The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight
What to expect after a year in space
Space is the final frontier for understanding how extreme environments affect human physiology. Following twin astronauts, one of which spent a year-long mission on the International Space Station, Garrett-Bakelman et al. examined molecular and physiological traits that may be affected by time in space (see the Perspective by Löbrich and Jeggo). Sequencing the components of whole blood revealed that the length of telomeres, which is important to maintain in dividing cells and may be related to human aging, changed substantially during space flight and again upon return to Earth. Coupled with changes in DNA methylation in immune cells and cardiovascular and cognitive effects, this study provides a basis to assess the hazards of long-term space habitation.
Structured Abstract
INTRODUCTION
To date, 559 humans have been flown into space, but long-duration (>300 days) missions are rare (n = 8 total). Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are needed now to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology. The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of one of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission enabled us to compare the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on a genetically matched subject.
RATIONALE
The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation. However, previous studies collected very limited data, did not integrate simultaneous effects on multiple systems and data types in the same subject, or were restricted to 6-month missions. Measurement of the same variables in an astronaut on a year-long mission and in his Earth-bound twin indicated the biological measures that might be used to determine the effects of spaceflight. Presented here is an integrated longitudinal, multidimensional description of the effects of a 340-day mission onboard the International Space Station.
RESULTS
Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study. These included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome composition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function.
CONCLUSION
Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight. The persistence of the molecular changes (e.g., gene expression) and the extrapolation of the identified risk factors for longer missions (>1 year) remain estimates and should be demonstrated with these measures in future astronauts. Finally, changes described in this study highlight pathways and mechanisms that may be vulnerable to spaceflight and may require safeguards for longer space missions; thus, they serve as a guide for targeted countermeasures or monitoring during future missions.
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).
Abstract
To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress–related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.
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Supplementary Material
Summary
Materials and Methods
Figs. S1 to S15
Tables S1 to S11
Resources
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Information & Authors
Information
Published In
Science
Volume 364 | Issue 6436
12 April 2019
12 April 2019
Copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 24 July 2018
Accepted: 28 February 2019
Published in print: 12 April 2019
Acknowledgments
