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Responses of Humans to Space Flight in LEO: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by David A. Hart.

Homo sapiens and their predecessors evolved in the context of the boundary conditions of Earth, including a 1 g gravity and a geomagnetic field (GMF). These variables, plus others, led to complex organisms that evolved under a defined set of conditions and define how humans will respond to space flight, a circumstance that could not have been anticipated by evolution. Over the past ~60 years, space flight and living in low Earth orbit (LEO) have revealed that astronauts are impacted to varying degrees by such new environments. In addition, it has been noted that astronauts are quite heterogeneous in their response patterns, indicating that such variation is either silent if one remained on Earth, or the heterogeneity unknowingly contributes to disease development during aging or in response to insults. 

  • Space flight
  • Evolution
  • Homo sapiens
  • Boundary conditions of Earth
  • Geomagnetic field
  • Microgravity
  • Deep space
  • Low Earth orbit

1. Introduction

Humans can be exposed to microgravity for very short durations (i.e., minutes) via parabolic flight in an airplane, and then longer flights in capsules for hours and days, or with the advent of space stations, such as MIR or the International Space Station (ISS), for months to a year. Thus, one can be exposed acutely or chronically to microgravity, with the added exposure to increased radiation on the ISS. With chronic exposure, one may also start to decipher the primary responses and the potential secondary responses due to the complexity of the potential interactions. A number of responses of astronauts to living in LEO conditions have been noted (Table 1); however, the individual responses are quite heterogenous.
Table 1.
Summary of Human Responses to Long-Duration Living in LEO
a
.
Tissue/System Response Effective Counter Measures Presumed Cause
MSK System      
Muscle Atrophy Exercise protocols Microgravity
Bone Atrophy Partial (Exercise/Drugs) Microgravity
Ligaments ??—Not reported    
Tendons ??—Not reported    
CV System      
Heart Arrhythmia, LV mass, b Cardiac output Compression, Artificial gravity Microgravity, Radiation?
Vascular      
Fluid Redistribution Artificial gravity/Compression Microgravity
Tissue Altered function No—most recover on return Microgravity
  Remodeling
],20,21,22], in the brain [23[14][15][16],24,25], and in other tissues [26,27][17][18]. Some individuals who are at risk for kidney stones or gout could suffer from the consequences of high levels of calcium, and some biological systems may also be affected if the removal is not sufficient once the increases in calcium liberation become chronic and a secondary disease risk develops that was not evident on Earth. Therefore, there can be primary, secondary, and potentially tertiary consequences of space-flight-related bone loss.
As bone and muscle are reported to work together as a functional unit [28][19], and it is well known from studies on Earth that muscles atrophy quickly when they are not used, as reviewed in [11[1][3][20],13,29], it is not surprising that muscle atrophy occurs quickly on exposure to microgravity. As muscles function via neural input at neuromuscular junctions, the loss of muscle integrity in microgravity could be due to the direct effects of loading on muscles and/or the loss of the integrity of the neural component for muscle stimulation.
Whether the other components of the MSK system are directly affected by exposure to microgravity is not well documented. However, it is likely that the tendons may be indirectly affected by muscle atrophy since they are intermediary between the muscles and bone. Many tendons, such as the energy-storing Achilles tendon, function normally on Earth at ~80% of their ultimate stress, and, thus, prolonged muscle atrophy and weakening would lead to the underutilization of tendons and a slower adaptation to this altered state. Whether any adaptations in the tendons would occur primarily in a specific area of the tendon (i.e., enthesis into bone, mid-substance, or the myotendinous junction) remains to be determined.

