Beyond the Atmosphere: Space and Human Health

Ayça Döngel^T. , Elif Duymaz^E.

Since Yuri Gagarin performed the first human spacewalk in1961¹, research in the fields of astrobiology², gravity biology³, space biology⁴, and space medicine⁵ has discovered novel biological responses to the space environment. Such as the National Aeronautics and Space Administration (NASA), the Japan Aerospace Exploration Agency (JAXA), the European Space Agency (ESA), the Russian State Space Operations Agency (ROSCOSMOS), the China National Space Administration (CNSA) and the Canadian Space Agency (CSA)⁶. Space agencies aimed to use science for the benefit of humanity⁶. To contribute to advances in science and technology on Earth, space agencies conduct studies for the ongoing updating of space research. For example; technology developed through space missions has led to the creation of solar cell and satellite navigation systems^7-9. NASA Spinoffs aims to improve worldwide life with piezoelectric gravimeter and remote sensing toolkit technologies in 2022 goals⁹. In a similar manner, space biology has enabled the development of new technologies with a great deal of scientific knowledge contributing to terrestrial medicine and biological sciences^10,11. Scientists plan to establish an interdisciplinary field called aerospace bioprocess engineering in the future¹².

The term “spaceflight” refers to travel over the Karman line, which is 100 kilometers above sea level. The Karman line is an altitude above the atmosphere where the aerodynamic control surfaces of conventional aircraft are not dense enough for them to be effective; beyond that, there is space^6,13.  In terms of human health, spaceflight is classified into three categories: sub-orbital¹⁴, low earth orbit (LEO)¹⁵ and recon class missions¹⁶. Space radiation and microgravity are specifically the two main health risks connected to spaceflight¹⁷. Space radiation consists mainly of high-energy protons produced from solar particle events (SPE), heavy ions found in galactic cosmic rays (GCR), and secondary particles from interaction with the spacecraft shield^18-20. Flights within the LEO can take advantage of the shielding effects of the Earth’s magnetosphere; however, beyond LEO, on upcoming exploration missions to the Moon, Mars, and other planets, crews are predicted to be exposed to increased GCR and possibly high-intensity SPE^21,22. This review aims to outline the basic biological characteristics associated with their flight and the risks to human health that may be caused by space factors.

1. Space Factors

In order to establish functional bases on distant planets and missions beyond LEO, it is necessary to first identify the factors that make up the space environment and comprehensively determine their effects on living biology²³. According to NASA, there are five main hazards to human spaceflight: radiation, microgravity, distance, closed or hostile ecosystems, and isolation/containment²⁴.

1.1. Space Radiation

Ionizing radiation (IR) refers to short wavelengths (X-rays, gamma rays, cosmic rays, etc.) that cause significant adverse effects in the organism in a dose-dependent manner²⁵. Space radiobiology (SPRB) is a specialized subfield that examines the physical characteristics of IRradiated from space²⁷, in contrast to radiobiology, which is a multidisciplinary study of the biological impacts of IR²⁶. Additionally, space missions often result in low-dose IR exposure; therefore, SPRB also examines some low-dose radiobiological events and how they affect the dangers related to radiation exposure²⁷. One of the goals for SPRB is to simulate the space radiation environment on the surface of the Earth^21,28.

1.2. Microgravity

It is believed that the physical constant of gravity (g=9.1 m/s2) has not changed in the past four billion years²⁹. The term microgravity also referred to as weightlessness, is commonly used to describe accelerations close to 10^–3-10^–6g^30,31. Microgravity is one of the major factors contributing to the harsh space environment, which causes several significant changes in living systems. First of all, during the first few days in orbit, 60–80% of astronauts experience space adaptation syndrome (SAS), commonly known as space sickness (SMS)⁵.  Research opportunities exist that will help us better understand the biological impacts of this factor on cells in vitro by recreating microgravity with Earth-based devices^32-34.

1.3. Distance

The phenomenon of “disappearing earth” is expressed as an increase in longing and melancholy depending on the distance from the Earth³⁵. As moving away from Earth, work is being carried out to address technical problems such as the difficulty of real-time communication with a delay of up to 20 minutes and limitations in health services³⁶. Long-distance space exploration missions (LDSEMs) in particular attempt to maintain crew members’ physical and psychological health in order to standardize crew dynamics³⁷.

1.4. Closed or Hostile Ecosystems

The ecosystem inside the spacecraft can affect astronaut health if necessary precautions are not taken²⁴. Stress hormone levels can increase in a closed environment. It has also been reported that astronauts’ immune systems and metabolisms are affected by space flights in a closed ecosystem^24,38. In particular, the ventilation criteria of the spacecraft environment are critical to avoid exposure to various pollutants and celestial space dust^39,40.

1.5. Isolation/Imprisonment

In conditions of imprisonment and isolation, human psychology differs considerably. In long-duration space exploration missions, it has been reported that behavioral health risks need to be addressed for mission success. Earth-based studies simulating isolation in space in analog environments have shown that social isolation can lead to neurological disorders, an increase in anxiety, and immune system disorders^41-44.

