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Project Title:  Candidate Nutritional Countermeasure to Mitigate Adverse Effects of Spaceflight Reduce
Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 01/01/2017  
End Date: 12/31/2019  
Task Last Updated: 05/01/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Schreurs, Ann-Sofie  Ph.D. / NASA Ames Research Center 
Address:  Bone and Signaling Laboratory, Space Biosciences Division 
Bldg N236, Room 219 
Moffett Field , CA 94035 
Email: ann-sofie.schreurs@nasa.gov 
Phone: 650-604-6390  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Tahimic, Candice  Ph.D. NASA Ames Research Center 
Globus, Ruth  Ph.D. NASA Ames Research Center 
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2015-16 HERO NNJ15ZSA001N-Crew Health (FLAGSHIP, NSBRI, OMNIBUS). Appendix A-Crew Health, Appendix B-NSBRI, Appendix C-Omnibus 
Grant/Contract No.: Internal Project 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
(2) Nutrition:Risk of Inadequate Nutrition
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
(2) Degen07:Are there significant synergistic effects from other spaceflight factors (microgravity, stress, altered circadian rhythms, changes in immune responses, etc.) that modify the degenerative risk from space radiation?
(3) N7.1:We need to identify the most important nutritional factors for musculoskeletal health (IRP Rev E)
(4) Osteo07:We need to identify options for mitigating early onset osteoporosis before, during and after spaceflight (IRP Rev E)
Flight Assignment/Project Notes: NOTE: End date changed to 12/31/2019 per L. Lewis/ARC (Ed., 7/23/19)

NOTE: Period of performance changed to 1/1/2017-1/31/2019 per PI information; previously 10/1/2016-9/30/2018 (Ed., 7/15/19)

NOTE: Extended to 9/30/2018 per PI; original end date was 9/30/2017 (Ed., 5/3/18)

Task Description: In recent findings, we showed that dried plum (DP) diet conferred complete protection from the rapid bone loss induced by exposure to radiations, including gamma, protons, and High Z-High Energy (HZE) ions. Based on these very promising results on a new potential countermeasure for space radiation tissue damage, we propose to conduct additional studies and analyses, which are critical for moving the potential countermeasure to a higher countermeasure readiness level (CRL) level. We aim to test the DP diet to prevent bone loss induced by simulated spaceflight. This will be achieved by exposing mice to each factor (weightlessness and radiation) alone and combined. Furthermore, we will establish if DP protects other tissues at risk for astronauts, such as the central nervous system.

Research Impact/Earth Benefits: Countermeasures that address the combined effects of simulated microgravity and ionizing radiation have not been investigated in bone. Both these factors are inherent to the spaceflight environment and thus, countermeasures must be investigated regarding their protective effect when both are in combination. We sought to evaluate the potentially differing effects of microgravity and ionizing radiation when controlled independently on bone and the two factors in combination. For the purpose of this study, we have used the hindlimb unloading model, in combination with exposure to total body irradiation (132Cs gamma radiation, at 2 Gy dose) as analogs of weightlessness and radiation exposure. The relatively higher dose of radiation (2 Gy) was chosen as a positive control dose to ensure bone loss in rodents to allow for testing DP as a countermeasure for bone loss. We sought to determine if the DP diet prevents simulated-microgravity induced bone loss (HU), as well as if the diet is also effective at preventing simulated spaceflight-induced bone loss (combination of HU+irradiation (IR). To address these questions, we analyzed both cancellous and cortical bone microarchitecture as well as bone quality. Additionally, we aimed to determine if the DP diet had the capacity to protect osteoprogenitors after exposure to simulated microgravity, an essential part in the healthy maintenance of the skeletal tissue.

