infections, and their impact on long-term health, are inexistant likely due to our constant exposure to pathogens and thus, the related difficulties to register all these events during extended periods. Nevertheless, it may ultimately be possible to envisage, to some extent, the assessment of the impact of the exposure to some particular pathogens for which there are better registries, such as COVID-19 during the SARS-CoV-2 pandemic, with overall cell aging. Given the cellular nature of senescence and immunosenescence, a relationship could eventually be determined in blood cells or tissue biopsies. In this sense, it will be interesting to assess whether extended health problems due to infection, such long COVID, or long-term effects produced by some respiratory viruses such as the respiratory syncytial virus or influenza virus, are related to senescence or immunosenescence.

A persistent latent infection caused by the herpesvirus Kaposi’s sarcoma virus (KSV), promotes the proliferation of lymphatic endothelial cells and senescence, depending of the ratio between bFLIP and vCyclin (DiMaio et al., 2020). Human cytomegalovirus (HCMV) another herpesvirus is also an example of a virus in which the generation of senescence occurs with a mechanisms being proposed through the activation of p53, as well as p16 in primary human embryo lung fibroblasts and adult diploid fibroblasts (Noris et al., 2002; Zannetti et al., 2006, 16) ( Figure 2 ). When fibroblasts are infected with HCMV, this virus induces premature senescence and cell cycle arrest, likely mediated by the expression of the viral immediate-early 2 (IE2) protein (Ball et al., 2022). Additionally, there is evidence that indicates that the expression of other individual viral proteins may also promote cellular senescence, similar to the HCMV IE2 protein (Noris et al., 2002; Ball et al., 2022). Moreover, aging and viral infections seemingly influence HCMV-induced immune alterations that impair CD8⁺ T cell immunity later in life in a dose-dependent manner, which is related to HCMV-associated immune senescence (Redeker et al., 2017). Noteworthy, it has been reported in human diploid fibroblast WI-38 cells that treatment with pterostilbene, a stilbenoid chemically related to resveratrol, reduces viral infection and has an inhibitory effect over molecular determinants related to cellular senescence and reactive oxygen species produced by this virus (Wang et al., 2022).

It has been reported that Epstein-Barr virus (EBV), also a herpesvirus, induces replicative stress, DNA damage and activation of DNA damage response in cells, as well as cellular senescence by inducing transient B cell hyper-proliferation through upregulation of the viral latency proteins, such as EBNA2 and EBNA-LP (Nikitin et al., 2010; Hafez and Luftig, 2017). Moreover EBV infection causes metabolic reprogramming including decreased oxidative phosphorylation and purine nucleotide pools contributing to increased replication stress and persistent DNA damage as seen in B cells obtained from PBMCs (Hafez et al., 2017). EBV infection has also been seen to induce the expression of senescence-associated markers, such as KLRG-1 as seen in antigen-specific T cells isolated from peripheral blood of EBV-infected patients (Lanfermeijer et al., 2021). Additionally, it has been reported that EBV-infected B cells trigger a G1 cellular arrest phase and exhibit augmented markers of OIS, such as H3K9me3 senescence-associated heterochromatic foci, p16, p21 and p53 in (Nikitin et al., 2010; Nikitin et al., 2014; McFadden et al., 2016) ( Figure 2 ). Recently, it has been reported that co-infection with EBV and HCMV in young and middle-aged adults can alter T cell composition towards an aging-related T cell phenotype (Hofstee et al., 2023).

Interestingly, a relationship between aging and age-related pathologies, including neurodegenerative diseases, such as Parkinson’s, multiple sclerosis (MS), and Alzheimer’s disease (AD), has been associated with herpes simplex virus (HSV) infections (Duarte et al., 2019; Reyes et al., 2022). Several studies have reported a high prevalence of HSV-1 DNA in the brains of patients with MS and senile plaques of individuals with AD, which contain amyloid beta (Aβ) peptide and phosphorylated tau protein depositions in neurons (BergstOum et al., 1989; Miklossy, 2011). Additionally, in cortical neurons, HSV-1 infection leads to the accumulation of DNA lesions, including single- and double-strand breaks (SSBs and DSBs, respectively) ( Figure 2 ), which have recently been implicated in neuronal loss related to neurodegenerative diseases (De Chiara et al., 2016). HSV has also been associated with the induction of neuro-inflammation and senescence in the brainstem of female C57BL/6J mice, as observed by an increase in SA β-Gal activity, p16, p21 and p53 RNA levels (Sivasubramanian et al., 2022). The mechanisms behind this HSV-induced DNA damage remain to be elucidated. One report suggests that this is mediated by the downregulation of Ku80, a key component of non-homologous end joining (NHEJ). Ku80 is driven to proteasomal degradation affecting NHEJ, which produces DSB (De Chiara et al., 2016)

