Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration.

Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.

Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact.

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.

The effect of prolonged spaceflight on cerebrospinal fluid and perivascular spaces of astronauts and cosmonauts.

Long-duration spaceflight induces changes to the brain and cerebrospinal fluid compartments and visual acuity problems known as spaceflight-associated neuro-ocular syndrome (SANS). The clinical relevance of these changes and whether they equally affect crews of different space agencies remain unknown. We used MRI to analyze the alterations occurring in the perivascular spaces (PVS) in NASA and European Space Agency astronauts and Roscosmos cosmonauts after a 6-mo spaceflight on the International Space Station (ISS). We found increased volume of basal ganglia PVS and white matter PVS (WM-PVS) after spaceflight, which was more prominent in the NASA crew than the Roscosmos crew. Moreover, both crews demonstrated a similar degree of lateral ventricle enlargement and decreased subarachnoid space at the vertex, which was correlated with WM-PVS enlargement. As all crews experienced the same environment aboard the ISS, the differences in WM-PVS enlargement may have been due to, among other factors, differences in the use of countermeasures and high-resistive exercise regimes, which can influence brain fluid redistribution. Moreover, NASA astronauts who developed SANS had greater pre- and postflight WM-PVS volumes than those unaffected. These results provide evidence for a potential link between WM-PVS fluid and SANS.

Identification of gravity-responsive serum proteins in spaceflight mice using a quantitative proteomic approach with data-independent acquisition mass spectrometry.

Physical inactivity associated with gravity unloading, such as microgravity during spaceflight and hindlimb unloading (HU), can cause various physiological changes. In this study, we attempted to identify serum proteins whose levels fluctuated in response to gravity unloading. First, we quantitatively assessed changes in the serum proteome profiles of spaceflight mice using mass spectrometry with data-independent acquisition. The serum levels of several proteins involved in the responses to estrogen and glucocorticoid, blood vessel maturation, osteoblast differentiation, and ossification were changed by microgravity exposure. Furthermore, a collective evaluation of serum proteomic data from spaceflight and HU mice identified 30 serum proteins, including Mmp2, Igfbp2, Tnc, Cdh5, and Pmel, whose levels varied to a similar extent in both gravity unloading models. These changes in serum levels could be involved in the physiological changes induced by gravity unloading. A collective evaluation of serum, femur, and soleus muscle proteome data of spaceflight mice also showed 24 serum proteins, including Igfbp5, Igfbp3, and Postn, whose levels could be associated with biological changes induced by microgravity. This study examined serum proteome profiles in response to gravity unloading, and may help deepen our understanding of microgravity adaptation mechanisms during prolonged spaceflight missions.

Changes in the astronaut serum proteome during prolonged spaceflight.

The molecular mechanisms associated with spaceflight-induced biological adaptations that may affect many healthy tissue functions remain poorly understood. In this study, we analyzed temporal changes in the serum proteome of six astronauts during prolonged spaceflight missions using quantitative comprehensive proteome analysis performed with the data-independent acquisition method of mass spectrometry (DIA-MS). All six astronauts participated in a spaceflight mission for approximately 6 months and showed a decreasing trend in T-scores at almost all sites where dual-energy X-ray absorptiometry scans were performed. DIA-MS successfully identified 624 nonredundant proteins in sera and further quantitative analysis for each sampling point provided information on serum protein profiles closely related to several time points before (pre-), during (in-), and after (post-) spaceflight. Changes in serum protein levels between spaceflight and on the ground suggest that abnormalities in bone metabolism are induced in astronauts during spaceflight. Furthermore, changes in the proteomic profile occurring during spaceflight suggest that serum levels of bone metabolism-related proteins, namely ALPL, COL1A1, SPP1, and POSTN, could serve as highly responsive indicators of bone metabolism status in spaceflight missions. This study will allow us to accelerate research to improve our understanding of the molecular mechanisms of biological adaptations associated with prolonged spaceflight.

Transcriptional response of Arabidopsis thaliana's root-tip to spaceflight.

