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www.nature.com/npjmgrav ARTICLE OPEN Effects of exercise countermeasures on multisystem function in long duration spaceﬂight astronauts 1,2✉ 3 4 5 3 6 Jessica M. Scott , Alan H. Feiveson , Kirk L. English , Elisabeth R. Spector , Jean D. Sibonga , E. Lichar Dillon , 7 3 Lori Ploutz-Snyder and Meghan E. Everett Exercise training is a key countermeasure used to offset spaceﬂight-induced multisystem deconditioning. Here, we evaluated the effects of exercise countermeasures on multisystem function in a large cohort (N= 46) of astronauts on long-duration spaceﬂight missions. We found that during 178 ± 48 d of spaceﬂight, ~600 min/wk of aerobic and resistance exercise did not fully protect against multisystem deconditioning. However, substantial inter-individual heterogeneity in multisystem response was apparent with changes from pre to postﬂight ranging from −30% to +5%. We estimated that up to 17% of astronauts would experience performance- limiting deconditioning if current exercise countermeasures were used on future spaceﬂight missions. These ﬁndings support the need for reﬁnement of current countermeasures, adjunct interventions, or enhanced requirements for preﬂight physiologic and functional capacity for the protection of astronaut health and performance during exploration missions to the moon and beyond. npj Microgravity (2023) 9:11 ; https://doi.org/10.1038/s41526-023-00256-5 INTRODUCTION and Japan Aerospace Exploration Agency (JAXA) astronauts assigned to ISS ﬂight were eligible to participate in this For over 50 years International Space Agencies have continually investigation. Testing was performed during ISS Increments 26S- reﬁned countermeasures to protect astronaut health and perfor- 50S (April 2011 – September 2017). Forty-six astronauts (37 males, mance from the multisystem physiological deconditioning that 9 females; age: 46.8 ± 6.1 years, height: 176 ± 7.1 cm, weight: occurs during spaceﬂight . Initially, exercise countermeasures 79.2 ± 9.9 kg [mean ± SD]) were assigned to missions of 178 ± 48 d. consisted of elastic bands that provided little, if any, protection 10 (22%) astronauts had previously completed long-duration ISS against spaceﬂight-induced deterioration in cardiorespiratory ﬁt- 2,3 missions. All astronauts performed the standard medically ness and muscle size and strength . Since these early missions, required physiologic tests assessing muscle strength, aerobic increasingly advanced exercise hardware was developed such that ﬁtness, and bone health; a subset performed additional experi- astronauts on International Space Station (ISS) missions now mental tests of muscle strength and size, aerobic ﬁtness, and bone complete exercise training sessions using the Advanced Resistive health. Exercise Device (ARED), second generation treadmill (T2), and cycle ergometer with Vibration Isolation and Stabilization System (CEVIS). Planned lunar surface and deep space exploration missions may Inﬂight exercise training and food systems during ISS last up to three years during which astronauts will be exposed to missions microgravity during transport and partial gravity during surface Inﬂight aerobic exercise was performed using the T2 (Supple- stays on the Moon or Mars. Prior studies evaluating the mental Figure 1) and the CEVIS (Supplemental Fig. 2), and physiological effects of spaceﬂight were limited by the small 4 resistance exercise was performed with the ARED (Supplemental number of astronauts (n < 30) , the use of older exercise counter- 5 Fig. 3). Inﬂight exercise data are presented in Table 1. Median measure devices that were restricted in speed and/or load , the 6 [interquartile range (IQR)] number of completed aerobic exercise absence of assessment of countermeasures , and/or the evalua- 5,7–9 sessions was 65 (47, 76) and 84 (59, 109) for CEVIS and T2, tion of effects on a single system . There is therefore a respectively. Inﬂight resistance exercise training load was 181 lbs/ signiﬁcant need to evaluate the efﬁcacy of current ISS counter- session (150, 223), 192 lb (156, 215), 239 lb (198, 293), 122 lb (122, measures to determine whether modiﬁcations are needed for 153) for squats, deadlift, calf raises, and bench press, respectively. future human exploration missions. Here, we evaluated the effects Total exercise time (i.e., T2, CEVIS, and ARED) was ~600 min/wk per of ISS exercise countermeasures on multisystem function, crew member (range: ~450 min/wk to 720 min/wk). Dietary intake characterized heterogeneity in multisystem changes, and esti- during ﬂight was recorded using multiple techniques, as this has mated the proportion of astronauts that would experience changed over time on ISS. On average, astronauts consumed a performance-limiting deconditioning on future missions. total of 2296 ± 449 kcal/day, corresponding to 29 ± 5 kcal/kg/day (Supplemental Table 1). RESULTS Change in multisystem function Overall approach and astronaut characteristics A total of 27 performance and/or physiological endpoints were All National Aeronautics and Space Administration (NASA), Canadian Space Agency (CSA), European Space Agency (ESA), collected across four systems (muscle, cardiorespiratory, bone, and 1 2 3 Memorial Sloan Kettering Cancer Center, New York, NY, USA. Weill Cornell Medical College, New York, NY, USA. National Aeronautics and Space Administration 4 5 6 (NASA), Houston, TX, USA. Milligan University, Milligan College, Elizabethton, TN, USA. KBR, Houston, TX, USA. University of Texas Medical Branch, Galveston, TX, USA. University of Michigan, Ann Arbor, MI, USA. email: firstname.lastname@example.org; email@example.com Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; J.M. Scott et al. Table 1. Inﬂight Aerobic and Resistance Exercise Training. Aerobic Exercise Resistance Exercise CEVIS T2 Deadlift Heel Raise Squat Bench Press Sessions, number 65 (47, 76) 84 (59, 109) 121 (82, 146) 85 (65, 105) 117 (78, 148) Exercise time/session, mins 26 (23, 29) 27 (23, 29) N/A N/A N/A N/A Heart Rate, beats/min Average 135 (128, 141) 131 (121, 137) N/A N/A N/A N/A Peak 158 (150, 