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

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Abstract

The Wake Forest nonhuman primate (NHP) Radiation Late Effects Cohort (RLEC) is a unique and irreplaceable population of aging NHP radiation survivors which serves the nation’s need to understand the late effects of radiation exposure. Over the past 16 years, Wake Forest has evaluated > 250 previously irradiated rhesus macaques (Macaca mulatta) that were exposed to single total body irradiation (IR) doses of 1.14–8.5 Gy or to partial body exposures of up to 10 Gy (5% bone marrow sparing) or 10.75 Gy (whole thorax). Though primarily used to examine IR effects on disease-specific processes or to develop radiation countermeasures, this resource provides insights on resilience across physiologic systems and its relationship with biological aging. Exposure to IR has well documented deleterious effects on health, but the late effects of IR are highly variable. Some animals exhibit multimorbidity and accumulated health deficits, whereas others remain relatively resilient years after exposure to total body IR. This provides an opportunity to evaluate biological aging at the nexus of resilient/vulnerable responses to a stressor. Consideration of inter-individual differences in response to this stressor can inform individualized strategies to manage late effects of radiation exposure, and provide insight into mechanisms underlying systemic resilience and aging. The utility of this cohort for age-related research questions was summarized at the 2022 Trans-NIH Geroscience Interest Group’s Workshop on Animal Models for Geroscience. We present a brief review of radiation injury and its relationship to aging and resilience in NHPs with a focus on the RLEC.

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References

  1. Vanhooren V, Libert C. The mouse as a model organism in aging research: usefulness, pitfalls and possibilities. Ageing Res Rev. 2013;12(1):8–21. https://doi.org/10.1016/j.arr.2012.03.010.

    Article  PubMed  Google Scholar 

  2. Justice JN, Cesari M, Seals DR, Shively CA, Carter CS. Comparative approaches to understanding the relation between aging and physical function. J Gerontol a-Biol. 2016;71(10):1243–53. https://doi.org/10.1093/gerona/glv035.

    Article  Google Scholar 

  3. Rogers J, Gibbs RA. Comparative primate genomics: emerging patterns of genome content and dynamics. Nat Rev Genet. 2014;15(5):347–59. https://doi.org/10.1038/nrg3707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Walker ML, Gordon TP, Wilson ME. Menstrual cycle characteristics of seasonally breeding rhesus monkeys. Biol Reprod. 1983;29(4):841–8. https://doi.org/10.1095/biolreprod29.4.841.

    Article  CAS  PubMed  Google Scholar 

  5. Simmons HA. Age-associated pathology in rhesus macaques (Macaca mulatta). Vet Pathol. 2016;53(2):399–416. https://doi.org/10.1177/0300985815620628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mitchell SJ, Scheibye-Knudsen M, Longo DL, de Cabo R. Animal models of aging research: implications for human aging and age-related diseases. Annu Rev Anim Biosci. 2015;3:283–303. https://doi.org/10.1146/annurev-animal-022114-110829.

    Article  CAS  PubMed  Google Scholar 

  7. Kaeberlein M, Creevy KE, Promislow DE. The dog aging project: translational geroscience in companion animals. Mamm Genome. 2016;27(7–8):279–88. https://doi.org/10.1007/s00335-016-9638-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Freire-Cobo C, Rothwell ES, Varghese M, Edwards M, Janssen WGM, Lacreuse A, et al. Neuronal vulnerability to brain aging and neurodegeneration in cognitively impaired marmoset monkeys (Callithrix jacchus). Neurobiol Aging. 2023;123:49–62. https://doi.org/10.1016/j.neurobiolaging.2022.12.001.

    Article  CAS  PubMed  Google Scholar 

  9. Tardif SD, Mansfield KG, Ratnam R, Ross CN, Ziegler TE. The marmoset as a model of aging and age-related diseases. ILAR J. 2011;52(1):54–65. https://doi.org/10.1093/ilar.52.1.54.