Furthermore, some studies associate HSV infections with neuronal aging, which could lead to AD. It has been shown, both in vitro and in vivo, that neurons increase the level of histone modifications that act as aging markers in response to HSV latent infection and reactivation, such as histone H4 acetylation at Lysine 16 (H4K16ac), the SIN3 histone-modifying complex, and the histone deacetylase 1 (HDAC1) (Napoletani et al., 2021). Additionally, the histone regulator A (HIRA) is upregulated during viral latency and has a different localization in cortical neurons obtained from HSV-1-infected mouse brains (Napoletani et al., 2021).

Hepatitis B virus (HBV) can elicit chronic infections closely related to liver cell senescence (Tachtatzis et al., 2015). HBV infection can induce senescence of hepatocytes and other liver cells by altering the hepatic tissue environment. In fact, pro-inflammatory and angiogenic factors eventually favor carcinogenesis in neighboring non-senescent cells (Brenner et al., 2013; Karakousis et al., 2020). Therefore, cellular senescence may play an important role in HBV-related hepatocarcinogenesis (Park et al., 2007; Brenner et al., 2013). Interestingly, the HBV protein x (HBx protein) exerts a pro-senescent role, evidenced by increased expression of p16 and p21^Waf1/Cip1 in malignant liver cell lines, such as HepG2, Huh7 and SK-Hep1, and a decreased phosphorylation of the retinoblastoma protein (pRb), a tumor suppressor protein that is altered in many types of cancers (Weinberg, 1995; Sun et al., 1997; Morris and Dyson, 2001; Chen et al., 2007; Idrissi et al., 2016) ( Figure 2 ). However, it has been reported that the effect of HBx on senescence is somewhat dependent on the cell type infected, as this viral protein promoted the proliferation of HepG2 malignant liver cells (Idrissi et al., 2016). Interestingly, a novel anti-HBV candidate drug consisting of a nucleos(t)ide analog namely E-CFCP, is able to rescue senescence-associated phenotypes in primary human hepatocytes infected with HBV (Takamatsu et al., 2023).

Merkel cell polyomavirus (MCPyV) has also been related to senescence. In normal human dermal fibroblasts (nHDF) transfected with replication-competent MCPyV, it was found that these cells increased β-galactosidase-related activity and arresting the cells in G₂ (Siebels et al., 2020). Additionally, MCPyV infection induced cell cycle arrest in nHDF cells with ATM-dependent phosphorylation of Kap1 S824 (Siebels et al., 2020). Interestingly, in the same cell type it was shown that parvovirus B19 induces cellular senescence as seen by an increase in senescence markers, such as SA-β-Gal activity, DNA damage markers, morphological features and the expression of some SASP-related factors such as IL-8, IL-6 and IL-1β (Arvia et al., 2022) ( Figure 2 ).

Compared to RNA viruses, significantly less vaccines are available to combat DNA viruses, which are mostly persistent in humans. Hence the effects described above for these viruses are likely cumulative throughout the life of an individual and constantly renewed in the context of sporadic reactivations. This has led to the consideration that some of these viruses likely relate to chronic diseases, namely neurodegenerative. Given the persistent nature and high prevalence of some of these DNA viruses, namely herpesviruses, it will likely result extremely hard to pinpoint their particular effects over individuals, as molecular reactivations can occur at single-cell level without visible symptoms (Grinde, 2013; Duarte et al., 2021). In such scenario, the contribution of only some viruses to senescence-related diseases may be identified given our currently available tools to detect infection-related processes (Duarte et al., 2023).

A summary of interplays between senescence and different viruses is outlined in Table 1 .

Regarding bacterial infections and senescence, caveolin-1, has been reported to enhance the infection of Fusobacterium nucleatum in senescent gingival fibroblasts (Ahn et al., 2017) ( Figure 3 ), and in the context of respiratory tract infections Streptococcus pneumoniae inflammation was associated with lung from aged mice that were in turn linked with an increase in senescence markers, such as p16, IL-1α/β, TNF-α, IL-6, and CXCL1, that coincided with an augmented expression of a S. pneumoniae ligand on the cell surface (Shivshankar et al., 2011) ( Figure 3 ).