163) 153 (144, 162) N/A N/A N/A N/A % time in heart rate zone Above 70% peak heart rate 76 (65, 92) 69 (54, 81) N/A N/A N/A N/A Above 90% peak heart rate 13 (6, 27) 11 (4, 24) N/A N/A N/A N/A Speed, rpm (CEVIS) or mph (T2) All 78 (71, 97) 7 (6, 7) N/A N/A N/A N/A Peak 92 (88, 97) 8 (7, 9) N/A N/A N/A N/A Load, W (CEVIS) or lb (T2) All 137 (123, 153) 117 (107, 127) 192 (156, 215) 239 (198, 293) 181 (150, 223) 122 (98, 153) Peak 191 (173, 223) N/A 220 (180, 248) 249 (202, 306) 229 (194, 270) 131 (102, 160) Repetitions, number N/A N/A 230 (177, 313) 207 (131, 256) 189 (135, 233) 44 (38, 81) Load volume 5013 (3864, 5763) 2909 (2531, 3279) 38,300 (28,770, 45,855 (32,410, 31,659 (22,745, 4928 (4601, 61,681) 67,364) 46,150) 10,311) N/A not applicable, IQR interquartile range, rpm revolutions per minute, mph miles per hour, W Watts, lb pounds. Data presented as median, IQR Exercise time does not include warm up or cool down time. Load volume, exercise time x all load (aerobic) or reps x all load (resistance). body composition) during preﬂight and postﬂight ground-based leg press power remained below preﬂight values at postﬂight 3 testing (sample size for each endpoint varies due to astronaut (~30 days postﬂight) (Fig. 2). testing schedules; Supplemental Table 2). For each of these four systems, descriptive summaries are shown respectively in Supple- Factors associated with multisystem responses mental Tables 3–6. Estimates of percent change indicate mean We used rank-based Somers’ D to evaluate the association lower leg muscle cross-sectional area and strength were between in-ﬂight exercise and other characteristics with change in signiﬁcantly decreased (p < 0.05); but there was no evidence of a muscle (Fig. 3A), body composition (Fig. 3B), bone health (Fig. 3C), similar change in mean upper body muscle strength (Fig. 1a). On and cardiorespiratory ﬁtness (Fig. 3D) endpoints. This integrated average, cardiorespiratory ﬁtness (VO peak) declined by 7.4% ± matrix facilitates viewing speciﬁc correlations and general trends 2.0% from preﬂight to postﬂight (Fig. 1b). Means of total body across systems. In general, longer mission length was associated mass, lean mass, and fat mass were virtually unchanged postﬂight with greater loss of bone content, lower body muscle strength, (Fig. 1c). Changes in mean bone mineral density (BMD) were and VO peak. Relatively large negative correlations were found moderate, ranging from −2.1% ± 0.7% to −3.7% ± 0.6%; however between age and change in leg power (D = -0.46), leg work much greater declines were observed for bone content in the (D = −0.42), and VO peak (D = −0.23). In contrast, higher trabecular regions [(−5.3% ± 1.6% to −8.5% ± 2.5%); (Fig. 1d)]. resistance exercise volume load was associated with increased lower leg muscle strength and size, bone health, and lean mass, Variability in multisystem responses while treadmill volume was inversely associated with VO peak. There was substantial inter-individual heterogeneity in response Change in bone health was correlated with losses in body weight, across all endpoints. Supplemental Figure 4 outlines exemplar lean mass, and fat mass, indicating that both quantity and quality individual responses for quadriceps size (Supplemental Figure 4A), of exercise are important in maintaining bone health. VO peak (Supplemental Figure 4B), and bone content in trabecula femur (Supplemental Figure 4C). Given the observed variability in Multisystem function and programmatic risk pre to postﬂight change between systems, we next estimated Primary goals of NASA are to protect astronaut health and change effect sizes to quantify signal-to-noise ratios independent performance and to safely and efﬁciently complete mission tasks of sample size, where “signal” is the mean change and “noise” is such as extravehicular activity (EVA) and vehicle egress after the within-subject standard deviation of repeated preﬂight landing back on Earth or on a partial gravity surface. Mission measurements. Estimated effect sizes obtained after ﬁtting performance is associated with speciﬁc absolute and quantiﬁable mixed-model regression show negative effect sizes for 23 4,11,12 physiologic and functional capabilities . We therefore quanti- endpoints with large losses (−1.0 or lower) for cardiorespiratory ﬁed the risk of reduced performance to estimate programmatic ﬁtness, lower-body muscle size and strength, and all bone health endpoints, whereas smaller effect sizes were observed for body risk on future exploration missions to provide operationally critical composition and upper body muscle strength endpoints (Fig. 2). information to NASA program leaders. Clinical thresholds for Of the 11 endpoints that were serially evaluated postﬂight, the reductions in health and performance are likely not directly means of 9 were at or near preﬂight values by postﬂight 2 relevant to the astronaut task performance criteria because of the (~7 days postﬂight); however, mean cardiorespiratory ﬁtness and physical and cognitive demand to perform tasks with extremely npj Microgravity (2023) 11 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; J.M. Scott et al. a. b. -5 -5 -10 -10 -15 -15 -20 -20 VO2peak VE Upper Body Lower Body Leg CSA d. c. -5 -5 -10 -10 -15 -20 -15 -20 Body mass Fat mass Lean mass Fig. 1 Estimates of mean percent change. (a) muscle strength and size; (b) cardiorespiratory ﬁtness; (c) body composition, and (d) bone mineral density and bone content. Data are mean and 95% conﬁdence interval (CI). Endpoint Change pre-flight to R+1 Change pre-flight to R+7 Change pre-flight to R+30 Total mass -0.13 (-1.40, 0.86) Fat mass -0.34 (-6.06, 1.34) Lean mass 0.26 (-0.59, 1.55) VO peak -1.53 (-11.21, -3.55) -1.15 (-8.42, -2.66) 0.13 (-2.35, 3.58) Ventilation -0.48 (-10.15, 1.72) -0.08 (-5.73, 4.25) -0.33 (-8.10, 2.35) Ventilatory threshold 0.20 (-4.57, 7.66) -0.08 (-6.28, 5.14) 0.09 (-6.46, 7.81) DXA Total hip -1.67 (-4.30, -2.28) DXA Trochanter -1.55 (-4.88, -2.51) DXA Femoral neck -0.84 (-3.47, -0.80) DXA L1-L4 -1.51 (-3.61, -1.66) QCT/Trabecular Femoral -1.52 (-8.79, -2.63) QCT/Trabecular Trochanter -1.41 (-8.41, -2.21 