    Article  CAS  PubMed  Google Scholar 

  10. D’Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743–53. https://doi.org/10.1161/CIRCULATIONAHA.107.699579.

    Article  PubMed  Google Scholar 

  11. Fraser HC, Kuan V, Johnen R, Zwierzyna M, Hingorani AD, Beyer A, et al. Biological mechanisms of aging predict age-related disease co-occurrence in patients. Aging Cell. 2022;21(4):e13524. https://doi.org/10.1111/acel.13524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kirkland JL, Stout MB, Sierra F. Resilience in aging mice. J Gerontol A Biol Sci Med Sci. 2016;71(11):1407–14. https://doi.org/10.1093/gerona/glw086.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Whitson HE, Cohen HJ, Schmader KE, Morey MC, Kuchel G, Colon-Emeric CS. Physical resilience: not simply the opposite of frailty. J Am Geriatr Soc. 2018;66(8):1459–61. https://doi.org/10.1111/jgs.15233.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56. https://doi.org/10.1093/gerona/56.3.m146.

    Article  CAS  PubMed  Google Scholar 

  15. Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173(5):489–95. https://doi.org/10.1503/cmaj.050051.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hadley EC, Kuchel GA, Newman AB, Workshop S, Participants. Report: NIA workshop on measures of physiologic resiliencies in human aging. J Gerontol A Biol Sci Med Sci. 2017;72(7):980–90. https://doi.org/10.1093/gerona/glx015.

    Article  PubMed  PubMed Central  Google Scholar 

  17. LeBrasseur NK. Physical resilience: opportunities and challenges in translation. J Gerontol A Biol Sci Med Sci. 2017;72(7):978–9. https://doi.org/10.1093/gerona/glx028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Whitson HE, Duan-Porter W, Schmader KE, Morey MC, Cohen HJ, Colon-Emeric CS. Physical resilience in older adults: systematic review and development of an emerging construct. J Gerontol A Biol Sci Med Sci. 2016;71(4):489–95. https://doi.org/10.1093/gerona/glv202.

    Article  PubMed  Google Scholar 

  19. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217. https://doi.org/10.1016/j.cell.2013.05.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huffman DM, Justice JN, Stout MB, Kirkland JL, Barzilai N, Austad SN. Evaluating health span in preclinical models of aging and disease: guidelines, challenges, and opportunities for geroscience. J Gerontol A Biol Sci Med Sci. 2016;71(11):1395–406. https://doi.org/10.1093/gerona/glw106.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sedrak MS, Gilmore NJ, Carroll JE, Muss HB, Cohen HJ, Dale W. Measuring biologic resilience in older cancer survivors. J Clin Oncol. 2021;39(19):2079–89. https://doi.org/10.1200/JCO.21.00245.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Calabrese EJ. Hormesis mediates acquired resilience: using plant-derived chemicals to enhance health. Annu Rev Food Sci Technol. 2021;12:355–81. https://doi.org/10.1146/annurev-food-062420-124437.

    Article  PubMed  Google Scholar 

  23. Epel ES. The geroscience agenda: toxic stress, hormetic stress, and the rate of aging. Ageing Res Rev. 2020;63:101167. https://doi.org/10.1016/j.arr.2020.101167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Calabrese EJ, Baldwin LA. Radiation hormesis: its historical foundations as a biological hypothesis. Hum Exp Toxicol. 2000;19(1):41–75. https://doi.org/10.1191/096032700678815602.

    Article  CAS  PubMed  Google Scholar 

  25. Al-Jumayli M, Brown SL, Chetty IJ, Extermann M, Movsas B. The biological process of aging and the impact of ionizing radiation. Semin Radiat Oncol. 2022;32(2):172–8. https://doi.org/10.1016/j.semradonc.2021.11.011.

    Article  PubMed  Google Scholar 

  26. Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, et al. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med. 2004;140(12):1037–51. https://doi.org/10.7326/0003-4819-140-12-200406150-00015.

    Article  PubMed  Google Scholar 

  27. Dainiak N, Albanese J. Medical management of acute radiation syndrome. J Radiol Prot. 2022;42(3). https://doi.org/10.1088/1361-6498/ac7d18.

  28. Zablotska LB, Bazyka D, Lubin JH, Gudzenko N, Little MP, Hatch M, et al. Radiation and the risk of chronic lymphocytic and other leukemias among chornobyl cleanup workers. Environ Health Perspect. 2013;121(1):59–65. https://doi.org/10.1289/ehp.1204996.

    Article  PubMed  Google Scholar 

  29. Ron E, Preston DL, Mabuchi K, Thompson DE, Soda M. Cancer incidence in atomic bomb survivors. Part IV: comparison of cancer incidence and mortality. Radiat Res. 1994;137(2 Suppl):S98-112.

