As the world's space agencies and commercial entities continue to expand beyond Low Earth Orbit (LEO), novel approaches to carry out biomedical experiments with animals are required to address the challenge of adaptation to spaceflight and new planetary environments. The extended time and distance of space travel along with reduced involvement of Earth-based mission support increase the cumulative impact of the risks encountered in space. To respond to these challenges, it becomes increasingly important to develop the capability to manage animal safety and well-being during transportation and research experiments in space. One approach may be to take advantage of an organism's self-regulatory system, which enables them to better adapt and mitigate harmful environmental factors encountered in spaceflight. Recent technological advances have enabled researchers to suppress or enhance metabolism “on demand” in a variety of animal species. These animal models can be used as “pathfinders,” which are capable of tolerating the environmental extremes exhibited in spaceflight, including altered gravity, exposure to space radiation, chemically reactive planetary environments, and temperature extremes. In this report, we survey several of the pivotal metabolic flexibility studies and discuss the importance of utilizing animal models with metabolic flexibility with particular attention given to the ability to suppress the organism's metabolism in spaceflight experiments beyond LEO. The presented analysis demonstrates the adjuvant benefits of these factors to minimize damage caused by exposure to spaceflight and extreme planetary environments. Examples of microorganisms and animal models with dormancy capabilities suitable for space research are considered in the context of their survivability under hostile or deadly environments outside of Earth. Potential steps toward implementation of metabolic control technology in spaceflight architecture and its benefits for animal experiments and manned space exploration missions are discussed.
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References
1.
TateK. Cosmic menagerie: a history of animals in space (Infographic). Space.com, June28, 2014.
2.
NASA Johnson Space Center.. Apollo 17 mission report. JSC-07904, March1973.
PultarovaT. 2013. Crew of bion M1 found dead upon landing. Space Safety Magazine, October20, 2013.
5.
RothMB, NystulT. Buying time in suspended animation. Sci Am. 2005; 292:48–55.
6.
BlackstoneE, MorrisonM, RothMB. H2S induces a suspended animation-like state in mice. Science. 2005; 308(5721):518.
7.
GaliciaE, PalmaE, SelchF, GomezD, GrikoYV. Metabolic control as a strategy for payload cost reduction and mitigation of negative space environmental factors. Gravit Space Res. 2011; 25:54–6.
BiggarKK, StoreyKB. The emerging roles of microRNAs in the molecular responses of metabolic rate depression. J Mol Cell Biol. 2011; 3(3):167–75.
10.
StoreyKB, StoreyJM. Tribute toP.L. Lutz: putting life on ‘pause’ – molecular regulation of hypometabolism. J Exp Biol. 2007; 210:1700–714.
11.
CareyHV, AndrewsMT, MartinSL. Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol Rev. 2003; 83:1153–81.
12.
GuppyM, WithersP. Metabolic depression in animals: physiological perspectives and biochemical generalizations. Biol Rev Camb Philos Soc. 1999; 74:1–40.
13.
TøienØ, BlakeJ, EdgarDM, GrahnDA, HellerHG, BarnesBM. Hibernation in black bears: independence of metabolic suppression from body temperature. Science. 2011; 331:906–909.
14.
NieY, SpeakmanJR, WuQ, ZhangC, HuY, XiaM, YanL, HamblyC, WangL, WeiW, ZhangJ, WeiF. Exceptionally low daily energy expenditure in the bamboo-eating giant panda. Science. 2015; 6244:171–4.
15.
V.T.B.. 1906. Human hibernation: a practice common with famine-stricken districts of Russia. The New York Times, November19, p. 8.
16.
DarkJ, MillerDR, ZuckerI. Reduced glucose availability induces torpor in Siberian hamsters. Am J Physiol. 1994; 267:496–501.
17.
NystulTG, RothMB. Carbon monoxide-induced suspended animation protects against hypoxic damage in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2004; 101:9133–6.
18.
DirkesMC, GulikTMV, HegerM. The physiology of artificial hibernation. J Clin Transl Res. 2015; 2:78–93.
19.