Task Progress & Bibliography Information FY2020 
Task Progress: In this study, we investigated the bone protective potential of Dried Plum (DP) against independent and combined effects of simulated microgravity (Hindlimb Unloading, HU) and ionizing radiation (IR) on the microarchitecture and mechanical properties of skeletal tissue. A diet supplemented with DP prevented most of the simulated spaceflight-induced damages to both the appendicular (i.e., tibia) and axial (i.e., vertebrae) skeleton. When mice were fed the control diet, a relatively high dose (2 Gy) of low-LET (linear energy transfer) gamma radiation exclusively decreased the bone volume fraction (BV/TV) and trabecular separation (Tb.Sp) of cancellous tissue in the tibia. Based on our results, cancellous bone loss was caused by a thinning, not a decrease in the number, of existing trabeculae, which overall expanded the space between trabeculae. Hindlimb unloading (HU) for 14 days caused bone loss within both cancellous and cortical regions of the tibia and the L4 vertebrae. HU also led to reduced compressive strength of the vertebral body. The independent effects of HU and radiation (IR) remained of similar magnitude in each tissue compartment when mice were exposed to HU and IR simultaneously. Regardless of the treatment (with one exception, Ct.Th proximal tibia), consumption of the dried plum diet prevented detrimental skeletal changes. Mice fed the control diet and exposed solely to IR displayed a 20% decrement in percent bone volume and a 7% increase in the Tb.Sp of the tibia’s cancellous region relative to the sham control. These parameters were unaffected by HU alone. HU groups exhibited a lesser 11% decrement in trabecular thickness (Tb.Th). When IR was combined with HU, BV/TV decreased by another 5%. These results indicate that HU and IR were not clearly additive in this experiment. Among the parameters analyzed, IR only induced changes in Tb.Th and Tb.Sp. Unlike reports by others, there were no significant changes in trabecular number (Tb.N) from any of the treatment groups relative to the sham-irradiated control group. When HU was combined with IR, Tb.Th decreased by 9%.

Our results indicate bone loss was caused by a thinning, not a decrease in the number, of existing trabeculae, which expanded the space between trabeculae. The trabeculae contribute to percent bone volume and microarchitectural integrity. Since HU affects the cortical as well as cancellous tissue, we also determined the extent of cortical bone loss. The cortical region (cortical shell) exhibited a decrease in cortical thickness when mice fed the control diet were exposed to HU, either independently or in combination with IR.

When mice were fed the DP diet, IR-induced cancellous bone loss was entirely prevented, consistent with the radio-protective results reported in our previous study. DP also protected the tibia when IR was combined with HU, which is a novel finding in this report. The decrease in trabecular thickness incurred by HU and HU + IR was entirely prevented by consumption of the DP diet. The DP diet also protected from HU-induced decrease in cortical thickness. Unlike the proximal tibia, the distal tibia did not show changes in cortical structure. In contrast, in the proximal tibia HU and IR together, not each treatment alone, caused a decrease in cortical thickness of the proximal tibia. This finding suggests that DP diet cannot fully prevent from all aspects of bone structural deficits induced by simulated spaceflight.

In order to confirm our results, we examined another skeletal site, the vertebra, which is a representative axial bone. Under conditions of simulated weightlessness and consumption of control diet, BV/TV and Tt.Tb.Th of the vertebral body were reduced accompanied by a reduction in cortical thickness and cortical bone area. Collectively, these findings indicate an overall deterioration of bone via thinning of the vertebrae’s trabeculae and cortical tissue. This deterioration of the microarchitecture directly impacted the overall strength of the tissue, as reflected in the decrease in maximum load tolerable by the vertebral body, as well as the decrease in material stiffness as measured by mechanical compression testing. Taken together, these changes in both microarchitecture and strength have the potential to lead to fracture. However, these changes were not observed when mice were exposed to IR alone. In contrast to other studies where high-LET 56Fe radiation was utilized in combination with HU, our results did not indicate an additive effect of IR on the deterioration of strength and structure of the L4 vertebrae. HU-induced damage to the vertebral body was entirely prevented when mice consumed the DP diet. Interestingly, there was a statistically significant increase in Tt.BV/TV for sham-irradiated, normally loaded (NL) mice fed the DP compared to the sham-irradiated, NL mice fed the control diet (CD). This elevated Tt.BV/TV was consistent for all treatment groups fed DP when compared to NL, CD-fed mice, suggesting a potential anabolic effect of DP.