QCT/Trabecular Femoral neck -1.41 (-13.41, -3.68) QCT/Cortical Femoral -0.77 (-2.54, 0.08) QCT/Cortical Trochanter -0.88 (-3.21, -0.18) QCT/Cortical Femoral neck -0.36 (-2.98, 1.22) Leg Press Force -0.60 (-10.70, 2.27) -0.23 (-7.57, 4.39) 0.26 (-3.99, 7.62) Leg Press Power -2.36 (-16.43, -7.92) -1.90 (-13.74,-5.81) -0.77 (-8.82, 0.84) Leg Press Work -1.30 (-16.23, -3.34) -0.68 (-11.61, 1.43) -0.04 (-7.36, 6.76) Leg Press 1-RM -0.60 (-7.23, -0.96) 0.23 (-2.66, 5.85) Quadriceps CSA -2.09 (-8.54, -2.95) Hamstrings CSA -2.01 (-7.95, -2.54) Calf CSA -3.03 (-15.75, -7.82) Bench Press Force -0.08 (-5.55, 4.46) 0.20 (-3.39, 6.01) 0.12 (-5.24, 6.88) Bench Press Power -0.15 (-8.19, 4.78) 0.36 (-3.98, 12.03) 0.33 (-5.18, 12.54) Bench Press work -0.27 (-5.54, 2.46) 0.16 (-3.11, 4.94) 0.33 (-2.22, 6.02) Bench Press 1-RM 0.60 (0.32, 6.22) 1.50 (5.50, 10.80) Fig. 2 Estimated effect sizes of change across multisystem function. Effect size estimates are color-coded to reﬂect their signs and magnitudes with darker colors reﬂecting larger losses or gains. Abbreviations: QCT Quantitative Computed Tomography, DXA Dual Energy X-ray Absorptiometry; RM repetition maximum, CSA cross-sectional area, VO peak peak oxygen consumption. Data are mean estimated effect size and 95% conﬁdence interval (CI). Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 11 Change from pre-flight (%) Change from pre-flight (%) Change from pre-flight (%) Change from pre-flight (%) J.M. Scott et al. Fat Mass Lean Mass Leg Arm a. Leg Leg 1 Arm Arm Arm 1 Quad Ham b. Exercise Isometric Leg Work Isometric Calf CSA Power RM Power Work RM CSA CSA Repetitions 0.19 0.05 Force Force Load -0.11 0.21 Exercise Load Volume 0 0.15 Repetitions 0.22 -0.03 -0.08 0.04 0.02 0.33 0.23 0 0.09 0.12 -0.15 Other Load 0.11 -0.1 0.12 -0.11 0 0.05 0.08 0.02 0.03 0.42 0.03 Age -0.16 0.22 Load 0.18 0.01 -0.03 0.04 0.05 0.3 0.3 0.05 0.15 0.12 0.15 Volume Height -0.04 0.04 Other Weight -0.03 0.19 Age -0.08 -0.46 -0.42 0.03 -0.04 0.06 0.04 -0.01 -0.39 0.3 -0.15 Sex (Female) 0.08 -0.17 Height -0.09 -0.09 -0.09 0.11 -0.1 0.2 0.12 0.32 -0.09 0.42 0 Mission 0.15 0.03 Weight -0.1 -0.29 -0.13 0.01 -0.27 0.15 -0.03 0.13 -0.15 0.36 -0.03 Length Fat Mass -0.16 -0.12 -0.08 0.07 -0.35 0.03 -0.23 -0.08 0.09 0.64 -0.09 Lean Mass -0.01 -0.28 -0.14 -0.06 -0.2 0.22 0.05 0.22 -0.09 0.31 0.02 VO peak Ventilation d. Sex 0 0.18 0.11 0.05 0 -0.07 -0.03 -0.18 0.14 0.05 0.08 (Female) Exercise Mission -0.13 -0.24 -0.24 -0.1 -0.29 0.28 -0.04 -0.04 -0.21 0.18 -0.3 Length TM Time above -0.06 0.3 70% BMD BMD BMD BMD L1-L4 Trabecula Cortical Trabecula Cortical Trabecula Cortical c. TM Time above total hip trochanter femoral femur femur trochanter trochanter femoral neck femoral neck -0.14 0.08 90% neck Exercise TM Speed 0.03 0.08 Repetitions -0.1 -0.24 0 -0.15 -0.08 -0.2 -0.13 -0.26 0.06 -0.1 TM Load Volume 0.3 0.08 Load 0.13 0.08 -0.07 0.02 0.07 -0.11 0.05 0.06 0.05 -0.19 CE Time above Load 0.03 0.33 0.22 0.1 0.05 0.06 0.24 0.17 0.24 0.23 0.14 0.04 70% Volume CE Time above Other 0 0.1 90% Age -0.18 -0.12 -0.11 -0.12 -0.13 -0.03 -0.13 -0.15 0.01 0.04 Height -0.14 -0.11 -0.13 -0.23 -0.13 -0.24 -0.1 -0.18 -0.24 -0.32 CE Load Volume -0.03 0.03 Weight -0.14 -0.05 -0.23 -0.09 -0.12 -0.16 -0.12 -0.06 -0.17 -0.18 Other Fat Mass -0.1 0 -0.09 0.1 -0.08 0.18 -0.11 0.31 0 0.05 Age -0.23 -0.1 Lean Mass -0.17 -0.1 -0.23 -0.21 -0.2 -0.27 -0.18 -0.23 -0.18 -0.19 Height -0.09 -0.13 Sex 0.06 0.02 0.16 0.09 0.02 0.2 0.01 0.15 -0.01 0.2 Weight -0.12 -0.03 (Female) Sex (Female) -0.08 0.08 Mission -0.35 -0.36 -0.18 -0.26 -0.42 0.02 -0.46 -0.12 -0.03 0.15 Length Mission Length -0.18 -0.11 Fig. 3 Association between baseline characteristics and inﬂight countermeasures with change in. (a) muscle, (b) body composition, (c) bone health and (d) cardiorespiratory ﬁtness. Correlations are color-coded to reﬂect magnitude with darker colors reﬂecting higher correlation. Abbreviations: RM repetition maximum, CSA cross-sectional area, BMD bone mineral density, TM treadmill, CE cycle ergometer, VO peak peak oxygen consumption, time above 70% and 90%, time in heart rate zone above 70% and 90% of peak heart rate, respectively. Data are rank-based Somers’ D. high mortality risk and small error margin. Consequently, in this Spaceﬂight-induced multisystem deconditioning was a signiﬁ- cant concern observed after even short duration (~14 day) paper we used previous spaceﬂight analog literature to deﬁne thresholds. Speciﬁcally, we deﬁned high risk as a 20% or greater Mercury, Gemini, and Apollo missions . Exercise was selected as a mandatory inﬂight intervention on all missions given its efﬁcacy to reduction in an endpoint because that threshold was associated improve multisystem capacity. Standard-of-care exercise on earlier with signiﬁcant performance decrements in a ground-based ISS missions (2001-2009; mission length: 91 to 215 days) consisted analog study that evaluated simulated EVA and egress task 4,11,12 of combined aerobic and strength training implemented using a performance . We used mixed-model regression to estimate ﬁrst-generation treadmill with vibration isolation and stabilization P , the proportion of astronauts that would be expected to have a (TVIS), CEVIS, and the interim resistive exercise device (iRED). The 20% or greater loss at the ﬁrst postﬂight session. As outlined in treadmill and iRED were, however, limited in speed (max: 11.3 km/ Table 2, P was highest for lower-body work [P = 17%, 95% 20 20 h) and load (max: 136 kg) , and exercise prescriptions therefore conﬁdence interval (CI): 7%, 36%], lower-body power (P = 14%, primarily consisted of high volume (~110 min/day), moderate 95% CI: 6%, 33%), calf muscle size (P = 11%, 95% CI: 3%, 31%), intensity (55%-75% of VO peak or repetition maximum) exercise . and cardiorespiratory ﬁtness (P = 7%, 95% CI: 2%, 22%). P was 20 20 Intriguingly, even with high exercise volumes, bone mineral negligible for all body composition and bone endpoints except for 9 15 density losses , muscle atrophy , and decrements in cardior- the trabecular content of the femoral neck (P = 15%, 95% CI: 6%, 20 16 espiratory ﬁtness were apparent. In 