DoyleKP, SuchlandKL, CiesielskiTM, LessovNS, GrandyDK, ScanlanTS, Stenzel-PooreMP. Novel thyroxine derivatives, thyronamine and 3-iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury. Stroke. 2007; 38:2569–76.
20.
PadilloPA, RothMB. Oxygen deprivation causes suspended animation in the zebrafish embryo. Proc Natl Acad Sci U S A. 2001; 98:7331–5.
21.
FrappellP, LanthierC, BaudinetteRV, MortolaJP. Metabolism and ventilation in acute hypoxia: a comparative analysis in small mammalian species. Am J Physiol Regul Integr Comp Physiol. 1992; 262:1040–6.
22.
LeeCC. Is human hibernation possible?. Annu Rev Med. 2008; 59:177–86.
23.
ZhangF, WangS, LuoY, JiX, NemotoEM, ChenJ. When hypothermia meets hypotension and hyperglycemia: the diverse effects of adenosine 5′-monophosphate on cerebral ischemia in rats. J Cereb Blood Flow Metab. 2009; 29:1022–1034.
24.
WilzM, HeldmaierG. Comparison of hibernation, estiv ation and daily torpor in the edible dormouse, Glis glis. J Comp Physiol [B]. 2000; 170:511–21.
25.
WilliamsTD, ChambersJB, HendersonRP, RashotteME, OvertonJM. Cardiovascular responses to caloric restriction and thermoneutrality in C57BL/6J mice. Am J Physiol Regul Integr Comp Physiol. 2002; 282:R1459–67.
26.
JensenTL, KiersgaardMK, SørensenDB, MikkelsenLF. Fasting of mice: a review. Lab Anim. 2013; 47(4):225–40.
27.
HoelzlF, BieberC, CornilsJS, GerritsmannH, StalderGL, WalzerC, RufT. How to spend the summer? Free-living dormice (Glis glis) can hibernate for 11 months in non-reproductive years. J Comp Physiol B. 2015; 185:931–9.
28.
RoszakDB, ColwellRR. Survival strategies of bacteria in the natural environment. Microbiol Rev. 1987; 51:365e379.
29.
HoehlerTM, JørgensenBB. Microbial life under extreme energy limitation. Nat Rev Microbiol. 2013; 11:83–94.
30.
LennonJT, JonesES. Microbial seed banks: the ecological and evolutionary implications of dormancy. Nat Rev. 2011; 9:119–30.
31.
NovikovaND, GusevOA, PolikarpovN, DeshevayaE, LevinskikhMA, AlekseevA, OkudaT, SugimotoM, SychevVN, GrigorievAI. Survival of dormant organisms after long-term exposure to the space environment. Acta Astronaut. 2011; 68:1574–80.
32.
HorneckG, BückerH, ReitzG, RequardtH, DoseK, MartensKD, MennigmannHD, WeberP. Microorganisms in the space environment. Science. 1984; 225:226–8.
33.
HorneckG, RettbergP, ReitzG, WehnerJ, EschweilerU, StrauchK, PanitzC, StarkeV, Baumstark-KhanC. Protection of bacterial spores in space, a contribution to the discussion on panspermia. Orig Life Evol Biosph. 2001; 31:527–47.
34.
HorneckG. Responses of Bacillus subtilis spores to space environment: results from experiments in space. Orig Life Evol Biosph. 1993; 23:37–52.
35.
RettbergP, EschweilerU, StrauchK, ReitzG, HorneckG, WankeH, BrackA, BarbierB. Survival of microorganisms in space protected by meteorite material: Results of the experiment EXOBIOLOGIE of the PERSEUS mission. Adv Space Res. 2002; 30:1539–45.
36.
SanchoLG, de la TorreR, HorneckG, AscasoC, de los RíosA, PintadoA, WierzchosJ, SchusterM. Lichens survive in space: results from the 2005 LICHENS experiment. Astrobiology. 2007; 7(3):443–54.
37.
JönssonKI, RabbowI, SchillRO, Harms-RingdahlM, RettbergP. Tardigrades survive exposure to space in low Earth orbit. Curr Biol. 2008; 18(17):729–31.
38.
