Acute infectious diseases represent a leading international cause of death, and in its most severe manifestation presents as sepsis. Sepsis is a life-threatening condition with organ dysfunction due to a dysregulated host response to an infection, as defined by the Third International Consensus Definitions for Sepsis and Septic Shock (Singer et al., 2016). It affects approximately 48 million adults per year worldwide, with 11 million sepsis-related deaths reported (Rudd et al., 2020). The pathophysiology of sepsis is a complex spatiotemporal connected pathway of innate and adaptive immune system dysfunction leading to an early pro-inflammatory response and eventual immunosuppression leading to end-organ failure (Jarczak et al., 2021). Despite advances in treatment, sepsis-related hospital mortality continues to approach 50% and represents a significant burden on healthcare spending (Markwart et al., 2020; van den Berg et al., 2022). The underlying etiology of a sepsis is broad and includes bacterial, viral, and fungal acute infectious pathogens (Koçak Tufan et al., 2021; Lin et al., 2018).

Uniquely, elderly individuals pose a particularly high risk of developing sepsis as a response to routine acute infectious disease with increased mortality and morbidity (Esme et al., 2019; Guidet et al., 2018; Yoshikawa and Norman, 2017), and make up the majority of individuals hospitalized (Rowe and McKoy, 2017). It has s been estimated that individuals > 60 years old demonstrate a 20% increased risk of developing sepsis (Martin et al., 2006). As individuals age, cognitive and physical domains diminish in capacity, leading to a state of frailty, predisposing individuals to infections and deleterious downstream morbidity and mortality (Trevisan et al., 2023). A commonly described driver of human aging that has been described across disease states is the phenomenon of cellular senescence, which may contribute to adverse outcomes in the setting of acute infectious diseases and the subsequent development of sepsis (Nasa et al., 2012).

Cellular senescence is characterized by a stable exit from the cell cycle with continued secretion of a milieu of pro-inflammatory cytokines and chemokines that, through a paracrine mechanism, induce further cellular senescence of nearby cells (Gorgoulis et al., 2019). The senescence associated secretory phenotype (SASP) also drives a state of chronic sterile inflammation that when coupled with an infection causes a propensity for cytokine storm and organ damage (Camell et al., 2021). Characteristically, senescent cells are particularly difficult for the immune system to clear, thus resulting in an accumulation of senescent cells as individuals age (Prata nd Mckoy, 2018). Beyond local senescent cell accumulation and burden are the deleterious effects of age on an individual’s immune function, dubbed immunosenescence, resulting in an increased predilection for infection and decreased or altered response to infection (Fulop et al., 2018; Camell et al., 2021).

Senescent cells can be selectively targeted with a new class of drugs “senotherapeutics” which consists of two classes (Zhang et al., 2023). Senolytics selectively kill senesecent cells, while senomorphics modulate their proinflammatory secretions (Zhang et al., 2023). The potential role of cellular senescence and the role of senolytic medications to reduce their burden in the setting of acute infectious diseases has been demonstrated in preclinical models. However, the data in humans is less robust. Given the critical role of the immune system in the pathophysiology of sepsis, there is also a growing understanding that acute infections can increase the senescent cell burden, and how that negatively impacts clinical recovery. Despite this evolving knowledge based, there remains a substantial gap in the literature studying cellular senescence in sepsis. Previous work has sought to describe the mechanistic involvement of senescence in acute infection using in-vitro models and suggest a critical role of this effect of aging on sepsis pathophysiology, however a paucity of data in human patients exists (Reyes et al., 2023; Schmitt et al., 2023; Kelley et al., 2020). To address this gap, t he goal of this systematic review is to comprehensively summarize the current state of medical literature as it relates to cellular senescence in acute human infections, excluding in-vitro models, to serve as a basis for future identifying literature gaps to inform explorations in more severe forms of infections, such as sepsis, more specifically.