2009, in response to 33%). frequent TVIS and iRED hardware failures and anomalies, the ISS exercise hardware was upgraded to the T2 and the ARED to allow for higher speeds (max: 19.3 km/h) and loads (max: 272 kg). Our DISCUSSION group recently reported that incorporation of high-intensity/lower Here, we provide a comprehensive report of physiological volume exercise prescription in 12 astronauts reduced decrements adaptations to spaceﬂight with contemporary exercise counter- in bone mineral density, muscle strength and endurance, and measures. In addition to demonstrating the exercise interventions cardiorespiratory ﬁtness after long-duration spaceﬂight relative to were not fully protective against spaceﬂight-related multisystem 7 astronauts who exercised with the iRED and TVIS . These ﬁndings, declines, we estimated that up to 17% of astronauts on future together with our current results in a larger cohort of astronauts, missions would have 20% or greater loss in one of more of lower support the notion that current ISS exercise countermeasures body muscle performance, bone health, and cardiorespiratory provide improved protection of musculoskeletal and cardiore- ﬁtness. It is noteworthy that there were declines in almost all spiratory endpoints during long-duration spaceﬂight relative to endpoints, suggesting that the cumulative multisystem decre- previous countermeasures. ments could result in a signiﬁcant impact in the ability to perform Nevertheless, the results here indicate that current exercise physically demanding mission tasks. countermeasures appear insufﬁcient to maintain preﬂight npj Microgravity (2023) 11 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA J.M. Scott et al. 20 21 metabolic health and muscle , but not against cardiac, or bone Table 2. Proportion of astronauts that would be expected to have a changes . Recapitulation of ground-based loading cycles of daily 20% or greater loss at the ﬁrst postﬂight session. activities during 84 days of bed rest attenuated, but did not eliminate, the decline in several musculoskeletal and cardiovas- Endpoint P 95% Conﬁdence interval cular health parameters . Nevertheless, ﬁndings from systematic reviews indicate that nutritional countermeasures could amelio- Muscle strength, power, and size 24 rate musculoskeletal and cardiopulmonary deconditioning , Leg Press Work 17.3 7.5 36.0 while ﬁndings from bed rest studies indicate that including Leg Press Power 14.5 5.8 32.7 plyometric exercise (hopping and whole body vibration) may be adjunct options to mitigate musculoskeletal loss on exploration Bench Press Power 12.7 4.8 30.1 missions where resources are limited . Finally, lower body Calf CSA 10.9 3.2 30.9 negative pressure (LBNP) coupled with exercise could offset the Leg Press Force 8.8 2.8 24.9 spaceﬂight-induced headward shift in vascular and cerebrospinal Bench Press Work 3.6 0.9 14.3 ﬂuid and mitigate declines in cardiorespiratory ﬁtness . To this Bench Press Force 2.2 0.4 11.2 27,28 end, Lee and colleagues demonstrated that LBNP and exercise Leg Press 1RM 2.0 0.6 6.0 maintained cardiorespiratory ﬁtness during 30 days of bed rest. Bench Press 1RM 0.5 0.1 2.6 Two additional points are noteworthy. First, the large collection of correlational data in Fig. 3 provides several intriguing Quadricep CSA 0.1 0.0 3.8 conceptual views. Sex was not associated with any meaningful Hamstring CSA 0.0 0.0 2.1 correlations suggesting that female astronauts are not at a Cardiorespiratory ﬁtness disadvantage with respect to response to exercise counter- Peak Workload 12.7 4.4 32.3 measures. However, age and mission length were important VO peak 7.3 2.3 22.2 predictors, inversely associated with bone content, lower body Ventilation 6.6 1.9 21.8 muscle strength, and VO peak. As evidenced by inverse correla- Ventilatory threshold 0.0 0.0 2.1 tions with mission length, many bone endpoints were vulnerable to increasing mission duration. Resistance and treadmill volume Body composition loads were the key countermeasure factors associated with Fat mass 4.0 1.5 9.9 improved strength, bone, body composition, and cardiorespira- BMD trochanter 0.0 0.0 0.0 tory endpoints. These ﬁndings are important for the design of BMD femoral neck 0.0 0.0 0.0 exercise devices and prescriptions for longer-duration exploration BMD total hip 0.0 0.0 0.0 missions that require mid-mission performance in partial gravity BMD L1-L4 0.0 0.0 0.0 environments, and underscore that many individual character- Body mass 0.0 0.0 0.0 istics, as well as spaceﬂight factors beyond those characterized in our study, likely inﬂuence physiologic responses. Lean mass 0.0 0.0 0.0 Second, the tools employed here provide an evidence-based Bone Volume method to evaluate the likelihood that astronauts will maintain Trabecula Femoral neck 14.7 5.8 32.7 threshold performance levels. We found the proportion of Trabecula Femur 2.2 0.5 9.4 astronauts that could have a 20% or greater loss at the ﬁrst Trabecula Trochanter 1.8 0.4 8.6 postﬂight session was highest for lower body muscle size and Cortical femoral neck 0.0 0.0 0.0 strength endpoints. These ﬁndings, together with the inverse Cortical trochanter 0.0 0.0 0.0 association between age and change lower body endpoints, suggest additional countermeasures targeting the lower body Cortical femur 0.0 0.0 0.0 may be needed for older astronauts. Whether adjunct interven- RM repetition maximum, CSA cross sectional area, VO2peak peak oxygen tions could mitigate spaceﬂight-related changes in lower body consumption, BMD bone mineral density muscle strength and size is not known. However, interventions Values are %, 95% conﬁdence interval. such as protein supplementation and anti-inﬂammatory drugs could synergize with exercise training to offset the blunted physiological and functional status and that additional optimiza- 29 anabolic response to exercise training in older individuals . ISS tion may be necessary to fully offset spaceﬂight-induced decline. EVAs are long-duration activities (up to 8 hours) and require a high During future missions, astronauts will likely be exposed to level of cognitive effort, but