HorneckG, BückerH, ReitzG. Long-term survival of bacterial spores in space. Adv Space Res. 1994; 14:41–5.
De la TorreR, SanchoLG, HorneckG, de los RíosA, WierzchosJ, Olsson-FrancisK, CockellCS, RettbergP, BergerT, de VeraJ-P, OttS, FríasJM, González MelendiP, LucasMM, ReinaM, PintadoA, DemetsR. Survival of lichens and bacteria exposed to outer space conditions – results of the Lithopanspermia experiments. ICARUS. 2010; 208:735–48.
41.
SugimotoM, IshiiM, MoriIC, ShagimardanovaE, GusevOA, KiharaM, HokiT, SychevVN, LevinskikhMA, NovikovaND, GrigorievAI. Viability of barley seeds after long-term exposure to outer side of international space station. Adv Space Res. 2011; 48:1155–60.
42.
ShapiroR, Schulze-MakuchD. The search for alien life in our solar system: strategies and priorities. Astrobiology. 2009; 9:335–43.
43.
HegdeS, KalteneggerL. Colors of extreme exo-Earth environments. Astrobiology. 2013; 13:47–56.
44.
KounavesS. Life on Mars may be hidden like Earth's extremophiles. Nature. 2007; 449:281.
45.
Andrews-HannaJ, PhillipsRJ, ZuberMT. Meridiani Planum and the global hydrology of Mars. Nature. 2007; 446:163–6.
46.
LandisGA. Martian water: are there extant halobacteria on Mars?. Astrobiology. 2001; 1:161–4.
47.
GoordialJ, et al. Nearing the cold-arid limits of microbial life in permafrost of an upper dry valley, Antarctica. Int Soc Microb Ecol. 2016; 10:1613–1624.
48.
McKayCP, RaskJC, et al.An unusual inverted saline microbial mat community in an Interdune Sabkha in the Rub' al Khali (the Empty Quarter), United Arab Emirates. PLoS One. 2016; 11(3):e0150342.
49.
BecquerelP. La suspension de la vie au dessous de 1/20 K absolu par demagnetization adiabatique de l'alun de fer dans le vide les plus eléve [in French]. C R Hebd Séances Acad Sci Paris. 1950; 231:261–3.
50.
McMahonS, O'Malley-JamesJ, ParnellJ. Circumstellar habitable zones for deep terrestrial biospheres. Planet Space Sci. 2013; 85:312–8.
51.
BywatersKF. Perchlorate reducing bacteria: evaluating the potential for growth utilizing nutrient sources identified on Mars, 2016. Proceedings of the 47th Lunar and Planetary Science Conference, abstract 2946, 2016.
52.
GasullaF, HerreroJ, Esteban-CarrascoA, Ros-BarcelóA, BarrenoE, Miguel ZapataJ, GuéraA. Photosynthesis in lichen: light reactions and protective mechanisms, advances in photosynthesis – fundamental aspects. NajafpourM, ed. InTech, 2012. https://cdn.intechopen.com/pdfs-wm/28373.pdf (Last accessed on June2, 2017).
53.
KappenL, ValladaresF. Opportunistic growth and desiccation tolerance: the ecological success of poikilohydrous autotrophs. In Functional Plant Ecology. PugnaireF, ValladaresF, eds. pp.. New York: Taylor & Francis, 2007, pp. 7–65.
54.
HaleME. Growth. In The Lichens. AhmadjianV, HaleME, ed. New York: Academic Press, 1973, pp. 473–92.
55.
ElbertW, WeberB, BurrowsS, SteinkampJ, BüdelB, AndreaeMO, et al.Contribution of cryptogamic covers to the global cycles of carbon and nitrogen. Nat Geosci. 2012; 5:459–462.
56.
de VeraJ, Schulze-MakuchD, KhanA, LorekA, KonczA, MöhlmannD, SpohnT. Adaptation of an Antarctic lichen to Martian niche conditions can occur within 34 days. Plane Space Sci. 2014; 98:182–90.
57.
RayburnSR. The foundations of laboratory safety: a guide for the biomedical laboratory. New York: Springer-Verlag, 1190, p. 189.
58.