The present systematic review was performed in compliance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Open Access Page et al., 2021) and the study protocol was registered using the International Prospective Register of Systematic Reviews, CRD42023421473. A PRISMA 2020 checklist is available via Supplementary Table S1.

In this systematic review, we identified a relative paucity of human studies examining the effect of acute infectious diseases on cellular senescence. However, in all four of the conditions studied, patients with acute infection demonstrated higher senescent cell markers than controls. Senescence markers were amplified in serum, infected tissue, and peripheral immune cells, including T cells, monocytes, and macrophages (Asghar et al., 2018; Covre et al., 2019; Zheng et al., 2020; Evangelou et al., 2021; Fantecelle et al., 2021; Lee et al., 2021; Wang et al., 2021; Lipskaia et al., 2022; Nguyen et al., 2022; Roh et al., 2022; Martín-Escolano et al., 2023). A large number of manuscripts were screened for inclusion, however ultimately excluded due to them including exclusively in-vitro or cellular models without human patient samples.

There is a strong pool of literature supporting the upregulation of p16^INK4a and p21^CIP1 as reliable senescence markers in infected tissue (Evangelou et al., 2021; 2022; Fantecelle et al., 2021; Lee et al., 2021; Lipskaia et al., 2022). p16^INK4a is the most well-studied marker of senescence in the peripheral serum monocytes and has been shown to be increased in acute disease states (Asghar et al., 2018; Zheng et al., 2020; Lekva et al., 2022). Additionally, expression of p16^INK4a in peripheral T cells is a viable marker of normal human aging outside of infectious processes and appears to be correlated to patient frailty within and across age demographics (Liu et al., 2009; Englund et al., 2021). In the preclinical literature, this phenomenon does not appear to be exclusive to the four conditions included in this review. Senescence has been observed in vitro or ex vivo with other acute infections including influenza A virus and respiratory syncytial virus (Li et al., 2017; Schulz et al., 2024) but also in chronic viral infections including CMV, HCV, and HIV (Montano et al., 2022; Raviola et al., 2024). Senescence driven by these chronic viral infections is believed to accelerate cellular aging and contribute to a pro-tumor micro- and macro-environments (Asghar et al., 2018; Froidure et al., 2020).

Mechanistically, it appears that age-related accumulation of senescent cells predisposes an individual to acute infection with a cellular polarization towards inflammatory states. This is true for both peripheral tissue and circulating immune cells. Subsequently, the acute infection stimulates further the accumulation of senescent cells, which exacerbates disease phenotype through a positive feedback loop, ultimately creating excess inflammation (Zheng et al., 2020; Fantecelle et al., 2021; Wang et al., 2021; Lipskaia et al., 2022; Roh et al., 2022). This is supported by senescence induction by upregulation of MAPK signaling in SARS-CoV-2 (Wang et al., 2023) and excessive stem cell replication in acute malaria infection (Asghar et al., 2018). Additionally, SASP secretion in cutaneous L. braziliensis appears to create a positive-feedback loop with the immune system which induces substantial inflammation (Fantecelle et al., 2021). Based on the methodology of the reported studies, however, it remains unclear whether patients with increased senescence are more prone to acute infection, whether acute infections in and of themselves increase cellular senescence, or both.

Chronic sequelae of acute infections may also be a consequence of enhanced cellular senescence. In SARS-CoV-2, senescence caused by acute infection is shown to contribute to long-standing changes like emphysema and fibrosis by accelerating age-related changes (Wang et al., 2021). Lipskaia et al. postulated there may be a causal link between epithelial cell senescence and vascular thrombosis (Lipskaia et al., 2022). Subsequent studies revealed upregulated senescence, F3, and von Willebrand factor in epithelial cells of patients with severe SARS-CoV-2 (Wang et al., 2021; Nguyen et al., 2022). Furthermore, the antithrombotic protein ADAMTS13 was shown to be decreased and to have a strong inverse relation with cardiac injuries like acute coronary syndrome (Roh et al., 2022). All of these changes contribute to thrombosis of the pulmonary vasculature, which is a well-known cause of pulmonary fibrosis and may be implicated in the development of post-COVID-19 syndrome.

