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All sourcesNASA NTRSDOE OSTI
NASA NTRS2015

Flying Through the Ages: Rodent Research for Human Health

As humans, we evolved, developed, grew, and now function in a continuous 1-gravity environment. Habitation in space poses unique challenges to human cells and organ systems. Biomedical research with rodents (primarily mice and rats) can help to both unravel molecular, cellular and physiologic mechanisms relevant to humans and test candidate interventions that mitigate adverse effects of space on humans, such as muscle atrophy, bone loss and cardiovascular deconditioning. One favored hypothesis that may explain the detrimental effects of spaceflight on humans is that reduced mechanical loading in microgravity accelerates aging. Rodents provide a relevant model system to study this problem as they age 40 times faster than humans. Now scientists from both public and commercial sectors conduct rodent experiments on the ISS using a new capability developed primarily at ARC. Results from the maiden voyage of the Rodent Research Project on the ISS reveal that long duration effects of spaceflight appear far different than short duration effects. Thus, Rodent Research missions on the ISS usher in a new era for exploration and biological discovery in space.

Globus, Ruth↗
NASA NTRS2014

To the Bone: Spaceflight and the Skeletal System

During spaceflight, astronauts experience weightlessness and are exposed to novel types of radiation. These environmental conditions may contribute to bone loss and reduction of structural integrity of the skeleton, which have negative implications for long-duration missions. The aim of this talk is to provide an overview of skeletal changes observed both in astronauts and in ground-based models of spaceflight, focusing on the fundamental biology and the prevention of deleterious skeletal changes.

Alwood, Joshua↗
NASA NTRS2019

Overexpression of Catalase in Mitochondria Mitigates the Effects of Simulated Microgravity and Social Isolation on Cytokine Expression in Mouse Hippocampus

Space flight missions are becoming longer and more common and evidence points to the physiological toll the missions have on the human body. Aging, sedentary lifestyle, and spaceflight have similar degenerative effects on almost every part of our body; both exposure to the space environment and aging result in cardiovascular deconditioning, bone loss, muscle atrophy, brain changes, and immune response impairment. We hypothesize that exposure to the space environment generates excessive Reactive Oxygen Species (ROS), which results in neuroinflammation and aging-like degenerative symptoms in the brain. We used the hindlimb unloading (HU) model to mimic microgravity with either paired or single housed animals (social isolation). Responses to 30d (30 days) of HU were compared in wildtype or transgenic MCAT (Mitochondrial-targeted CATalase) mice, in which mitochondrial ROS is quenched by over-expression of human catalase. Expression of 4-Hydroxynonenal (4HNE) and Park7 (redox-sensitive chaperone and sensor of oxidative stress) were measured by ELISA (Enzyme-Linked ImmunoSorbent Assay), a protein array quantified from the hippocampal cytokines and 8-hydroxy-2'-deoxyguanosine in serum was measured by ELISA to assess oxidative DNA damage. Preliminary analysis of cage behavior patterns from video collected at the end of the study showed that MCAT HU mice (socially housed) were more active and conducted more exploratory activities compared to NL (Normally Loaded). Our biochemical results showed simulated microgravity and/or social isolation caused changes in levels of cytokines related to immune responses. Two-way ANOVA (Analysis of Variance) revealed significant interaction effects of HU and genotype in expression levels of five cytokines (out of 35) in socially-housed animals. Elevation of these generally pro-inflammatory cytokines by HU in WT (Wild Type) mice was mitigated in MCAT mice, suggesting a role for mitochondrial ROS signaling in inflammatory CNS (Central Nervous System) responses to microgravity. Interestingly, some of these cytokines in the hippocampus displayed strong correlations to the 4HNE levels. We also found substantive cytokine responses to social isolation in the hippocampus; housing and genotype interaction effects were significant (by 2-Factor ANOVA) for 15 cytokines, most of which were mitigated in MCAT mice.Taken together, our results showed that both simulated microgravity and social isolation influenced cytokine levels in the hippocampus and MCAT mice were at least partially protected from these changes. These findings implicate a potentially important role for mitochondrial ROS in CNS responses to the challenges posed by long duration spaceflight.