3. Countermeasures to Prevent or Reverse Space-Flight Effects on the MSK System

In an attempt to maintain the integrity of the MSK system components, considerable effort has gone into developing countermeasures targeting bone and muscle. These have focused on exercise protocols involving resistance exercises and some aerobic activities. Currently, astronauts on the ISS are supposed to exercise for a few hours/day in order to counteract the effects of microgravity on the MSK system, as reviewed in [18][9]. While such exercise protocols appear to be capable of helping to retain muscle integrity, they are not as efficient in preventing bone loss [30,31][21][22]. Based on such outcomes, either bone and muscle are regulated differently, or the type of exercise that is used is not appropriate to maintain bone integrity. While muscle does appear to respond to exercise in microgravity, in preclinical models, muscle changes can also be attenuated by artificial gravity [32][23]. Thus, artificial gravity may be a relevant approach to mitigate the effects of microgravity in space. However, in some studies using a bedrest analog, artificial gravity was not effective in mitigating muscle atrophy [33][24].
If the exercise protocols that are currently in place are not appropriate for bone, what may be more appropriate? While the answer is not known definitively at the present time, there may be clues in what is known about the regulation of bone on Earth. These include the following:
  • Astronauts lose more bone from the lower extremities than the upper extremities, as discussed in [11,12,17];
  • From the work of Frost [
  1. Astronauts lose more bone from the lower extremities than the upper extremities, as discussed in [3][7][8
  • 34
  • ,35,36], bone adapts to mechanical stimulation in response to GRF;
  1. ];
  2. From the work of Frost [25][26][27], bone adapts to mechanical stimulation in response to GRF;
  • The current exercise protocols do not mimic GRF, as GRF loading is likely more of an impact loading than a resistance loading, as discussed in [
  • 11,12,17,34,35].
  1. The current exercise protocols do not mimic GRF, as GRF loading is likely more of an impact loading than a resistance loading, as discussed in
  2. [3][7][8][25][26].
May persist
Microgravity
Eyes
Altered vision (fluid and/or neural)
Glasses—some recover on return
Microgravity
Immune System Viral reactivation, White blood cells Stress reduction Stress, Circadian disruption
DNA Epigenetic None—some reversible on return ??—likely multi-causal c
Bone Marrow Fat infiltration, Hematopoiesis? None—recovery on return Microgravity, Others?
Neural      
Central Cognition, Behavior, Working memory, Structural alterations None presently Microgravity, Others?
Peripheral Neuromuscular

Vestibular

Cardiovascular		 Exercise Microgravity
a This table summarizes many, but not all, of the responses of astronauts to life in LEO conditions. However, individual responses are quite variable, and not all astronauts experience the changes to the same degree. As most astronauts to date have been male, the potential to elucidate sex-specific alterations must await additional flights and tenure of female astronauts at locations such as the ISS. b Left ventricular mass. c Multi-causal = stress, circadian rhythm disruption, radiation, alterations to hematopoiesis.