Following resolution of these acute infections, we see mixed results whether senescence markers persist or return to baseline. Patients infected with P. falciparum showed resolution of serum senescence markers to baseline within the year following acute infection (Asghar et al., 2018). Following recovery of acute hepatitis C, however, serum senescence markers persist for over 2 years and are suspected to contribute to T cell exhaustion (Martín-Escolano et al., 2023). Serum samples from patients with severe SARS-CoV-2 showed persistently upregulated SASP 3 months after resolution of infection in an age-dependent and age-independent manner further supporting involvement of senescence in post-COVID-19 syndrome (Lekva et al., 2022).

Importantly, senescence markers may be clinically significant as predictors of disease presence and severity and can be used to guide treatment. The studies included in this review show the burden of senescence markers correlates with disease severity. For SARS-CoV-2, this is true of numerous markers including p21^CIP1 in peripheral blood mononuclear cells (Lin et al., 2023), telomere shortening in peripheral blood T cells (Froidure et al., 2020), serum SASP profile at time of admission (Roh et al., 2022), and MAPK signaling in the testes (r = 0.999, p < 0.001) (Wang et al., 2023). P. falciparum infection is also shown to be correlated with increased p16^INK4a expression, decreased telomerase activity, and shortened telomeres in peripheral white blood cells (Asghar et al., 2018). Finally, in L. braziliensis infection, the size of cutaneous lesions and parasitic load correlated with cutaneous SASP marker expression (Fantecelle et al., 2021).

Given the substantial involvement of cellular senescence in acute infection, this process may be a viable drug target. The senolytics navitoclax, fisetin, and quercetin plus dasatinib were shown to be effective at reducing senescent phenotype in vivo models of SARS-CoV-2 infection. Moreover, animal models treated with these senolytics displayed meaningful improvement of disease phenotype albeit with moderate adverse effects (Lee et al., 2021). F3 inhibitors are also being explored as possible therapeutic agents to prevent dysregulation of thrombosis seen with epithelial cell senescence in SARS-CoV-2 (Nguyen et al., 2022).

The mechanism by which cellular senescence influences an individual’s risk of acquiring infection and that infection being severe in nature are numerous and dependent on the infectious agent. Generally, it involves an alteration in immune cell populations systemically, a decline in the innate and adaptive immune function, and chronic inflammation (Wrona et al., 2024; Marrella et al., 2022). Although outside the scope of this review, these mechanisms are explored and reported in other narrative and literature reviews and we refer interested readers to the following excellent summaries (Reyes et al., 2023; Wrona et al., 2024; Marrella et al., 2022; Li et al., 2023).

The key limitation of this review was the study populations. Most included studies were limited to populations of severely to critically ill patients which raises concerns regarding the generalizability of these findings (Froidure et al., 2020; Evangelou et al., 2022). Further clinical research is essential to develop a thorough understanding of the role of cellular senescence in acute infection. Mechanistic questions remain including how acute infections affect the rate of senescent cell accumulation and aging and if these are transient events. There are also practical challenges to the clinical use of senescence markers including when they should be measured during a disease course and which markers should be measured. Furthermore, it is unclear if nucleic acid or protein assays are more reliable in clinical populations.

Current literature demonstrates robust upregulation of markers of cellular senescence in the setting of acute SARS-CoV-2, P. falciparum, L. braziliensis, and hepatitis C virus, and that markers of senescence correlate with disease severity and persist for months after resolution. Limitations in the number and types of infectious organisms studied, low sample sizes, modest longitudinal sampling, and a lack of consistency in markers measured, the method of measurement, and the definition of normal values represent ongoing gaps in the literature.