Treatments that are currently in use to mitigate the effects of mechanical unloading are not without limitations and risks. Exercise in combination with drug treatments such as bisphosphonates have shown beneficial effects in astronauts. However, in patients with osteoporosis, the use of bisphosphonates can increase the risk for atypical femoral fractures possibly due to suppressed bone turnover which may lead to cracks at the microscale and loss of mechanical strength. Although rare, other notable side effects that have been reported to accompany bisphosphonate therapy including osteonecrosis of the jaw and atrial fibrillation. Another limitation of bisphosphonates is that they act mostly on osteoclasts. Osteoblastogenesis from flushed bone marrow cells of the femur was strongly inhibited by exposure to HU, indicating that HU directly damages osteoblast progenitors, potentially affecting in situ bone formation. Mineralization of the osteoblast cells from DP-fed mice was partially restored and taken together with the cell growth data, indicates that DP could prevent the loss of structure and strength by protecting the marrow-derived osteoprogenitors. Ex vivo osteoblastogenesis was only performed on mice exposed to HU because it has been shown previously that low-LET in vivo gamma radiation does not negatively impact osteoblasts.

Overall, the ability of DP to protect osteoblast progenitor cells from HU-induced damage, as shown in this study, holds much promise for development of next generation anti-osteoporotic drugs due to the possibility that DP to act on both osteoblasts and osteoclasts. Our current study is limited to short-duration HU (2 weeks); since astronauts on long-term space missions may require a countermeasure for bone loss throughout the entirety of a multi-year mission beyond low Earth orbit (LEO), it is important in future studies to determine if DP is protective for long-term exposure to simulated, or actual, spaceflight. Further studies also are needed to gain more insight into any potential long-term side effects of consuming a dried plum diet. Dried plum’s potential as a countermeasure against both radiation- and microgravity-induced osteopenia such as loss of bone strength and structure in the tibia and vertebrae has important implications for astronauts in space as well as radiation workers, radiotherapy patients, and individuals with osteoporosis.

Bibliography Type: Description: (Last Updated: 08/21/2020)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Steczina S, Tahimic CGT, Pendleton M, M'Saad O, Lowe M, Alwood JS, Halloran BP, Globus RK, Schreurs AS. "Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice." Sci Rep. 2020 Apr 16;10(1):6484. https://doi.org/10.1038/s41598-020-63404-x ; PubMed PMID: 32300161; PubMed Central PMCID: PMC7162976 , Apr-2020
Project Title:  Candidate Nutritional Countermeasure to Mitigate Adverse Effects of Spaceflight Reduce
Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 01/01/2017  
End Date: 12/31/2019  
Task Last Updated: 07/25/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Schreurs, Ann-Sofie  Ph.D. / NASA Ames Research Center 
Address:  Bone and Signaling Laboratory, Space Biosciences Division 
Bldg N236, Room 219 
Moffett Field , CA 94035 
Email: ann-sofie.schreurs@nasa.gov 
Phone: 650-604-6390  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Tahimic, Candice  Ph.D. NASA Ames Research Center 
Globus, Ruth  Ph.D. NASA Ames Research Center 
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2015-16 HERO NNJ15ZSA001N-Crew Health (FLAGSHIP, NSBRI, OMNIBUS). Appendix A-Crew Health, Appendix B-NSBRI, Appendix C-Omnibus 
Grant/Contract No.: Internal Project 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
(2) Nutrition:Risk of Inadequate Nutrition
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
(2) Degen07:Are there significant synergistic effects from other spaceflight factors (microgravity, stress, altered circadian rhythms, changes in immune responses, etc.) that modify the degenerative risk from space radiation?
(3) N7.1:We need to identify the most important nutritional factors for musculoskeletal health (IRP Rev E)
(4) Osteo07:We need to identify options for mitigating early onset osteoporosis before, during and after spaceflight (IRP Rev E)
Flight Assignment/Project Notes: NOTE: End date changed to 12/31/2019 per L. Lewis/ARC (Ed., 7/23/19)

