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.

The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.

Growing evidence suggests that environmentally relevant elevations in CO2 (<5,000 ppm) may pose direct risks for human health. Increasing atmospheric CO2 concentrations could make adverse exposures more frequent and prolonged through increases in indoor air concentrations and increased time spent indoors. We review preliminary evidence concerning the potential health risks of chronic exposure to environmentally relevant elevations in ambient CO2, including inflammation, reductions in higher-level cognitive abilities, bone demineralization, kidney calcification, oxidative stress and endothelial dysfunction. This early evidence indicates potential health risks at CO2 exposures as low as 1,000 ppm—a threshold that is already exceeded in many indoor environments with increased room occupancy and reduced building ventilation rates, and equivalent to some estimates for urban outdoor air concentrations before 2100. Continuous exposure to increased atmospheric CO2 could be an overlooked stressor of the modern and/or future environment. Further research is needed to quantify the major sources of CO2 exposure, to identify mitigation strategies to avoid adverse health effects and protect vulnerable populations, and to fully understand the potential health effects of chronic or intermittent exposure to indoor air with higher CO2 concentrations. A review of studies on exposure to elevated CO2 concentrations in air suggests that health damages, such as inflammation or reductions in cognitive abilities, can occur at levels as low as 1,000 ppm.

Direct human health risks of increased atmospheric carbon dioxide

Transcranial Doppler is a widely used noninvasive technique for assessing cerebral artery blood flow. All previous high altitude studies assessing cerebral blood flow (CBF) in the field that have used Doppler to measure arterial blood velocity have assumed vessel diameter to not alter. Here, we report two studies that demonstrate this is not the case. First, we report the highest recorded study of CBF (7,950 m on Everest) and demonstrate that above 5,300 m, middle cerebral artery (MCA) diameter increases (n=24 at 5,300 m, 14 at 6,400 m, and 5 at 7,950 m). Mean MCA diameter at sea level was 5.30 mm, at 5,300 m was 5.23 mm, at 6,400 m was 6.66 mm, and at 7,950 m was 9.34 mm (P<0.001 for change between 5,300 and 7,950 m). The dilatation at 7,950 m reversed with oxygen. Second, we confirm this dilatation by demonstrating the same effect (and correlating it with ultrasound) during hypoxia (FiO2=12% for 3 hours) in a 3-T magnetic resonance imaging study at sea level (n=7). From these results, we conclude that it cannot be assumed that cerebral artery diameter is constant, especially during alterations of inspired oxygen partial pressure, and that transcranial 2D ultrasound is a technique that can be used at the bedside or in the remote setting to assess MCA caliber.

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Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia--an ultrasound and MRI study.

Visual impairment intracranial pressure (VIIP) syndrome is considered an unexplained major risk for future long-duration spaceflight. NASA recently redefined this syndrome as Spaceflight-Associated Neuro-ocular Syndrome (SANS). Evidence thus reviewed supports that chronic, mildly elevated intracranial pressure (ICP) in space (as opposed to more variable ICP with posture and activity on Earth) is largely accounted for by loss of hydrostatic pressures and altered hemodynamics in the intracranial circulation and the cerebrospinal fluid system. In space, an elevated pressure gradient across the lamina cribrosa, caused by a chronic but mildly elevated ICP, likely elicits adaptations of multiple structures and fluid systems in the eye which manifest themselves as the VIIP syndrome. A chronic mismatch between ICP and intraocular pressure (IOP) in space may acclimate the optic nerve head, lamina cribrosa, and optic nerve subarachnoid space to a condition that is maladaptive to Earth, all contributing to the pathogenesis of space VIIP syndrome. Relevant findings help to evaluate whether artificial gravity is an appropriate countermeasure to prevent this seemingly adverse effect of long-duration spaceflight.

Spaceflight-Induced Intracranial Hypertension and Visual Impairment: Pathophysiology and Countermeasures.

The effects of microgravity and cosmic rays on the cardiovascular system are major health concerns for astronauts in space. In this Review, Hughson and colleagues summarize the current evidence on risk estimation and dysfunction of the cardiovascular system in space, and discuss potential countermeasures, including physical exercise, antioxidants, nutraceuticals, and radiation shielding. National space agencies and private corporations aim at an extended presence of humans in space in the medium to long term. Together with currently suboptimal technology, microgravity and cosmic rays raise health concerns about deep-space exploration missions. Both of these physical factors affect the cardiovascular system, whose gravity-dependence is pronounced. Heart and vascular function are, therefore, susceptible to substantial changes in weightlessness. The altered cardiovascular function in space causes physiological problems in the postflight period. A compromised cardiovascular system can be excessively vulnerable to space radiation, synergistically resulting in increased damage. The space radiation dose is significantly lower than in patients undergoing radiotherapy, in whom cardiac damage is well-documented following cancer therapy in the thoracic region. Nevertheless, epidemiological findings suggest an increased risk of late cardiovascular disease even with low doses of radiation. Moreover, the peculiar biological effectiveness of heavy ions in cosmic rays might increase this risk substantially. However, whether radiation-induced cardiovascular effects have a threshold at low doses is still unclear. The main countermeasures to mitigate the effect of the space environment on cardiac function are physical exercise, antioxidants, nutraceuticals, and radiation shielding.

Heart in space: effect of the extraterrestrial environment on the cardiovascular system.

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and ele...