Reciprocally, bacterial infections have also been associated with the induction of senescence. For instance, bacterial infections have been reported to induce senescence by a persistent inflammatory response, with pathogen-associated molecular patterns (PAMPs), such as bacterial LPS being related to the induction of stem cell senescence via the activation of the pattern recognition receptor TLR4, and through the NFκB-p53-p21 signaling axis (Feng et al., 2018; Fan et al., 2022) ( Figure 3 ). Although Escherichia coli-infected cells may undergo cell death, some of these cells display cellular markers related to senescence, such as the formation of PML bodies, SA-β-Gal activity and SAHF (Secher et al., 2013) ( Figure 3 ). Additionally, bacterial genotoxins, such as those belonging to the family of cytolethal distending toxins (CDTs) that are encoded by Gram-negative pathogenic bacteria, have been reported to have their CDT nuclease activity involved in inducing double-strand and single-strand breaks in host DNA, triggering a DNA damage response and cell-cycle arrest, as well as cellular distension (Cortes-Bratti et al., 2001; Fedor et al., 2013). Consistently, the downregulation of TLR4 reduced this phenotype in infected cells (Yoon et al., 2022, 4). Furthermore, in a recent report (Merdji et al., 2021), it was shown that septic shock induces prolonged endothelial and vascular senescence in Wistar male rats, with a pro-inflammatory status remaining up to 90 days after septic challenge, which increased the long-term risk for adverse cardiovascular events.

Importantly, there is recent evidence that suggests that chronic infections caused by Mycobacterium tuberculosis are affected, at least in part, by senescence. In vivo analyses with murine models showed that the senescence marker known as killer cell lectin-like receptor G1 (KLRG1), is expressed at higher levels in T cells upon M. tuberculosis infection during aging and decreases after pharmacologically treating tuberculosis. This finding suggests a correlation between KLRG1 expression and disease progression (Voehringer et al., 2001; Cyktor et al., 2013; Simon et al., 2015). On the other hand, some studies have proposed that immunosenescence plays an important role in age-associated reactivation of tuberculosis and that KLRG1 is involved in this phenomenon, as evidenced using KLRG1 knock-out mice (Aguilera et al., 2018). Studies conducted in guinea pigs and humans have shown that M. tuberculosis induces changes in gene expression, DNA methylation and hypermethylation, which are associated with oxidative stress-induced senescence with increased levels of CXCL9, CXCL10 and TNF-α (Bobak et al., 2022) ( Figure 3 ). Interestingly, these studies reported that both, guinea pigs and aging humans infected with M. tuberculosis display similar epigenetic changes in transcription factors, such as NFKBIA, TCF7, CIITA, MYC, NFAT and DNMT1/3A (Torres et al., 2018). Lastly, a study carried out in old mice found that having aged memory CD8⁺ T cells translated into reduced M. tuberculosis control (Piergallini and Turner, 2019).

Another example of a chronic bacterial infection in which senescence has been observed is that mediated by Helicobacter hepaticus. Interestingly, recent reports suggest that the expression of the subunit of the cytolethal distending toxin of this bacterium, termed CdtB, is associated with increased senescence, as evidenced by the senescence markers SA-β-Gal, p21, and p53 (Guerra et al., 2011; Guidi et al., 2013; Péré-Védrenne et al., 2017). On the other hand, Helicobacter pylori cytotoxin-associated gen A (CagA) has been reported to lead to the up-regulation of p21 in an ERK-dependent manner, that in turn induces cellular senescence (Terebiznik et al., 2009; Lewinska and Wnuk, 2017; Aguilera et al., 2018) ( Figure 3 ).

H. pylori is capable of surviving outside the gastrointestinal tract and has been related to some skin chronic infections associated with senescence promoting redox imbalances (Handa et al., 2010), DNA damage (Hanada et al., 2014), inflammation and epigenetic changes in host cells that may provoke extragastric manifestations (Valenzuela et al., 2015), all of which are triggers and biomarkers of cellular senescence (Lewinska and Wnuk, 2017).