The National Space Biomedical Research Institute partnered with NASA to support this study during the solicitation, design, implementation, and analysis phases via the provision of scientific expertise. We thank S. Horner and N. Gokhale from Duke University Medical Center (Durham, NC, USA) for mtRNA validation assistance, I. Tulchinsky, and the Genomics, Epigenomics, and Applied Bioinformatics Core Facilities at Weill Cornell Medicine for sequencing and data services. We thank the NASA JSC Nutritional Biochemistry Lab personnel, especially Y. Bourbeau, who led efforts on this project for project coordination, sample collection, processing, and analysis; the Cardiovascular and Vision Laboratory personnel for the collection and analysis of vascular, ocular, and fluid shifts data; the NASA Human Research Program’s International Space Station Medical Project Team for their invaluable work to coordinate all of sample and data collection scheduling activities on the ground and during flight; D. Mollicone and C. Mott from Pulsar Informatics Inc., E. Hermosillo, and S. McGuire for support of the Cognition measures; Y.-R. Hasson from the Stanford Human Immune Monitoring Center for advice and support on cytokine profiling data; K. Bettinger from Stanford University for support with the Stanford Twins data repository; P. R. Kiela, D. Laubitz (University of Arizona), and E. Song (Northwestern University) for support of the Microbiome project sample collection; K. Kunstman (University of Illinois at Chicago) for shotgun metagenome library preparation and sequencing; S. Mehta (University of Illinois at Chicago) for help in statistical analysis; and J. Kim for laboratory support in targeted metabolomics. We thank the DRC Quantitative and Functional Proteomics Core and the UW Nutrition and Obesity Research Center for performing proteomics assays and New England Biolabs (NEB) for support. We thank J. X.-J. Yuan at the University of Arizona, Tuscon, for providing his support and laboratory for the Tucson sample collections. We thank J. Krauhs for her editorial assistance with the one-page summary. K.S. is also affiliated with the South Texas U.S. Department of Veterans Affairs as a staff physician. Funding: The study was supported by NASA: NNX14AH51G [all Twins Study principal investigators (PIs)]; NNX14AB02G (S.M.B.); NNX14AH27G/NCC 9-58 (M.B.); NN13AJ12G (A.R.H.); NNX14AN75G (S.M.C.L.); NNX17AB26G, NNX17AB26G, and TRISH: NNX16AO69A:0107 and NNX16AO69A:0061 (C.E.M.); NNX14AH52G (M.P.S.); and NNX14AH26G (F.W.T.). Additional support was provided by NIH grants AG035031, NIH/NIDDK P30 DK017047, and P30 DK035816 (K.S.); NSF grant CCF-1656201 (J.G.); and DLR space program grant 50WB1535 (M.H.), as well as the Bert L. and N. Kuggie Vallee Foundation, the WorldQuant Foundation, The Pershing Square Sohn Cancer Research Alliance, and the Bill and Melinda Gates Foundation (OPP1151054) for funding (C.E.M.). Author contributions: F.E.G.-B., M.D., S.J.G., R.C.G., L.L., B.R.M., M.J.M., C.M., T.M., J.N., B.D.P., L.F.R., K.S., J.H.S., L.T., and M.H.V. led the investigator teams across the study. Conceptualization: G.B.I.S., C.E.K., and J.B.C.; S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); M.B. (Twins Study PI; Cognition); S.M.C.L. [Twins Study PI, Cardiovascular and Oxidative Stress (Cardio Ox); Twins Study co-investigator (Co-I), Fluid Shifts and Ocular]; S.M.S. and S.R.Z. (Biochem Profile); M.H. (Biochem Profile); A.P.F. (Twins Study PI; Epigenetics); M.B.S. (Fluid Shifts NASA site PI and Cardio Ox Co-I); B.R.M. (Fluids Shifts, Co-I); D.J.E. (Fluid Shifts, Co-I); B.K.R. (PI, Fluids Shifts and Co-I, Cardio Ox); I.D.V. (Co-I, Cardio Ox); D.D.S. (Co-I, Cardio Ox); K.S. (Co-I, Targeted Metabolomics, Cardio Ox); A.R.H. (Co-I, Fluid Shifts and Cardio Ox); V.Y.H.H. (Co-I, Fluid Shifts Proteomics); H.H.P., J.H.S., and J.M.S. (Fluid Shifts; Mitochondrial Function); T.V., A.N.H., and M.Af. (Targeted Urine Proteomics); M.P.S. (Twins Study PI; Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); B.D.P. (Integrative Analysis); S.J.G., A.K., F.W.T., and M.H.V. (Microbiome); C.E.M. (Twins study PI; Transcriptome, and Integration); and D.D.S. (Co-I, Cardio Ox). Data Curation: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); M.B. (Twins Study PI; Cognition); J.I.F. and L.F.R. (Epigenetics); S.R.Z. (Biochem Profile); R.P.H. (Immune Response); S.M.C.L. (Twins Study PI, Cardiovascular; Twins Study Co-I, Fluid Shifts and Ocular); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); D.J.E. (Fluid Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); I.D.V. (Co-I, Cardio Ox); K.S. (Co-I, Cardio Ox); M.D. and R.S. (Targeted Metabolomics); J.H.S. and J.M.S. (Mitochondrial Function); D.N.S. (Integrative Analysis); G.E.C., S.J.G., P.J., M.G.M.