Cdc42 Protein Drives Lung Cell Aging in COVID-19 Infected Individuals

Medical News: Uncovering a Key Protein’s Role in Lung Aging
In an intriguing study, researchers from Southern Medical University in China explored how a specific protein, known as the Cdc42 Protein, might accelerate aging processes in lung cells as a result of exposure to the SARS-CoV-2 spike protein. This discovery sheds light on why some individuals, especially older adults, experience severe complications or long-term health issues after contracting COVID-19. This Medical News report aims to break down these findings, explaining how this protein may trigger aging at a cellular level and what it means for treatment possibilities.


Cdc42 expression increases in senescent cells induced by spike protein. (A) Expression of spike protein in ACE2/A549 cells transfected with plasmids for 72 h; (B) SA-β-Gal staining of ACE2/A549 cells in different treatment groups and the red arrow indicates spike protein-mediated membrane fusion, bar =100μm; (C) Western blot analysis of senescence indicators p16, p21 in ACE2/A549 cells under different treatment factors and (D) quantitative analysis; (E) mRNA levels of p16, p21, and SASP in ACE2/A549 cells in different groups.

Investigating Cellular Aging with COVID-19’s Spike Protein
The study used both live virus and spike protein exposure to induce cellular changes in a model. The spike protein, a defining feature of the virus responsible for its entry into human cells, was administered to lab mice engineered with human-like receptors. Remarkably, the results showed that exposure to the spike protein triggered characteristics commonly associated with aging cells. This study delves into how the spike protein activated pathways that speed up the cellular aging process in lung tissue.
 
Key Findings of the Study: The Cdc42 Protein Connection
Central to the study is a protein called Cdc42, which is associated with cell structure and division. Cell division cycle protein 42, commonly known as Cdc42, is a small GTPase enzyme that belongs to the Rho protein family. It is essential for several core cellular functions, such as restructuring the actin cytoskeleton, maintaining cell polarity, and supporting cell growth. When Cdc42 becomes overly active, it has been linked to a range of serious health issues, including cancer development and neurodegenerative disorders. Beyond these roles, recent studies have drawn attention to its significant involvement in cellular aging. Suppressing Cdc42 activity has shown potential to renew the regenerative abilities of aging intestinal stem cells. Additionally, Cdc42 plays a role in the aging of hematopoietic and mesenchymal stem cells. Research involving older mice has utilized a Cdc42 inhibitor known as Casin, which has effectively lowered chronic inflammation and extended average lifespans.
 
When the lung cells were exposed to the spike protein, there was a noticeable increase in Cdc42 activity. This heightened activity then triggered a cellular aging process known as senescence, where cells cease to divide and start producing inflammatory molecules that can harm nearby cells. The study's authors explain that the surge in Cdc42, brought on by the spike protein, pushes cells into this aged state, ultimately harming lung tissue over time.
 
The researchers observed these effects in several ways. First, they saw that specific aging markers, such as proteins named p16 and p21, were more present in spike-protein-exposed cells. These proteins are known to indicate aging, and their increase suggests that the cells were moving into an “aged” state. Notably, Cdc42’s role in activating this pathway links it directly to COVID-19’s ability to create aged or damaged tissue. This study suggests that when Cdc42 activity is heightened by the spike protein, it may set off a chain reaction that intensifies lung injury, inflammation, and the overall aging process of these cells.
 
How Blocking Cdc42 Could Help
To examine if there was a way to halt or reverse the aging effects caused by Cdc42, researchers introduced a Cdc42 inhibitor called ML141. When given to the mice exposed to the spike protein, ML141 showed promising results. The inhibitor not only reduced cellular aging markers but also helped limit inflammation and lung tissue damage. The ability to decrease the inflammatory response is critical, as it could mean fewer complications for patients with COVID-19, especially those facing post-acute symptoms or lung issues.
 
This experiment highlights the potential of drugs that target Cdc42 as a possible solution to manage or even prevent long-term complications of COVID-19, especially in those experiencing lingering respiratory or inflammatory symptoms.
 
Wnt/β-Catenin Signaling Pathway’s Role in Aging
Another significant finding in this research is the involvement of the Wnt/β-catenin signaling pathway, a system that regulates cell growth and tissue maintenance. When cells are under stress, such as from infection, this pathway can shift into overdrive, contributing to cellular aging. Here, the study found that the spike protein not only activated Cdc42 but also led to the movement of β-catenin, a key player in this pathway, into the cell’s nucleus. This nuclear migration of β-catenin is associated with accelerated aging and has been noted in other age-related conditions, such as lung disease and fibrosis.
 
In experiments where Cdc42 was blocked, there was a significant decrease in β-catenin’s activity in the cell nucleus, demonstrating that Cdc42 might be the main driver of this cellular aging response. Blocking Cdc42 essentially slowed down this age-related pathway, providing valuable insights into potential therapeutic strategies against COVID-19’s long-term effects.
 
Why This Matters for COVID-19 Patients
Understanding how COVID-19 could trigger cell aging offers a potential explanation for the lingering symptoms many patients experience even after the infection clears. Known as “long COVID,” these symptoms include persistent fatigue, respiratory issues, and cognitive difficulties. The study indicates that the spike protein may have effects long after the initial infection, inducing cellular damage that contributes to these chronic conditions.
 
Implications and Future Research Directions
As scientists continue to study COVID-19’s impact on the body, this study opens new paths for therapeutic exploration. Drugs that inhibit Cdc42 could be developed as treatments aimed at reducing lung aging and inflammation for COVID-19 survivors. However, further research is necessary to fully understand how to best target this protein without affecting other vital cell functions.
Another promising aspect of the study is its implications for aging-related diseases more generally. Since cellular senescence is a factor in many age-related conditions, findings on Cdc42 and the Wnt/β-catenin pathway may have broader applications beyond COVID-19.
 
Conclusion
In conclusion, this study highlights how COVID-19’s spike protein could promote lung cell aging, leading to the kinds of complications seen in older or chronically ill patients. By triggering an increase in Cdc42 and activating the Wnt/β-catenin signaling pathway, the spike protein appears to push lung cells into a state that resembles accelerated aging. These aged cells release inflammatory signals that damage surrounding tissue, creating a cycle of inflammation and injury. Blocking Cdc42 with the inhibitor ML141 showed promise in reducing these aging markers and lung damage, offering a hopeful outlook for new treatments aimed at reducing long-term complications in COVID-19 patients.
 
As we learn more about how COVID-19 affects the body, strategies targeting proteins like Cdc42 could become essential in managing both COVID-related and age-related health conditions.
 
The study findings were published in the peer-reviewed journal: Frontiers in Cellular and Infection Microbiology.
https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1449423/full
 
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https://www.thailandmedical.news/news/cftr-s-role-in-reversing-senescence-in-sars-cov-2-infected-cells