RESEARCH ◥ state within the time period of the study. These RESEARCH ARTICLE SUMMARY included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome compo- HUMAN PHYSIOLOGY sition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. The NASA Twins Study: In addition, some factors were significantly af- fected by the stress of re- ◥ A multidimensional analysis of a ON OUR WEBSITE turning to Earth, including Read the full article inflammation cytokines year-long human spaceflight at http://dx.doi. and immune response gene org/10.1126/ networks,aswellascog- science.aau8650 nitive performance. For Francine E. Garrett-Bakelman et al. .................................................. a few measures, persistent changes were observed even after 6 months on INTRODUCTION: To date, 559 humans have microbial shifts, and alterations in gene reg- Earth, including some genes’ expression levels, been flown into space, but long-duration ulation. However, previous studies collected increased DNA damage from chromosomal in- (>300 days) missions are rare (n = 8 total). very limited data, did not integrate simulta- versions, increased numbers of short telomeres, Long-duration missions that will take humans neous effects on multiple systems and data and attenuated cognitive function. to Mars and beyond are planned by public types in the same subject, or were restricted to Downloaded from and private entities for the 2020s and 2030s; 6-month missions. Measurement of the same CONCLUSION: Given that the majority of the therefore, comprehensive studies are needed variables in an astronaut on a year-long mis- biological and human health variables remained now to assess the impact of long-duration sion and in his Earth-bound twin indicated stable, or returned to baseline, after a 340-day spaceflight on the human body, brain, and the biological measures that might be used to space mission, these data suggest that human overall physiology. The space environment determine the effects of spaceflight. Presented health can be mostly sustained over this du- is made harsh and challenging by multiple here is an integrated longitudinal, multidimen- ration of spaceflight. The persistence of the http://science.sciencemag.org/ factors, including confinement, isolation, and sional description of the effects of a 340-day molecular changes (e.g., gene expression) and exposure to environmental stressors such as mission onboard the International Space Station. the extrapolation of the identified risk factors microgravity, radiation, and noise. The selec- forlongermissions(>1year)remainestimates tion of one of a pair of monozygotic (identical) RESULTS: Physiological, telomeric, transcrip- andshouldbedemonstratedwiththesemea- twin astronauts for NASA’s first 1-year mission tomic, epigenetic, proteomic, metabolomic, sures in future astronauts. Finally, changes de- enabled us to compare the impact of the space- immune, microbiomic, cardiovascular, vision- scribed in this study highlight pathways and flight environment on one twin to the simulta- related, and cognitive data were collected mechanismsthatmaybevulnerabletospace- neous impact of the Earth environment on a over 25 months. Some biological functions flight and may require safeguards for longer genetically matched subject. were not significantly affected by spaceflight, space missions; thus, they serve as a guide for including the immune response (T cell recep- targeted countermeasures or monitoring dur- on May 20, 2020 RATIONALE: The known impacts of the space- tor repertoire) to the first test of a vaccination ing future missions.▪ flight environment on human health and per- in flight. However, significant changes in formance, physiology, and cellular and molecular multiple data types were observed in associ- The list of author affiliations is available in the full article online. Email: [email protected] processes are numerous and include bone ation with the spaceflight period; the major- Cite this article as F. E. Garrett-Bakelman et al., Science 364, density loss, effects on cognitive performance, ity of these eventually returned to a preflight eaau8650 (2019). DOI: 10.1126/science.aau8650 Subjects Twins Study Analyses Biochemical Cognition Epigenomics Gene expression Integrative Analyses Immune Results Metabolomics Microbiome Postflight Proteomics Inflight Physiology Preflight Ground Flight Telomeres Multidimensional, longitudinal assays of the NASA Twins Study. (Left and middle) Genetically identical twin subjects (ground and flight) were characterized across 10 generalized biomedical modalities before (preflight), during (inflight), and after flight (postflight) for a total of 25 months (circles indicate time points at