they are relatively low physical prolonged periods of microgravity and then exposed to Lunar intensity (~30% of maximal effort) and infrequently performed (~3 gravity. It is not known whether the transition from prolonged EVAs per 6-month mission). Oxygen utilization is monitored periods in microgravity to Lunar gravity will constitute signiﬁcant during all ISS EVAs from a safety perspective and the overall EVA health and safety risks; however, based on ﬁndings from Apollo intensity is dependent on the crewmember and the speciﬁc tasks missions it is likely that astronauts will experience orthostatic comprising the EVA . In comparison, partial gravity EVAs on the intolerance, balance problems, and spatial orientation chal- 17 lunar surface not only will be more frequent (up to 3 to 4/week, lenges . Future exploration missions to the Moon or Mars will and up to 24 total hrs per week) and performed on unknown and also require physiologically demanding tasks such as constructing irregular terrain, but also will require new unrehearsed tasks with habitats and operating geologic equipment . Finally, these complex logistics and a higher level of physical and cognitive missions may also include return (splashdown) in the ocean, demand for some tasks (e.g., ambulation, habitat construction, where astronauts may be required to perform physiologically geological sampling). Collectively, the ﬁndings herein can be used demanding egress tasks unaided . Thus, additional counter- to understand task performance expectations, to select feasible measures may be required to offset spaceﬂight-induced decondi- tioning. For instance, during 70 days of bed rest (a spaceﬂight and acceptable tasks for crew to perform, and to identify areas analog), exercise and nutrition countermeasures coupled with where additional technology or hardware is needed to assist with low-dose testosterone were protective against decrements in task performance. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 11 J.M. Scott et al. Perspectives to optimize astronaut health, safety, and performance on future exploration missions to the Moon and Mars. These ﬁndings highlight the need to better personalize counter- measures to target the endpoint of interest for each individual astronaut. To this end, several important research gaps should be METHODS addressed to optimize astronaut health, safety, and performance on Overview of research design long-duration missions. For example, the stratiﬁcation of astronauts All National Aeronautics and Space Administration (NASA), into homogeneous subgroups based on preﬂight and inﬂight Canadian Space Agency (CSA), European Space Agency (ESA), characteristics should be performed to investigate whether targeted and Japan Aerospace Exploration Agency (JAXA) astronauts exercise prescriptions could improve individual responses .Addi- assigned to ISS ﬂight were eligible to participate in this tional research evaluating multimodal exercise, nutrition, and other investigation. This study was approved by the Institutional Review adjunct interventions are also needed. Finally, model systems such Board at NASA Johnson Space Center (JSC, Houston, TX), the as human induced pluripotent stem cells, organoid, and organ-on-a- Japan Aerospace Exploration Agency (JAXA) Institutional Review chip technologies should be leveraged to evaluate whether an Board, the European Space Agency (ESA) Medical Board, and the astronaut’s own cells could allow for the development of Human Research Multilateral Review Board. All astronauts personalized countermeasures prior to spaceﬂight, or modiﬁcation completed standard preﬂight medical screening, received clear- of countermeasures during exploration mission . ance from ﬂight surgeons, and provided written informed consent before participating in the study. All astronauts included in this Limitations paper performed the standard medically required physiologic Our study limitations require consideration. First, this study tests involving muscle strength, aerobic ﬁtness, and bone health; a represents a large cohort of astronauts on long-duration space- subset performed additional experimental tests of muscle ﬂight missions; however, relative to ground-based trials this strength and size, aerobic ﬁtness, and bone health. Inﬂight represents a relatively low number of participants. Second, exercise and nutrition data were collected throughout the because exercise is a mandatory intervention for all astronauts astronauts’ missions. Supplemental Figs. 1–3 are courtesy of NASA on ISS missions, the effects of exercise on multisystem function (https://www.nasa.gov/multimedia/guidelines/index.html) and the during spaceﬂight relative to a non-exercise control are not authors afﬁrm that human research participants provided known, which may impact quality of evidence of human exercise informed consent for publication of the images in NASA image training studies during spaceﬂight . Although ﬁndings from gallery. ground-based studies using spaceﬂight analogs such as bed rest indicate that exercise mitigates a substantial amount of decondi- Participants and facilities tioning , there was considerable variability in the actual exercise Testing for this study was performed during ISS Increments 26S- performed with respect to the standard exercise prescription 50S (April 2011 – September 2017). 