-C., and M.H.V. (Microbiome); A.N.H. and T.V. (Urine Proteomics); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); S.A. (Untargeted Plasma Proteomics); K.C. (Untargeted Plasma Metabolomics); C.M. and C.E.M. (Twins study PI); E.A., D.B., F.E.G.-B., and M.M. (Transcriptome); B.D.P. (Integrative Analysis); and D.N.S. (Integrative Analysis). Formal Analysis: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics), M.J.M. (Telomeres and Cytogenetics; FISH), L.T. (Telomeres and Telomerase; qRT-PCR); M.B. (Twins Study PI; Cognition); J.N. (Cognition); A.P.F., L.F.R., G.J., and J.G. (Epigenetics); R.P.H. (Immune Response); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); S.M.S. and S.R.Z. (Biochem Profile); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); M.G.Z. (Cardio Ox); I.D.V. (Co-I, Cardio Ox); D.D.S. (Co-I, Cardio Ox); K.S., M.D., and R.S. (Targeted Metabolomics); H.H.P., J.H.S., and J.M.S. (Mitochondrial Functional Assays); T.V. and A.N.H. (Urine Proteomics); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); S.A. (Untargeted Plasma Proteomics); K.C. (Untargeted Plasma Metabolomics); B.D.P. (Integrative Analysis); R.S. and M.D. (Metabolomics); P.J. (Microbiome); E.M., L.L., and A.A. (Vaccination study); and C.M., C.E.M., and A.M. (Transcriptome, Integrative Analysis). Funding and Acquisition: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); M.B. (Twins Study PI; Cognition); D.F.D. (Cognition); R.C.G. (Cognition); S.M.S. and S.R.Z. (Biochem Profile); M.H. (Biochem Profile); A.P.F. (Twins Study PI, Epigenetics); J.G. (Epigenetics); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); M.B.S. (Fluid Shifts and Ocular NASA Site PI; Cardio Ox Co-I); B.R.M. (Fluids Shifts and Ocular; CardioOX, Co-I); D.J.E. (Fluid Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; UCSD Site PI, Cardio Ox); I.D.V. (Co-I, Cardio Ox); A.R.H. (Co-I, Fluid Shifts and Ocular; Cardio Ox); M.P.S. (Twins Study PI, Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); V.Y.H.H. (Co-I, Fluid Shifts); F.W.T. (PI), M.H.V. (Co-I) (Microbiome), C.E.M. (PI, Transcriptome), C.M., F.E.G.-B., and A.M.M. (Co-I, Transcriptome), G.S.G. (Co-I, Transcriptome); D.D.S. (Co-I, Cardio Ox); and B.R.M. (Co-I, Fluid Shifts and Ocular; Cardio Ox). Investigation: M.J.M. (Telomeres and Cytogenetics; FISH), L.T. (Telomeres and Telomerase; qRT-PCR); M.B. (Twins Study PI; Cognition); J.N. (Cognition); R.C.G. (Cognition); S.M.S. and S.R.Z. (Biochem Profile); L.F.R., R.T., C.M.C., and J.I.F. (Epigenetics); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); M.B.S. (Fluid Shifts and Ocular; Cardio Ox, Co-I); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); D.J.E. (Fluid Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); M.G.Z. (Cardio Ox); I.D.V. (Co-I, Cardio Ox); K.S., M.D., B.V.E. (Targeted Metabolomics); M.D. (Cardio Ox); B.V.E. (Cardio Ox); A.R.H. (Co-I, Fluid Shifts and Ocular; Cardio Ox); H.H.P., J.H.S., and J.M.S. (Mitochondrial Function Assays); Fluid Shifts); T.V. and A.N.H. (Urine Proteomics); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); B.D.P. (Integrative Analysis); S.A. (Untargeted Plasma Proteomics); V.R. (Plasma Cytokine Profiling); S.J.G. and P.J. (Microbiome); K.C., B.L.M., and S.C. (Untargeted Plasma Metabolomics); E.M., L.L., and A.A. (Vaccination study); and C.E.M., G.S.G., D.B., F.E.G.