2. Human Health in Space

Six features of spaceflight biology have been identified from studies on model organisms and astronaut health that provide insight into the fundamental molecular changes that occur during space travel. Oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic alterations, telomere length changes, and microbiome adjustments are some of these features (Figure 1)²⁴.

Figure 1. Space factors and their biological effects on living things²⁴. The physiological/biological effects of the dangers created by the space environment for living things and their relations with each other have been mapped.

2.1. Skeletal Muscle system

Research conducted before, during, and after spaceflight has demonstrated that exposure to microgravity disrupts various physiological systems, with the skeletal and muscular systems being particularly affected^45,48. Decreases in mechanical loading on the skeleton due to microgravity cause deterioration of the skeletal architecture leading to significant losses in bone mineral density (BMD) and its bone strength. Biochemical studies have shown that bone metabolism changes during spaceflight. Biomarkers of bone resorption increase, while biomarkers of bone formation decrease, resulting in net bone loss. In addition to microgravity, it is claimed that lack of exercise, low nutritional diversity, and mobility in limited space in spacecraft can contribute to bone ^47-52. Muscular atrophy is another health issue caused by microgravity. It is stated that the decrease in muscle volume due to continuous exposure to microgravity during long-term space flight may increase the risk of astronaut injury, especially in the spine and lower extremities, while on duty, after returning to earth, or later in life^53,54.

2.2. Cardiovascular System

Beyond LEO, the cardiovascular system (CVS) is expected to have deleterious effects from exposure to space radiation, including cardiac remodeling, fibrosis, and (micro)vascular damage⁵⁵. Microgravity has various effects on CVS physiology, such as reduced circulating blood volumes, decreased arterial blood diastolic pressure, reduced left ventricular size, and post-flight orthostatic intolerance^56-58. Blood and other body fluids go from the lower extremities to the upper body during spaceflight because there is no hydrostatic gradient under microgravity circumstances. Positional changes in body fluids cause physiological changes that are evident as a puffy face linked with facial edema chicken legs due to diminished leg volume⁵⁹. In addition, changes occurring in the space environment CVS can promote oxidative stress and inflammation, which can disturb vascular endothelial cells (ECs) and accelerate the progression of cardiovascular disease⁶⁰.

2.3. Nervous System

Long-term exploration of space places significant importance on maintaining the health of the brain and central nervous system (CNS), as sensorimotor and cognitive functions are essential for many important tasks⁶¹. The human brain experiences a variety of changes in the space environment according to research on astronauts returning from missions to the International Space Station (ISS). Such as micro and macro structural changes in gray and white matter, changes in cerebrospinal fluid (CSF) and fluid distribution, and changes in behavioral and cognitive performance^62-64. For instance, exposure of the vestibular/sensorimotor system to real or simulated microgravity caused structural and functional changes such as conflicts between actual and expected signals collected from the external environment^65-67. Acute consequences of space radiation exposure during missions beyond LEO include a broad spectrum and can include everything from impacted cognitive function to CNS damage and even death if astronauts are exposed to extremely high doses of particles. The long-term effects of radiation exposure may include an increased risk of cancer development or permanent damage to brain structures^62,68. Long-term spaceflight increases the brain’s total intracranial volume; it has also been discovered to cause structural changes in the brain, as well as conditions like spaceflight-associated neuro-ocular syndrome (SANS), formerly known as visual impairment and intracranial pressure (VIIP), cognitive impairments, or performance-related effects like neuro vestibular issues⁶⁹. The long-term isolation environment in space missions also has psychological and physiological effects. Isolation studies such as the Mars500 have shed light on microstructural changes in the brain’s white matter^63,70. Misalignment of the circadian clock system, which is among the physiological functions affected by spaceflight, has been reported to affect astronauts’ health, sleep/wake cycles, and performance²⁴.

2.4. Other Systems

The primary respiratory organ, the lungs, carries out gas exchange through passive diffusion, which is measured by the ventilation-perfusion ratio (V/Q), which calls for the proper mixing of inhaled gas and blood flow across the alveolar membrane. In the normal human lung, gravity couples ventilation with perfusion through mechanical effects; therefore, it is stated that microgravity may cause organ deformation by increasing the lung weight due to fluid accumulation. In addition, it has been pointed out that exposure to dust particles in the aerospace environment can cause particulate accumulation in the respiratory tract⁷¹.  Long-term reports have connected astronauts’ opportunistic infections to immune system disorders, another important regulator impacted by the space environment⁷². It is anticipated that crew members on exploration-class space missions will experience clinical risk due to persistent reductions in the function of particular innate or adaptive immune cells or changes in cytokine production profiles. It is also believed that the space environment increases the risk of cancer due to genetic changes^73-75. Reproductive systems and fertility are on the agenda of scientists in terms of future colonies on other planets or deep space travels, but microgravity and radiation are on the reproductive system. It has only been shown in animal models that it may have negative effects on its functions^76,77. A recent study reported that normal reproductive function occurs in mouse sperm frozen under space radiation conditions⁷⁸. The gut microbiome, which is found in the digestive tract, is crucial for preserving astronaut health while in space, just as it is for people on Earth. Studies involving both animal and human participants have been carried out to track alterations in the gut microbiota under actual or simulated spaceflight circumstances. Microbiome dysbiosis, gastrointestinal problems, and infection are all connected to a variety of clinical outcomes, including neurological and metabolic conditions^38,79. Other illnesses that may be dangerous to human health in space are documented to include hormonal dysfunction⁸³, skin issues⁸¹, lipid dysregulation²⁴, liver damage, and renal nephrolithiasis (kidney stones)⁸⁰.