46 astronauts (37 males, 9 parameters of intensity, duration and frequency. Third, although females; age: 46.8 ± 6.1 y, height: 176 ± 7.1 cm, weight: we included numerous endpoints spanning multiple systems, 79.2 ± 9.9 kg [mean ± SD]) were assigned to missions of 178 ± 48 standard measures did not include endpoints related to recently d. This study was approved by the Institutional Review Board at identiﬁed health concerns such as Spaceﬂight-Associated Neuro- NASA Johnson Space Center (JSC, Houston, TX), the Japan Ocular Syndrome (SANS) . Updated standard measures for ISS Aerospace Exploration Agency (JAXA) Institutional Review Board, astronauts, however, include a breadth of additional core the European Space Agency (ESA) Medical Board, and the Human measurements related to cardiovascular, immunology, microbiol- Research Multilateral Review Board; all subjects provided written ogy, and biochemistry. Additional research is needed to evaluate informed consent before participating in the study. All astronauts the effects of countermeasures on systems not evaluated in the completed standard preﬂight medical screening and received present study. Fourth, countermeasures consisted of exercise on clearance from their ﬂight surgeons before participating in the three different devices designed for use on the ISS. The feasibility tests included in this study. We acknowledge that some astronauts and efﬁcacy of exercise on exploration class exercise hardware, included in this study were also participants in other studies . The such as ﬂywheel devices (currently planned for early Artemis 22 goal of this paper however is to report multisystem adaptations to missions) could differ . Finally, other uncontrolled confounders spaceﬂight from a large cohort of astronauts, and as such we such as diet composition, pharmacological use, and degree of included all available astronaut health data. radiation exposure could also contribute to the observed heterogeneity in physiological changes. Countermeasures Inﬂight aerobic exercise was performed using the second- CONCLUSIONS generation treadmill (T2) and the Cycle Ergometer with Vibration In summary, we found that ~600 min/wk of aerobic and resistance Isolation System (CEVIS), and resistance exercise was performed exercise during International Space Station missions was not fully with the ARED . Resistance exercise was prescribed 3-6 d/wk and protective against multisystem deconditioning in the overall aerobic exercise was prescribed 5-6 days per week. T2 was astronaut cohort. Near-future exploration class missions will not modiﬁed from a commercial Woodway Path treadmill (Woodway, have an ISS-like suite of exercise hardware. One of the most notable Waukesha, WI) to support walking and running exercise between -1 differences is that no treadmill is planned for the initial phase of 2.4 and 19.3 km·h . The user is loaded via a shoulder and waist Artemis missions and the resistance exercise load quality may not be harness which is attached to bungee cords and terminally, the comparable to the ISS ARED. Exploration upmass, power, and treadmill deck surface. CEVIS operates similarly to a standard cycle volume limitations combined with the requirements for astronauts ergometer providing workloads between 25 and 350 W at pedal to perform more physically and cognitively demanding exploration speeds from 30-120 revolutions per minute. Crewmembers wore tasks with increased autonomy (less ground-based support) high- cycling shoes that snapped into the pedals and strapped light the necessity to develop integrated and optimized counter- themselves with a belt to the CEVIS frame or used the frame measures targeted at protecting human performance. Our ﬁndings handles to remain appropriately positioned on the cycle. ARED provide important information regarding countermeasures for simulates free weights with a constant load of 11–272 kg provided spaceﬂight and suggest multimodal interventions will be required by vacuum cylinders and an inertial load effected by ﬂywheels npj Microgravity (2023) 11 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA J.M. Scott et al. placed in the load path; both barbell and cable exercises can be Start and stop time stamps are part of the exercise data stream. performed . For resistance exercise, exercise time was based simply on the Generally, aerobic exercise was 30-60 mins in duration and start and stop time. Total exercise time was estimated including either prescribed as continuous steady exercise or in intervals. warm-up and cool-down times. Resistance exercise prescriptions were approximately 60 min in 11 crewmembers used a weekly Food Frequency Question- duration and included upper and lower body exercise with the naire . 12 crewmembers used an excel spreadsheet to log all core group of exercises, including squats, deadlift, heel raise, intake, and more recently 20 crewmembers used an iPad App, the bench press, overhead press, and upright rows. The program ISS Food Intake Tracker (ISS FIT). Nutrient intake data were typically consists of 1.5–2.0 h per day total of aerobic and determined using Nutrition Data System for Research software resistance exercise, each performed 6 d per week. Although versions 2007, 2010, 2012, and 2014, developed by the Nutrition 2.5 h are scheduled for daily exercise on the ISS , typically, Coordinating Center, University of Minnesota. exercise time was divided into 30-45 min of aerobic training and 60–75 min of resistance training with hardware conﬁguration and Endpoints post-exercise hygiene comprising the remainder of total allotted Most of the astronauts (n = 38) performed the bench press time. Aerobic training consisted of interval or continuous steady- 1-repetition maximum and leg press 1-repetition maximum 60 to state exercise on either CEVIS or T2. CEVIS protocols were 90 days before ﬂight, 5 to 7 days after landing, and once more developed using the preﬂight VO peak test with prescribed work 30 days after landing as previously described . Brieﬂy, to obtain a rates (W) between 70-100% VO peak. ASCRs adjusted the 1 repetition maximum for leg press, crewmembers completed a protocols throughout the mission based on individual perfor- warm-up at ~50% load for 10 repetitions, the load was increased mance during training sessions and crew feedback. T2 protocols 15–20% each set with decreasing repetitions until the subject were based on preﬂight training and prescribed at 70–100% could only complete 1 repetition at which point the load was HR . For most crewmembers, external (harness/bungee) loading max increased 5–10% until failure. Participants rested 3–5 mins began at 60% bodyweight (static load measured when standing between sets. To obtain a 1 repetition maximum for bench press stationary on the treadmill belt) and increased as tolerated crewmembers completed a warm-up at ~30% load for 10 throughout the