Plants are expected to play a critical role in the biological life support systems of crewed spaceflight missions, including in the context of upcoming missions targeting the Moon and Mars. Therefore, understanding the response of plants to spaceflight is essential for improving the selection and engineering of plants and spaceflight conditions. In particular, understanding the root-tip's response to spaceflight is of importance as it is the center of orchestrating the development of the root, the primary organ for the absorption of nutrients and anchorage. GLDS-120 is a pioneering study by Paul et al. that used transcriptomics to evaluate the spaceflight response of the root-tip of the model plant Arabidopsis thaliana in dark and light through separate analyses of three genotype groups (Wassilewskija, Columbia-0, and Columbia-0 PhyD) and comparison of genotype responses. Here, we provide a complementary analysis of this dataset through a combined analysis of all samples while controlling for the genotypes in a paired analysis. We identified a robust transcriptional response to spaceflight with 622 DEGs in light and 200 DEGs in dark conditions. Gene enrichment analysis identified 37 and 13 significantly enriched terms from biological processes in light and dark conditions, respectively. Prominent enrichment for hypoxia-related terms in both conditions suggests hypoxia is a key stressor for root development during spaceflight. Additional enriched terms in light conditions include the circadian cycle, light response, and terms for the metabolism of flavonoid and indole-containing compounds. These results further our understanding of plants' responses to the spaceflight environment.

Neurovascular dysfunction associated with erectile dysfunction persists after long-term recovery from simulations of weightlessness and deep space irradiation.

There has been growing interest within the space industry for long-duration manned expeditions to the Moon and Mars. During deep space missions, astronauts are exposed to high levels of galactic cosmic radiation (GCR) and microgravity which are associated with increased risk of oxidative stress and endothelial dysfunction. Oxidative stress and endothelial dysfunction are causative factors in the pathogenesis of erectile dysfunction, although the effects of spaceflight on erectile function have been unexplored. Therefore, the purpose of this study was to investigate the effects of simulated spaceflight and long-term recovery on tissues critical for erectile function, the distal internal pudendal artery (dIPA), and the corpus cavernosum (CC). Eighty-six adult male Fisher-344 rats were randomized into six groups and exposed to 4-weeks of hindlimb unloading (HLU) or weight-bearing control, and sham (0Gy), 0.75 Gy, or 1.5 Gy of simulated GCR at the ground-based GCR simulator at the NASA Space Radiation Laboratory. Following a 12-13-month recovery, ex vivo physiological analysis of the dIPA and CC tissue segments revealed differential impacts of HLU and GCR on endothelium-dependent and -independent relaxation that was tissue type specific. GCR impaired non-adrenergic non-cholinergic (NANC) nerve-mediated relaxation in the dIPA and CC, while follow-up experiments of the CC showed restoration of NANC-mediated relaxation of GCR tissues following acute incubation with the antioxidants mito-TEMPO and TEMPOL, as well as inhibitors of xanthine oxidase and arginase. These findings indicate that simulated spaceflight exerts a long-term impairment of neurovascular erectile function, which exposes a new health risk to consider with deep space exploration.

An experimentally informed computational model of neurovestibular adaptation to altered gravity.

Transitions to altered gravity environments result in acute sensorimotor impairment for astronauts, leading to serious mission and safety risks in the crucial first moments in a new setting. Our understanding of the time course and severity of impairment in the early stages of adaptation remains limited and confounded by unmonitored head movements, which are likely to impact the rate of adaptation. Here, we aimed to address this gap by using a human centrifuge to simulate the first hour of hypergravity (1.5g) exposure and the subsequent 1g readaptation period, with precisely controlled head tilt activity. We quantified head tilt overestimation via subjective visual vertical and found ∼30% tilt overestimation that did not decrease over the course of 1 h of exposure to the simulated gravity environment. These findings extended the floor of the vestibular adaptation window (with controlled vestibular cueing) to 1 h of exposure to altered gravity. We then used the empirical data to inform a computational model of neurovestibular adaptation to changes in the magnitude of gravity, which can offer insight into the adaptation process and, with further tuning, can be used to predict the temporal dynamics of vestibular-mediated misperceptions in altered gravity.

Simulation of Human Movement in Zero Gravity.