Impaired cerebrovascular autoregulation and reduced CO2 reactivity after long duration spaceflight

To determine if 6 months in microgravity resulted in significant changes in the major central and peripheral veins indicating a redistribution of venous blood flow. Ten astronauts participated in the study. Jugular vein (JV), portal vein (PV), femoral vein (FV), tibial vein (TibV), and gastrocnemius vein (Gast V) were assessed by echography for the measurement of vessel cross-sectional area. Inflight exams were conducted by astronauts using a volume capture method in which images collected were processed to produce a 3D reconstruction of the vessel which was later analyzed by a trained sonographer. Measurements were conducted pre-flight, at the beginning of the flight (day 15), near the end of the flight (4–5.5 months), and post-flight. During the flight, JV, PV, JV/PV ratio, and FV were found significantly increased from pre-flight at 15 days and 4–5.5 months (JV: 178 and 225 %, p < 0.05; PV: 36 and 45 %, p < 0.05; JV/PV ratio: 102 and 120 %, p < 0.05; FV: 124 and 169 %, p < 0.05). Conversely, calf veins decreased at day 15 and at 4–5.5 months (TibV: −45 % and−52 %, p < 0.05; Gast V: −68 and −55 %, p < 0.05). All veins returned to base line conditions 4 days after returning to Earth. The increase in JV, PV, and FV cross-sectional area during spaceflight confirmed that there was venous blood pooling in the cephalic, splanchnic, and pelvic regions. Further investigation is needed to determine the consequences of this fluid stagnation on the brain, eye, splanchnic, and pelvic organ morphology and or function.

Measurements of jugular, portal, femoral, and calf vein cross-sectional area for the assessment of venous blood redistribution with long duration spaceflight (Vessel Imaging Experiment).

This review summarizes our current understanding of cerebral blood flow regulation with exposure to microgravity, outlines potential mechanisms associated with post-flight orthostatic intolerance, and proposes future directions for research and linkages with cerebrovascular disorders found in the general population. It encompasses research from cellular mechanisms (e.g. hind limb suspension: tissue, animal studies) to whole body analysis with respect to understanding human responses using space analogue studies (bed rest, parabolic flight) as well as data collected before, during, and after spaceflight. Recent evidence indicates that cerebrovascular autoregulation may be impaired in some astronauts leading to increased susceptibility to syncope upon return to a gravitational environment. The proposed review not only provides insights into the mechanisms of post-flight orthostatic intolerance, but also increases our understanding of the mechanisms associated with pathophysiological conditions (e.g. unexplained syncope) with clinical applications in relation to postural hypotension or intradialytic hypotension.

Cerebrovascular autoregulation: lessons learned from spaceflight research

INTRODUCTION The objective was to determine the effects of 6 mo of microgravity exposure on conduit artery diameter and wall thickness. METHODS Diagnostic images of the common carotid artery (CC) and superficial femoral artery (FA) were obtained using echography which astronauts performed on themselves after receiving minimal training in the use of ultrasound imaging. Echographic video was recorded using a volume capture method directed by a trained sonographer on the ground through videoconferencing. Vessel properties were later assessed by processing the downlinked video. Data were collected from 10 astronauts who performed the echographic video capture at the beginning of the spaceflight (day 15) and near the end of the spaceflight (day 115 to 165). In-flight and postflight measurements were compared to preflight assessments. RESULTS No significant changes with spaceflight were found for CC and FA diameter. Intima-media thickness (IMT) of the CC was found to be significantly increased (12% ± 4) in all astronauts during the spaceflight (early and late flight) and remained elevated 4 d after returning to Earth. Similarly, FA IMT was increased during the flight but returned to preflight levels 4 d postflight. CONCLUSION The experiment demonstrated that, using the volume capture method of echography, untrained astronauts were able to capture enough echographic data to display vessel images of good quality for analysis. The increase in both CC and FA IMT during the flight suggest an adaptation to microgravity and to the confined environment of spaceflight which deserves further investigation.

Carotid and Femoral Artery Intima-Media Thickness During 6 Months of Spaceflight.

The objective was to design and validate a method of tele-operated echocardiography. The method was tested in a hospital facility with an expert sonographer located in a room 10 m away from the patient. An ultrasound probe, fixed to a motorized probe holder, was located on the patient by a non-sonographer and was remotely controlled by the expert sonographer via an Internet connection. Scans were performed on 41 cardiac patients. The quality of the cardiac views obtained using tele-echocardiography was lower than that of reference echocardiography, but generated similar measurements in 93%-100% of the cases. Bland-Altman plots and statistical comparison of tele- and reference echocardiography measures revealed no differences (p > 0.05). Of the 71 valve leaks or aortic stenoses present, 61 (86%) were detected using tele-echocardiography. These results indicate that tele-echocardiography provided reliable diagnoses and acceptable measurements in 86% and 93% of cases, respectively, with no false-positive diagnoses being reported.

Kathryn Zuj

Papers

Impaired cerebrovascular autoregulation and reduced CO2 reactivity after long duration spaceflight

Measurements of jugular, portal, femoral, and calf vein cross-sectional area for the assessment of venous blood redistribution with long duration spaceflight (Vessel Imaging Experiment).

Cerebrovascular autoregulation: lessons learned from spaceflight research

Carotid and Femoral Artery Intima-Media Thickness During 6 Months of Spaceflight.

Teles-operated echocardiography using a robotic arm and an internet connection.