Throughout human history, there has been great interest in and investigation into phenomena beyond the atmosphere. Significant breakthroughs have been made in the exploration of other planets and deep space, from the first man walking on the Moon to the present day. These breakthroughs have brought along technological developments in various branches of science, including biological sciences around the world. Today, deep space travels planned, especially to Mars, bring along concerns about the adaptation of humans to the space environment. Long-term space missions and voyages face obstacles due to the hazards of the space environment and potential diseases. Scientists devote significant effort to creating systems that safeguard and sustain human health during deep space exploration. 

References:

1. Furukawa, S., Nagamatsu, A., Nenoi, M., Fujimori, A., Kakinuma, S., Katsube, T., Wang, B., Tsuruoka, C., Shirai, T., Nakamura, A. J., Sakaue-Sawano, A., Miyawaki, A., Harada, H., Kobayashi, M., Kobayashi, J., Kunieda, T., Funayama, T., Suzuki, M., Miyamoto, T., … Takahashi, A. (2020). Space Radiation Biology for “Living in Space.” BioMed Research International, 2020. https://doi.org/10.1155/2020/4703286
2. Prasad, B., Richter, P., Vadakedath, N., Haag, F. W. M., Strauch, S. M., Mancinelli, R., Schwarzwälder, A., Etcheparre, E., Gaume, N., & Lebert, M. (2021). How the space environment influences organisms: an astrobiological perspective and review. International Journal of Astrobiology, 20(2), 159–177. https://doi.org/10.1017/S1473550421000057
3. Grimm, D. (2019). Guest Edited Collection: Gravitational biology and space medicine. Scientific Reports 2019 9:1, 9(1), 1–4. https://doi.org/10.1038/s41598-019-51231-8
4. Vandenbrink, J. P., & Kiss, J. Z. (2016). Space, the final frontier: A critical review of recent experiments performed in microgravity. Plant Science : An International Journal of Experimental Plant Biology, 243, 115. https://doi.org/10.1016/J.PLANTSCI.2015.11.004
5. Hodkinson, P. D., Anderton, R. A., Posselt, B. N., & Fong, K. J. (2017). An overview of space medicine. British Journal of Anaesthesia, 119, i143–i153. https://doi.org/10.1093/BJA/AEX336
6. Smith, M. G., Kelley, M., & Basner, M. (2020). A brief history of spaceflight from 1961 to 2020: An analysis of missions and astronaut demographics. Acta Astronautica, 175, 290. https://doi.org/10.1016/J.ACTAASTRO.2020.06.004
7. Maiwald, V., Schubert, D., Quantius, D., & Zabel, P. (2021). From space back to Earth: supporting sustainable development with spaceflight technologies. Sustainable Earth 2021 4:1, 4(1), 1–16. https://doi.org/10.1186/S42055-021-00042-9
8. Dietrich, D., Dekova, R., Davy, S., Fahrni, G., & Geissbühler, A. (2018). Applications of Space Technologies to Global Health: Scoping Review. Journal of Medical Internet Research, 20(6). https://doi.org/10.2196/JMIR.9458
9. NASA Spinoff 2022 Feature Stennis Space Center Technologies | NASA. (n.d.-i). Retrieved July 15, 2022, from https://www.nasa.gov/centers/stennis/news/releases/2022/NASA-Spinoff-2022-Feature-Stennis-Space-Center-Technologies
10. Orlov, O. I., Belakovskiy, M. S., Kussmaul, A. R., & Tomilovskaya, E. S. (2022). Using the Possibilities of Russian Space Medicine for Terrestrial Healthcare. Frontiers in Physiology, 0, 947. https://doi.org/10.3389/FPHYS.2022.921487
11. Tran, Q. D., Tran, V., Toh, L. S., Williams, P. M., Tran, N. N., & Hessel, V. (2021). Space Medicines for Space Health. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.1c00681 
12. Berliner, A. J., Lipsky, I., Ho, D., Hilzinger, J. M., Vengerova, G., Makrygiorgos, G., McNulty, M. J., Yates, K., Averesch, N. J. H., Cockell, C. S., Wallentine, T., Seefeldt, L. C., Criddle, C. S., Nandi, S., McDonald, K. A., Menezes, A. A., Mesbah, A., & Arkin, A. P. (2022). Space bioprocess engineering on the horizon. Communications Engineering 2022 1:1, 1(1), 1–8. https://doi.org/10.1038/s44172-022-00012-9
13. BARRATT, M. R. (2020). THE BERT & PEGGY DUPONT LECTURE: THE HUMAN IN SPACE: A NEW PHYSIOLOGY. Transactions of the American Clinical and Climatological Association, 131, 201. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358469/
