Insight into role of aging in response to SARS-CoV-2 infection

Older adults and those with underlying medical conditions are at a higher risk of developing severe coronavirus disease (COVID-19), the illness caused by the infectious agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Previous studies have shown that older people are at a higher risk of COVID-19 because of physiological changes that come with aging and potential comorbidities, including diabetes, hypertension, and heart problems.

Researchers at the University of California, Irvine set out to determine the differences between young people and older adults regarding their host responses against SARS-CoV-2. The team revealed that independent of disease severity, COVID-19 was linked to a significant shift in plasma inflammatory factors. The research is posted to the pre-print server medRxiv*.

Aging and immune response

The effects of aging on the immune system show at multiple levels, including reduced production of T lymphocytes (T cells) and B lymphocytes (B cells) in the bone marrow and thymus and the diminished function of mature lymphocytes or white blood cells.

Many respiratory viral illnesses predispose older adults to severe illness, including the current COVID-19 pandemic, which has infected over 104 million people. More than 2.26 million have succumbed to the viral illness.

When a person gets infected with SARS-CoV-2, the virus targets the lung airway and alveolar epithelial cells, macrophages in the lung, and vascular endothelial cells. The infection triggers a robust innate and adaptive immune response to eradicate the virus. In worse cases, the immune system goes out of control, triggering a cytokine storm. Most people with severe COVID-19 develop acute respiratory distress syndrome (ARDS) and multi-organ failure.

In the United States, the estimated fatality rate of COVID-19 is about 1 to 2 percent, while 40 to 80 percent of patients develop only mild symptoms or none at all. Age is a significant risk factor for developing severe COVID-19, but more data is needed to explain why this group is most affected by the pandemic.

The elderly are the most likely to develop severe complications tied to COVID-19, including respiratory failure, shortness of breath, pneumonia, and ARDS. Further, aging is tied to immunosenescence, leading to the significant increase in susceptibility to respiratory viral infections, increased baseline inflammation, also known as 'inflammaging,' and attenuated vaccine response. Aging is also linked to diminished T cells and B cells, increased circulatory inflammatory mediators like interleukin-6 (IL-6) and C 21 reactive protein and increased effector memory cells.

Impact of aging on the host response to COVID-19

The study provides novel insights into the impact of aging on the host response to SARS-CoV-2 infection. The researchers conducted the study to determine the differences between young people and older individuals when it comes to how their immune systems combat the threat of SARS-CoV-2.

It is estimated that an estimated 80 percent of COVID-19 deaths are seen among people more than 65 years old. People with comorbidities are also at a higher risk of severe illness, and most of the elderly have these underlying health conditions.

The researchers conducted a phenotypic transcriptional and functional examination of the peripheral mononuclear cells to arrive at the study findings. They collected blood samples from patients admitted to the University of California Irvine Medical Center (UCIMC) and participating in the National Institutes of Health (NIH) ACT-1 trial. The team stratified the blood samples by disease severity, including healthy donors, mild or moderate COVID-19, and severe COVID-19.

Age was also considered as a factor, wherein those who are less than 60 years old are young, and those who are more than 60 are aged. Patients with asymptomatic and mild illness were identified as those with a positive SARS-CoV-2 result for reasons unrelated to COVID-19 symptoms, including elective surgeries, heart attack, and exacerbation of autoimmune illness, among others.

Meanwhile, severely ill patients were profiled, including patients requiring hospitalization or admission to the intensive care unit (ICU). Their blood samples were collected longitudinally over several days after symptom onset.

The researchers collected the whole blood samples in EDTA vacutainer tubes, while peripheral blood mononuclear cells (PBMC) and blood plasma samples were also isolated. The team used the Human XL Cytokine Discovery Premixed Kit to measure immune mediators, which can test cytokines, chemokines, growth factors, and effector molecules.

Other tests included an antibody enzyme-linked immunosorbent assay (ELISA), single-cell RNA sequencing, and PBMC and monocyte immunophenotyping.

The researchers performed a combination of immunological, single-cell transcriptomic, and functional assays using blood samples from 49 healthy donors, 20 mild or asymptomatic COVID-19 patients, and 47 severely ill COVID-19 patients, with longitudinal sampling based on days 10 post symptom onset (DPS).

The study findings showed that there is profound lymphopenia in aged patients, wherein there are reduced levels of white blood cells, including B cells, T cells, and natural killer cells (NK cells). The lymphopenia worsened over time and is linked to lower levels of plasma cytokines, which are viral for T cell survival in older patients with severe illness.

Further, the single-cell RNA sequencing showed amplified activation, cytotoxicity, exhaustion, and type-1 interferon signaling in memory T cells and NK cells. Even though cytokine storms can be seen in healthy and aged groups, older adults manifested increased levels of chemokines that mobilize inflammatory myeloid cells. Lastly, the team observed the re-distribution of dendritic cells (DC) and monocytes with severe disease tied to a rewiring towards a more regulatory phenotype.

The team concluded that many of these critical changes in the body and immune system were reversed in younger people, but not in the elderly.

The researchers recommend future studies to stratify young and aged patients by clinical scores. This way, the determinants of disease resolution and survival in severe COVID-19 patients can be identified.

“More importantly, addressing the impact of age on qualitative differences in humoral responses and long-term durability of T cell responses to SARS-CoV-2 would be critical in designing vaccine and therapeutic strategies in the aged population,” the researchers conclude.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.

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