Pseudomonas aeruginosa has been reported to induce senescence in macrophages exhibiting decreased phagocytosis ability. This senescence process was reported to be regulated by interactions between NADPH oxidase gp91phox and NF-κB p65 via ROS as a second messenger (Li et al., 2018). Porphyromonas gingivalis is another pathogen associated with elevated expression of senescent cellular markers in immune cells, such as DCs with bacterial invasion leading to an increase in the secretion of inflammatory exosomes which in turn amplify immune senescence in paracrine to bystander cells (Elsayed et al., 2021). Additionally, there is an increased expression of SA-β-Gal, p16, p53, and p21^Waf1/Clip1, among others (Elsayed et al., 2021) ( Figure 3 ). Importantly, Porphyromonas gingivalis and Porphyromonas asaccharolytica can induce cellular senescence through the secretion of the bacterial metabolite butyrate, and an unbalanced increase of these butyrate-producing bacteria has been associated with colorectal tumorigenesis (Okumura et al., 2021).

Finally, the probiotic bacterium Lactobacillus fermentum has been reported to play a protective role against senescence in a model of premature hydrogen peroxide-induced senescence of murine preadipocyte cell line (3T3-L1), by limiting DNA damage, SASP activation, and stress-induced stimulation of PI3K/Akt/mTOR pathway in these cells, which highlights the potential of using probiotics as pro-longevity strategies (Kumar et al., 2020) ( Figure 3 ).

An increasing amount of evidence indicates that pathogenic bacterial infections induce senescence in host cells, and that some harmless bacteria can actually counteract these effects. It will be interesting to know whether treatment with antibiotics can limit bacteria-induced senescence and the contribution of bacterial components, i.e. dead bacteria, to senescence in related studies, as this has not been assessed extensively. Furthermore, it will be important to acquire increased knowledge on the effects of commensal bacteria over senescence and potential counteractions as reported for probiotic bacteria in order to determine the molecular determinants that govern this phenomenon, mainly in host tissues at the interphase with the environment.

Information regarding bacterial infections and their interplay with senescence is summarized in Table 1 .

Innate immune cells, such as neutrophils, macrophages, dendritic cells (DCs) and, natural killer (NK) cells, are the first line of defense against pathogens, which may be responsible for limiting the spread of infection and, more importantly, play a key role in promoting the initiation of an adaptive immune response against these agents (Stegelmeier et al., 2019). Several reports indicate that innate immune cell functions are altered with aging (Solana et al., 2012). Indeed, different studies have reported that aging affects neutrophil function by impairing chemotaxis, phagocytosis, and free radical production, all of which are necessary for engulfing and eliminating some pathogens such as bacteria (Butcher et al., 2001; Hazeldine and Lord, 2015) ( Figure 4 ). Macrophages also experience reduced phagocytic capacity and decreased expression of MHC class II with aging (Plowden et al., 2004), which affects their microbicidal activity and impairs T cell activation (Villanueva et al., 1990; Plowden et al., 2004) ( Figure 4 ).

Likewise, aging impacts DCs, which are key professional antigen-presenting cells (APCs) responsible for bridging innate and adaptive immune responses (Roney, 2019). Upon aging, DCs display a reduced expression of Toll-like receptors (TLRs), which limits their maturation and likely their potential for priming naïve T cells (Jing et al., 2009) ( Figure 4 ). Indeed, it has been shown that aging reduces DC-mediated priming of CD4⁺ and CD8⁺ T cells (Pereira et al., 2011) (Sridharan et al., 2011) ( Figure 4 ). The reduction of CD4⁺ T cell activation will harm T cell-dependent humoral responses, which in addition to the adverse effects of aging over B cells, will significantly reduce the host’s antibody responses.

T cells and their subpopulations are key cellular components of the adaptive immune system and are derived from hematopoietic stem cells from the bone marrow (Janeway, 2001). The almost exclusive antigen-specificity of each T cell allows the organism to respond to a virtual infinite number of foreign antigens and/or pathogens, which may be encountered throughout the individual’s life (Janeway, 2001; Moser and Leo, 2010). With this broad capacity to recognize numerous antigens, the number of cells that can recognize and respond to any individual antigen is highly limited (Rosenblum et al., 2016). Therefore, to produce sufficient specific effector cells to fight an infection, an activated T cell must proliferate so that its progeny exerts effector cells in enough numbers to affect the pathogen effectively (Hilleman, 2004). For this reason, a limitation in the number of cell divisions, or associated processes, could potentially impair immune function against pathogens (Effros, 1998). This deterioration of the immune system can lead to increased susceptibility to infections, reduced effectiveness of vaccines, and possibly an increased occurrence of several diseases in the elderly (Renshaw et al., 2002; Pera et al., 2015).

