Engineering Human Stasis for Long-Duration Spaceflight

Nordeen, Claire; Martin, Sandra L.

doi:10.1152/physiol.00046.2018

Cited by 39 publications

(19 citation statements)

References 110 publications

(127 reference statements)

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“…Bastide et al, 2017) and its potential to provide solutions to overcome the physiological challenges of long duration space flight (Choukèr et al, 2019;Jackson & Kochanek, 2019;Nordeen & Martin, 2019) expose the need to understand the cellular response to cooling at the molecular level. Elucidating these processes will ultimately provide solutions to pharmacologically activate beneficial pathways without the need for cooling and inactivate detrimental pathways to expand the remit of controlled cooling for medical applications.…”

Section: Discussionmentioning

confidence: 99%

“…The mammalian response to cold is not scaled to temperature (Figs 1 and 2) and is finely balanced between beneficial and detrimental outcomes (Hattori et al , 2017), limiting its therapeutic scope. The importance of controlled cooling as a clinical tool (Gordon, 2001; Peretti et al , 2015; Kutcher et al , 2016; Bastide et al , 2017) and its potential to provide solutions to overcome the physiological challenges of long duration space flight (Choukèr et al , 2019; Jackson & Kochanek, 2019; Nordeen & Martin, 2019) expose the need to understand the cellular response to cooling at the molecular level. Elucidating these processes will ultimately provide solutions to pharmacologically activate beneficial pathways without the need for cooling and inactivate detrimental pathways to expand the remit of controlled cooling for medical applications.…”

Section: Discussionmentioning

confidence: 99%

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Cold‐induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

et al. 2020

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Cooling patients to sub-physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature-specific changes to the higher-order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18°C, a temperature synonymous with that experienced by patients undergoing controlled deep hypothermia during surgery. Cells exposed to 18°C exhibit largely nuclearrestricted transcriptome changes. These include the nuclear accumulation of mRNAs encoding components of the negative limbs of the core circadian clock, most notably REV-ERBa. This response is accompanied by compaction of higher-order chromatin and hindrance of mRNPs from engaging nuclear pores. Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of negative limb gene proteins that reset the circadian clock. We show that cold-induced upregulation of REV-ERBa is sufficient to trigger this reset. Our findings uncover principles of the cellular cold response that must be considered for current and future applications involving therapeutic deep hypothermia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cold‐induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

et al. 2020

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“…1-2) and is finely balanced between beneficial and detrimental outcomes (Hattori et al, 2017), limiting its therapeutic scope. The importance of controlled cooling as a clinical tool (Peretti et al, 2015;Gordon, 2001;Bastide et al, 2017;Kutcher et al, 2016) and its potential to provide solutions to overcome the physiological challenges of long duration space flight (Nordeen & Martin, 2019;Choukèr et al, 2019;Jackson & Kochanek, 2019), expose the need to understand the cellular response to cooling at the molecular level. Elucidating these processes will ultimately provide solutions to pharmacologically activate beneficial pathways without the need for cooling and inactivate detrimental pathways to expand the remit of controlled cooling for medical applications.…”

Section: Discussionmentioning

confidence: 99%

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Fischl

McManus

Oldenkamp

et al. 2020

Preprint

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Cooling patients to sub-physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature-specific changes to the higher-order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18°C, a temperature synonymous with that experienced by patients undergoing controlled deephypothermia during surgery. Cells exposed to 18°C exhibit largely nuclear-restricted transcriptome changes. These include the nuclear accumulation of core circadian clock suppressor gene transcripts, most notably REV-ERBα. This response is accompanied by compaction of higher-order chromatin and hindrance of mRNPs from engaging nuclear pores.Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of suppressor gene proteins that resets the circadian clock. We show that cold-induced upregulation of REV-ERBα alone is sufficient to trigger this resetting. Our findings uncover principles of the cellular cold-response that must be considered for current and future applications involving therapeutic deep-hypothermia.

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“…Torpor ensures very low energy consumption, and thus would minimize the need to store sufficient food and liquids for life‐support systems, and therefore spares payload for the propulsion system. Compared with an active human, a metabolically quiescent astronaut requires substantially less oxygen, food, water, and waste disposal, as well as living space (Nordeen & Martin, 2019). For example, water and food intake could be reduced by up to 75% if an astronaut's metabolism is suppressed by torpor (Chouker et al ., 2019).…”

Section: Synthetic Torpor In Humans Why It Is a Desirable Solution Fmentioning

confidence: 99%

Human torpor: translating insights from nature into manned deep space expedition

et al. 2020

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During a long‐duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed‐loop bioregenerative life‐support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics ‘hibernation’, could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation‐like state (synthetic torpor) in non‐hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor–arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor–arousal transition in both non‐flying hibernating mammals and non‐hibernating species, and aim to provide translational insights into long‐duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long‐duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

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Engineering Human Stasis for Long-Duration Spaceflight

Cited by 39 publications

References 110 publications

Cold‐induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Cold‐induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm

Human torpor: translating insights from nature into manned deep space expedition

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