Many thanks to our special guest authors: Krishi Korrapati and Cooper Lytle.
Krishi is a second year medical student at Chicago Medical School at Rosalind Franklin University. During the night, he dreams of poetry as politics and interstellar exploration one day alleviating inequity on earth. During the day, he is training for an Ironman, interpreting Spanish, doing theater, and trying to learn how to fly a plane. He likes to gild everything with lightheartedness and with gravity.
Cooper is a second year medical student at Chicago Medical School at Rosalind Franklin University. He is an aspiring bread maker and maple syrup connoisseur, who enjoys seeing his house plants grow and spending long days at art museums with his wife.
Spaceflight is known to challenge the human body in many different ways, with some potential outcomes including burns, sterility, cancer, immune dysregulation, and hormonal changes. Although these maladaptive changes are well-documented, surprisingly, good things can happen as well. In this post we will discuss ways in which the stressors of space travel can induce a resilient hormetic* response in the human body through mechanisms of cross-adaptation and even prime pathways of wound healing.
Firstly, cross-adaptation is the process by which exposure to a stressor elicits an adaptation that can be advantageous when exposed to a subsequent stressor. Simultaneous exposures to multiple stressors can lead to synergistic* adaptations (or maladaptations) as well; this is termed ‘combined adaptation’. This latter model is more realistic to the environment of space because the body forms responses to hypoxia (reduced oxygen), heat, cold, microgravity, hyperbaria (increased pressure), hypobaria (decreased pressure), and fasting all at once, not in isolation (Ashely et al., 2024). These physiological pathways can be seen as a mode of resilience in extreme space settings.
One example of cross-adaptation is that heat acclimation boosts tolerance to hypoxia and enhances exercise performance in temperate conditions later on. In a single bout of acute exercise such as downhill running, heat shock proteins* (HSP) 72 and 90α will be produced in muscles and leukocytes (white blood cells), which primes an individual for further exercise. What does it mean to be primed to further exercise? Damage on a cellular level is decreased and this manifests as better performance. Very interestingly, HSPs were found to be upregulated not only after exposure to heat but also to cold (Matz et al., 1995), stress, and UV ionizing light (Cao et al., 1999).
The mechanism is as follows: heat stress prevents folding of outer membrane proteins which is bad; think wrinkly and stiff. These proteins accumulate in the space around the cell. Another protein in the cell (specifically an inner membrane protease) called DegS detects these abnormal proteins and cooperates with the sigmaE transcription factor (a transcription factor helps make the precursors to proteins). Together these intracellular molecules trigger the production of HSPs. Raw cellular damage and abnormal proteins can also elicit HSPs by parallel pathways (Hu et al., 2022). Normally, HSPs function as chaperone proteins* that maintain correct folding and stop aggregation. So it is thought that HSP production reduces the damage to cells by folding and managing these irregularly folded and accumulated proteins.
Other examples of cross-adaptations include cold preparing the body for hypoxia and nutritional deprivation potentiating metabolic efficiency. Cold environments release HSPs and force vasodilation (dilation of blood vessels). These HSPs ultimately re-establish normal protein-protein interactions and proper folding, especially those that are unstable and stressed. In cases of nutritional deprivation, there is a loss of metabolically active tissue but also the basal metabolic rate (energy burned at rest) of each unit cell mass decreases as a compensation. This translates to efficiently managing energy stores and reducing cell damage to stress later on. The mechanisms, though unclear, overlap: induction of HSPs, increased coupling of ATP* production to substrate oxidation*, and reduction in protein turnover and sodium/potassium ATPase (Emery et al., 2005). This information should be conveyed with great sensitivity for those who have experienced eating and exercise disorders.
We now can see that HSPs seem to be the key to cross-adaptation. More noteworthy is that HSPs have an integral role in wound healing too (Li et al., 2016). In zebrafish models, the injection of extraneous HSP60 proteins specifically contributes to the critical regeneration of hair cells and amputated fins. At the site of injury, HSPD1 was found to be deficient in leukocytes that infiltrated the injury site. Likewise HSP60 topically applied in diabetic mouse skin accelerated wound healing compared with controls. Although a chaperone protein intracellularly, HSP60 functions extracellularly in injury inflammation and tissue regeneration, most likely by facilitating the M2 or anti-inflammatory phase of macrophages*. These results were corroborated in human patients with diabetes mellitus too: increased levels of HSPs 70 and 27 promoted wound healing in foot ulcers by recruiting fibroblasts* to the injury site and initiating protein homeostasis compared to controls (although an increase was associated with more infection). Naturally, we can combine this data to postulate that controlled physiological stressors that induce the transcription of heat shock proteins can be used to prime astronauts and space travellers for improved wound healing. In a combined adaptation setting, perhaps a stressor can be induced immediately after an injury too, to facilitate its healing using the mechanisms of HSPs (Singh, 2015).