NowakowskaA. Hypometabolism in land snails: controlled or passive phenomenon? In Hypometabolism: Strategies of Survival in Vertebrates and Invertebrates. NowakowskaA, CaputaM, eds. Kerala, India: Research Signpost, 2011, pp. 1–17.
59.
BakerHB. Jamaican land snails. Nautilus. 1934; 48:6–14.
60.
SuzukiD, MiyamotoT, KikawadaT, WatanabeM, SuzukiT. A leech capable of surviving exposure to extremely low temperatures. PLoS One. 2014; 9(1):e86807.
61.
KukalO, DumanJG, SerianniAS. Cold-induced mitochondrial degradation and cryoprotectant synthesis in freeze-tolerant arctic caterpillars. J Comp Physiol B. 1989; 158:661–71.
62.
NapolitanoMJ. Nagele RG, Shain DH. The ice worm, Mesenchytraeus solifugus, elevates adenylate levels at low physiological temperature. Comp Biochem Physiol A Mol Integr Physiol., 2004; 137:227–35.
63.
AntipovVV, GazenkoOG, ParfenovGP, SaksonovPP. Results of a biological experiment conducted aboard the automatic station “Zond-5.”. Aerosp Med., 1969; 40:1244–7.
64.
ClementG, SlenzkaK. Animals and plants in space. In Fundamentals of Space Biology: Research on Cells, Animals, and Plants in Space. ClementG, SlenzkaK, eds. New York: Springer, 2006, Chapter 2, pp. 51–79.
MasiniMA, AlbiE, BarmoC, BonfiglioT, BruniL, CanesiL, et al.The impact of long-term exposure to space environment on adult mammalian organisms: a study on mouse thyroid and testis. PLoS One. 2012; 7(4):e35418.
70.
ZhongN, GarmanRA, SquireME, DonahueLR, RubinCT, HadjiargyrouM, JudexS. Gene expression patterns in bone after 4 days of hind-limb unloading in two inbred strains of mice. Aviat Space Environ Med. 2005; 76(6):530–5.
71.
LescaleC, SchentenV, DjeghloulD, BennabiM, GaignierF, VandammeK, StrazielleC, KuzniakI, PetiteH, DosquetC, FrippiatJP, GoodhardtM. Hind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging. FASEB J. 2015; 29:455–63.
72.
MilsteadJR, SimskeSJ, BatemanTA. Spaceflight and hindlimb suspension disuse models in mice. Biomed Sci Instrum. 2004; 40:105–110.
73.
FedorovVB, GoropashnayaAV, Tøien Ø, StewartNC, ChangC, WangH, YanJ, ShoweLC, ShoweMK, DonahueSW, BarnesBM. Preservation of bone mass and structure in hibernating black bears (Ursus americanus) through elevated expression of anabolic genes. Funct Integr Genomics. 2012; 12:357–65.
74.
TinkerDB, HarlowHJ, BeckTD. Protein use and muscle-fiber changes in free-ranging, hibernating black bears. Physiol Zool. 1998; 71:414–24.
75.
HersheyJD, RobbinsCT, NelsonOL, LinDC. Minimal seasonal alterations in the skeletal muscle of captive brown bears. Physiol Biochem Zool. 2008; 81:138–47.
MusacchiaXJ, VolkertWA, BarrRE. Radioresistance in hamsters during hypothermic depressed metabolism induced with helium and low temperatures. Radiat Res. 1971; 46:353–61.
78.
GazizovaGR, TyapkinaOV, LogachevaMD, NurullinLF, VikhlyantsevIM, IshiharaA, IshiokaN, GusevOA. Long-living hibernators: the first glance on the genome's structure and activity in edible dormice. 52th CRYO 2015 Annual Meeting of the Society for Cryobiology, Kazan Federal University, Russia, 2015. http://cryo2015.com/data/program_FNO_A5_Pass15_final_kor8.pdf (Last accessed on October23, 2016).
79.
BartholomewG, CadeT. Temperature regulation, hibernation, and aestivation in the little pocket mouse, Perognathus longimembris. J Mammal. 1957; 38:60–72.
80.