MCAT↗
NASA NTRSDate not supplied

Human placenta-derived stromal cells mitigate select immune responses to simulated weightlessness

Space flight presents unique risks to human health. Microgravity and social isolation are important space flight stressors which have vast impact on multiple systems such as the musculoskeletal, immune and central nervous system (CNS). To explore candidate countermeasures against tissue decrements caused by spaceflight, we performed a pilot study with PLacental-eXpanded stromal (PLX) cells. PLX cells secrete factors that modulate the immune system, but do not trigger host immune responses, enabling treatment in subjects that have intact immune systems. These cells had previous success in treating critical limb ischemia and acute radiation syndrome in murine models. In this study, 4-month-old female mice underwent 30 days of hindlimb unloading (HU) in single housing conditions to simulate long-term weightlessness and isolation. HU and normally ambulating controls were administered with PLX cells or sham-injected with Plasmalyte. We hypothesized that administration of PLX cells will mitigate some of the effects caused by prolonged HU. We found that treatment with PLX cells was well tolerated as indicated by body weights, circulating corticosterone levels and immune organ response to injection of the cells. HU led to the expected decreases in soleus muscle weights and bone loss. We did not observe any protective properties of the PLX cells in the musculoskeletal system but found that the cell treatment partially protected from a subset of HU-induced immune and CNS changes. In the hippocampus, protein levels of 9 of 44 cytokines were downregulated by HU. PLX administration mitigated changes in expression of 8 of these cytokines, including IL-2, IL-6 and MCP-1. To our knowledge, this is the first report on the protective effects of PLX-PAD against HU-induced changes in the cytokine milieu of the CNS. Our findings warrant further studies, which includes testing in actual spaceflight.

Microgravity↗
NASA NTRSDate not supplied

Exploration Exercise System (EES) Development

Exploration class missions will be required to have an exercise device that is lightweight, has a small footprint, and is capable of providing enough physical stimulus and exercise variability to be an effective countermeasure against muscle and bone loss that results from the microgravity environment. Exploration exercise device prototypes should be evaluated on the ground and in-orbit for feasibility of use in microgravity for long and short duration exploration missions and efficacy of the device to maintain multi-system health and performance. The European Enhanced Exploration Exercise Device (E4D) was selected as the exploration prototype device to be evaluated on ISS for efficacy and feasibility of use as a single multi-modality device for the exercise system for exploration missions. This effort supports the continued development, testing, and verification of E4D hardware and software, internal NASA integration (Human Health and Performance, ISS Vehicle Office, Engineering, and Flight Operations), and external integration across NASA, ESA, and the Danish Aerospace Company (DAC). Providing a feasibility and acceptability assessment from a physiological efficacy and hardware durability standpoint are critical for informing use and risk associated with use on exploration missions. Clearly defined objectives from end users, stakeholders, and Subject Matter Experts (SMEs) will be tested by crewmembers during acute use sessions and long duration use of the exercise device while on ISS. This effort will include a flight study where crewmembers will be asked to exercise using only the E4D during the duration of their mission and participate in a battery of physiological testing to evaluate the efficacy. Hardware is scheduled to launch in FY25 followed by 2 years of operational use after activation and checkout. A final recommendation will be provided to the Artemis program on acceptability of the device for exploration missions. The E4D needs a vibration isolation stabilization (VIS) system that serves as a platform for the exercise hardware to protect the vehicle from loads imparted during exercise. Exploration forward VIS systems will need to protect the vehicle and provide sufficient stabilization for the exerciser during performance of all critical exercises. These enabling capabilities need to be achieved within exploration vehicle power, thermal, mass, and volume limitations.