In the era of expanding manned space missions, understanding the biomechanical impacts of zero gravity on human movement is pivotal. This study introduces a novel and cost-effective framework that demonstrates the application of Microsoft's Azure Kinect body tracking technology as a motion input generator for subsequent OpenSim simulations in weightlessness. Testing rotations, locomotion, coordination, and martial arts movements, we validate the results' realism under the constraints of angular and linear momentum conservation. While complex, full-body coordination tasks face limitations in a zero gravity environment, our findings suggest possible approaches to device-free exercise routines for astronauts and reveal insights into the feasibility of hand-to-hand combat in space. However, some challenges remain in distinguishing zero gravity effects in the simulations from discrepancies in the captured motion input or forward dynamics calculations, making a comprehensive validation difficult. The paper concludes by highlighting the framework's practical potential for the future of space mission planning and related research endeavors, while also providing recommendations for further refinement.

Team Dynamics and Collaborative Problem-Solving for Lunar Construction: Lessons From Complex Construction Scenarios on Earth.

OBJECTIVE: This paper surveys the existing literature surrounding problem-solving and team dynamics in complex and unpredictable scenarios, and evaluates the applicability of studying Earth-based construction teams to identify training needs for Lunar construction crews. BACKGROUND: Lunar and other space exploration construction crews will work in extreme environments and face unpredictable challenges, necessitating real-time problem-solving to address unexpected contingencies. This work will require coordination with Mission Control and autonomous assistants, so crew training must account for multi-agent, distributed teamwork. METHOD: A narrative literature review identified processes, attributes, and skills necessary for the success of Lunar construction teams. We summarized relevant frameworks and synthesized collective findings into over-arching trends and remaining research gaps. RESULTS: While significant literature exists surrounding team performance, very little systematic inquiry has been done with a focus on Lunar construction crews and operations, particularly with respect to dynamic problem-solving and team-based decision-making. Established and standardized metrics for evaluating team performance are lacking, resulting in significant variation in reported outcomes between studies. CONCLUSION: Lunar and other space exploration construction teams will need training that focuses on developing the right approach to team-based problem-solving, rather than on preparing response execution for known contingencies. An investigation of successful Earth-based construction crews may facilitate the development of relevant metrics for training future Lunar construction crews. APPLICATION: Metrics and team training protocols developed for future Lunar construction teams may be adaptable and applicable to a wide range of extreme teams facing uncertain challenges, such as aircrews, surgical teams, first responders, and construction crews.

Artificial gravity during a spaceflight analog alters brain sensory connectivity.

Spaceflight has numerous untoward effects on human physiology. Various countermeasures are under investigation including artificial gravity (AG). Here, we investigated whether AG alters resting-state brain functional connectivity changes during head-down tilt bed rest (HDBR), a spaceflight analog. Participants underwent 60 days of HDBR. Two groups received daily AG administered either continuously (cAG) or intermittently (iAG). A control group received no AG. We assessed resting-state functional connectivity before, during, and after HDBR. We also measured balance and mobility changes from pre- to post-HDBR. We examined how functional connectivity changes throughout HDBR and whether AG is associated with differential effects. We found differential connectivity changes by group between posterior parietal cortex and multiple somatosensory regions. The control group exhibited increased functional connectivity between these regions throughout HDBR whereas the cAG group showed decreased functional connectivity. This finding suggests that AG alters somatosensory reweighting during HDBR. We also observed brain-behavioral correlations that differed significantly by group. Control group participants who showed increased connectivity between the putamen and somatosensory cortex exhibited greater mobility declines post-HDBR. For the cAG group, increased connectivity between these regions was associated with little to no mobility declines post-HDBR. This suggests that when somatosensory stimulation is provided via AG, functional connectivity increases between the putamen and somatosensory cortex are compensatory in nature, resulting in reduced mobility declines. Given these findings, AG may be an effective countermeasure for the reduced somatosensory stimulation that occurs in both microgravity and HDBR.

Database of space life investigations and information on spaceflight plant biology.