    Article  CAS  PubMed  Google Scholar 

  30. Douple EB, Mabuchi K, Cullings HM, Preston DL, Kodama K, Shimizu Y, et al. Long-term radiation-related health effects in a unique human population: lessons learned from the atomic bomb survivors of Hiroshima and Nagasaki. Disaster Med Public Health Prep. 2011;5(Suppl 1 (0 1)):S122-33. https://doi.org/10.1001/dmp.2011.21.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen MA, Klijn JG, van Leeuwen FE. Cause-specific mortality in long-term survivors of breast cancer: a 25-year follow-up study. Int J Radiat Oncol Biol Phys. 2006;64(4):1081–91. https://doi.org/10.1016/j.ijrobp.2005.10.022.

    Article  PubMed  Google Scholar 

  32. Wakeford R. The cancer epidemiology of radiation. Oncogene. 2004;23(38):6404–28. https://doi.org/10.1038/sj.onc.1207896.

    Article  CAS  PubMed  Google Scholar 

  33. Upton AC, Kimball AW, Furth J, Christenberry KW, Benedict WH. Some delayed effects of atom-bomb radiations in mice. Cancer Res. 1960;20((8)Pt2):1–60.

    Google Scholar 

  34. Strehler BL. Origin and comparison of the effects of time and high-energy radiations on living systems. Q Rev Biol. 1959;34(2):117–42. https://doi.org/10.1086/402632.

    Article  CAS  PubMed  Google Scholar 

  35. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–58. https://doi.org/10.1111/acel.12344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Miousse IR, Kutanzi KR, Koturbash I. Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications. Int J Radiat Biol. 2017;93(5):457–69. https://doi.org/10.1080/09553002.2017.1287454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fanning KM, Pfisterer B, Davis AT, Presley TD, Williams IM, Wasserman DH, et al. Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling. Am J Physiol Regul Integr Comp Physiol. 2017;313(3):R290–7. https://doi.org/10.1152/ajpregu.00108.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. DeBo RJ, Lees CJ, Dugan GO, Caudell DL, Michalson KT, Hanbury DB, et al. Late effects of total-body gamma irradiation on cardiac structure and function in male rhesus macaques. Radiat Res. 2016;186(1):55–64. https://doi.org/10.1667/RR14357.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Michalson KT, Macintyre AN, Sempowski GD, Bourland JD, Howard TD, Hawkins GA, et al. Monocyte polarization is altered by total-body irradiation in male rhesus macaques: implications for delayed effects of acute radiation exposure. Radiat Res. 2019;192(2):121–34. https://doi.org/10.1667/RR15310.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. French MJ, Wuerker R, Dugan G, Olson JD, Sanders BR, Tooze JA, et al. Long-term immunological consequences of radiation exposure in a diverse cohort of rhesus macaques. Int J Radiat Oncol Biol Phys. 2022. https://doi.org/10.1016/j.ijrobp.2022.10.024.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Macintyre AN, French MJ, Sanders BR, Riebe KJ, Shterev ID, Wiehe K, et al. Long-term recovery of the adaptive immune system in rhesus macaques after total body irradiation. Adv Radiat Oncol. 2021;6(5):100677. https://doi.org/10.1016/j.adro.2021.100677.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ruggiero AD, Davis MA, Davis AT, DeStephanis D, Williams AG, Vemuri R, et al. Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence. Geroscience. 2022. https://doi.org/10.1007/s11357-022-00660-x.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kavanagh K, Dendinger MD, Davis AT, Register TC, DeBo R, Dugan G, et al. Type 2 diabetes is a delayed late effect of whole-body irradiation in nonhuman primates. Radiat Res. 2015;183(4):398–406. https://doi.org/10.1667/Rr13916.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bacarella N, Ruggiero A, Davis AT, Uberseder B, Davis MA, Bracy DP, et al. Whole body irradiation induces diabetes and adipose insulin resistance in nonhuman primates. Int J Radiat Oncol Biol Phys. 2020;106(4):878–86. https://doi.org/10.1016/j.ijrobp.2019.11.034.

