This web page was produced as an assignment for an undergraduate course at Davidson College. Learn more about the author
Influenza, a respiratory illness, poses an exceptionally high risk to older adults due to their weakened immune system. With age, the cells of the immune system progressively lose their capacity to divide and effectively combat infections, thereby increasing the vulnerability of older individuals to various diseases, including influenza.
Influenza, commonly known as the flu, is a highly contagious respiratory illness caused by influenza viruses. The virus can spread through the air when an infected person coughs or sneezes. Symptoms of the flu include fever, runny nose, sore throat, and persistent fatigue. While most young people recover when infected, influenza is particularly dangerous for infants and older adults. The increased severity of influenza in older adults is often attributed to their age-related decline in immunity1. Researchers, led by Kasmani and colleagues, sought to explore this phenomenon further. They utilized both single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) techniques on lung tissue obtained from young and aged female mice at various time points (days 0, 3, and 9) following influenza infection. Groups of three young (16–18-week-old) and three aged (80–82-week-old) female mice were infected with different influenza virus variants, and their lung tissue was collected after infection for sequencing analysis2.
While both sequencing methods investigate gene expression levels, scRNA-seq allows gene expression to be examined at a single-cell resolution. In contrast, bulk RNA-seq provides an average gene expression profile for the entire cell population. Through scRNA-seq, the researchers observed distinct differences in the diversity of cell types in the lung tissues of young and aged mice. The lungs contain epithelial cells, which line the skin surfaces, body cavities, and blood vessels. These cells play a crucial role in mediating innate immune responses and regulating adaptive immune responses, involving dendritic cells (DCs), T cells, and B cells, all of which are central to allergic and other inflammatory diseases of the airways3. This diversity in cell types likely contributes to variations in gene expression between the two age groups. For instance, the lungs of aged mice exhibited significantly higher levels of Cdkn1a expression than those of young mice. Cdkn1a is a protein that inhibits cell division in the cell cycle. This upregulation is expected as cells gradually lose their ability to divide with aging.
Differences in inflammation levels between young and aged mice were also assessed. Inflammation, the body’s immune response to harmful stimuli, can worsen respiratory diseases. Inflammation levels increased with the progression of the flu. Notably, aged mice exhibited higher inflammatory responses compared to their younger counterparts. This result aligns with previous findings suggesting that aged mice often display heightened inflammatory responses during influenza infection4. Furthermore, the researchers observed a reduced frequency of CD4 T cells in aged mice compared to younger mice. CD4 T cells are white blood cells that coordinate and regulate the immune response. When the body encounters a pathogen, such as a virus, immune cells process and present antigens to the CD4 T cells, initiating an immune response. Due to a weakened immune system, aged mice experience delayed CD4 T cell activity, which hampers their ability to combat these immune responses effectively and efficiently.
These findings hold significant implications for understanding the impact of aging on susceptibility to viral infections like the flu. The immune system serves as the body’s primary defense mechanism against infections, and a decline in immune function makes it easier for diseases to take hold. Aging is often accompanied by a weakening of the immune system, largely due to cells becoming less able to divide and replicate for biological processes. This weakening is compounded by reduced expression of critical immune cells, such as CD4 T cells, in aged individuals. As a result, older adults are at an increased risk of developing diseases, as their immune systems are less equipped for an effective defense. This phenomenon stresses why illness is particularly concerning for the elderly, as their immune systems are not as robust as they were in their younger years. Aging is an inevitable natural process, and as we all have older adults in our lives, it is crucial to understand how diseases impact this population to provide them with adequate care and support.
One ethical consideration is the choice to use mice in this study. While mouse and human lung tissue differ in size and anatomy, they share many similarities in terms of the structure and function of their respective cell types. Given that intentionally infecting humans with influenza and sequencing their lungs is ethically implausible, using animals as model organisms is a more appropriate approach for such research. Furthermore, starting from the sixth decade of life, the human immune system undergoes significant aging-related changes, leading to decreased protection against infections and impaired wound healing5. Older individuals often experience reduced mobility, fragile skin, cognitive decline, and a compromised immune system. Thus, this demographic requires increased awareness and medical attention due to their heightened susceptibility to diseases and mortality.
References
- Flu symptoms & diagnosis, 2023 Centers for Disease Control and Prevention.
- Kasmani M. Y., P. Topchyan, A. K. Brown, R. Brown, X. Wu, et al., 2023 A spatial sequencing atlas of age-induced changes in the lung during influenza infection. Nature Communications 14. https://doi.org/10.1038/s41467-023-42021-y
- Schleimer R. P., A. Kato, R. Kern, D. Kuperman, and P. C. Avila, 2007b Epithelium: At the interface of innate and adaptive immune responses. The Journal of allergy and clinical immunology 120: 1279–1284. https://doi.org/10.1016/j.jaci.2007.08.046
- Kang I., M. Hong, H. Nolasco, S. H. Park, J. M. Dan, et al., 2004 Age-Associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. The Journal of Immunology (1950) 173: 673–681. https://doi.org/10.4049/jimmunol.173.1.673
- Weyand C. M., and J. J. Goronzy, 2016 Aging of the Immune System. Mechanisms and Therapeutic Targets. Annals of the American Thoracic Society 13: S422–S428. https://doi.org/10.1513/annalsats.201602-095aw
© Copyright 2022 Department of Biology, Davidson College, Davidson, NC 28036.
You did a great job of explaining the RNA-seq methods that were used in this research, and I found it interesting to learn about how specific proteins can affect cell division with aging when they are upregulated. I agree with your conclusions about how this work can be used to inform the type of care and medical attention we provide for the elderly as we consider the effects of aging on their immune systems and susceptibility to disease. It would be interesting to see how future applications of this work could be incorporated into the recommendations and medical advice given to older populations.
I really enjoyed learning more about why the immune system gets more fragile as we grow older. The explanation multiple different findings(cell division, inflammation, and T cell count) was really interesting as it gave multiple insights on what contributes to the weakened immune response. I was interested in the fact that inflammation is heightened in older cells, was it expected to do so? I understand the ethical implications of running this experiment in mice or humans, but would it be possible to do an observational study in humans with consenting subjects that already have the flu?