Kent Lawrence Kalogera↗
NASA NTRS2024

Metabolic Stress in Space: ROS-Induced Mutations in Mice Hint at A New Path to Cancer

Long-duration spaceflight beyond Earth's magnetosphere poses serious health risks, including muscle atrophy, bone loss, liver and kidney damage, and the Spaceflight-Associated Neuro-ocular Syndrome (SANS). RNA-seq of mice aboard the International Space Station (ISS) for 37 days revealed extraordinary hypermutation in tissue-specific genes, with guanine base conversion predominating, potentially contributing to spaceflight-associated health risks. Our results suggest that the genome-wide accelerated mutation that we measured, seemingly independent of radiation dose, was induced by oxidative damage from higher atmospheric carbon dioxide (CO 2 ) levels and increased reactive oxygen species (ROS) on the ISS. This accelerated mutation, faster via RNA transcription than replication and more numerous than by radiation alone, unveils novel hotspots in the mammalian proteome. Notably, these hotspots correlate with commonly mutated genes across various human cancers, highlighting the ISS as a crucial platform for studying accelerated mutation, genome instability, and the induction of disease-causing mutations in model organisms. Our results suggest that metabolic processes can contribute to somatic mutation, and thus may play a role in the development of cancer. A metabolic link to genetic instability potentially has far-reaching implications for various diseases, with implications for human health on Earth and in space.

mice↗
NASA NTRS2018

Overview and Evaluation of a Computational Bone Physiology Modeling Toolchain and Its Application to Testing of Exercise Countermeasures

Prolonged microgravity exposure disrupts natural bone remodeling processes and can lead to a significant loss of bone strength, increasing injury risk during missions and placing astronauts at a greater risk of bone fracture later in life. Resistance-based exercise during missions is used to combat bone loss, but current exercise countermeasures do not completely mitigate the effects of microgravity. To address this concern, we present work to develop a personalizable, site-specific computational modeling toolchain of bone remodeling dynamics to understand and estimate changes in volumetric bone mineral density (BMD) in response to microgravity-induced bone unloading and in-flight exercise. The toolchain is evaluated against data collected from subjects in a 70-day bed rest study and is found to provide insight into the amount of exercise stimulus needed to minimize bone loss, quantitatively predicting post-study volumetric BMD of control subjects who did not perform exercise, and qualitatively predicting the effects of exercise. Results suggest that, with additional data, the toolchain could be improved to aid in developing customized in-flight exercise regimens and predict exercise effectiveness.

Schepelmann, Alexander↗
NASA NTRS2019

Overview and Evaluation of a Computational Bone Physiology Modeling Toolchain and Its Application to Testing of Exercise Countermeasures

Prolonged microgravity exposure disrupts natural bone remodeling processes and can lead to a significant loss of bone strength, increasing injury risk during missions and placing astronauts at a greater risk of bone fracture later in life. Resistance-based exercise during missions is used to combat bone loss, but current exercise countermeasures do not completely mitigate the effects of microgravity. To address this concern, we present work to develop a personalizable, site-specific computational modeling toolchain of bone remodeling dynamics to understand and estimate changes in volumetric bone mineral density (BMD) in response to microgravity-induced bone unloading and in-flight exercise. The toolchain is evaluated against data collected from subjects in a 70-day bedrest study and is found to provide insight into the amount of exercise stimulus needed to minimize bone loss, quantitatively predicting post-study volumetric BMD of control subjects who did not perform exercise, and qualitatively predicting the effects of exercise. Results suggest that, with additional data, the toolchain could be improved to aid in developing customized in-flight exercise regimens and predict exercise effectiveness.