    Article  CAS  PubMed  Google Scholar 

  45. Hale LP, Rajam G, Carlone GM, Jiang C, Owzar K, Dugan G, et al. Late effects of total body irradiation on hematopoietic recovery and immune function in rhesus macaques. PLoS One. 2019;14(2):e0210663. https://doi.org/10.1371/journal.pone.0210663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Andrews RN, Bloomer EG, Olson JD, Hanbury DB, Dugan GO, Whitlow CT, et al. Non-human primates receiving high-dose total-body irradiation are at risk of developing cerebrovascular injury years postirradiation. Radiat Res. 2020;194(3):277–87. https://doi.org/10.1667/RADE-20-00051.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Andrews RN, Caudell DL, Metheny-Barlow LJ, Peiffer AM, Tooze JA, Bourland JD, et al. Fibronectin produced by cerebral endothelial and vascular smooth muscle cells contributes to perivascular extracellular matrix in late-delayed radiation-induced brain injury. Radiat Res. 2018;190(4):361–73. https://doi.org/10.1667/Rr14961.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Andrews RN, Dugan GO, Peiffer AM, Hawkins GA, Hanbury DB, Bourland JD, et al. White matter is the predilection site of late-delayed radiation-induced brain injury in non-human primates. Radiat Res. 2019;191(3):217–31. https://doi.org/10.1667/RR15263.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Andrews RN, Metheny-Barlow LJ, Peiffer AM, Hanbury DB, Tooze JA, Bourland JD, et al. Cerebrovascular remodeling and neuroinflammation is a late effect of radiation-induced brain injury in non-human primates. Radiat Res. 2017;187(5):599–611. https://doi.org/10.1667/Rr14616.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hanbury DB, Peiffer AM, Dugan G, Andrews RN, Clinc JM. Long-term cognitive functioning in single-dose total-body gamma-irradiated rhesus monkeys (Macaca mulatta). Radiat Res. 2016;186(5):447–54. https://doi.org/10.1667/Rr14430.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Farris M, McTyre ER, Okoukoni C, Dugan G, Johnson BJ, Blackstock AW, et al. Cortical thinning and structural bone changes in non-human primates after single-fraction whole-chest irradiation. Radiat Res. 2018;190(1):63–71. https://doi.org/10.1667/RR15007.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Little MP, Brenner AV, Grant EJ, Sugiyama H, Preston DL, Sakata R, et al. Age effects on radiation response: summary of a recent symposium and future perspectives. Int J Radiat Biol. 2022;1–11. https://doi.org/10.1080/09553002.2022.2063962.

  53. Sills WS, Tooze JA, Olson JD, Caudell DL, Dugan GO, Johnson BJ, et al. Total-body irradiation is associated with increased incidence of mesenchymal neoplasia in a radiation late effects cohort of rhesus macaques (Macaca mulatta). Int J Radiat Oncol Biol Phys. 2022;113(3):661–74. https://doi.org/10.1016/j.ijrobp.2022.02.019.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cohen EP, Olson JD, Tooze JA, Bourland JD, Dugan GO, Cline JM. Detection and quantification of renal fibrosis by computerized tomography. PLoS One. 2020;15(2):e0228626. https://doi.org/10.1371/journal.pone.0228626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the laboratory and veterinary technicians and research assistants who conducted assessments. We also give special thanks to John Olson at WFSM for assistance with the animal cohort, and data retrieval, and members of the Register Laboratory for performing clinical biochemical assays.

Funding

This work was supported by the National Institutes of Health (NIH) program grant to Wake Forest University School of Medicine to support the NIAID-funded Radiation Survivor Cohort, U01 AI150578, (Drs. Cline and Schaaf), and the NIA-supported administrative supplement to evaluate aging outcomes and biological mechanism in this cohort. The authors were also supported by career development grants K01 AG059837 (Dr. Justice), and K01 AG056663 (Dr. Quillen).

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  1. George W. Schaaf and Jamie N. Justice made equal contributions to this manuscript.

Authors and Affiliations

  1. Department of Pathology, Section On Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    George W. Schaaf & J. Mark Cline

  2. Department of Internal Medicine, Section On Gerontology and Geriatric Medicine, and Stich Center for Health Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Jamie N. Justice

  3. Department of Internal Medicine, Section On Molecular Medicine, and Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Ellen E. Quillen

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  1. George W. Schaaf
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Correspondence to George W. Schaaf.

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All Radiation Late Effects Cohort experimental animal work is conducted at the Wake Forest University School of Medicine, an AAALAC-accredited institution, with IACUC approval.

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Drs. Cline and Schaaf have funding from Roche Pharmaceutical for work unrelated to this manuscript.

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Schaaf, G.W., Justice, J.N., Quillen, E.E. et al. Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review. GeroScience 45, 3371–3379 (2023). https://doi.org/10.1007/s11357-023-00812-7

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