14. Pollock, R. D., Jolley, C. J., Abid, N., Couper, J. H., Estrada-Petrocelli, L., Hodkinson, P. D., Leonhardt, S., Magor-Elliott, S., Menden, T., Rafferty, G., Richmond, G., Robbins, P. A., Ritchie, G. A. D., Segal, M. J., Stevenson, A. T., Tank, H. D., & Smith, T. G. (2021). Pulmonary Effects of Sustained Periods of High-G Acceleration Relevant to Suborbital Spaceflight. Aerospace Medicine and Human Performance, 92(8), 633–641. https://doi.org/10.3357/AMHP.5790.2021
15. Paul, A. M., Cheng-Campbell, M., Blaber, E. A., Anand, S., Bhattacharya, S., Zwart, S. R., Crucian, B. E., Smith, S. M., Meller, R., Grabham, P., & Beheshti, A. (2020). Beyond Low-Earth Orbit: Characterizing Immune and microRNA Differentials following Simulated Deep Spaceflight Conditions in Mice. IScience, 23(12). https://doi.org/10.1016/J.ISCI.2020.101747
16. Crucian, B. E., Choukèr, A., Simpson, R. J., Mehta, S., Marshall, G., Smith, S. M., Zwart, S. R., Heer, M., Ponomarev, S., Whitmire, A., Frippiat, J. P., Douglas, G., Lorenzi, H., Buchheim, J. I., Makedonas, G., Ginsburg, G. S., Mark Ott, C., Pierson, D. L., Krieger, S. S., … Sams, C. (2018). Immune system dysregulation during spaceflight: Potential countermeasures for deep space exploration missions. Frontiers in Immunology, 9(JUN), 1437. https://doi.org/10.3389/fimmu.2018.01437
17. Patel, S. (2020). The effects of microgravity and space radiation on cardiovascular health: From low-Earth orbit and beyond. International Journal of Cardiology. Heart & Vasculature, 30, 100595. https://doi.org/10.1016/J.IJCHA.2020.100595
18. Carnell, L. S. (2020). Spaceflight medical countermeasures: a strategic approach for mitigating effects from solar particle events. Https://Doi.Org/10.1080/09553002.2020.1820603, 97(S1), S125–S131. https://doi.org/10.1080/09553002.2020.1820603
19. Slaba, T. C., & Singleterry, R. C. (2020). Correct modeling results are needed to inform mission planning and shield design. Life Sciences in Space Research, 25, 143–147. https://doi.org/10.1016/J.LSSR.2019.11.001
20. Loffredo, F., Vardaci, E., Bianco, D., Di Nitto, A., & Quarto, M. (2022). Protons Interaction with Nomex Target: Secondary Radiation from a Monte Carlo Simulation with Geant4. Applied Sciences 2022, Vol. 12, Page 2643, 12(5), 2643. https://doi.org/10.3390/APP12052643
21. Simonsen, L. C., Slaba, T. C., Guida, P., & Rusek, A. (2020). NASA’s first ground-based Galactic Cosmic Ray Simulator: Enabling a new era in space radiobiology research. PLoS Biology, 18(5). https://doi.org/10.1371/JOURNAL.PBIO.3000669
22. Norbury, J. W., Slaba, T. C., Aghara, S., Badavi, F. F., Blattnig, S. R., Clowdsley, M. S., Heilbronn, L. H., Lee, K., Maung, K. M., Mertens, C. J., Miller, J., Norman, R. B., Sandridge, C. A., Singleterry, R., Sobolevsky, N., Spangler, J. L., Townsend, L. W., Werneth, C. M., Whitman, K., … Zeitlin, C. (2019). Advances in space radiation physics and transport at NASA. Life Sciences in Space Research, 22, 98–124. https://doi.org/10.1016/J.LSSR.2019.07.003
23. Kanapskyte, A., Hawkins, E. M., Liddell, L. C., Bhardwaj, S. R., Gentry, D., & Santa Maria, S. R. (2021). Space Biology Research and Biosensor Technologies: Past, Present, and Future. Biosensors, 11(2). https://doi.org/10.3390/BIOS11020038
24. Afshinnekoo, E., Scott, R. T., MacKay, M. J., Pariset, E., Cekanaviciute, E., Barker, R., Gilroy, S., Hassane, D., Smith, S. M., Zwart, S. R., Nelman-Gonzalez, M., Crucian, B. E., Ponomarev, S. A., Orlov, O. I., Shiba, D., Muratani, M., Yamamoto, M., Richards, S. E., Vaishampayan, P. A., … Beheshti, A. (2020). Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep Space Exploration. Cell, 183(5), 1162. https://doi.org/10.1016/J.CELL.2020.10.050
25. Tuieng, R. J., Cartmell, S. H., Kirwan, C. C., & Sherratt, M. J. (2021). The Effects of Ionising and Non-Ionising Electromagnetic Radiation on Extracellular Matrix Proteins. Cells, 10(11). https://doi.org/10.3390/CELLS10113041