mission. Resistance training followed a 9-day repetitions, the load was increased 10-20% each set with periodized program with linear progression of loads and decreasing repetitions until the subject could only complete 1 undulating volume across two 12-week mesocycles. After a two- repetition at which point the load was increased 5-10% until week acclimatization period, loads were set at 70% of the failure. repetition-maximum (RM) prescribed for that session (e.g., for a A subset of the astronauts (n = 17) completed additional tests 4 ×6 repetition session, loads in Week 3 were 70% of 6-RM) with of upper and lower body muscle strength and performance 60 to loading intensity increasing 5% each week. Strength increases 90 days before ﬂight and up to 39 days after landing, categorized over the ﬁrst mesocycle allowed most crewmembers to reach into 3 postﬂight phases: (Post1: R + 1, R + 2; Post2: R + 6toR + 9, intensities of 110-120% of their early mission repetition- Post3: R + 25 to R + 39). Lower body muscle performance was maximums by Week 12. For the second mesocycle, loads were determined before and after spaceﬂight using a leg press and reduced to 70% of the crewmember’s new repetition-maximum bench press test battery recently developed in our laboratory . and the progression of the ﬁrst mesocycle was repeated. A Modiﬁed and instrumented leg press and bench press stations variation of squat, deadlift, and heel raises were each prescribed were used to assess isometric strength and dynamic power as daily for control subjects followed by rotating exercises focusing previously described . To measure upper and lower body on upper body and stability musculature. isometric strength, subjects performed 3 maximal efforts for 5 s Aerobic exercise endpoints were CEVIS and T2 average session −1 each with 30 s of rest between each effort. To assess upper and duration and average HR (b·min and % maximum) for 30 s, lower body dynamic power and work capacity, subjects 2 min, and 4 min intervals, and continuous sessions. Session performed 21 consecutive ballistic, concentric-only bench press durations and heart rate parameters were calculated for the and bilateral leg press actions with the load ﬁxed at 30% (bench periods of “active” exercise time on the cycle ergometer or press) and 40% (leg press) of the measured maximal isometric treadmill, i.e., excluding warmup and cooldown periods at the force (MIF), which has previously been shown to elicit maximal beginning and end of each session, and containing only the power output . A magnetic brake (Fitness Technology) was used interval/continuous exercise period and the time between to catch the weight as soon as the sled reached its peak height so intervals. The %maximum HR parameter was calculated as the that no eccentric muscle actions were performed. Power and total average HR of the individual exercise sessions for that crew work were calculated . member, divided by the crew member’sHR (determined pre- max Cross-sectional area (CSA) of the lower leg muscles was ﬂight as part of Peak Aerobic performance testing), then multi- obtained from MRI scans pre and postﬂight on 12 astronauts. plied by 100%. For resistance exercise, total volume was calculated Images were acquired from the level of the ankle mortise to the for each subject for the categories of squat, heel raise, and deadlift iliac crest. The methods and reliability of this technique have been exercises, then normalized to mission duration (total volume/ previously reported by our laboratory . Muscle cross-sectional mission duration in days). Warmup exercises were not included in area was manually traced using Image-J (National Institutes of the data set. The 3 exercise categories included the following Health, Bethesda, MD, USA, version 1.42) . variations: “squat”: back squat, single leg squat, sumo squat; “heel Cardiorespiratory ﬁtness was evaluated during upright peak raise”: heel raise and single leg heel raise; “deadlift”: deadlift, cycle ergometry tests (Lode Excalibur Sport; Lode B.V., Groningen, Romanian deadlift, and sumo deadlift, and bench press. For each the Netherlands) performed once or twice before launch (between exercise category, total volume was calculated for each subject by L-90 d and L-28), and between 2 and 4 days after landing. The summing the volume (load x reps) for across the entire mission. In protocol consisted of a 3-minute warm-up at 50 W, followed by addition, average load (kg), average relative load (kg·kg body- -1 1-minute stepwise increments of 25 W to volitional fatigue. Heart weight ), average repetitions per session, and average repetitions rate (HR) and heart rhythm were monitored continuously (GE per week were calculated for each subject for the 3 exercise CASE, GE Healthcare, Chicago, IL). Ventilation and expired gas categories. Aerobic and resistance exercise training variables were recorded and are presented descriptively. Aerobic time spent fractions (F O and F CO ) were measured continuously using the E 2 E 2 exercising was based on the start and end times of the main set of Portable Pulmonary Function System (PPFS) as previously exercise and did not include warm-up and cool-down periods. described .VO peak was deﬁned as the highest 30-s average Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 11 J.M. Scott et al. and was conﬁrmed by the attainment of at least two of three Statistical Methods criteria: 1) respiratory exchange ratio of > 1.09; 2) heart rate >90% For each of the physiological and performance endpoints of age-predicted maximum; 3) a plateau in VO (an increase of < (Supplemental Table 2) mixed-model linear regression was used −1 150 mL · min ) from the previous stage. Ventilatory threshold to estimate the mean response at each time point. These models was deﬁned as the point at which VCO began to increase work well to adjust for random data dropout, as is pervasive in this disproportionate to VO and V /VO increased with no concomi- 2 E 2 observational study. To compensate for non-normality of resi- tant increase in V /VCO . E 2 duals, bootstrapping (200 samples) was used to obtain improved Dual