NOTE: Period of performance changed to 1/1/2017-1/31/2019 per PI information; previously 10/1/2016-9/30/2018 (Ed., 7/15/19)

NOTE: Extended to 9/30/2018 per PI; original end date was 9/30/2017 (Ed., 5/3/18)

Task Description: In recent findings, we showed that dried plum (DP) diet conferred complete protection from the rapid bone loss induced by exposure to radiations, including gamma, protons, and High Z-High Energy (HZE) ions. Based on these very promising results on a new potential countermeasure for space radiation tissue damage, we propose to conduct additional studies and analyses, which are critical for moving the potential countermeasure to a higher countermeasure readiness level (CRL) level. We aim to test the DP diet to prevent bone loss induced by simulated spaceflight. This will be achieved by exposing mice to each factor (weightlessness and radiation) alone and combined. Furthermore, we will establish if DP protects other tissues at risk for astronauts, such as the central nervous system.

Research Impact/Earth Benefits: Countermeasures that address the combined effects of simulated microgravity and ionizing radiation have not been investigated in bone. Both these factors are inherent to the spaceflight environment and thus, countermeasures must be investigated regarding their protective effect when both are in combination. We sought to evaluate the potentially differing effects of microgravity and ionizing radiation when controlled independently on bone and the two factors in combination. For the purpose of this study, we have used the hindlimb unloading model, in combination with exposure to total body irradiation (132Cs gamma radiation, at 2 Gy dose) as analogs of weightlessness and radiation exposure. The relatively higher dose of radiation (2 Gy) was chosen as a positive control dose to ensure bone loss in rodents to allow for testing DP as a countermeasure for bone loss. We sought to determine if the DP diet prevents simulated-microgravity induced bone loss (HU), as well as if the diet is also effective at preventing simulated spaceflight-induced bone loss (combination of HU+irradiation (IR)). To address these questions, we analyzed both cancellous and cortical bone microarchitecture as well as bone quality. Additionally, we aimed to determine if the DP diet had the capacity to protect osteoprogenitors after exposure to simulated microgravity, an essential part in the healthy maintenance of the skeletal tissue.

Task Progress & Bibliography Information FY2019 
Task Progress: The spaceflight environment poses multiple challenges to homeostasis, including microgravity and ionizing radiation. Together, these factors contribute to cellular stress, and effects include increased generation of reactive oxygen species (ROS), oxidative and DNA damage, cell cycle arrest, and cell senescence. We have shown that a purified diet supplemented with dried plum (DP, 25%) conferred full protection of cancellous structure from the rapid bone loss caused by exposure to ionizing radiation (Schreurs et al., 2016). Based on these promising results for a new countermeasure to prevent space radiation induced-tissue damage, we will conduct additional studies to advance the potential countermeasure to a higher CRL (countermeasure readiness level). We will test the DP diet for its ability to prevent bone loss caused by simulated microgravity as well as exposure to radiation. This will be achieved by exposing mice to each factor (simulated microgravity and radiation) alone and in combination. We hypothesize that spaceflight conditions lead to oxidative damage and bone loss, and that DP, a dietary additive rich in antioxidant and polyphenolic compounds, is an effective countermeasure for multiple tissues, including bone. To achieve these aims, we exposed 16-week-old, C57Bl6/J male mice to different treatments to simulate spaceflight: simulated weightlessness using the well-established Hindlimb-Unloading (HU) system and/or total body irradiation (TBI). Mice were assigned to the following groups: 14 days of normal ambulation (NL) or HU alone, or in combination with total body irradiation, at a dose of 2 Gy 137Cs (0.8G/min). Mice were fed with control diet (CD, AIN93M, Teklad) or AIN93M experimental diet supplemented with DP (25%) 14 days before onset of HU treatment. TBI with 2 Gy 137CS was performed 3 days after onset of HU according to protocols previously shown to cause cancellous bone loss. All groups were sacrificed 14 days after initiating HU. The results analysis are ongoing and will be reported in future reports.

