Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence

Ruggiero, Alistaire; Davis, Matthew; Davis, Ashley; DeStephanis, Darla; Williams, Abigail G.; Vemuri, Ravichandra; Fanning, K. M.; Sherrill, Chrissy; Cline, J. Mark; Caudell, David L.; Kavanagh, Kylie

doi:10.1007/s11357-022-00660-x

Cited by 4 publications

(2 citation statements)

References 75 publications

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“…It is likely that ROS-induced damage and/or apoptosis of HSPC early post-TBI is responsible for hematopoietic DEARE via loss or dysfunction of HSPC, which is alleviated via PGE-pre. Similarly, DEARE in adipose cells reflects progenitor cell damage and reduced number, not cellular senescence ( 113 ). The studies that reported HSC premature senescence were in mice that received sublethal 6 Gy TBI and were evaluated within 2 months post-TBI, which differs significantly from our use of lethal TBI in our H-ARS model and analysis of HSC senescence at 12 months post-TBI.…”

Section: Discussionmentioning

confidence: 99%

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

Pelus

Plett

et al. 2023

Radiation Research

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Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.

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Section: Discussionmentioning

confidence: 99%

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

Pelus

Plett

et al. 2023

Radiation Research

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“…The alkaloid dendrobine suppresses cellular senescence and SASP in chondrocytes which alleviates the progression of inflammation and osteoarthritis in rats 122 . A senolytic combination of dasatinib and quercetin has been reported to suppress inflamm‐aging by augmenting anti‐inflammatory responses in immune functions and preventing the accumulation of senescent cells in a preclinical trial 123 . Treatment with quercetin ameliorates advanced glycation end‐products‐induced premature senescence and SASP in human gingival fibroblasts and has been implicated in the amelioration of inflamm‐aging in diabetic periodontitis 124 .…”

Section: Cellular Senescence and Inflamm‐aging: Decoding The Relation...mentioning

confidence: 99%

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

Sharma

2024

Cell Biochemistry & Function

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There is strong evidence that most individuals in the elderly population are characterized by inflamm‐aging which refers to a subtle increase in the systemic pro‐inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm‐aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm‐aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro‐inflammatory tissue environment that provides a rationale for immune system‐independent activation of inflamm‐aging and associated diseases. There is also accumulating evidence that inflamm‐aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence‐based molecular etiology of inflamm‐aging as well as the dynamic reciprocal interactions between inflamm‐aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm‐aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm‐aging with cellular senescence both as an underlying cause and therapeutic target for further studies.

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Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review

et al. 2023

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Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence

Cited by 4 publications

References 75 publications

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

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

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review

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