Journal
RADIATION RESEARCH
Volume 198, Issue 3, Pages 221-242Publisher
RADIATION RESEARCH SOC
DOI: 10.1667/RADE-22-00071.1
Keywords
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Funding
- National Institute of Allergy and Infectious Diseases (NIAID) [HHSN266200500043C, HHSN272201000046C, 1U01AI107340-01, 2R44 AI088288-03A1, UH2/UH3AI128894-04]
- National Institute on Aging (NIA) [R01AG046246-01]
- National Institutes of Health (NIH), Department of Health and Human Services (DHHS)
- Department of Defense [PR140896, PR141527, PR140433P1]
- Indiana University Grand Challenges Precision Health Initiative
- National Cancer Institute (NCI) [P30 CA082709]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U54 DK106846]
- NIH, DHHS
- NIH instrumentation grant [1S10D012270]
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This study developed aging murine models of hematopoietic acute radiation syndrome (H-ARS) and investigated the radiation dose response relationships in middle-aged and geriatric mice. The findings revealed that radioresistance increased with age, particularly in males, and identified sex-specific functional and molecular changes in aging hematopoietic cells after irradiation.
The hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to;10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30. Radioresistance increased with age and diverged dramatically between sexes. The LD50/30 in young adult mice averaged 853 cGy and was similar between sexes, but increased in middle age to 1,005 cGy in males and 920 cGy in females, with further sex divergence in geriatric mice to 1,008 cGy in males but 842 cGy in females. Correspondingly, neutrophils, platelets, and functional hematopoietic progenitor cells were all increased with age and rebounded faster after irradiation. These effects were higher in aged males, and neutrophil dysfunction was observed in aged females. Upstream of blood production, hematopoietic stem cell (HSC) markers associated with age and myeloid bias (CD61 and CD150) were higher in geriatric males vs. females, and sex-divergent gene signatures were found in HSCs relating to cholesterol metabolism, interferon signaling, and GIMAP family members. Fluid intake per gram body weight decreased with age in males, and decreased after irradiation in all mice. Geriatric mice of substrain C57BL/6JN sourced from the National Institute on Aging were significantly more radiosensitive than C57BL/6J mice from Jackson Labs aged at our institution, indicating mouse source and substrain should be considered in geriatric radiation studies. This work highlights the importance of sex, vendor, and other considerations in studies relating to hematopoiesis and aging, identifies novel sex-specific functional and molecular changes in aging hematopoietic cells at steady state and after irradiation, and presents well-characterized aging mouse models poised for MCM efficacy testing for treatment of acute radiation effects in the elderly. (C) 2022 by Radiation Research Society
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