Schepelmann, Alexander↗
NASA NTRS1994

Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage

Loss of bone mass during periods of skeletal unloading remains an important clinical problem. To determine the extent to which resorption contributes to the relative loss of bone during skeletal unloading of the growing rat and to explore potential means of preventing such bone loss, 0.1 mg P/kg alendronate was administered to rats before unloading of the hindquarters. Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading. Total osteoclast number increased in alendronate-treated animals, but values were similar to those in controls when corrected for the increased bone area. However, the osteoclasts had poorly developed brush borders and appeared not to engage the bone surface when examined at the ultrastructural level. We conclude that alendronate prevents the relative loss of mineralized tissue in growing rats subjected to skeletal unloading, but it does so primarily by inhibiting the resorption of the primary and secondary spongiosa, leading to altered bone modeling in the metaphysis.

NASA Discipline Musculoskeletal↗
NASA NTRS1999

Computer Aided Modeling to Determine the Effectiveness of Resistive Exercises as Countermeasures for Bone Mineral Density Loss

Due to the loss of gravitational loading, astronauts have a tendency to lose bone mineral density in their lumbar spine and lower extremities on orbit. NASA requires astronauts to perform exercises during space flight to help reduce the amount of demineralization. To test these exercises on earth, 17 week bed rest studies are conducted that consist of specific diet and exercise regimes. Developing a finite element model of these exercises will help to quantify the stress distribution imposed by of each of these exercises. To help develop this model, MRI images are acquired from individuals participating in the bed rest studies. The MRIs can be used to create a subject specific model of each individual for testing. The MRIs are processed in the Magnetic Resonance Imaging Data Transfer System program to develop a three-dimensional finite element model of the femur for evaluation. Modifications were made to the MRIDTS that simplified the model creation process. These modifications made it possible to construct two separate models of different portions of a bone simultaneously and then later connect them manually. This helped alleviate the warping problem associated with the drastic changes in geometry found in some body parts, such as the joints. The code was also modified to incorporate material properties of various bone components into the model. Interior meshing was also incorporated into the program to allow for both the cortical shell and the entire bone to be modeled. A prototype model of the right femur of an adult female is being constructed and tested to determine the feasibility of finite element analysis as a tool for evaluating exercise effectiveness. The model is being run through the ANSYS finite element program on the Alabama Super Computer Network. After the model is validated, models of bedrest subjects can be generated to investigate exercise countermeasures.

Murphy, Benjamin M.↗
NASA NTRS2006

Skeletal Recovery Following Long-Duration Spaceflight Missions as Determined by Preflight and Postflight DXA Scans of 45 Crew Members

Introduction: The loss of bone mineral in astronauts during spaceflight has been investigated throughout the more than 40 years of bone research in space. Consequently, it is a medical requirement at NASA that changes in bone mass be monitored in crew members by measurements of bone mineral density (BMD) with dual-energy x-ray absorptiometry (DXA). This report is the first to evaluate medical data to address the recovery of bone mineral that is lost during spaceflight. Methods: DXA scans are performed before and after flight in astronauts who serve on long-duration missions (4-6 months) to ensure that medical standards for flight certification are met, to evaluate the effects of spaceflight and to monitor the restoration to preflight BMD status after return to Earth. Through cooperative agreements with the Russian Space Agency, the Bone and Mineral Lab at NASA Johnson Space Center (Houston, TX), also had access to BMD data from cosmonauts who had flown on long-duration missions yielding data from a total of 45 individual crew members. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing); plotted data were fitted to an exponential mathematical model that determined i) BMD change at day 0 after landing and ii) the number of days after which 50% of the lost bone was recovered ("Recovery Half-Life"). These fits were performed for BMD of the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. Results: In sum, averaged losses of bone mineral after spaceflight ranged between 2-9% for sites in the axial and appendicular skeleton. The fitted postflight BMD values predicted a 50% recovery of bone loss for all sites within 9 months.

