Neurodegeneration & Neuroinflammation 
in Deep Space

• High-energy particles from ionising radiation can damage the CNS by inducing neuroinflammation, a chronic condition characterised by the prolonged activation of microglial cells and astrocytes. This heightened activity resembles the natural ageing process and leads to the production of reactive oxygen and nitrogen species (ROS and RNS), which can harm intracellular proteins, neuronal membrane lipids, DNA, and mitochondrial DNA (mtDNA). Severe damage to neuronal membranes may result in apoptosis, while mtDNA mutations and deletions can impair mitochondrial function, causing further ROS/RNS production and oxidative stress, potentially spreading to nearby cells and inhibiting mtDNA repair pathways. Such oxidative stress can also damage DNA, leading to apoptosis.
  
  
• Radiation exposure can also cause tau hyperphosphorylation, amyloid-beta (Aβ) plaque accumulation, dendritic spine thinning, and demyelination, all of which are associated with Alzheimer's disease (AD). Low-dose ionising radiation has been shown to alter gene expression related to synaptic signaling, glutamate transmission, neuroplasticity, and learning. Specifically, gamma ray exposure at 0.1 Gy has been linked to changes in genes involved in these processes, though the long-term effects are still uncertain.
  
  
• Additionally, low-dose ionising radiation affects dendritic spines, which are critical for learning and memory due to their role in excitatory synapses. A decrease in dendritic spine density and complexity, observed in animal models after 1 Gy of gamma radiation, suggests potential deficits in learning, memory, and synaptic strength long after exposure. High doses of X-ray radiation have been associated with late-onset demyelination, possibly due to genetic damage in oligodendrocytes, which produce the myelin sheath around CNS neurons. This demyelination is linked to mild cognitive impairment (MCI) and AD, affecting learning and memory.
  
  
• Radiation also decreases neurogenesis in the sub-granular zone (SGZ) of the dentate gyrus and the sub-ventricular zone (SVZ) near the olfactory bulb, key areas for neuron production. The impact of neurogenesis on AD progression is debated; some studies suggest decreased neurogenesis in early-stage AD, while others find an increase in later stages as a compensatory response to neuronal loss. Nonetheless, it is clear that radiation affects neurogenesis rates, which are associated with AD in various ways.
  

• RADIATION
  Outside Earth’s protective magnetic field and atmosphere, ionising radiation in space poses a serious risk to STs during deep-space missions. High-energy galactic cosmic rays, remnants from supernovas, and solar storms, like solar particle events and coronal mass ejections, can harm the body and spacecraft and have potential long-term health consequences.
  Although astronauts and cosmonauts aboard the International Space Station (ISS) are exposed to higher levels of radiation than people on Earth, several factors limit however their impact. Indeed, the ISS orbits at an altitude of approximately 400 kilometres (about 250 miles) above the Earth, which is still within the protective layers of the Earth’s atmosphere and magnetosphere which provide significant protection against solar and cosmic radiation. The magnetosphere deflects and traps many of the high-energy particles from the sun and cosmic rays, reducing the amount of radiation that reaches the ISS. Secondly, the ISS itself is designed with shielding materials that help protect the crew from radiation. The modules are constructed using materials that can absorb and deflect radiation, and certain areas of the ISS offer more protection where astronauts/cosmonauts can go during periods of increased solar activity. Finally, while the ISS provides some protection, the duration of exposure is also a factor. Most astronauts/cosmonauts spend about six months on the ISS, which limits their total radiation dose compared to more extended missions or those travelling beyond low Earth orbit.

• ISOLATION & CONFINEMENT
  The psychological stress of long-duration space missions, coupled with confinement to a small spacecraft, can have significant mental health implications. Expedition crews selected for a stay onboard the space station are carefully chosen, trained, and supported to ensure they will be able to work effectively as a team for the duration of their six to 12-month missions. Crews for a Moon or Mars mission will undergo even more careful assessment, selection, and preparation since they will travel farther and potentially for longer than previous humans in an isolated and confined environment, with only a few other people. Additionally, crews will likely be international and multi-cultural, making cross-cultural sensitivity and team dynamics paramount to mission success.

• DISTANCE FROM EARTH
  The space station orbits around 400 km (240 miles) above Earth. The Moon is 1,000 times farther from Earth than the space station. In contrast, Mars is, on average, 225 million kilometres (140 million miles) from Earth. With a communication delay of up to 20 minutes one-way while on Mars, STs must be able to solve problems and identify solutions as a team without help from their mission control. The types of food and medicine to be packed for a multi-year trip without access to a grocery store or pharmacy are also essential to consider. Unlike space station crews, which regularly receive supplies from cargo flights from Earth, STs going to Mars will have to bring all of the food, equipment, and medical supplies they need.

• ALTERED GRAVITY FIELDS (/MICROGRAVITY)
  STs are exposed to a unique gravitational environment in space which can impact various physiological systems in the human body and induce several health outcomes, such as muscle and bone loss, cardiovascular changes, and fluid redistribution. On a Mars mission, STs will encounter three different gravity fields. On the six-month trek between the planets, crews will be weightless. While living and working on Mars, crews will be in approximately one-third of Earth’s gravity. Finally, upon returning home, crews will have to readapt to Earth’s gravity. Transitioning from one gravity field to another is not as easy as it seems. It affects spatial orientation, head-eye and hand-eye coordination, balance, and locomotion, and some crew members can experience space motion sickness (SMS). Landing a spacecraft on Mars, for instance, could be challenging as STs adjust to the gravity field of another celestial body. In addition, when shifting from weightlessness to gravity, STs may experience post-flight orthostatic intolerance, where they are unable to maintain their blood pressure when standing up, which can lead to lightheadedness and fainting.
  
  

• HOSTILE & CLOSED ENVIRONMENTS
  The ecosystem inside the spacecraft plays a big role in everyday life in space. Microbes can change characteristics in space, and micro-organisms that naturally live on the human body are transferred more easily from person to person in closed habitats, such as the space station. Stress hormone levels are elevated and the immune system is altered, which could lead to increased susceptibility to allergies or other illnesses. Earth-based analogues do not perfectly simulate the spaceflight environment, making them insufficient for studying on the ground how human immune systems react in space. However, analogue studies could provide insight into how certain spaceflight stressors may affect the human immune system.
  

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