HaymakerW, LookB, BentonE, SimmondsR. Biomedical results of Apollo. Chapter 4: The Apollo 17 Pocket Mouse Experiment. NASA SP-368, 1975.
81.
SouzaK, HoganR, BallardR, eds. Life into space: space life sciences experiments. NASA Ames Research Center 1965–1990. Washington D.C.: National Aeronautics and Space Administration, 1995. NASA Reference Publication-1372 (online version).
82.
BarnesBM. Freeze avoidance in a mammal: body temperatures below 0 degree C in an Arctic hibernator. Science. 1989; 244(4912):1593–5.
83.
Von der OheCG, GarnerCC, Darian-SmithC, HellerHC. Synaptic protein dynamics in hibernation. J Neurosci. 2007; 27(1):84–92.
84.
WeltzinMM, ZhaoHW, DrewKL, BucciDJ. Arousal from hibernation alters contextual learning and memory. Behav Brain Res. 2006; 167(15):128–33.
85.
GinsburgMD, BelayevL. Biological and molecular mechanisms of hypothermic neuroprotection. In Therapeutic Hypothermia. MayerSA, SesslerDI, eds. Boca Raton, FL: Taylor & Francis Group, 2005, pp. 85–141.
86.
PariharVK, AllenB, TranKK, MacaraegTG, ChuEM, KwokSF, ChmielewskiNN, CraverBM, BaulchJE, AcharyaMM, CucinottaFE, LimoliCL. What happens to your brain on the way to Mars. Sci Adv. 2015; 1(4):e1400256.
87.
BlancoMB, ZehrSM. Striking longevity in a hibernating lemur. J Zool. 2015; 296:177–188.
88.
KrystalAD, SchoplerB, KobbeS, WilliamsC, RakatondrainibeH, YoderAD, KlopferP. The relationship of sleep with temperature and metabolic rate in a hibernating primate. PLoS One. 2013; 8(9):e69914.
89.
TuponeD, MaddenCJ, MorrisonSF. Central activation of the A1 adenosine receptor (A1AR) induces a hypothermic, torpor-like state in the rat. J Neurosci. 2013; 33:14512–25.
90.
HortonND, KaftaniDJ, BruceDS, BaileyEC, KroberAS, JonesJR, TurkerM, KhattarN, SuTP, BollingSF, OeltgenPR. Isolation and partial characterization of an opioid-like 88 kDa hibernation-related protein. Comp Biochem Physiol B Biochem Mol Biol. 1998; 119:787–805.
91.
ScanlanTS, SuchlandKL, HartME, ChielliniG, HuangY, KruzichPJ, FrascarelliS, CrossleyDA, BunzowJR, Ronca-TestoniS, LinET, HattonD, ZucchiR, GrandyDK. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med. 2004; 10:638–42.
92.
GitelsonJI, LisovskyGM, MacelroyRD. Manmade Closed Ecological Systems: A New Means to Solve some Critical Problems of Human Life Support on Earth and in Space. London: Taylor & Francis, 2003.
AlekseevVR, SychevVN. Effect of Space station conditions on resting egg survivorship and parameters of life cycle in D. Magna. Abstract of COSPAR 2006, Beijing, China, 2006.
95.
Committee on Ethics Principles and Guidelines for Health Standards for Long Duration and Exploration Spaceflights; Board on Health Sciences Policy; Institute of Medicine; KahnJ, LivermanCT, McCoyMA, eds. Washington, DC: National Academies Press, June23, 2014. (Last accessed on June2, 2017).
96.
Warm-flashD, CiftciogluN, FoxD, McKayDS, FriedmanL, BettsB, KirschvinkJ. Living interplanetary flight experiment (LIFE): an experiment on the survivability of microorganisms during interplanetary transfer. Workshop on the Exploration of Phobos and Deimos, 2007. www.lpi.usra.edu/meetings/phobosdeimos2007/pdf/7043.pdf (Last accessed on June2, 2017).
Workshop on planetary protection knowledge gaps for human extraterrestrial missions on March 24–26, 2015. Moffett Field, CA: NASA's Ames Research Center. www.nasa.gov/ames/ppw2015workshop (Last accessed on June2, 2017).