-B., and A.M.M. (Transcriptome, Integrative Analysis). Methodology: M.J.M. (Telomeres and Cytogenetics; FISH), L.T. (Telomeres and Telomerase; qRT-PCR); M.B. (Twins Study PI; Cognition); J.N. (Cognition); R.C.G.(Cognition); T.M.M. (Cognition); G.J., J.G., and J.I.F. (Epigenetics); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); M.B.S. (NASA Site PI, Fluid Shifts and Ocular; Cardio Ox, Co-I); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular; Cardio Ox, Co-I); D.J.E. (Fluid Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); M.G.Z. (Cardio Ox); I.D.V. and D.D.S. (Co-I, Cardio Ox); A.R.H. (Co-I, Fluid Shifts and Ocular; Cardio Ox, Co-I); H.H.P., J.H.S., and J.S. (Mitochondrial Function Assays); T.V., A.N.H., and M.Af. (Urine Proteomics); V.Y.H.H. (Proteomics); S.J.G., A.K., F.W.T., and M.H.V. (Microbiome); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); S.A. (Untargeted Plasma Proteomics); V.R. (Plasma Cytokine Profiling); K.C. (Untargeted Plasma Metabolomics); B.D.P. (Integrative Analysis); E.M., L.L., and A.A. (Vaccination study); C.M. (Transcriptome, Integrative Analysis); K.S. and M.D. (Targeted Metabolomics); S.M.S., S.R.Z., M.H., and B.E.C. (Biochem Profile blood and urine collection, processing, and analysis); S.S., S.Z., K.S., M.D., and D.D.S. (Urine collection and processing); A.M.K.C. and K.N. (Cell-free mtDNA); and L.L., A.F., J.I.F., C.K.S., and F.E.G.-B. (Blood Collection and Processing). Project administration: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); M.B. (Twins Study PI; Cognition); L.F.R. (Epigenetics); R.P. (subject consent, scheduling, and sample logistics); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); S.M.S. (Twins Study PI, Biochem Profile); M.B.S. (Fluid Shifts and Ocular, Co-I; Cardio Ox, Co-I); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); M.P.S. (Twins study PI; Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); B.D.P. (Integrative Analysis); F.W.T. (Microbiome PI); M.H.V. (Microbiome Co-I); C.E.M. and F.E.G.-B. (Blood Collection and Processing and transcriptome studies); K.S. (Targeted Metabolomics); M.Ar.; S.L.; and M.C. Resources: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics), K.G. (Telomeres; sample coordination, NASA IRB); M.B. (Twins Study PI; Cognition); S.M.S. (Biochem Profile); M.H. (Biochem Profile); B.E.C. (Biochem Profile); R.P. (laboratory facilities, materials, and instrumentation); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); M.B.S. (Fluid Shifts and Ocular, Co-I; Cardio Ox, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); I.D.V. (Co-I, Cardio Ox); D.D.S. (Co-I, Cardio Ox); K.S. (Co-I, Cardio Ox); A.R.H. (Co-I, Fluid Shifts and Ocular; Cardio Ox); T.V. (Fluid Shifts and Ocular); A.N.H. (Fluid Shifts and Ocular); G.E.C., S.J.G., P.J., and M.G.M.-C. (Microbiome); M.P.S. (Twins study PI; Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); and D.S. (Data Storage Repository). Software: C.E.M. (Transcriptome); D.S. (Data Storage Repository); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); and B.D.P. (Integrative Analysis). Supervision: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); M.B. (Twins Study PI; Cognition); S.M.S. (Twins Study PI, Biochem Profile); A.P.F. (Twins Study PI); J.G. (Epigenetics); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); M.B.S. (Fluid Shifts and Ocular, Co-I; Cardio Ox, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); I.D.V. (Co-I, Cardio Ox); D.D.S. (Co-I, Cardio Ox); K.S. (Co-I, Targeted Metabolomics); H.H.P. (Fluid Shifts and Ocular); J.M.S. (Fluid Shifts and Ocular); M.P.S. (Twins study PI; Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); S.J.G., A.K., F.W.T., and M.H.V. (Microbiome); K.C. (Untargeted Plasma Metabolomics); and C.E.M. and F.E.G.