which data were collected). (Right) Data were integrated to guide biomedical metrics across various “-omes” for future missions (concentric circles indicate, from inner to outer, cytokines, proteome, transcriptome, and methylome). Garrett-Bakelman et al., Science 364, 144 (2019) 12 April 2019 1of1 RESEARCH ◥ adverse effects of these adaptations are especially RESEARCH ARTICLE clear upon return to Earth. Regular vigorous ex- ercise, combined with adequate nutrition during spaceflight, mitigate some of the spaceflight- HUMAN PHYSIOLOGY induced muscle (9, 12) and bone loss (13) that occur during both short- and long-duration missions. However, recent evidence suggests The NASA Twins Study: that long-duration missions on the International Space Station (ISS) have resulted in some astro- nauts developing ocular changes, including optic A multidimensional analysis of a disc edema and choroidal folds (14, 15), termed spaceflight-associated neuro-ocular syndrome year-long human spaceflight (SANS) (16). The incidence and severity of ocular symptoms varies, and the exact mechanism for Francine E. Garrett-Bakelman1,2*, Manjula Darshi3*, Stefan J. Green4*, the development of SANS is not well understood, Ruben C. Gur5*, Ling Lin6*, Brandon R. Macias7*, Miles J. McKenna8*, which has limited NASA’s ability to develop an Cem Meydan1,9*, Tejaswini Mishra6*, Jad Nasrini5*, Brian D. Piening6*†, effective countermeasure. Lindsay F. Rizzardi10*‡, Kumar Sharma3*, Jamila H. Siamwala11*§, Lynn Taylor8*, Although our understanding of the physio- Martha Hotz Vitaterna12*, Maryam Afkarian13, Ebrahim Afshinnekoo1,9, Sara Ahadi6, logical and functional consequences of 4- to Aditya Ambati6, Maneesh Arya7, Daniela Bezdan1,9, Colin M. Callahan10, Songjie Chen6, 6-month missions has increased greatly over Augustine M. K. Choi1, George E. Chlipala4, Kévin Contrepois6, Marisa Covington14, the 18 years of continuous human presence on Downloaded from Brian E. Crucian14, Immaculata De Vivo15, David F. Dinges5, Douglas J. Ebert7, the ISS, there is almost no experience with Jason I. Feinberg10, Jorge A. Gandara1, Kerry A. George7, John Goutsias10, spaceflight length greater than 6 months. Future missions, however, could be as long as 3 years, George S. Grills1¶, Alan R. Hargens11, Martina Heer16#, Ryan P. Hillary6, including transit to and from Mars and possible Andrew N. Hoofnagle17, Vivian Y. H. Hook11, Garrett Jenkinson10**, Peng Jiang12, exploration of the planet, yet only four indi- Ali Keshavarzian18, Steven S. Laurie7, Brittany Lee-McMullen6, Sarah B. Lumpkins19, viduals have participatedinspaceflightmissions Matthew MacKay1, Mark G. Maienschein-Cline4, Ari M. Melnick1, Tyler M. Moore5, lasting 1 year or more. Moreover, investigations http://science.sciencemag.org/ 1†† 11 7 6 11‡‡ Kiichi Nakahira , Hemal H. Patel , Robert Pietrzyk , Varsha Rao , Rintaro Saito , have not consistently implemented an integrated, 6 11 11 1 Denis N. Salins , Jan M. Schilling , Dorothy D. Sears , Caroline K. Sheridan , cross-discipline study design or utilized multiomic 14 10 6 17 Michael B. Stenger , Rakel Tryggvadottir , Alexander E. Urban , Tomas Vaisar , approaches to biospecimen analyses. Thus, we 11 6 11 20 Benjamin Van Espen , Jing Zhang , Michael G. Ziegler , Sara R. Zwart , have limited knowledge of the full range of the 14 21 22 8 John B. Charles §§, Craig E. Kundrot §§, Graham B. I. Scott §§, Susan M. Bailey §§, interactions of molecular, physiological, and cog- Mathias Basner5§§, Andrew P. Feinberg10§§, Stuart M. C. Lee7§§, nitive dynamics that occur during long-duration Christopher E. Mason1,9,23,24§§, Emmanuel Mignot6§§, Brinda K. Rana11§§, spaceflight. Given the increasing number of Scott M. Smith14§§, Michael P. Snyder6§§, Fred W. Turek12§§ vehicles providing access to spaceflight (17)and proposed missions to Mars, studies are needed To understand the health impact of long-duration spaceflight, one identical twin astronaut to better understand the impact of prolonged was monitored before, during, and after a 1-year mission onboard the International spaceflight on human biology and health. Ge- on May 20, 2020 Space Station; his twin served as a genetically matched ground control. Longitudinal netic, immune system, and metabolic functions assessments identified spaceflight-specific changes, including decreased body mass, are of particular concern given exposure to space telomere elongation, genome instability, carotid artery distension and increased intima- radiations, restricted diet, reduced physical work media thickness, altered ocular structure, transcriptional and metabolic changes, requirements, disrupted circadian rhythms, and DNA methylation changes in immune and oxidative