Extensive spaceflight life investigations (SLIs) have revealed observable space effects on plants, particularly their growth, nutrition yield, and secondary metabolite production. Knowledge of these effects not only facilitates space agricultural and biopharmaceutical technology development but also provides unique perspectives to ground-based investigations. SLIs are specialized experimental protocols and notable biological phenomena. These require specialized databases, leading to the development of the NASA Science Data Archive, Erasmus Experiment Archive, and NASA GeneLab. The increasing interests of SLIs across diverse fields demand resources with comprehensive content, convenient search facilities, and friendly information presentation. A new database SpaceLID (Space Life Investigation Database http://bidd.group/spacelid/ ) was developed with detailed menu search tools and categorized contents about the phenomena, protocols, and outcomes of 459 SLIs (including 106 plant investigations) of 92 species, where 236 SLIs and 57 plant investigations are uncovered by the existing databases. The usefulness of SpaceLID as an SLI information source is illustrated by the literature-reported analysis of metabolite, nutrition, and symbiosis variations of spaceflight plants. In conclusion, this study extensively investigated the impact of the space environment on plant biology, utilizing SpaceLID as an information source and examining various plant species, including Arabidopsis thaliana, Brassica rapa L., and Glycyrrhiza uralensis Fisch. The findings provide valuable insights into the effects of space conditions on plant physiology and metabolism.

A hydrodynamic injection approach for capillary electrophoresis using rotor-stator valves.

Sample injection is a critical step in a capillary electrophoresis (CE) analysis. Electrokinetic injection is the simplest approach and is often selected for implementation in portable CE instruments. However, in order to minimize the effect of sample matrix upon the results of a CE analysis, hydrodynamic injection is preferred. Although portable CE instruments with hydrodynamic injection have been reported, injection has always been performed at the grounded end of the capillary. This simplifies fluidic handling but limits coupling with electrochemical detectors and electrospray ionization-mass spectrometry (ESI-MS). We demonstrated previously that injection at the high-voltage (HV) end of the capillary could be performed using an HV-compatible rotary injection valve (fixed-volume injection). However, the mismatch between the bore sizes of the channels on the rotor-stator valve and the separation capillary caused peak tailing and undesired mixing, impairing analytical performance. In this work, we present an HV-compatible hydrodynamic injection approach that overcomes the issues associated with the fixed-volume injection approach reported previously. The performance of the CE instrument was demonstrated by analyzing a mixture of 13 amino acids by CE coupled to laser-induced fluorescence, which showed relative standard deviations for peak area and migration time below 5% and 1%, respectively, for triplicate analysis. Additionally, replicate measurements of a mixture of amino acids, peptides, nucleobases, and nucleosides by CE coupled to electrospray ionization-mass spectrometry (CE-ESI-MS) were performed to evaluate peak tailing, and results were similar to those obtained with a commercial CE-ESI-MS setup.

A voltage trade study for the design of capillary electrophoresis instruments for spaceflight.

Capillary electrophoresis (CE) systems have undergone extensive development for spaceflight applications. A flight-compatible high voltage power supply and the necessary voltage isolation for other energized components can be large contributors to both the volume and mass of a CE system, especially if typical high voltage levels of 25-30 kV are used. Here, we took advantage of our custom CE hardware to perform a trade study for simultaneous optimization of capillary length, high voltage level, and separation time, without sacrificing method performance. A capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4 D) method recently developed by our group to target inorganic cations and amino acids relevant to astrobiology was used as a test case. The results indicate that a 50 cm long capillary with 15 kV applied voltage (half of that used in the original method) can be used to achieve measurement goals while minimizing instrument size.

Assessment of venous pressure by compression sonography of the internal jugular vein during 3 days of bed rest.