-B. (Blood Collection and Processing and transcriptome studies). Validation: M.J.M. (Telomeres and Cytogenetics; FISH), L.T. (Telomeres and Telomerase; qRT-PCR); C.E.M., A.C., K.N., N.S.G., and S.M.H. (mtDNA and mtRNA PCR); M.B. (Twins Study PI; Cognition); J.N. (Cognition); T.M.M. (Cognition); S.M.C.L. (Twins Study PI, Cardio Ox; Co-I, Fluid Shifts and Ocular), S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); D.J.E. (Fluid Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); S.M.S. and S.R.Z. (Biochem Profile); I.D.V. (Co-I, Cardio Ox PCR Based Telomere Length); K.S., M.D., and B.V.E. (Targeted Metabolomics); H.H.P. and J.M.S. (Proteomics); and L.L., F.E.G.-B., T.M., and C.M. (Ambient return controls). Visualization: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); M.J.M. (Telomeres and Cytogenetics; FISH), L.T. (Telomeres and Telomerase; qRT-PCR); M.B. (Twins Study PI; Cognition); J.N. (Cognition); L.F.R. (Epigenetics); S.R.Z. (Biochem Profile); S.M.C.L. (Twins Study PI, Cardio Ox; Twins Study Co-I, Fluid Shifts and Ocular); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); H.H.P. (Fluid Shifts and Ocular); S.J.G., P.J., and M.G.M.-C. (Microbiome); M.M., C.E.M., and C.M. (Transcriptome, Integrative Analysis); and T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis). Writing, original draft: S.M.B. (Twins Study PI; Telomeres, Telomerase, DNA damage/cytogenetics); K.G. (Telomeres); M.B. (Twins Study PI; Cognition); L.F.R. (Epigenetics); S.M.C.L. (Twins Study PI, Cardiovascular; Twins Study Co-I, Fluid Shifts and Ocular); S.M.S. (Twins Study PI, Biochem Profile); S.R.Z. (Biochem Profile); S.S.L. (Fluids Shifts and Ocular, Co-I); B.R.M. (Fluids Shifts and Ocular, Co-I); D.J.E. (Fluid Shifts, Co-I); B.K.R. (PI, Fluids Shifts and Ocular; Co-I, Cardio Ox); M.G.Z. (Physiology and Proteomics); M.D. (Cardio Ox); T.M. (Untargeted Plasma Metabolomics and Proteomics, Plasma Cytokine Profiling, Integrative Analysis); S.J.G., P.J., A.K., F.W.T., and M.H.V. (Microbiome); H.H.P., J.M.S., and J.H.S. (Mitochondrial Function); C.E.M., C.M., F.E.G.-B., and M.M. (Twins Study PI, Transcriptome, Telomere Validation, Integration); D.D.S., K.S., and M.D. (Metabolomics); and A.H., T.V., and M.Af. (Urine Proteomics). Editing and manuscript finalization: F.E.G.-B., L.F.R., T.M., C.M., and C.E.M. Writing, review and editing: All authors reviewed and edited the manuscript. Competing interests: S.M.B. is a cofounder and scientific advisory board member of KromaTiD, Inc. C.E.M. is a cofounder and board member for Biotia, Inc., and Onegevity Health, Inc., as well as an advisor for Abbvie, Inc.; ArcBio; Daiichi Sankyo; DNA Genotek; Karius, Inc.; and Whole Biome, Inc. M.P.S. is a cofounder and scientific advisory board member of Personalis, SensOmics, Qbio, January, and Fitricine, and a scientific advisory board member of Genapsys, Epinomics, Jungla, and Jupyter. A.M.K.C. is a cofounder and stock holder and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. A.M.K.C. also has a use patent on carbon monoxide. A.M.K.C. served as a consultant for TEVA Pharmaceuticals in July 2018. A.M.M. is a consultant for Janssen. Data and materials availability: The NASA Life Sciences Data Archive (LSDA) is the repository for all human and animal research data, including that associated with this study. LSDA has a public facing portal where data requests can be initiated (https://lsda.jsc.nasa.gov/Request/dataRequestFAQ). The LSDA team provides the appropriate processes, tools, and secure infrastructure for archival of experimental data and dissemination while complying with applicable rules, regulations, policies, and procedures governing the management and archival of sensitive data and information. The LSDA team enables data and information dissemination to the public or to authorized personnel either by providing public access to information or via an approved request process for information and data from the LSDA in accordance with NASA Human Research Program and JSC Institutional Review Board direction.
