Takanori Katsube

Objectives: To investigate how graded early-life dietary restriction (DR) influences radiation-induced adaptive responses (AR), genotoxicity, lethality, and oxidative stress in a mouse model. Methods: Female C57BL/6J mice were subjected to 25%, 50%, or 75% DR beginning immediately after weaning. Radiation adaptive responses were evaluated using a classical priming/challenge protocol. Survival after total-body irradiation, micronucleus formation, and reactive oxygen species (ROS) production in bone marrow cells were assessed. Results: Mild DR (25%) preserved both survival and cytogenetic adaptive responses despite increased radiosensitivity. Moderate DR (50%) did not exhibit a detectable survival AR while preserving cytogenetic adaptation. Severe DR (75%) did not exhibit detectable survival or cytogenetic ARs and showed increased radiation-induced lethality and genotoxicity. Moderate DR also increased baseline and radiation-induced ROS levels. Conclusion: Early-life nutritional status significantly modifies radiation responses in a severity- and endpoint-dependent manner in mice. These findings identify nutritional status as an important biological modifier of radiation response and suggest that developmental nutritional conditions may contribute to variability in radiation sensitivity. Further studies using clinically relevant models are needed to determine the translational implications of these findings.

Dietary restriction (DR) has been extensively investigated for its capacity to extend lifespan and mitigate age-associated pathologies. In the context of ionizing radiation (IR), DR—implemented through caloric reduction, selective nutrient restriction, or fasting-based regimens—has emerged as a significant modulator of both cellular and systemic responses to radiation exposure. Growing evidence suggests that DR influences radiation outcomes in a highly context-dependent manner, exerting either protective or sensitizing effects depending on tissue type, metabolic status, timing of intervention, and radiation conditions. This review synthesizes current knowledge regarding the mechanisms through which DR modulates responses to IR, with particular emphasis on oxidative stress regulation, inflammatory signaling, mitochondrial homeostasis, DNA damage responses, cellular quality-control pathways, and carcinogenic processes. We further discuss how distinct dietary paradigms interact with nutrient-sensing and stress-adaptive networks to influence radiation sensitivity and tissue recovery. Emerging evidence indicates that the timing, intensity, and composition of dietary interventions critically shape tissue responses to IR, underscoring the importance of considering nutritional status in radiation risk assessment and therapeutic planning. By integrating established findings with emerging mechanistic insights, this review highlights the translational potential of DR for improving outcomes in radiation oncology and reducing radiation-induced injury.

Ionizing radiation, though indispensable in medicine, energy, and space exploration, imposes complex biological stresses that disrupt redox homeostasis, inflammation control, and genomic integrity, ultimately contributing to fibrosis, immunosuppression, and carcinogenesis. Despite advances in pharmacological radioprotectors and technological safeguards, their incomplete efficacy and safety concerns highlight the need for integrative and sustainable mitigation strategies. Emerging evidence supports that nutrition- and lifestyle-based interventions can attenuate radiation-induced injury and enhance intrinsic defense mechanisms without compromising therapeutic efficacy. Nutritional modulation through balanced energy intake, micronutrients, and bioactive compounds such as antioxidants, vitamins, omega-3 fatty acids, and phytochemicals helps stabilize redox balance, suppress inflammatory signaling, and promote DNA repair and mitochondrial stability. Micronutrients including selenium and zinc stimulate antioxidant enzymes and DNA repair systems, while phytochemicals such as resveratrol, curcumin, and epigallocatechin gallate activate Nrf2 and inhibit NF-κB pathways, restoring cellular homeostasis. Complementary lifestyle factors including regular physical activity, adequate sleep, circadian rhythm alignment, and stress management, further enhance immune surveillance, genomic stability, and metabolic adaptation. Collectively, these integrative approaches provide synergistic, multi-pathway protection against radiation-induced damage. Future directions should focus on multi-omics–guided mechanistic studies and well-designed clinical trials to establish personalized, evidence-based frameworks for radiation mitigation.

