#aging increases vulnerability to respiratory viral infections, including by #SARSCoV2. Delval et al. established a causal role for age-related pre-existing #senescent cells in the severity of #COVID19 symptoms in an aging hamster model. Selective depletion of senescent cells using senolytic agents mitigated the risk of severe COVID-19 symptoms linked to aging.
Aging considerably influences the severity of COVID-19: older individuals experience heightened illness, with increased hospitalizations and mortality rates. Cellular senescence has been proposed as a potential contributor to the severity of COVID-19 infection in older individuals1,2; however, empirical evidence that substantiates this connection in vivo is currently lacking. Virus-induced senescent cells have been implicated in SARS-CoV-2 infections2, yet the specific contribution of age-related senescent cells remains unclear. In this issue of Nature Aging, Delval and colleagues3 present compelling evidence that links age-related senescent cells (including those pre-existing before the infection), via a causal relationship, to the pathogenic severity of experimental COVID-19 in an aging hamster model (Fig. 1). These findings underscore the urgent need for clinical trials that focus on senolytic agents — a group of small molecules that selectively kill senescent cells — to mitigate the immediate and long-term health effects of SARS-CoV-2 infection.
Cellular senescence is a recognized causal factor of aging4,5. This cellular process is a lasting cell-cycle cessation in response to stress or damage, characterized by altered cellular function and a unique senescence-associated secretory phenotype (SASP). In a previous study by Camell and colleagues, senescent cells demonstrated an amplified inflammatory response, impaired antiviral defense mechanisms and heightened expression of viral entry proteins to viral infection6. However, this study lacked direct in vivo evidence linking cellular senescence to SARS-CoV-2 infection.
In the study by Delval et al.3, the relationship between cellular senescence and SARS-CoV-2 infection was elucidated in aged hamsters. The authors first compared the burden of age-related pre-existing senescent cells within the lungs of aged hamsters to that of their young counterparts. Senescence-associated genes were notably upregulated in the older cohort, including those encoding the common senescent cell markers p16INK4a (hereafter, p16) and SASP factors. Furthermore, aged hamster lungs exhibited an increase in p16-positive senescent cells, senescence-associated β-galactosidase (SA-β-Gal) activity and expression of proteins in the B-cell lymphoma 2 (BCL-2) pathway, a known senescent cell anti-apoptotic pathway7. These findings highlight the possible role of pre-existing age-related senescent cells in increasing susceptibility to SARS-CoV-2 infection in aged hamsters. To examine the effect of age-related senescent cells on susceptibility to SARS-CoV-2 infection, Delval and the team used senolytics to deplete senescent cells in the lungs of aged hamsters. They used ABT-263, a BCL-2-family inhibitor that has previously been established as an effective senolytic in mouse models8,9, and demonstrated that ABT-263 treatment reduced p16-high senescent cells within the lungs of the aged hamsters, as evidenced by immunohistochemistry, immunofluorescence and SA-β-Gal activity. These findings suggest that aged hamsters could serve as a pertinent model for investigating the effects of senolytics in COVID-19. Viral load is a widely used parameter to evaluate viral infection, including for SARS-CoV-2 (ref. 10). Delval et al. found that the viral load at 3 and 7 days after infection was higher in aged hamsters than in their younger counterparts, and that aged hamsters retained infectious viruses at 7 days after infection. This heightened viral load may be attributable to increased viral entry6. The researchers subsequently assessed the expression of angiotensin-converting enzyme 2 (ACE2; the SARS-CoV-2 entry receptor) and found that it was elevated in the lungs of aged hamsters. They observed a colocalization of ACE2 with p16, indicating an upregulation of ACE2 in senescent cells. Additionally, it is possible that the epithelial cells surrounding a senescent cell may also contribute as a source of ACE2 when stimulated with the SASP6, as illustrated in Fig. 1.
In addition to viral load, Delval and colleagues examined the age-dependent characteristics of COVID-19-like lung disease. By 3 days after infection, aged hamsters developed bronchointerstitial pneumonia, congestion and intra-alveolar and interstitial cell infiltration. By 7 days after infection, symptoms intensified and there were additional complications, such as alveolar collapse, necrosis, hemorrhage, micro-vasculitis and discrete thrombi. By 22 days after infection, some inflammation and type II hyperplasia persisted; there were significantly more inflammatory foci in aged hamsters. Aged hamsters also demonstrated higher collagen deposition and basal membrane disorganization around bronchi and blood vessels than did younger hamsters. Although both age groups exhibited respiratory disease symptoms and weight loss after infection, aged hamsters demonstrated slower weight recovery and failed to regain their initial body weight by 22 days after infection. Collectively, aged hamsters exhibited a higher viral load, increased basal ACE2 expression and more severe post-acute lung sequelae, which led Delval et al. to explore the possible mechanism that is responsible for the age-associated vulnerabilities.
Given the known implications of cellular senescence in viral infection and aging, Delval and colleagues assessed senescence markers and found increased p16-positive lung cells during infection in aged hamsters. Detecting viral antigens within a subset of senescent cells suggests the coexistence of pre-existing senescent cells with those induced by the viral infection2,11, notably in the context of aging. Next, the authors examined the influence of senescent cells on SARS-CoV-2 replication. Hamsters were treated daily with ABT-263 from one day prior to SARS-CoV-2 infection until they were euthanized. ABT-263 notably reduced viral load and ACE2 expression within the lungs of aged hamsters. These reductions suggest that eliminating pre-existing senescent cells before infection may mitigate the severity of SARS-CoV-2 infection. However, the precise role of pre-existing versus viral-induced senescent cells in viral replication remains unclear. Therefore, the exact molecular and cellular mechanisms that underlie these beneficial effects warrant further exploration and comprehensive investigation.
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https://www.nature.com/articles/s43587-023-00450-w
In aged hamsters, the accumulation of senescent cells with aging (pre-existing senescent cells) and SASP factors upregulate ACE2 (the SARS-CoV-2 entry receptor) expression in lung tissues, which predisposes lung tissue to be more susceptible to SARS-CoV-2 virus entry and increases viral load. Meanwhile, viral infection actively induces more senescent cells (virus-induced senescent cells) in aged hamsters than in young ones, thus reinforcing a detrimental positive feedback loop. Together, these events contribute to the development of severe infection sequelae. Conversely, removing senescent cells in aged hamsters with the senolytic agent ABT-263 decreases viral load, lowers levels of SASP factors and improves outcomes. SnC, senescent cell; VIS, virus-induced senescence.