26. Kirsch, D. G., Diehn, M., Kesarwala, A. H., Maity, A., Morgan, M. A., Schwarz, J. K., Bristow, R., Demaria, S., Eke, I., Griffin, R. J., Haas-Kogan, D., Higgins, G. S., Kimmelman, A. C., Kimple, R. J., Lombaert, I. M., Ma, L., Marples, B., Pajonk, F., Park, C. C., … Bernhard, E. J. (2018). The Future of Radiobiology. JNCI Journal of the National Cancer Institute, 110(4), 329. https://doi.org/10.1093/JNCI/DJX231
27. Strigari, L., Strolin, S., Morganti, A. G., & Bartoloni, A. (2021). Dose-Effects Models for Space Radiobiology: An Overview on Dose-Effect Relationships. Frontiers in Public Health, 9, 733337. https://doi.org/10.3389/FPUBH.2021.733337
28. Walsh, L., Schneider, U., Fogtman, A., Kausch, C., McKenna-Lawlor, S., Narici, L., Ngo-Anh, J., Reitz, G., Sabatier, L., Santin, G., Sihver, L., Straube, U., Weber, U., & Durante, M. (2019). Research plans in Europe for radiation health hazard assessment in exploratory space missions. Life Sciences in Space Research, 21, 73–82. https://doi.org/10.1016/J.LSSR.2019.04.002
29. Shapshak, P. (2018). Astrobiology – an opposing view. Bioinformation, 14(6), 346–349. https://doi.org/10.6026/97320630014346
30. Huang, B., Li, D. G., Huang, Y., & Liu, C. T. (2018). Effects of spaceflight and simulated microgravity on microbial growth and secondary metabolism. Military Medical Research, 5(1). https://doi.org/10.1186/S40779-018-0162-9
31. Demontis, G. C., Germani, M. M., Caiani, E. G., Barravecchia, I., Passino, C., & Angeloni, D. (2017). Human Pathophysiological Adaptations to the Space Environment. Frontiers in Physiology, 8(AUG), 547. https://doi.org/10.3389/FPHYS.2017.00547
32. Garrett-Bakelman, F. E., Darshi, M., Green, S. J., Gur, R. C., Lin, L., Macias, B. R., McKenna, M. J., Meydan, C., Mishra, T., Nasrini, J., Piening, B. D., Rizzardi, L. F., Sharma, K., Siamwala, J. H., Taylor, L., Vitaterna, M. H., Afkarian, M., Afshinnekoo, E., Ahadi, S., … Turek, F. W. (2019). The NASA twins study: A multidimensional analysis of a year-long human spaceflight. Science, 364(6436). https://doi.org/10.1126/science.aau8650
33. Anil-Inevi, M., Sarigil, O., Kizilkaya, M., Mese, G., Tekin, H. C., & Ozcivici, E. (2020). Stem Cell Culture Under Simulated Microgravity. Advances in Experimental Medicine and Biology, 1298, 105–132. https://doi.org/10.1007/5584_2020_539
34. Yatagai, F., Honma, M., Dohmae, N., & Ishioka, N. (2019). Biological effects of space environmental factors: A possible interaction between space radiation and microgravity. Life Sciences in Space Research, 20, 113–123. https://doi.org/10.1016/J.LSSR.2018.10.004
35. Gushin, V., Ryumin, O., Karpova, O., Rozanov, I., Shved, D., & Yusupova, A. (2021). Prospects for Psychological Support in Interplanetary Expeditions. Frontiers in Physiology, 12. https://doi.org/10.3389/FPHYS.2021.750414
36. Doarn, C., Polk, J., & Shepanek, M. (2019). Health challenges including behavioral problems in long-duration spaceflight. Neurology India, 67(Supplement), S190–S195. https://doi.org/10.4103/0028-3886.259116
37. Bell, S. T., Brown, S. G., & Mitchell, T. (2019). What we know about team dynamics for long-distance space missions: A systematic review of analog research. Frontiers in Psychology, 10(MAY). https://doi.org/10.3389/FPSYG.2019.00811/
38. Turroni, S., Magnani, M., KC, P., Lesnik, P., Vidal, H., & Heer, M. (2020). Gut Microbiome and Space Travelers’ Health: State of the Art and Possible Pro/Prebiotic Strategies for Long-Term Space Missions. Frontiers in Physiology, 11. https://doi.org/10.3389/FPHYS.2020.553929
39. Checinska Sielaff, A., Urbaniak, C., Mohan, G. B. M., Stepanov, V. G., Tran, Q., Wood, J. M., Minich, J., McDonald, D., Mayer, T., Knight, R., Karouia, F., Fox, G. E., & Venkateswaran, K. (2019). Characterization of the total and viable bacterial and fungal communities associated with the International Space Station surfaces. Microbiome, 7(1). https://doi.org/10.1186/S40168-019-0666-X
40. Kobrick, R. L., & Agui, J. H. (2019). Preparing for planetary surface exploration by measuring habitat dust intrusion with filter tests during an analogue Mars mission. Acta Astronautica, 160, 297–309. https://doi.org/10.1016/J.ACTAASTRO.2019.04.040