Compression sonography has been proposed as a method for non-invasive measurement of venous pressures during spaceflight, but initial reports of venous pressure measured by compression ultrasound conflict with prior reports of invasively measured central venous pressure (CVP). The aim of this study is to determine the agreement of compression sonography of the internal jugular vein (IJVP) with invasive measures of CVP over a range of pressures relevant to microgravity exposure. Ten healthy volunteers (18-55 years, five female) completed two 3-day sessions of supine bed rest to simulate microgravity. IJVP and CVP were measured in the seated position, and in the supine position throughout 3 days of bed rest. The range of CVP recorded was in line with previous reports of CVP during changes in posture on Earth and in microgravity. The correlation between IJVP and CVP was poor when measured during spontaneous breathing (r = 0.29; R2  = 0.09; P = 0.0002; standard error of the estimate (SEE) = 3.0 mmHg) or end-expiration CVP (CVPEE ; r = 0.19; R2  = 0.04; P = 0.121; SEE = 3.0 mmHg). There was a modest correlation between the change in CVP and the change in IJVP for both spontaneous ΔCVP (r = 0.49; R2  = 0.24; P < 0.0001) and ΔCVPEE (r = 0.58; R2  = 0.34; P < 0.0001). Bland-Altman analysis of IJVP revealed a large positive bias compared to spontaneous breathing CVP (3.6 mmHg; SD = 4.0; CV = 85%; P < 0.0001) and CVPEE (3.6 mmHg; SD = 4.2; CV = 84%; P < 0.0001). Assessment of absolute IJVP via compression sonography correlated poorly with direct measurements of CVP by invasive catheterization over a range of venous pressures that are physiologically relevant to spaceflight. However, compression sonography showed modest utility for tracking changes in venous pressure over time. NEW FINDINGS: What is the central question of this study? Compression sonography has been proposed as a novel method for non-invasive measurement of venous pressures during spaceflight. However, the accuracy has not yet been confirmed in the range of CVP experienced by astronauts during spaceflight. What is the main finding and its importance? Our data show that compression sonography of the internal jugular vein correlates poorly with direct measurement of central venous pressures in a range that is physiologically relevant to spaceflight. However, compression sonography showed modest utility for tracking changes in venous pressure over time.

Exploring the complexities of drug formulation selection, storage, and shelf-life for exploration spaceflight.

Medications have been a part of space travel dating back to the Apollo missions. Currently, medical kits aboard the International Space Station (ISS) contain medications and supplies to treat a variety of possible medical events. As we prepare for more distant exploration missions to Mars and beyond, risk management planning for astronaut healthcare should include the assembly of a medication formulary that is comprehensive enough to prevent or treat anticipated medical events, remains safe and chemically stable, and retains sufficient potency to last for the duration of the mission. Emerging innovation and technologies in pharmaceutical development, delivery, quality maintenance, and validation offer promise for addressing these challenges. The present editorial will summarize the current state of knowledge regarding innovative formulary optimization strategies, pharmaceutical stability assessment techniques, and storage and packaging solutions that could enhance drug safety and efficacy for future exploration spaceflight missions.

Brain and Behavioral Evidence for Reweighting of Vestibular Inputs with Long-Duration Spaceflight.

Microgravity alters vestibular signaling. In-flight adaptation to altered vestibular afferents is reflected in post-spaceflight aftereffects, evidenced by declines in vestibularly mediated behaviors (e.g., walking/standing balance), until readaptation to Earth's 1G environment occurs. Here we examine how spaceflight affects neural processing of applied vestibular stimulation. We used fMRI to measure brain activity in response to vestibular stimulation in 15 astronauts pre- and post-spaceflight. We also measured vestibularly-mediated behaviors, including balance, mobility, and rod-and-frame test performance. Data were collected twice preflight and four times postflight. As expected, vestibular stimulation at the preflight sessions elicited activation of the parietal opercular area ("vestibular cortex") and deactivation of somatosensory and visual cortices. Pre- to postflight, we found widespread reductions in this somatosensory and visual cortical deactivation, supporting sensory compensation and reweighting with spaceflight. These pre- to postflight changes in brain activity correlated with changes in eyes closed standing balance, and greater pre- to postflight reductions in deactivation of the visual cortices associated with less postflight balance decline. The observed brain changes recovered to baseline values by 3 months postflight. Together, these findings provide evidence for sensory reweighting and adaptive cortical neuroplasticity with spaceflight. These results have implications for better understanding compensation and adaptation to vestibular functional disruption.

Hindlimb unloading, a physiological model of microgravity, modifies the murine bone marrow IgM repertoire in a similar manner as aging but less strongly.