Reference

Schreurs AS, Shirazi-Fard Y, Shahnazari M, Alwood JS, Truong TA, Tahimic CG, Limoli CL, Turner ND, Halloran B, Globus RK. Dried plum diet protects from bone loss caused by ionizing radiation. Sci Rep. 2016 Feb 11;6:21343.

Bibliography Type: Description: (Last Updated: 08/21/2020)  Show Cumulative Bibliography Listing
 
Articles in Other Journals or Periodicals Steczina S, Tahmic GT, Pendleton M, M'Saad O, Lowe M, Alwood JS, Halloran B, Globus RK, Schreurs AS. "Dietary countermeasure prevents simulated spaceflight-induced osteopenia in mice." Nature Communications. Submitted as of July 2019. , Jul-2019
Project Title:  Candidate Nutritional Countermeasure to Mitigate Adverse Effects of Spaceflight Reduce
Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 01/01/2017  
End Date: 01/31/2019  
Task Last Updated: 09/29/2016 
Download report in PDF pdf
Principal Investigator/Affiliation:   Schreurs, Ann-Sofie  Ph.D. / NASA Ames Research Center 
Address:  Bone and Signaling Laboratory, Space Biosciences Division 
Bldg N236, Room 219 
Moffett Field , CA 94035 
Email: ann-sofie.schreurs@nasa.gov 
Phone: 650-604-6390  
Congressional District: 18 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Ames Research Center 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Tahimic, Candice  Ph.D. NASA Ames Research Center 
Globus, Ruth  Ph.D. NASA Ames Research Center 
Project Information: Grant/Contract No. Internal Project 
Responsible Center: NASA JSC 
Grant Monitor: Norsk, Peter  
Center Contact:  
Peter.norsk@nasa.gov 
Solicitation / Funding Source: 2015-16 HERO NNJ15ZSA001N-Crew Health (FLAGSHIP, NSBRI, OMNIBUS). Appendix A-Crew Health, Appendix B-NSBRI, Appendix C-Omnibus 
Grant/Contract No.: Internal Project 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Degen:Risk Of Cardiovascular Disease and Other Degenerative Tissue Effects From Radiation Exposure (IRP Rev F)
(2) Nutrition:Risk of Inadequate Nutrition
(3) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Degen06:What are the most effective biomedical or dietary countermeasures to mitigate degenerative tissue risks? By what mechanisms are the countermeasures likely to work? Are these CMs additive, synergistic, or antagonistic to other Risks? (IRP Rev F)
(2) Degen07:Are there significant synergistic effects from other spaceflight factors (microgravity, stress, altered circadian rhythms, changes in immune responses, etc.) that modify the degenerative risk from space radiation?
(3) N7.1:We need to identify the most important nutritional factors for musculoskeletal health (IRP Rev E)
(4) Osteo07:We need to identify options for mitigating early onset osteoporosis before, during and after spaceflight (IRP Rev E)
Flight Assignment/Project Notes: NOTE: Period of performance changed to 1/1/2017-1/31/2019 per PI information; previously 10/1/2016-9/30/2018 (Ed., 7/15/19)

NOTE: Extended to 9/30/2018 per PI; original end date was 9/30/2017 (Ed., 5/3/18)

Task Description: In recent findings, we showed that dried plum (DP) diet conferred complete protection from the rapid bone loss induced by exposure to radiations, including gamma, protons, and High Z-High Energy (HZE) ions. Based on these very promising results on a new potential countermeasure for space radiation tissue damage, we propose to conduct additional studies and analyses, which are critical for moving the potential countermeasure to a higher countermeasure readiness level (CRL) level. We aim to test the DP diet to prevent bone loss induced by simulated spaceflight. This will be achieved by exposing mice to each factor (weightlessness and radiation) alone and combined. Furthermore, we will establish if DP protects other tissues at risk for astronauts, such as the central nervous system.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2017 
Task Progress: New project for FY2017.

Bibliography Type: Description: (Last Updated: 08/21/2020)  Show Cumulative Bibliography Listing
 
 None in FY 2017