The causative role of age-associated pre-existing senescent cells on COVID-19 severity

In a recent study published within the Nature Aging Journal, researchers investigated the role of senescent cells within the context of SARS-CoV-2 infection.

Study: Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters. Image Credit: SewCreamStudio/Shutterstock.com

Background

Older adults are more vulnerable to respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting from age-related impairments in lung function and immune responses.

The buildup of senescent cells within the aging lung contributes to this susceptibility and results in inflammation and tissue damage. Senescent cells release harmful aspects often called senescence-associated secretory phenotypes (SASP), which worsen inflammation and disease outcomes.

Targeting senescent cells with senolytic drugs, corresponding to ABT-263, has shown promise in improving outcomes in various diseases.

The role of senescent cells in coronavirus disease 2019 (COVID-19) is just not yet fully understood, but studies in aged mice infected with a beta-coronavirus demonstrated the advantages of senolytic treatment.

Concerning the study

On this study, the researchers conducted experiments using young and aged Syrian golden hamsters to analyze the results of SARS-CoV-2 infection and the potential efficacy of ABT-263 treatment.

The animals were infected with the virus after which euthanized at different time points to gather lung tissues for evaluation. The viral load was quantified, and gene expression was analyzed using quantitative reverse transcription polymerase chain response (RT-PCR).

Histopathological assessments, immunohistochemistry, and immunofluorescence techniques were employed to judge lung tissue changes, protein expression, and cellular senescence.

The researchers also performed transcriptomic and proteomic analyses to look at gene and protein expression changes in response to SARS-CoV-2 infection and ABT-263 treatment.

The information obtained from these analyses were subjected to statistical evaluation. The study was conducted inside the biosafety level 3 facility of the Institut Pasteur de Lille.

Study results

The outcomes showed that senescent cells related to aging and age-related diseases were significantly increased within the lungs of the aged hamsters in comparison with young hamsters. These senescent cells expressed specific markers, including p16INK4a, and exhibited heightened activity of senescence-associated β-galactosidase (SA-β-Gal).

Along with senescent cells, aged hamsters displayed a better viral load and more severe lung damage following SARS-CoV-2 infection. That is attributed to the upper expression levels of genes encoding viral proteins and increased angiotensin-converting enzyme 2 (ACE2) receptor expression within the aging lung tissue.

These observations provided a basis for studying the impact of ABT-263, a B-cell lymphoma (BCL-2) family inhibitor known to eliminate senescent cells, on SARS-CoV-2 infection selectively.

The researchers also reported that treatment with ABT-263 significantly reduced the variety of senescent cells within the lungs of aged hamsters. Immunohistochemistry and immunofluorescence techniques confirmed the depletion of p16INK4a-expressing cells.

ABT-263 also led to a decrease within the activity of SA-β-Gal, further supporting the elimination of senescent cells. Moreover, the drug downregulated the expression of senescence-associated aspects and SASP-related genes, that are known to be upregulated in aged hamsters.

Remarkably, ABT-263 treatment demonstrated several useful effects within the context of SARS-CoV-2 infection. It reduced the viral load within the lungs of aged hamsters, potentially resulting from the depletion of ACE-2-expressing senescent cells.

This reduction was accompanied by a decrease within the expression of interferons (INFs) and interferon-stimulated genes (ISGs), indicating the modulation of the antiviral response. ABT-263 treatment also ameliorated acute lung disease by reducing inflammation, hemorrhage, syncytia formation, and alveolar destruction.

Moreover, ABT-263 exhibited long-term effects on the implications of SARS-CoV-2 infection. It reduced the areas of inflammation and kind II hyperplasia within the lungs, leading to improved histological scores.

The drug also showed a possible to mitigate fibrotic changes, as evidenced by a discount within the variety of inflammatory foci and a decrease within the disorganization of the basal membrane.

Proteomic evaluation indicated that ABT-263 treatment downregulated proteins related to chronic lung diseases, including those involved within the ubiquitin-proteasome system and cell adhesion molecules.

Conclusions

To summarize, the study’s findings showed a better viral load within the lungs of aged hamsters, likely resulting from increasing viral entry and replication together with a weakened antiviral response.

Aged hamsters also showed increased cellular senescence characterised by elevated p16INK4a, BCL-XL, and SA-β-Gal activity. ABT-263 treatment reduced senescent cells and senescence-associated aspects in SARS-CoV-2-infected aged hamsters.

It also lowered viral load by eliminating ACE2-expressing senescent cells, alleviating acute lung disease, and improving lung histology.

ABT-263 treatment resulted in systemic improvements, reducing SASP-related compounds, thrombosis, and inflammation. Nevertheless, it had limited effects on body weight recovery and lung collagen deposition.

These findings suggest that senolytic drugs like ABT-263 have therapeutic potential for mitigating COVID-19 severity in older patients and people with other senescence-related conditions.

Further research is required to validate these findings and explore alternative senolytic agents that provide promising strategies to enhance COVID-19 outcomes in older individuals.