BACKGROUND: The spaceflight environment is an extreme environment that affects the immune system of approximately 50% of astronauts. With planned long-duration missions, such as the deployment of the Lunar Gateway and possible interplanetary missions, it is mandatory to determine how all components of the immune system are affected, which will allow the establishment of countermeasures to preserve astronaut health. However, despite being an important component of the immune system, antibody-mediated humoral immunity has rarely been investigated in the context of the effects of the space environment. It has previously been demonstrated that 30 days aboard the BION-M1 satellite and 21 days of hindlimb unloading (HU), a model classically used to mimic the effects of microgravity, decrease murine B lymphopoiesis. Furthermore, modifications in B lymphopoiesis reported in young mice subjected to 21 days of HU were shown to be similar to those observed in aged mice (18-22 months). Since the primary antibody repertoire composed of IgM is created by V(D) J recombination during B lymphopoiesis, the objective of this study was to assess the degree of similarity between changes in the bone marrow IgM repertoire and in the V(D)J recombination process in 2.5-month-old mice subjected to 21 days of HU and aged (18 months) mice. RESULTS: We found that in 21 days, HU induced changes in the IgM repertoire that were approximately 3-fold less than those in aged mice, which is a rapid effect. Bone remodeling and epigenetics likely mediate these changes. Indeed, we previously demonstrated a significant decrease in tibial morphometric parameters from day 6 of HU and a progressive reduction in these parameters until day 21 of HU, and it has been shown that age and microgravity induce epigenetic changes. CONCLUSION: These data reveal novel immune changes that are akin to advanced aging and underline the importance of studying the effects of spaceflight on antibody-mediated humoral immunity.

Effects of a microgravity SkinSuit on lumbar geometry and kinematics.

PURPOSE: Astronauts returning from long ISS missions have demonstrated an increased incidence of lumbar disc herniation accompanied by biomechanical and morphological changes associated with spine elongation. This research describes a ground-based study of the effects of an axial compression countermeasure Mk VI SkinSuit designed to reload the spine and reduce these changes before return to terrestrial gravity. METHODS: Twenty healthy male volunteers aged 21-36 without back pain participated. Each lay overnight on a Hyper Buoyancy Flotation (HBF) bed for 12 h on two occasions 6 weeks apart. On the second occasion participants donned a Mk VI SkinSuit designed to axially load the spine at 0.2 Gz during the last 4 h of flotation. Immediately after each exposure, participants received recumbent MRI and flexion-extension quantitative fluoroscopy scans of their lumbar spines, measuring differences between spine geometry and intervertebral kinematics with and without the SkinSuit. This was followed by the same procedure whilst weight bearing. Paired comparisons were performed for all measurements. RESULTS: Following Mk VI SkinSuit use, participants evidenced more flexion RoM at L3-4 (p = 0.01) and L4-5 (p = 0.003), more translation at L3-4 (p = 0.02), lower dynamic disc height at L5-S1 (p = 0.002), lower lumbar spine length (p = 0.01) and greater lordosis (p = 0.0001) than without the Mk VI SkinSuit. Disc cross-sectional area and volume were not significantly affected. CONCLUSION: The MkVI SkinSuit restores lumbar mobility and lordosis following 4 h of wearing during hyper buoyancy flotation in a healthy control population and may be an effective countermeasure for post space flight lumbar disc herniation.

Team Self-Maintenance during Long-Duration Space Exploration: A Conceptual Framework.

OBJECTIVE: We developed a conceptual framework of Team Self-Maintenance (TSM) within long-duration space exploration (LDSE), which we define as the process of monitoring, adjusting, and maintaining the psychological well-being of a team in the absence of external support. BACKGROUND: Specific to LDSE and isolated, confined, and extreme (ICE) environments, periods of routine can have a debilitating effect on the crew's well-being and performance, and TSM is a critical process for avoiding these detrimental effects. METHOD: Based on themes drawn from nine subject matter expert interviews combined with an extensive literature review on related concepts, we developed an integrative conceptual framework of the key inputs, processes, and outputs involved in TSM within LDSE contexts. RESULTS: Our TSM framework suggests team well-being as a key outcome that must be maintained during LDSE and information sharing, self-regulation, resource recovery, and emotional support as the key processes that enable team well-being. We also identify several contextual inputs that can serve as intervention points for enabling effective TSM. CONCLUSION: Our framework suggests that future research and practice aimed at effective LDSE should emphasize team well-being, rather than just performance, and that there are many open questions in terms of how teams will manage their own socio-emotional needs (e.g., conflict, recovery activities, and boredom) without external systems and support. APPLICATION: This conceptual framework describes the primary inputs, processes, and outcomes involved in the team self-maintenance process. This framework reflects context-specific theorizing most likely to be applicable only to LDSE contexts.