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

By Vijay Kumar MalesuReviewed by Lily Ramsey, LLMJul 10 2023

In a recent study published in the Nature Aging Journal, researchers investigated the role of senescent cells in 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), due to age-related impairments in lung function and immune responses.

The accumulation of senescent cells in the aging lung contributes to this susceptibility and leads to inflammation and tissue damage. Senescent cells release harmful factors known as senescence-associated secretory phenotypes (SASP), which worsen inflammation and disease outcomes.

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

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

About the study

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

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

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

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

The data obtained from these analyses were subjected to statistical analysis. The study was conducted within the biosafety level 3 facility of the Institut Pasteur de Lille.

Study results

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

In addition to senescent cells, aged hamsters displayed a higher viral load and more severe lung damage following SARS-CoV-2 infection. This is attributed to the higher expression levels of genes encoding viral proteins and increased angiotensin-converting enzyme 2 (ACE2) receptor expression in 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 number of senescent cells in the lungs of aged hamsters. Immunohistochemistry and immunofluorescence techniques confirmed the depletion of p16INK4a-expressing cells.

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

Remarkably, ABT-263 treatment demonstrated several beneficial effects in the context of SARS-CoV-2 infection. It reduced the viral load in the lungs of aged hamsters, potentially due to the depletion of ACE-2-expressing senescent cells.

This reduction was accompanied by a decrease in 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.

Furthermore, ABT-263 exhibited long-term effects on the consequences of SARS-CoV-2 infection. It reduced the areas of inflammation and type II hyperplasia in the lungs, resulting in improved histological scores.

The drug also showed a potential to mitigate fibrotic changes, as evidenced by a reduction in the number of inflammatory foci and a decrease in the disorganization of the basal membrane.

Proteomic analysis indicated that ABT-263 treatment downregulated proteins associated with chronic lung diseases, including those involved in the ubiquitin-proteasome system and cell adhesion molecules.

Conclusions

To summarize, the study's findings showed a higher viral load in the lungs of aged hamsters, likely due to increasing viral entry and replication along with a weakened antiviral response.

Aged hamsters also showed increased cellular senescence characterized by elevated p16INK4a, BCL-XL, and SA-β-Gal activity. ABT-263 treatment reduced senescent cells and senescence-associated factors 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. However, 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 those with other senescence-related conditions.

Further research is needed to validate these findings and explore alternative senolytic agents that offer promising strategies to improve COVID-19 outcomes in older individuals.