Authors
Funding Information
National Science Foundation: CCF-1656201
National Institutes of Health: AG035031
National Institutes of Health: 1R01MH117406
National Institutes of Health: R21AO129851
National Aeronautics and Space Administration: NNX14AH51G
National Aeronautics and Space Administration: NNX14AB02G
National Aeronautics and Space Administration: NNX14AH27G
National Aeronautics and Space Administration: NNX14AN75G
National Aeronautics and Space Administration: NNX17AB26G
National Aeronautics and Space Administration: NNX14AH52G
National Aeronautics and Space Administration: NNX14AH26G
DLR Space program: 50WB1535
National Aeronautics and Space Administration: NNX14AH51G
National Aeronautics and Space Administration: NNX14AH50G
WorldQuant Foundation:
National Aeronautics and Space Administration: NNX14AH50G
National Aeronautics and Space Administration: NNX17AB26G
National Aeronautics and Space Administration: NNX16AO69A:0061
National Aeronautics and Space Administration: NNX16AO69A:0107
Starr Foundation: I9-A9-071
Pershing Square Foundation: PSSCRA
National Aeronautics and Space Administration: NNX14AH52G
NASA Astrobiology Institute: NN13AJ12G
NIDDK: DP3DK094352
NIDDK: DP3DK094352
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Consideration of the chronobiological impacts, specially melatonin
Dear Authors,
This is a very intensive study that was done and I congratulate the whole scientific personnel to bring forward such observations as the future is coming with such challenges to be faced. I would like to ask about the chronobiological rhythms, like impact on the melatonin cycles? In a simulated environment compared to the one on earth such changes are viable. As an epigenetics and chromatin biologist, I wonder about the overall effects that may impact the observations enlisted in the study; specifically the shortening of telomere and ageing. Also, gene regulation and certain studies have related epigenetic alterations to such circadian rhythms. Unfortunately, I couldn't find the details for the exposure to such diurnal cycles being elaborated. Maybe I missed it. Your insights would be helpful.
Thanks,
Somnath Paul.
Comments on "The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight"
This letter addresses "The NASA Twins Study" by Garrett-Bakelman et al. (1) which studied the biological effects of a 340-day mission onboard the International Space Station in a male astronaut compared to those in his monozygotic twin. This study showed that the majority of measured biological variables remained stable, or returned to baseline, after a nearly year-long human spaceflight. However, the authors assert that persistence of certain molecular changes (e.g., gene expression) should be considered in longer duration missions.
Despite its undeniable strengths, the authors have not fully addressed the following issues:
1. The authors rightly claimed that metabolic and nutritional status, physical activity, and weight loss may affect telomere length. However, space radiation (in particular, HZE or high (H) atomic number (Z) and energy (E) particles) also plays a key role in telomeric change. Might the elongation of telomeres during space flight be interpreted as an adaptive (positive) response to multiple changes in the environment (such as higher levels of radiation, microgravity, etc.)? Different aspects of this issue were initially raised in 2003 (2) and are discussed in recent publications (3, 4). Although elongation of telomeres in space is possibly a natural, protective adaptive response, telomerase activity is also a hallmark of cancer which grants immortality to malignant cells. Might telomerase activity, coupled with immune system dysregulation possibly increase an astronaut's risk of cancer in long term missions?
2. The NASA Twin study might illustrate a subtle difference between low dose exposures to low- vs high-LET (linear energy transfer) radiation. While neither the residents of high background radiation areas of Ramsar, Iran (5) nor Kerala, India (6) exhibit telomere alterations, the Twin Study (1) did document such change, possibly due to the effects of high-LET HZE particles.
Competing Interests
Authors declare no competing interests.
References:
1. F. E. Garrett-Bakelman et al., The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science 364, eaau8650 (2019).
2. S. M. Mortazavi, J. R. Cameron, A. Niroomand-rad, Adaptive response studies may help choose astronauts for long-term space travel. Advances in space research : the official journal of the Committee on Space Research (COSPAR) 31, 1543 (2003).