41. Zivi, P., De Gennaro, L., & Ferlazzo, F. (2020). Sleep in Isolated, Confined, and Extreme (ICE): A Review on the Different Factors Affecting Human Sleep in ICE. Frontiers in Neuroscience, 14, 851. https://doi.org/10.3389/fnins.2020.00851
42. Mhatre, S. D., Iyer, J., Puukila, S., Paul, A. M., Tahimic, C. G. T., Rubinstein, L., Lowe, M., Alwood, J. S., Sowa, M. B., Bhattacharya, S., Globus, R. K., & Ronca, A. E. (2022). Neuro-consequences of the spaceflight environment. Neuroscience & Biobehavioral Reviews, 132, 908–935. https://doi.org/10.1016/J.NEUBIOREV.2021.09.055
43. Patel, Z. S., Brunstetter, T. J., Tarver, W. J., Whitmire, A. M., Zwart, S. R., Smith, S. M., & Huff, J. L. (2020). Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars. Npj Microgravity 2020 6:1, 6(1), 1–13. https://doi.org/10.1038/s41526-020-00124-6
44. Suedfeld, P. (2018). Antarctica and space as psychosocial analogues. REACH, 9–12, 1–4. https://doi.org/10.1016/J.REACH.2018.11.001
45. Lee, S. J., Lehar, A., Meir, J. U., Koch, C., Morgan, A., Warren, L. E., Rydzik, R., Youngstrom, D. W., Chandok, H., George, J., Gogain, J., Michaud, M., Stoklasek, T. A., Liu, Y., & Germain-Lee, E. L. (2020). Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight. Proceedings of the National Academy of Sciences of the United States of America, 117(38), 23942–23951. https://doi.org/10.1073/pnas.2014716117
46. Rittweger, J., Albracht, K., Flück, M., Ruoss, S., Brocca, L., Longa, E., Moriggi, M., Seynnes, O., Di Giulio, I., Tenori, L., Vignoli, A., Capri, M., Gelfi, C., Luchinat, C., Francheschi, C., Bottinelli, R., Cerretelli, P., & Narici, M. (2018). Sarcolab pilot study into skeletal muscle’s adaptation to long-term spaceflight. NPJ Microgravity, 4(1), 18. https://doi.org/10.1038/S41526-018-0052-1
47. Stavnichuk, M., Mikolajewicz, N., Corlett, T., Morris, M., & Komarova, S. V. (2020). A systematic review and meta-analysis of bone loss in space travelers. Npj Microgravity 2020 6:1, 6(1), 1–9. https://doi.org/10.1038/s41526-020-0103-2
48. Vico, L., & Hargens, A. (2018). Skeletal changes during and after spaceflight. Nature Reviews Rheumatology 2018 14:4, 14(4), 229–245. https://doi.org/10.1038/nrrheum.2018.37
49. Vico, L., van Rietbergen, B., Vilayphiou, N., Linossier, M. T., Locrelle, H., Normand, M., Zouch, M., Gerbaix, M., Bonnet, N., Novikov, V., Thomas, T., & Vassilieva, G. (2017). Cortical and Trabecular Bone Microstructure Did Not Recover at Weight-Bearing Skeletal Sites and Progressively Deteriorated at Non-Weight-Bearing Sites During the Year Following International Space Station Missions. Journal of Bone and Mineral Research, 32(10), 2010–2021. https://doi.org/10.1002/JBMR.3188
50. Gabel, L., Liphardt, A. M., Hulme, P. A., Heer, M., Zwart, S. R., Sibonga, J. D., Smith, S. M., & Boyd, S. K. (2022). Pre-flight exercise and bone metabolism predict unloading-induced bone loss due to spaceflight. British Journal of Sports Medicine, 56(4), 196–203. https://doi.org/10.1136/BJSPORTS-2020-103602
51. Lang, T., Van Loon, J. J. W. A., Bloomfield, S., Vico, L., Chopard, A., Rittweger, J., Kyparos, A., Blottner, D., Vuori, I., Gerzer, R., & Cavanagh, P. R. (2017). Towards human exploration of space: the THESEUS review series on muscle and bone research priorities. NPJ Microgravity, 3(1). https://doi.org/10.1038/S41526-017-0013-0
52. Genah, S., Monici, M., & Morbidelli, L. (2021). The Effect of Space Travel on Bone Metabolism: Considerations on Today’s Major Challenges and Advances in Pharmacology. International Journal of Molecular Sciences, 22(9). https://doi.org/10.3390/IJMS22094585
53. Comfort, P., McMahon, J. J., Jones, P. A., Cuthbert, M., Kendall, K., Lake, J. P., & Haff, G. G. (2021). Effects of Spaceflight on Musculoskeletal Health: A Systematic Review and Meta-analysis, Considerations for Interplanetary Travel. Sports Medicine, 51(10), 2097–2114. https://doi.org/10.1007/s40279-021-01496-9
54. Furukawa, S., Chatani, M., Higashitani, A., Higashibata, A., Kawano, F., Nikawa, T., Numaga-Tomita, T., Ogura, T., Sato, F., Sehara-Fujisawa, A., Shinohara, M., Shimazu, T., Takahashi, S., & Watanabe-Takano, H. (2021). Findings from recent studies by the Japan Aerospace Exploration Agency examining musculoskeletal atrophy in space and on Earth. Npj Microgravity 2021 7:1, 7(1), 1–10. https://doi.org/10.1038/s41526-021-00145-9