Sibonga, J. D.↗
NASA NTRS1995

Methodologies to determine forces on bones and muscles of body segments during exercise, employing compact sensors suitable for use in crowded space vehicles

Work under this grant was carried out by the author and by a graduate research assistant. An instrumented bicycle ergometer was implemented focusing on the stated objective: to estimate the forces exerted by each muscle of the feet, calf, and thigh of an individual while bicycling. The sensors used were light and compact. These were probes to measure muscle EMG activity, miniature accelerometers, miniature load sensors, and small encoders to measure angular positions of the pedal. A methodology was developed and implemented to completely describe the kinematics of the limbs using data from the sensors. This work has been published as a Master's Thesis by the Graduate student supported by the grant. The instrumented ergometer along with the sensors and instrumentation were tested during a KC-135 Zero-Gravity flight in July, 1994. A complete description of the system and the tests performed have been published as a report submitted to NASA Johnson Space Center. The data collected during the KC-135 flight is currently being processed so that a kinematic description of the bicycling experiment will be soon determined. A methodology to estimate the muscle forces has been formulated based on previous work. The methodology involves the use of optimization concepts so that the individual muscle forces that represent variables in dynamic equations of motion may be estimated. Optimization of a criteria (goal) function such as minimization of energy will be used along with constraint equations defined by rigid body equations of motion. Use of optimization principles is necessary, because the equations of motion alone constitute an indeterminate system of equations with respect to the large amount of muscle forces which constitute the variables in these equations. The number of variables is reduced somewhat by using forces measured by the load cells installed on the pedal. These load cells measure pressure and shear forces on the foot. The author and his collaborators at NASA and at the University of Alabama, Tuscaloosa, are continuing the work of reducing the experimental data from the KC-135 flight, and the implementation of the optimization methods to estimate muscle forces. As soon as results from these efforts are available, they will be published in reputable journals. Results of this work will impact studies addressing bone density loss and development of countermeasures to minimize bone loss in zero gravity conditions. By analyzing muscle forces on Earth and in Space during exercise, scientists could eventually formulate new exercises and machines to help maintain bone density. On Earth, this work will impact studies concerning arthritis, and will provide the means to study possible exercise countermeasures to minimize arthritis problems.

Figueroa, Fernando↗
NASA NTRS1987

Bone and muscle - The structural system in long duration space missions

Losses of bone mineral and muscle mass have been observed, and in varying degrees measured, following all long duration missions in space. These observations portend an unacceptable threat to the crews' ability to return to earth, without protracted rehabilitation, following periods of a year or more in microgravity. The impact to crew capabilities and productivity in space is not well understood. Past research has dealt with bone loss and muscle atrophy as two separate problems with little discernible relationship. This paper reviews the available information on both and suggests a combined structural approach for future research.

Buchanan, Paul↗
NASA NTRS2002

The Hematopoietic Stem Cell Therapy for Exploration of Space

Astronauts experience severe/invasive disorders caused by space environments. These include hematological/cardiac abnormalities, bone and muscle losses, immunodeficiency, neurological disorders and cancer. While the cause of these symptoms are not yet fully delineated, one possible explanation could be the inhibition of hematopoietic stem cell (HSC) growth and hematopoiesis in space. HSCs differentiate into all types of blood cells, and growing evidence indicates that the HSCs also have the ability to transdifferentiate to various tissues, including muscle, skin, liver, neuronal cells and possibly bone. Therefore, a hypothesis was advanced in this laboratory that the hematopoietic stem cell-based therapy, herein called the hematopoietic stem cell therapy (HSCT), could mitigate some of the disorders described above. Due to the magnitude of this project our laboratory has subdivided it into 3 sections: a) HSCT for space anemia; b) HSCT for muscle and bone losses; and c) HSCT for immunodeficiency. Toward developing the HSCT protocol for space anemia, the HSC transplantation procedure was established using a mouse model of beta thalassemia. In addition, the NASA Rotating Wall Vessel (RWV) culture system was used to grow HSCs in space condition. To investigate the HSCT for muscle loss and bone loss, donor HSCs were genetically marked either by transfecting the beta-galactosidase-containing plasmid, pCMV.SPORT-beta-gal or by preparing from b-galactosidase transgenic mice. The transdifferentiation of HSCs to muscle is traced by the reporter gene expression in the hindlimb suspended mice with some positive outcome, as studied by the X-gal staining procedure. The possible structural contribution of HSCs against muscle loss is being investigated histochemically.