3. J. J. Bevelacqua, S. Mortazavi, Commentary: human pathophysiological adaptations to the space environment. Frontiers in physiology 8, 1116 (2018).
4. J. Bevelacqua, J. Welsh, S. Mortazavi, Comments on 'An overview of space medicine'. British journal of anaesthesia 120, 874 (2018).
5. A. Movahedi, M. Mostajaboddavati, M. Rajabibazl, R. Mirfakhraie, M. Enferadi, Association of telomere length with chronic exposure to ionizing radiation among inhabitants of natural high background radiation areas of Ramsar, Iran. International journal of radiation biology, 1 (2019).
6. B. Das, D. Saini, M. Seshadri, Telomere length in human adults and high level natural background radiation. PloS one 4, e8440 (2009).
RE: Telomeres lengthened during spaceflight and the potential "fragile" effect
We read with great interest the article by Garrett-Bakelman and collaborators (1) providing a unique multidimensional analysis of a yearlong human spaceflight. We want to congratulate the authors for their impressive results. It seems that astronauts could experience an "accelerated ageing syndrome," which includes mitochondrial dysfunction, immunological defects, vascular changes and cognitive deficits associated with increased oxidative stress, inflammation, and insulin resistance. Data related to alterations in telomere length have caught our attention. It is well established that telomeres progressively shorten with age and that critically short and dysfunctional telomeres may contribute to ageing and ageing-associated diseases in humans (2). We recently demonstrated that, along with ageing, telomeres increasingly display accumulation of aberrant structures such as fragile sites characterized by the presence of multiple or diffuse telomeric signals on the chromatid arm. These sites seem to represent areas of de-condensed telomeric chromatin due to stalled DNA replication forks, which suggested that telomeric replication defects contribute to ageing associated-telomere erosion in humans (3). Fragile telomeres may appear as telomeric elongation when assessed by a quantitative real-time polymerase chain reaction (qRT-PCR) method. Authors showed a transient telomere elongation associated with a rapid shortening of astronaut's telomeres upon return to Earth. Although the underlying mechanisms are currently unknown, the incomplete telomere replication and intense telomeric replication stress during spaceflight cannot be ruled out. Astronauts might accumulate fragile telomeres during their activity in the space, as a result of intense replication stress that may alter length measures of telomeres that might look longer. In this perspective, it has been shown that ionizing radiation alters telomere homeostasis (4) while increasing levels of oxidative stress in human cell cultures promotes the formation of fragile structures (5). The importance of such a hypothesis remains to be tested as well as its significance for potential risks, such as cardiovascular disease and cancer, in future human spatial missions.
References:
1. F. E. Garrett-Bakelman et al., The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science. 364, eaau8650 (2019).
2. E. H. Blackburn, E. S. Epel, J. Lin, Human telomere biology: A contributory and interactive factor in ageing, disease risks, and protection. Science. 350, 1193–1198 (2015).
3. V. Boccardi et al., Telomeres Increasingly Develop Aberrant Structures in Aging Humans. J. Gerontol. A. Biol. Sci. Med. Sci. (2018).
4. J. Kesäniemi et al., Exposure to environmental radionuclides associated with tissue-specific impacts on telomerase expression and telomere length. Sci. Rep. 9, 850 (2019).
5. V. Boccardi et al., Stn1 is critical for telomere maintenance and long-term viability of somatic human cells. Ageing Cell. 14, 372–81 (2015).
RE: Discussion about Cognition Performance Results
As reported in the cognition performance section and subsequent discussion, there was some decline in TW's cognition measures such as speed, processing, and emotion recognition. To what extend can these declines be attributed to lack of social interaction? A lack of social interaction, with the condition being in-person interactions, has been associated with structural changes and processing. Humans are social creatures and need this interaction. I've also heard isolation can shrink cortex density. I'm curious to know how this could relate to the cognition performance results and partially explain any piece?
RE: Diet
Did the twins consume the same diet throughout the study?
Ideally, TW and HR both consumed the same. Diet affects microbiome. Microbiome is the third brain.