An important biomedical development in the last century is the generation of vaccines, which have prevented the spread of infectious diseases, eradicated some of them, and saved millions of lives (Tomori, 2011). Vaccines have been the main asset to controlling and preventing COVID-19 (Remmel, 2021). When analyzing the effectivity of vaccines in terms of age-ranges in the population, their efficacy decreases with age, with increased infection susceptibility in the elderly, which occurs similarly for other viral and bacterial infections upon vaccination (Nicoletti et al., 1993; Crooke et al., 2019). These alterations may be related to immunosenescence.

Although studies regarding vaccines against pathogens such as influenza have shown mixed results in effectivity throughout age groups, most of these studies reveal that the antibody responses of young individuals are more robust as compared to those of older individuals (Mosterín Höpping et al., 2016). At the cellular level, this has been attributed to the DC-T cell axis, as reported by Panda et al. (2010). Furthermore, defective TLR signaling in primary human DCs from elderly individuals led to a decreased production of proinflammatory cytokines, which was associated with a weaker antibody response to influenza vaccination (Lefebvre et al., 2016) ( Figure 4 ). Moreover, pathogens have several virulence factors that may induce senescence hallmarks directly or indirectly in host cells (Redeker et al., 2017). Furthermore, the extended lifespan of humans has been associated with detriments to the immune system, and it has been recently demonstrated that pathogens may use senescent cells to establish persistent infections in older organisms (Fülöp et al., 2013).

Some of these alterations can be attributed to a phenomenon known as T cell replicative senescence (Chou and Effros, 2013), a stage characterized by dysregulated immune function with the loss of the expression of costimulatory molecules in T cells, namely CD28 and CD27 (Weiskopf et al., 2009) ( Figure 4 ). These are important molecules for promoting cell proliferation and the survival of CD8⁺ T cells (Effros et al., 2005, 8). T cell replicative senescence is also associated with shortened telomeres and increased production of proinflammatory cytokines (Effros, 2004) ( Figure 4 ). These alterations are related to phenotypic changes in CD8⁺ T lymphocytes. It has been shown that senescent CD8⁺ T cells, which tend to accumulate in the elderly, often have antigenic specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may contribute to driving immune senescence and causing functional and phenotypic changes in T cells compartment. Impaired T cell function has been pointed out as an important factor in responses to pathogens upon aging.

Consequently, a host may display with aging a reduced capacity to respond to recurrent infections (Dock and Effros, 2011; Fülöp et al., 2013, 8). T cells in old age have also been identified in patients with chronic infections, such as with the HIV (Miller, 1996; Akbar and Fletcher, 2005). Clinically, these defects correlate with increased morbidity and mortality in the elderly upon infectious diseases (Vicente et al., 2016). Furthermore, upon aging changes in T cell differentiation, when compared to younger individuals, shows a bias towards the formation of a T follicular helper phenotype, instead of a Th1 phenotype (Lefebvre et al., 2016). A Th1 phenotype is generally essential for viral clearance, so a decrease in these cells will directly impact infection resolution (Lefebvre et al., 2016). Altogether, these T cell alterations will affect B cell activation, their differentiation and antibody production. Indeed, analyses of plasma cells revealed that antibody production was affected at the levels of antigen-specific antibodies to be produced upon vaccination, and not as a reduction in antibody avidity, which correlated with the phenotype bias of T helper cells (Sasaki et al., 2011).

The main question regarding the occurrence of the above-described immunological effects seems to be related to the processing and presentation of antigens (Pamer, 1999), as well as to environmental cytokines, as these can affect both, ongoing immune responses and the maintenance of lymphoid populations (Ku et al., 2000; Akbar et al., 2016).