High-fat diets (HFDs) have become increasingly prevalent in modern societies, driving rising rates of obesity and metabolic syndrome. Concurrently, radiation exposure from medical treatments and environmental sources poses health risks shaped by both biological and environmental factors. This review explores the intersection between HFDs and radiation sensitivity/susceptibility, focusing on how diet-induced metabolic alterations influence the body’s response to radiation. Evidence from preclinical and clinical studies indicates that HFDs significantly alter metabolism, leading to increased oxidative stress and immune system dysregulation. These metabolic changes can exacerbate radiation-induced oxidative stress, inflammation, and DNA damage, potentially increasing radiation sensitivity in normal tissues. Conversely, obesity and HFD-induced metabolic disruptions may activate cellular pathways involved in DNA repair, cell survival, and inflammatory responses, fostering tumor resistance and modifying the tumor microenvironment, which may impair the efficacy of radiation therapy in cancer treatment. Understanding the interplay between diet and radiation exposure is critical for optimizing public health guidelines and improving therapeutic outcomes. These findings underscore the need for further research into dietary interventions that may mitigate radiation-associated risks.

Radiotherapy remains a cornerstone in cancer treatment, leveraging ionizing radiation to eradicate malignant cells. Its efficacy, however, is frequently challenged by the heterogeneous sensitivity of tumors and surrounding tissues to radiation. Therefore, understanding the molecular mechanisms underlying radiosensitivity is crucial for improving treatment outcomes. Among the myriad of molecular players involved, the tumor suppressor protein p53 stands out as a central regulator with significant implications for radiosensitivity. Known as the “guardian of the genome”, p53 plays a pivotal role in maintaining genomic stability and orchestrating cellular responses such as cell cycle arrest, DNA repair, apoptosis, and senescence in response to various stress signals, including radiation-induced DNA damage. Activation of p53 triggers the transcription of target genes involved in DNA repair pathways, such as p21, MDM2, and GADD45, facilitating the repair of radiation-induced DNA damage or the elimination of irreparably damaged cells. This, in turn, influences the overall radiosensitivity of tissues. Mutations in the TP53 gene, which encodes p53, are among the most frequent genetic alterations in human cancers. Loss or dysfunction of p53 can compromise the cellular response to radiation, leading to increased resistance to therapy and poorer clinical outcomes. Conversely, intact p53 function is associated with enhanced radiosensitivity due to its ability to promote cell cycle arrest and apoptosis in response to radiation-induced DNA damage. In conclusion, elucidating the molecular mechanisms by which p53 influences radiosensitivity is essential for advancing our understanding of the radiation response in cancer cells and developing more effective therapeutic approaches to cancer treatment. This review provides a comprehensive overview of the multifaceted role of p53 in modulating cellular responses to radiation, emphasizing its influence on radiosensitivity.

Radiotherapy remains a cornerstone in cancer treatment, leveraging ionizing radiation to eradicate malignant cells. Its efficacy, however, is frequently challenged by the heterogeneous sensitivity of tumors and surrounding tissues to radiation. Therefore, understanding the molecular mechanisms underlying radiosensitivity is crucial for improving treatment outcomes. Among the myriad of molecular players involved, the tumor suppressor protein p53 stands out as a central regulator with significant implications for radiosensitivity. Known as the “guardian of the genome,” p53 plays a pivotal role in maintaining genomic stability and orchestrating cellular responses such as cell cycle arrest, DNA repair, apoptosis, and senescence in response to various stress signals, including radiation-induced DNA damage. Activation of p53 triggers the transcription of target genes involved in DNA repair pathways, such as p21, MDM2, and GADD45, facilitating the repair of radiation-induced DNA damage or the elimination of irreparably damaged cells. This, in turn, influences the overall radiosensitivity of tissues. Mutations in the TP53 gene, which encodes p53, are among the most frequent genetic alterations in human cancers. Loss or dysfunction of p53 can compromise the cellular response to radiation, leading to increased resistance to therapy and poorer clinical outcomes. Conversely, intact p53 function is associated with enhanced radiosensitivity due to its ability to promote cell cycle arrest and apoptosis in response to radiation-induced DNA damage. In conclusion, elucidating the molecular mechanisms by which p53 influences radiosensitivity is essential for advancing our understanding of radiation response in cancer cells and developing more effective therapeutic approaches in cancer treatment. This review provides a comprehensive overview of the multifaceted role of p53 in modulating cellular responses to radiation, emphasizing its influence on radiosensitivity.