Controlled stress→ HSPs→ Cross-adaptation→ Better wound healing.
We concede that the changes will be different depending on the individual and a constellation of personal factors such as their fitness, socioeconomic considerations, genetic predispositions, and motivation. Moreover what is considered “healthy” or “beneficial” in one setting will not necessarily be fruitful in another, the simplest example being heat or cold acclimatization being rendered useless when in the other temperature extreme. There is also impaired adaptation from some combinations of stressors e.g. heat and hypoxia together decreasing heat adaptation later on (McCleave et al., 2018). More research is needed on the specific numbers of heat shock proteins (because there are many) and their crossover from being upregulated in specific settings to their applicability in others, especially in wound healing. How else can HSPs be induced? What is their timescale? How will this influence pre-flight training regiments? Besides opening room for more inquiry, this paper demonstrates the anti-fragility of humans in the context of space exploration. We ask the question not of how space travel can devastate the human body but how space travel can further unveil its capacity, not unlike elite and extreme athletes in the most remote corners of the world- the closest beings we have to superhumans.
Questions? Let us know for the next post!
*Definitions
Adenosine triphosphate (ATP) is an energy-carrying molecule known as “the energy currency of life” or “the fuel of life,” because it’s the universal energy source for all living cells. Every living organism consists of cells that rely on ATP for their energy needs. ATP is made by converting the food we eat into energy. It’s an essential building block for all life forms. Without ATP, cells wouldn’t have the fuel or power to perform functions necessary to stay alive, and they would eventually die. All forms of life rely on ATP to do the things they must do to survive (https://www.verywellhealth.com/atp-6374347 – accessed 06 September 2024).
Chaperone proteins, or molecular chaperones, are proteins that assist others to fold properly during or after synthesis, to refold after partial denaturation, and to translocate to the cellular locales at which they reside and function (https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/chaperone-protein – accessed 06 September 2024).
A fibroblast is a connective tissue cell that makes and secretes collagen proteins (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/fibroblast – accessed 06 September 2024).
Heat shock proteins (HSPs) are a diverse group of proteins that are expressed under normal physiological conditions to perform a range of housekeeping functions that maintain regular cell metabolism. Under conditions of stress, the expression of these proteins is rapidly upregulated to protect the cell from various kinds of damage (https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/heat-shock-protein – accessed 06 September 2024).
Hormesis can be defined as “a process in which exposure to a low dose of a chemical agent or environmental factor that is damaging at higher doses induces an adaptative beneficial effect on the cell or organism” (https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hormesis – accessed 06 September 2024).
A macrophage is a type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/macrophage# – accessed 06 September 2024).
Oxidation is a chemical reaction that takes place when a substance comes into contact with oxygen or another oxidizing substance. Examples of oxidation are rust and the brown color on a cut apple (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/oxidation – accessed 06 September 2024).
Synergy means that the combined power of a group of things when they are working together that is greater than the total power achieved by each working separately (https://dictionary.cambridge.org/dictionary/english/synergy – accessed 06 September 2024).
References
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Cao, Y., Ohwatari, N., Matsumoto, T. et al. TGF-β1 mediates 70-kDa heat shock protein induction due to ultraviolet irradiation in human skin fibroblasts. Pflügers Arch 438, 239–244 (1999). https://doi.org/10.1007/s004240050905
Hu C, Yang J, Qi Z, et al. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm. 2022;3(3). doi:https://doi.org/10.1002/mco2.161
Emery PW. Metabolic changes in malnutrition. Eye. 2005;19(10):1029-1034. doi:https://doi.org/10.1038/sj.eye.6701959
Kanhaiya Singh, Neeraj K. Agrawal, Sanjeev K. Gupta, Gyanendra Mohan, Sunanda Chaturvedi, Kiran Singh, Decreased expression of heat shock proteins may lead to compromised wound healing in type 2 diabetes mellitus patients, Journal of Diabetes and its Complications, Volume 29, Issue 4, 2015, Pages 578-588, ISSN 1056-8727,
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NIH researchers unveil new wound-healing role for protein-folding gene in mice. Genome.gov. Published 2019. Accessed August 21, 2024. https://www.genome.gov/news/news-release/NIH-researchers-unveil-new-wound-healing-role-for-protein-folding-gene-in-mice
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