2. Effects on Elements of the Musculoskeletal System (MSK)

The elements of the MSK system, such as the bone, muscle, ligaments, tendons, and menisci, all subscribe to the “use it or lose it” principle on Earth. That is, particularly for bone and muscle, if the tissues are not subjected to biomechanical loading at a level that is specified by the set point, the tissues will undergo atrophy, even on Earth, as reviewed in [13][1]. On Earth, this can be demonstrated by short- and long-duration bed rest via the removal of an individual from the ground reaction forces (GRF), which are required to continually maintain the integrity of the bone and the muscles, as discussed in [2,11,14][2][3][4]. If one removes a tissue, such as knee menisci, from its in vivo loading environment, it rapidly leads to the induction of a cassette of catabolic genes within 4 h, which can contribute to the atrophy of the tissue [15][5]. The induction of the catabolic genes can be prevented by intermittent hydrostatic compression in vitro above a threshold [15][5]. Similarly, one can detect the onset of bone turnover in individuals during bedrest within a few days [16][6]. Thus, atrophy via catabolism develops when the mechanical loading decreases below a certain level, such as what an astronaut experiences in microgravity.
With the exposure to microgravity on the ISS, there is a fairly rapid induction of bone loss and muscle atrophy, as discussed in [11,12,17][3][7][8]. The bone loss is more from the lower extremities than the upper extremities, likely indicating that the bones of the lower extremities are more exposed to GRF on Earth, and thus, are more likely to be influenced by its loss. The loss of bone is quite variable, with different astronauts losing considerable bone per month (~2%), while others lose much less (~0.1%) per month. There is also a rapid loss of muscle integrity and induction of atrophy [18][9].
While bone loss can be extensive following exposure to microgravity, there has never been a recorded bone fracture in astronauts while in space. However, bone loss can likely be considered a primary response to microgravity due to the fact that bone requires the gravity-mediated GRF that it evolved to address in response to one of the boundary conditions of Earth. Thus, GRF appears to be central to the regulation of bone, but whether it is the only regulator remains to be confirmed.
However, a secondary consequence of bone loss is the mobilization of the calcium that is liberated from the bone. As calcium is well known to be an important regulator of many enzyme systems and biochemical pathways, the blood levels are tightly regulated and much of the liberated calcium is likely removed from the body by the kidneys and then ends up in the urine. Calcium signaling is important in the heart and vascular systems [19[10][11][12][13
Therefore, perhaps to retain bone requires an impact loading of the lower extremities at the foot to mimic GRF loading. Furthermore, while it is believed that muscle and bone form a functional unit [28][19], the failure of the current protocols, mainly resistance exercise, to prevent bone loss but allow for the retention of muscle integrity could mean that the current protocols do not allow for fidelity in the functioning of this bone–muscle unit. It is known that active muscles release myokines, which are mediators such as irisin, that can influence other cell types, including bone cells [37][28]. However, it is also known that some people respond to aerobic exercises and not resistance exercises, and vice versa [38][29], as discussed in [13][1]. Perhaps the current protocols do not lead to the release of the appropriate myokines, which can also influence bone and contribute to the effectiveness of an impact loading protocol, or possibly due to sleep disturbances and alterations to circadian rhythms. The released mediators are not effective [39][30].
While the basis for the differences in the responses of bone and muscle to countermeasures may be due to the countermeasures themselves, the findings thus far may indicate that one should also perhaps look in directions that have not yet been examined in detail. Both bone and muscles are innervated, but in muscle, the functioning is directly related to the extensive network of neuromuscular junctions. In contrast, while bone [40,41,42][31][32][33] and bone marrow [43,44][34][35] are innervated, the pattern of innervation of bone indicates that not all cells in the bone are in proximity with nerve endings. Thus, some cells in the bone may play an amplification role regarding the influence of the neural input into the bone environment. Such cells could be the equivalent of the pluripotent regulatory cells that have been postulated to play a role in tissue regulation [45][36]. In microgravity, such a regulatory mechanism may be compromised, and exercise alone cannot overcome this deficit.
Interestingly, the pharmacological alternative to exercise has also been considered to address the bone loss problem in space [46][37]. That is, the use of bisphosphonates that are prescribed on Earth for patients with age-related or post-menopausal osteoporosis can also be used in space [46][37]. Such drugs can be administered as a once-per-year infusion (zoledronic acid) or weekly via the oral route (alendronate and others). While the long-term use of some bisphosphonates does have some side-effects on Earth, such as atypical femoral fractures and osteonecrosis of the jaw, perhaps astronauts will only have to take the drugs in microgravity, and the bone loss on the Moon (1/6 g) or on Mars (1/3 g) will be less. In follow-up studies to those that were reported by Natsu-ume et al. [15][5], it was found that intermittent loading with 1 or 0.5 MPa completely prevented the induction of the catabolic cassette of genes, while 0.25 MPa was only partially preventative, and 0.1 MPa did not prevent the elaboration of the catabolic genes [Hart et al., unpublished observations]. Thus, in space, a partial g environment may be sufficient to re-establish an intensity of GRF-like loading in order to prevent bone loss. However, in stations such as the planned Gateway on the Moon, astronauts would still be required to take these drugs over an extended period of time.
Interestingly, and relevant to the above discussion, patients with spinal cord injuries (SCI) lose bone below the level of the injury [47][38], the bone loss is inconsistently attenuated by exercise protocols, and the bone loss does respond, in part, to anti-bone resorptive reagents, such as bisphosphonates and other anti-resorptive reagents such as denosumab, as reviewed in [48][39]. Thus, there are some interesting parallels between bone loss due to the loss of neural input via SCI and the bone loss after exposure to microgravity. Perhaps these parallels should stimulate some further research to explore a potential neural regulatory basis for bone loss in microgravity environments.