Immunosenescence includes another primary feature that relates to impaired hematopoietic stem cell function, such as decreased numbers of circulating naïve T cells from aged mice as compared to young mice, and an inverted CD4/CD8 ratio, together with increased levels of proinflammatory cytokines, such as IL- 6 and TNF-α ( Figure 4 ) (Deeks, 2011; Jiang et al., 2013). There is also evidence regarding an alteration in the profile of CD4⁺ T cells (Th), from a Th1 phenotype toward Th2, which may result in a shift in the balance between humoral and cell-mediated immune responses to pathogens (Linton, 2001; Spellberg and Edwards, 2001). Therefore, pathogens such as influenza, pneumococcus, and varicella-zoster virus (VZV), and emerging pathogens, such as West Nile virus (WNV) and severe acute respiratory syndrome (SARS)-associated coronavirus, may have a disproportionate symptomatology with high incidence and deaths in the elderly, as immunosenescence is more commonly seen in the affected when compared with healthy younger individuals (Yancik and Ries, 2000; Lin and Bhattacharyya, 2012).

Additionally, it is also possible that an aging immune system is inefficient in controlling latent virus reactivation (and gene expression), due to the intrinsic effects of senescence over T cells, which would allow prolonged persistence of viral antigens and continuous stimulation of virus-specific T cells leading to their exhaustion (Smithey et al., 2012; Fülöp et al., 2013).

B cells are an essential component of the adaptive immune system and are specialized in producing antibodies (Burton et al., 2000). For most antigens requiring high-affinity antibodies, the activation of B cells requires the help of CD4⁺ T cells. In this process, B cells uptake antigens through endocytosis by through their B cell receptors (BCRs, which later will be secreted as soluble antibodies), to further process and present their derived antigens in MHC-II molecules when peptidic in nature (Crotty, 2011). The peptide-MHC-II molecules interact with the T cell receptor (TCR) on the surface of antigen-specific Th cells (Crotty, 2011). If activating, this peptide-MHC-II-TCR engagement will promote an increase in the expression of co-activating molecules, such as CD40, CD40-L, and ICOS, and cytokines such as IL-21, IL-4, BAFF, and IFN-γ (93). These signals may promote B cell activation, inducing their proliferation, the initiation of the germinal center reaction, and antibody isotype switch (Vinuesa et al., 2005). The antibody isotype switch is the process whereby activated B cell change the type of antibody produced, from IgM to either IgG, IgE, or IgA depending on the functional requirements of such antibodies (Roco et al., 2019) ( Figure 4 ). These changes are critical for an effective humoral immune response, and several are affected during aging. Antibody class-switch is a process sustained by the enzyme activation-induced cytidine deaminase (AID) (Stavnezer, 2011). Some reports indicate no difference in the expression of AID B cells from young and old mice (Russell Knode et al., 2019). However, mitogen-stimulated B cells from aged mice generate low levels of class-switched antibodies (Frasca et al., 2004), which was attributed to a reduced expression of AID and E47, the latter belonging to a set of proteins that regulate AID expression (Frasca et al., 2004).

The impact of aging on humoral immunity is linked to several biological processes in B cells, which have been reported in humans and mice (Frasca et al., 2005; Buffa et al., 2011). For instance, maturation and differentiation of B cells from precursors in the bone marrow are necessary to maintain the proportion of different subsets of B cells in various tissues, in a process that is in contrast to what happens to T cells (Alter-Wolf et al., 2009). In this regard, it has been reported that the B2 B cell subset is poorly generated in aged mice (Alter-Wolf et al., 2009) ( Figure 4 ). This B cell subset is short-lived, metabolically quiescent, involves follicular and marginal B cells, and is the primary subtype of B cells that responds to protein antigens (Alter-Wolf et al., 2009). One of the main signals involved in this process is the availability of IL-7 produced by stromal cells, and since the bone marrow microenvironment is altered in aged mice, this leads to a reduced production of this cytokine by stromal cells (Stephan et al., 1998). In addition, age-associated B cells have been identified as a subset of B cells with a specific phenotype and transcriptional signature, which continuously increase in the splenic B cell compartment of old mice and depends on TLR7 and TLR9 activation, but not on BCR engagement and the costimulatory molecule CD40 (Hao et al., 2011) ( Figure 4 ). These cells have also been detected in young lupus-prone NZB/WF1 mice and peripheral blood samples of elderly women with autoimmune diseases (Cancro, 2020). Antibody production also changes during aging, with several reports indicating that older individuals’ antibodies are less protective than younger individuals (Nicoletti et al., 1993; Howard et al., 2006).

The importance of highlighting the detrimental effect of aging on antibody production relies on the susceptibility of older individuals to infection by different pathogens, which leads to a significant severity of disease and increased mortality, a matter of great concern, especially considering that globally, people are living longer (Keilman, 2021)