Roach, Allana Nicole↗
NASA NTRS1972

Weight simulator

Device applies compressive force to bone to minimize loss of bone calcium during weightlessness or bedrest. Force is applied through weights, or hydraulic, pneumatic or electrically actuated devices. Device is lightweight and easy to maintain and operate.

Howard, W. H.↗
NASA NTRS2010

On-Demand Urine Analyzer

A lab-on-a-chip was developed that is capable of extracting biochemical indicators from urine samples and generating their surface-enhanced Raman spectra (SERS) so that the indicators can be quantified and identified. The development was motivated by the need to monitor and assess the effects of extended weightlessness, which include space motion sickness and loss of bone and muscle mass. The results may lead to developments of effective exercise programs and drug regimes that would maintain astronaut health. The analyzer containing the lab-on-a- chip includes materials to extract 3- methylhistidine (a muscle-loss indicator) and Risedronate (a bone-loss indicator) from the urine sample and detect them at the required concentrations using a Raman analyzer. The lab-on- a-chip has both an extractive material and a SERS-active material. The analyzer could be used to monitor the onset of diseases, such as osteoporosis.

Farquharson, Stuart↗
NASA NTRS2016

A Flexible Method for Producing F.E.M. Analysis of Bone Using Open-Source Software

Individuals who experience decreases in load-bearing bone densities can be subject to a higher risk of bone fracture during daily activity. Astronauts may lose up to nine percent of their load-bearing bone density for every month they spend in space [1]. Because of this, specialized countermeasures reduce percent loss in bone density and reduce fracture risk upon returning to Earth. Astronauts will typically not be at risk for fracture during spaceflight, because of the lesser loads experienced in microgravity conditions. However, once back on Earth, astronauts have an increased risk for bone fracture as a result of weakened bone and return to 1G conditions [2]. It is therefore important to understand the significance of any bone density loss in addition to developing exercises in an attempt to limit losses in bone strength. NASA seeks to develop a deeper understanding of fracture risk through the development of a computational bone strength model to assess the bone fracture risk of astronauts pre-flight and post-flight. This study addresses the several key processes needed to develop such strength analyses using medical image processing and finite element modeling.

biomechanics↗
NASA NTRS2006

Current ISS Exercise Countermeasures: Where are we now?

Current International Space Station (ISS) crew schedules include 1.5 h/d for completion of resistive exercise and 1 h/d of aerobic exercise , 6 d/wk. While ISS post flight decrements in muscle strength, bone m ineral density, and aerobic capacity improved in some crewmembers, de conditioning was still evident even with this volume of exercise. Res ults from early ISS expeditions show maximum loss in bone mineral density of the lumbar spine and pelvis in excess of 1.5% per month, with all crewmembers demonstrating significant bone loss in one or more re gions. Similarly, post flight muscle strength losses in the hamstring and quadriceps muscle groups exceeded 30% in the immediate post miss ion period in some crewmembers. Measures of aerobic capacity early in the mission show average decrements of 15%, but with onboard aerobic exercise capability, the crew has been able to "train up" over the co urse of the mission. These findings are highly variable among crewmem bers and appear to be correlated with availability and reliability of the inflight resistive exercise device (RED), cycle ergometer, and t readmill. This suite of hardware was installed on ISS with limited op erational evaluation in groundbased test beds. As a result, onorbit hardware constraints have resulted in inadequate physical stimulus, d econditioning, and increased risk for compromised performance during intra and extravehicular activities. These issues indicate that the c urrent ISS Countermeasures System reliability or validity are not ade quate for extendedduration exploration missions. Learning Objective: A better understanding of the status of ISS exercise countermeasures , their ability to protect physiologic systems, and recommendations for exploration exercise countermeasures.

Hayes, J. C.↗