Concurrent exposure to ionizing radiation (IR) and psychological stress (PS) may affect the development of adverse health consequences in scenarios such as space missions, radiotherapy and nuclear accidents. IR can induce DNA damage and cell apoptosis in the kidneys, thus potentially leading to renal fibrosis, which is the ultimate outcome of various chronic progressive nephropathies and the morphological manifestation of a continuous coordinated response after renal injury. However, little is known regarding the effects of concurrent IR exposure and PS on renal damage, particularly renal fibrosis. In this study, using a chronic restraint-induced PS (CRIPS) model, we exposed Trp53-heterozygous mice to total body irradiation with 0.1 or 2 Gy ⁵⁶Fe ions on the eighth day of 28 consecutive days of a restraint regimen. At the end of the restraint period, the kidneys were collected. The histopathological changes and the degree of kidney fibrosis were assessed with H&E and Masson staining, respectively. Fibronectin (FN) and alpha smooth muscle actin (α-SMA), biomarkers of fibrosis, were detected by immunohistochemistry. Analysis of 8-hydroxy-2 deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, was performed with immunofluorescence, and terminal deoxynucleotidyl transferase-mediated nick end labeling assays were used to detect apoptotic cells. Histopathological observations did not indicate significant structural damage induced by IR or CRIPS + IR. Western blotting revealed that the expression of α-SMA was much higher in the CRIPS + IR groups than the CRIPS groups. However, no differences in the average optical density per area were observed for FN, α-SMA and 8-OHdG between the IR and CRIPS + IR groups. No difference in the induction of apoptosis was observed between the IR and CRIPS + IR groups. These results suggested that exposure to IR (0.1 and 2 Gy ⁵⁶Fe ions), 28 consecutive days of CRIPS or both did not cause renal fibrosis. Thus, CRIPS did not alter the IR-induced effects on renal damage in Trp53-heterozygous mice in our experimental setup.

Humans are exposed to both psychological stress (PS) and radiation in some scenarios such as manned deep-space missions. It is of great concern to verify possible enhanced deleterious effects from such concurrent exposure. Pioneer studies showed that chronic restraint-induced PS (CRIPS) could attenuate Trp53 functions and increase gamma-ray-induced carcinogenesis in Trp53-heterozygous mice while CRIPS did not significantly modify the effects on X-ray-induced hematopoietic toxicity in Trp53 wild-type mice. As high-linear energy transfer (LET) radiation is the most important component of space radiation in causing biological effects, we further investigated the effects of CRIPS on high-LET iron-particle radiation (Fe)-induced hematopoietic toxicity in Trp53-heterozygous mice. The results showed that CRIPS alone could hardly induce significant alteration in hematological parameters (peripheral hemogram and micronucleated erythrocytes in bone marrow) while concurrent exposure caused elevated genotoxicity measured as micronucleus incidence in erythrocytes. Particularly, exposure to either CRISP or Fe-particle radiation at a low dose (0.1 Gy) did not induce a marked increase in the micronucleus incidence; however, concurrent exposure caused a significantly higher increase in the micronucleus incidence. These findings indicated that CRIPS could enhance the deleterious effects of high-LET radiation, particularly at a low dose, on the hematopoietic toxicity in Trp53-heterozygous mice.

Investigation on possible induction of adaptive response (AR) by high-liner energy transfer (LET) particle radiation for protection against low-LET photon radiation-induced detrimental effects has not yet been performed in utero. This study verified if an AR could be induced by high-LET particle radiation from accelerated heavy ions against low-LET X-ray radiation-induced detrimental effects on fetal mice. Total body irradiation of pregnant C57BL/6J mice were performed by delivering a priming dose ranging from 10 mGy to 320 mGy of particle radiation on gestation day 11 followed one day later by a challenge dose at 3500 mGy from X-ray radiation. The monoenergetic beams of carbon, silicon and iron with the LET values of about 15, 55, and 200 KeV/μm, respectively, were examined. Significant suppression by the priming radiation of the detrimental effects (fetal death, malformation, or low body weight) was used as the endpoints for judgment of a successful AR induction on gestation day 18. Existence of AR was not observed. On the other hand, the priming dose of high-LET particle radiation, in some cases, even increased the detrimental effects induced by the challenge dose from low-LET X-ray radiation. Although existence of AR induced by high-LET radiation in cultured mammalian cells in vitro and in certain tissues of laboratory mice in vivo was demonstrated, the present study did not suggest that low dose of high-LET particle radiation could induce an AR in fetal mice in utero under the setup of our experimental system.