Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome

Abstract

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.

Effect of age and sex on gene expression-based radiation biodosimetry using mouse peripheral blood

“…2c). These results support the idea that aging is characterized by increased inter-individual variability of gene expression and are consistent with a less uniform radiation response of older mice compared with young animals [Patterson et al, 2022].…”

“…One of the hallmarks associated with the antimicrobial and inflammatory action of neutrophils is the activation of a powerful oxidative burst, during which large amounts of oxygen are consumed and converted to superoxide radicals, which then act as precursor of hydrogen peroxide and other reactive oxygen species that are generated by their heme enzyme myeloperoxidase [Winterbourn et al, 2016]. Although we show that geriatric mice possess higher percentages of neutrophils both at steady state, and in the case of female mice after irradiation, as well, they exhibit a higher frequency of infection-related morbidities compared with young populations [Patterson et al, 2022], implying they may be dysfunctional. Furthermore, sex differences in neutrophil activity have been manifested with female hormones delaying apoptosis, as well as stimulating chemotaxis and recruitment of neutrophils to sites of infection [Jaillon et al, 2019].…”

Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome

“…Colony forming cells were analyzed as previously described ( 43, 44 ). Total nucleated BM cells from non-irradiated mice were plated at 2 × 10 4 per dish in ColonyGEL 1202 Mouse Complete Medium (Reach Bio, Seattle, WA).…”

Radiation and Chemical Program Research for Multi-Utility and Repurposed Countermeasures: A US Department of Health and Human Services Agencies Perspective

“…H-ARS can include prolonged immunosuppression, impaired function of hematopoietic stem cells, and multiorgan DEARE in long-term survivors of TBI doses. [50][51][52][53][54][55][56][57][58] Included within the murine H-ARS modeling repertoire are young adult, 57,59-62 outbred, 56 pediatric, 58 and geriatric 63 mice that have been instrumental in efficacy studies for the development of MCMs. However, murine models have limitations.…”