55. Vernice, N. A., Meydan, C., Afshinnekoo, E., & Mason, C. E. (2020). Long-term spaceflight and the cardiovascular system. Precision Clinical Medicine, 3(4), 284–291. https://doi.org/10.1093/PCMEDI/PBAA022
56. MacNamara, J. P., Dias, K. A., Sarma, S., Lee, S. M. C., Martin, D., Romeijn, M., Zaha, V. G., & Levine, B. D. (2021). Cardiac Effects of Repeated Weightlessness during Extreme Duration Swimming Compared with Spaceflight. Circulation, 143(15), 1533–1535. https://doi.org/10.1161/CIRCULATIONAHA.120.050418
57. Rabineau, J., Hossein, A., Landreani, F., Haut, B., Mulder, E., Luchitskaya, E., Tank, J., Caiani, E. G., van de Borne, P., & Migeotte, P. F. (2020). Cardiovascular adaptation to simulated microgravity and countermeasure efficacy assessed by ballistocardiography and seismocardiography. Scientific Reports 2020 10:1, 10(1), 1–13. https://doi.org/10.1038/s41598-020-74150-5
58. Iwase, S., Nishimura, N., Tanaka, K., & Mano, T. (2020). Effects of Microgravity on Human Physiology. Beyond LEO – Human Health Issues for Deep Space Exploration [Working Title]. https://doi.org/10.5772/INTECHOPEN.90700
59. Burki, T. (2021). The final frontier: health in space. Lancet (London, England), 398(10296), 199–200. https://doi.org/10.1016/S0140-6736(21)01644-5
60. Lee, S. M. C., Ribeiro, L. C., Martin, D. S., Zwart, S. R., Feiveson, A. H., Laurie, S. S., Macias, B. R., Crucian, B. E., Krieger, S., Weber, D., Grune, T., Platts, S. H., Smith, S. M., & Stenger, M. B. (2020). Arterial structure and function during and after long-duration spaceflight. Journal of Applied Physiology, 129(1), 108–123. https://doi.org/10.1152/japplphysiol.00550.2019
61. Tays, G. D., Hupfeld, K. E., McGregor, H. R., Salazar, A. P., De Dios, Y. E., Beltran, N. E., Reuter-Lorenz, P. A., Kofman, I. S., Wood, S. J., Bloomberg, J. J., Mulavara, A. P., & Seidler, R. D. (2021). The Effects of Long Duration Spaceflight on Sensorimotor Control and Cognition. Frontiers in Neural Circuits, 15, 723504. https://doi.org/10.3389/fncir.2021.723504 
62. Jandial, R., Hoshide, R., Waters, J. D., & Limoli, C. L. (2018). Space–brain: The negative effects of space exposure on the central nervous system. Surgical Neurology International, 9(1). https://doi.org/10.4103/SNI.SNI_250_17
63. Roy-O’Reilly, M., Mulavara, A., & Williams, T. (2021). A review of alterations to the brain during spaceflight and the potential relevance to crew in long-duration space exploration. NPJ Microgravity, 7(1). https://doi.org/10.1038/S41526-021-00133-Z
64. Lee, J. K., Koppelmans, V., Pasternak, O., Beltran, N. E., Kofman, I. S., Dios, Y. E. De, Mulder, E. R., Mulavara, A. P., Bloomberg, J. J., & Seidler, R. D. (2021). Effects of Spaceflight Stressors on Brain Volume, Microstructure, and Intracranial Fluid Distribution. Cerebral Cortex Communications, 2(2), 1–14. https://doi.org/10.1093/TEXCOM/TGAB022
65. Ganapathy, K., Da Rosa, M., & Russomano, T. (2019). Neurological changes in outer space. Neurology India, 67(1), 37. https://pubmed.ncbi.nlm.nih.gov/30860089/
66. Russomano, T., Da Rosa, M., & Dos Santos, M. (2019). Space motion sickness: A common neurovestibular dysfunction in microgravity. Neurology India, 67(8), 214. https://doi.org/10.4103/0028-3886.259127
67. Dixon, J. B., & Clark, T. K. (2020). Sensorimotor impairment from a new analog of spaceflight-altered neurovestibular cues. Journal of Neurophysiology, 123(1), 209–223. https://doi.org/10.1152/jn.00156.2019
68. Davis, C. M., Allen, A. R., & Bowles, D. E. (2021). Consequences of space radiation on the brain and cardiovascular system. Journal of Environmental Science and Health. Part C, Toxicology and Carcinogenesis, 39(2), 180–218. https://doi.org/10.1080/26896583.2021.1891825
69. Michael, A. P. (2018). Spaceflight Induced Changes in the Central Nervous System. Into Space – A Journey of How Humans Adapt and Live in Microgravity. https://doi.org/10.5772/INTECHOPEN.74232
