cGAS/STING Pathway Mediates Accelerated Intestinal Cell Senescence and SASP After GCR Exposure in Mice
Santosh Kumar1, Kamendra Kumar1, Jerry Angdisen1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Research Building, Room E504, 3970 Reservoir Rd., NW, Washington, DC 20057, USA.
Cells
|November 26, 2025
Summary
Galactic cosmic radiation (GCR) simulation causes lasting DNA damage, oxidative stress, and immune activation in the mouse gut. This space radiation exposure leads to intestinal dysfunction and barrier compromise, requiring protective countermeasures for astronauts.
Area of Science:
- Space medicine and radiation biology
- Gastrointestinal (GI) health and radiation injury
- Molecular mechanisms of radiation-induced tissue damage
Background:
- Long-duration space missions expose astronauts to galactic cosmic radiation (GCR), a significant health risk.
- GCR, composed of high-charge, high-energy (HZE) ions, can cause chronic tissue injury.
- Understanding GCR's impact on the gastrointestinal tract is crucial for astronaut health.
Purpose of the Study:
- To investigate the intestinal outcomes in mice following simulated GCR exposure.
- To identify molecular and functional changes in the gut after low-dose GCR simulation (GCRsim).
- To assess the long-term effects of GCRsim on intestinal integrity and function.
Main Methods:
- Wild-type mice were exposed to a low dose (50 cGy) of 33-ion mixed-field GCR simulation (GCRsim).
- Intestinal tissues and serum were analyzed 5 months post-exposure for DNA damage, oxidative stress, senescence, and immune markers.
- Gene expression analysis was performed for nutrient transporters, gut hormones, and DNA-degrading nucleases; biochemical markers of intestinal injury were also measured.
Main Results:
- GCRsim induced sustained DNA double-strand breaks (DSBs), oxidative stress, and intestinal epithelial cell (IEC) senescence.
- Elevated circulating LINE-1 DNA and impaired DNA clearance were observed, alongside chronic activation of the cGAS-STING innate immune pathway.
- GCRsim altered nutrient absorption gene expression, compromised the intestinal barrier (indicated by decreased serum citrulline and increased I-FABP), and affected gut hormone levels.
Conclusions:
- Low-dose GCR simulation causes persistent intestinal dysfunction, including DNA damage, senescence, and immune dysregulation.
- Impaired extracellular DNA clearance and chronic cGAS-STING pathway activation contribute to GCR-induced GI injury.
- These findings underscore the need for countermeasures to protect astronaut gastrointestinal health during deep-space missions.