4. Vascular Alterations in Microgravity and Living in Low Earth Orbit 

As astronauts on Earth grow, mature, and function mainly in an upright position, and have tissues that require adequate nutrition and oxygenation, the heart and vascular system has evolved to work effectively against the 1g of Earth in order to maintain system integrity and the ability to remain mobile in such an environment. Therefore, living in a microgravity environment, such as on the ISS or in short-term space flight and long-term space flight, would alleviate the need to work against gravity and require the system set point to adapt to the new conditions. Thus, both acute and chronic adaptations may be evident. Changes to the cardiovascular system have been very evident, and such adaptations have been the subject of considerable investigation [49,50,51,52,53,54,55][40][41][42][43][44][45][46]. While the adaptations to microgravity have been shown, similar to other response patterns, the response of individual astronauts is variable. In addition, sex differences have been noted in the adaptations and their persistence post-space flight [56,57][47][48]. Such alterations can persist for extended periods of time post-flight [58][49].
As the vascular adaptations to microgravity involve the redistribution of fluids, there can be increased cerebral fluid [53,59][44][50] and increased fluid pressures in organs such as the eyes of both astronauts [60,61,62][51][52][53] and preclinical models, such as mice [63][54]. This can lead to visual disturbances [64][55], possibly related to effects on the eye itself [65][56], or the optic nerve [66][57]. Some of the astronauts have their vision sufficiently altered to require the wearing of glasses.
In order to address the vascular changes, the development of effective countermeasures is needed [67][58]. The use of artificial gravity has been proposed [68][59] as a solution to the problem, as well as the use of negative pressure [69,70][60][61]. However, this area is in need of more investigation, as the reversibility of the changes may be compromised with increasing the duration of the exposure to microgravity, as well as aging during time in space. However, as will be discussed in later sections, it is likely that effective countermeasures will not be developed for this aspect of space flight in isolation, and that a more holistic perspective on the inter-relationships regarding human adaptations to space flight will be needed. In addition, as there is heterogeneity in the vascular responses to space by astronauts, the basis for such heterogeneity may also provide some clues as to the best way to overcome the vascular consequences of space flight.
Of note, the heart is fundamentally an electrical system that also generates electromagnetic fields. Therefore, it is also potentially affected by magnetic storms that may be encountered in space [71][62]. As discussed by Baevsky et al. [71][62], exposure to variations in the geomagnetic field of Earth and magnetic storms are risk factors for cardiovascular disorders. As discussed earlier, calcium ions are also fundamental to the functioning of the heart. In addition, there is an increased exposure of the heart to radiation on the ISS and when living in LEO [72,73,74][63][64][65]. Thus, even in LEO, there are multiple potential stressors that can contribute to the risk of developing cardiovascular disease, such as fluid redistribution due to microgravity, altered calcium regulation, radiation exposure, and magnetic storms. Therefore, developing countermeasures to minimize the impact of the combined and inter-related factors on cardiovascular health will be a challenge, particularly as missions go beyond LEO. Of importance will be the need to make sure that astronauts do not have any underlying subclinical cardiovascular issues prior to missions [75][66], conditions that could exacerbate the impact of the space environment.

5. Functional and Structural Brain Changes in Low EOarth Orbit and Microgravity

Brain changes at the functional [76,77,78,79][67][68][69][70] and structural [80][71] levels can occur during space flight and when living in LEO conditions for long periods of time. Such changes may be the result of fluid shifts and the response to microgravity [81][72]; however, the space environment contains multiple stressors, including radiation, elevated CO2 levels, psychological stress, sleep deprivation, nutritional issues, and others [77,82,83,84,85][68][73][74][75][76] that could contribute to alterations in cognition and neural activities. Such changes could compromise the functioning of astronauts during planned deep-space missions [86,87,88][77][78][79].
While some aspects of these space-associated changes in the brain can be captured by analogs such as head-down tilt bedrest studies [89][80], it is not clear that all of the changes will be detected on Earth, due to the complexity of the changes in space. Interestingly, use of artificial gravity can alleviate some of the neural changes occurring as a result of the bedrest analog condition [90][81]. In order to mitigate the impact of space-flight-induced changes to brain functioning, will require the development of effective countermeasures [91,92][82][83] and tools to detect subtle changes [93][84], which will require interventions, or biomarker approaches, that could potentially detect the onset of a process that could have a clinical impact [94,95,96][85][86][87]. Whether such functional and structural changes are reversible after chronic exposure in deep space, and whether they are associated with epigenetic alterations, remains to be determined.

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