70. Brem, C., Lutz, J., Vollmar, C., Feuerecker, M., Strewe, C., Nichiporuk, I., Vassilieva, G., Schelling, G., & Choukér, A. (2020). Changes of brain DTI in healthy human subjects after 520 days isolation and confinement on a simulated mission to Mars. Life Sciences in Space Research, 24, 83–90. https://doi.org/10.1016/J.LSSR.2019.09.004
71. Prisk, G. K. (2019). Pulmonary challenges of prolonged journeys to space: taking your lungs to the moon. The Medical Journal of Australia, 211(6), 271. https://doi.org/10.5694/MJA2.50312
72. Mann, V., Sundaresan, A., Mehta, S., Crucian, B., Doursout, M., & Devakottai, S. (2019). Effects of microgravity and other space stressors in immunosuppression and viral reactivation with potential nervous system involvement. Neurology India, 67(8), 198. https://doi.org/10.4103/0028-3886.259125
73. Akiyama, T., Horie, K., Hinoi, E., Hiraiwa, M., Kato, A., Maekawa, Y., Takahashi, A., & Furukawa, S. (2020). How does spaceflight affect the acquired immune system? NPJ Microgravity, 6(1). https://doi.org/10.1038/S41526-020-0104-1
74. Sarkar, R., & Pampaloni, F. (2022). In Vitro Models of Bone Marrow Remodelling and Immune Dysfunction in Space: Present State and Future Directions. Biomedicines 2022, Vol. 10, Page 766, 10(4), 766. https://doi.org/10.3390/BIOMEDICINES10040766
75. Cucinotta, F. A., & Saganti, P. B. (2022). Race and ethnic group dependent space radiation cancer risk predictions. Scientific Reports 2022 12:1, 12(1), 1–10. https://doi.org/10.1038/s41598-022-06105-x
76. Mishra, B., & Luderer, U. (2019). Reproductive hazards of space travel in women and men. Nature Reviews. Endocrinology, 15(12), 713. https://doi.org/10.1038/S41574-019-0267-6
77. Proshchina, A., Gulimova, V., Kharlamova, A., Krivova, Y., Besova, N., Berdiev, R., & Saveliev, S. (2021). Reproduction and the Early Development of Vertebrates in Space: Problems, Results, Opportunities. Life 2021, Vol. 11, Page 109, 11(2), 109. https://doi.org/10.3390/LIFE11020109
78. Wakayama, S., Ito, D., Kamada, Y., Shimazu, T., Suzuki, T., Nagamatsu, A., Araki, R., Ishikawa, T., Kamimura, S., Hirose, N., Kazama, K., Yang, L., Inoue, R., Kikuchi, Y., Hayashi, E., Emura, R., Watanabe, R., Nagatomo, H., Suzuki, H., … Wakayama, T. (2021). Evaluating the long-term effect of space radiation on the reproductive normality of mammalian sperm preserved on the International Space Station. Science Advances, 7(24), 5554–5565. https://doi.org/10.1126/sciadv.abg5554
79. Kirkpatrick, A. W., Hamilton, D. R., McKee, J. L., McDonald, B., Pelosi, P., Ball, C. G., Roberts, D. J., McBeth, P. B., Coccolini, F., Ansaloni, L., Peireira, B. M., Sugrue, M., Campbell, M. R., Kimball, E. J., & Malbrain, M. L. N. G. (2020). Do we have the guts to go? The abdominal compartment, intra-abdominal hypertension, the human microbiome and exploration class space missions. Canadian Journal of Surgery, 63(6), E581. https://doi.org/10.1503/CJS019219
80. Pavlakou, P., Dounousi, E., Roumeliotis, S., Eleftheriadis, T., & Liakopoulos, V. (2018). Oxidative Stress and the Kidney in the Space Environment. International Journal of Molecular Sciences, 19(10). https://doi.org/10.3390/IJMS19103176
81. Mehta, S. K., Szpara, M. L., Rooney, B. V., Diak, D. M., Shipley, M. M., Renner, D. W., Krieger, S. S., Nelman-Gonzalez, M. A., Zwart, S. R., Smith, S. M., & Crucian, B. E. (2022). Dermatitis during Spaceflight Associated with HSV-1 Reactivation. Viruses, 14(4). https://doi.org/10.3390/v14040789
82. Radstake, W. E., Baselet, B., Baatout, S., & Verslegers, M. (2022). Spaceflight Stressors and Skin Health. Biomedicines 2022, Vol. 10, Page 364, 10(2), 364. https://doi.org/10.3390/BIOMEDICINES10020364
83. Crucian, B. E., Makedonas, G., Sams, C. F., Pierson, D. L., Simpson, R., Stowe, R. P., Smith, S. M., Zwart, S. R., Krieger, S. S., Rooney, B., Douglas, G., Downs, M., Nelman-Gonzalez, M., Williams, T. J., & Mehta, S. (2020). Countermeasures-based Improvements in Stress, Immune System Dysregulation and Latent Herpesvirus Reactivation onboard the International Space Station – Relevance for Deep Space Missions and Terrestrial Medicine. Neuroscience & Biobehavioral Reviews, 115, 68–76. https://doi.org/10.1016/J.NEUBIOREV.2020.05.007