Energy X-ray Absorptiometry (DXA) scans were obtained estimates of the standard-error matrix. For each postﬂight session using a single densitometer (Hologic Discovery; Hologic Inc., (k), the percent change in the mean was estimated by PCT ¼ μ ^ μ ^ k 0 Waltham, MA, USA). Two bone densitometry technologists, 100 ´ where μ is the estimated mean at the k-th postﬂight ^ k certiﬁed by the International Society for Clinical Densitometry session, and μ ^ is the estimate of the preﬂight mean. In addition, (ISCD), performed and analyzed the scans. For a given crewmem- we estimated the effect size at each postﬂight session by μ ^ μ ^ ber, a single technologist performed both the pre and postﬂight k 0 ES ¼ 100 ´ , where σ^ is the estimated within-subject σ^ scans. Scans were performed at approximately 90 days preﬂight standard deviation. The delta-method was then used to obtain (L-90) and again 1-2 weeks after landing (R + 7). At each test approximate standard errors of PCT and ES along with 95% k k session, the following fan-beam DXA scans were performed: left conﬁdence limits. In addition, as measure of programmatic risk, and right hip, lumbar spine, whole body, and left heel. Scans were we also used mixed-model regression, this time to estimate P , performed and analyzed according to standard procedures the proportion of study subjects that would be expected to have a recommended by the manufacturer, except for hip and heel 20% or greater loss at the ﬁrst postﬂight session. It is not feasible scans. As reported for previous spaceﬂight and bed rest to use the raw data directly to calculate this proportion because of 44,45 studies , the global region of interest box for the hip was the relatively few numbers of subjects and the variability of the positioned manually, with the lateral margin placed adjacent to preﬂight baseline measurements. Instead, we used another the lateral cortex of the greater trochanter and the distal border version of the mixed-model, but applied to the preﬂight and ﬁrst placed a set number of lines from the lesser trochanter’s distal postﬂight data along with the possible inclusion of (a) a postﬂight margin. Heel scans were obtained using the forearm scan mode, random interaction (the variability of the slopes in Supplemental with the subject seated on the scanner and the foot restrained in a Figure 4 where the slopes are considered “random” because they lateral position within a custom jig. In addition to areal bone vary unpredictably between subjects) as well as (b) the inclusion mineral density (BMD, g� cm ) obtained from the scans listed of body weight as a covariate. Depending on the endpoint, above, whole body and regional lean mass (fat-free, bone-free neither, either, or both of (a) and (b) were used in the model as mass) and fat mass were determined from the whole body scans decided by an automated process based on model-ﬁt criteria. The using standard Hologic analysis software. The BMD precision delta method was also used to obtain a standard error and 95% values (Least Signiﬁcant Change, 95% conﬁdence limit) for the conﬁdence limits for P . All model ﬁtting was done using Stata scanning laboratory were as follows: total hip, 2.1%; trochanter, Statistical Software. Given the many predictor and response 3.0%; femur neck, 3.9%; lumbar spine, 2.3%; heel, 2.5%; and whole variables, we elected to portray groups of associations in a holistic body, 2.8%. Precision (Least Signiﬁcant Change, 95% conﬁdence way as opposed to identifying which speciﬁc predictors appear to limit) of soft tissue values from the whole body scans were: whole affect a speciﬁc response. Association between change in body lean mass, 2.5% and whole body fat mass, 5.9%. Calibration endpoint variables and inﬂight predictor variables was quantiﬁed of the Hologic densitometer was veriﬁed by regular scanning of a in terms of the rank-based Somers’ D to allow for non-linearity calibration phantom (at least weekly as well as on the day of and control the effect of outliers. subject testing), with scans analyzed using the manufacturer’s automated software. Reporting summary Pre- and postﬂight CT scans were performed at a local hospital Further information on research design is available in the Nature radiology center, using a single scanner (General Electric Portfolio Reporting Summary linked to this article. Advantage QXi) for all subjects. A single helical CT scan at each test session was used to image both the left and right hips (2.5- mm sections at 80 Kvp, 2880 mA), with a calcium hydroxyapatite DATA AVAILABILITY phantom placed under the subjects’ hips during the scan as a Data from this study may be obtained through a data request to the NASA Life reference standard. CT images were transferred to a computer Science Data Archive (https://lsda.jsc.nasa.gov/Request/dataRequest). workstation and processed to extract measures of volumetric BMD (vBMD) using analysis techniques described previously . Proces- Received: 26 July 2022; Accepted: 10 January 2023; sing included a step to calibrate the CT images from the native scanner Hounsﬁeld Units to equivalent concentration (g/cm )of calcium hydroxyapatite (HA) and determination of trabecular, cortical, and integral regions of interest for each of the left and right proximal femurs. 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Perform. 86,A7–A13 (2015). material in this article are included in the article’s Creative Commons license, unless 36. Loehr, J. A. et al. Musculoskeletal adaptations to training with the advanced indicated otherwise in a credit line to the material. If material is not included in the resistive exercise device. Med Sci. Sports Exerc 43, 146–156 (2011). article’s Creative Commons license and your intended use is not permitted by statutory 37. Smith, S. M., Zwart, S. R., Block, G., Rice, B. L. & Davis-Street, J. E. The nutritional regulation or exceeds the permitted use, you will need to obtain permission directly status of astronauts is altered after long-term space ﬂight aboard the Interna- from the copyright holder. To view a copy of this license, visit http:// tional Space Station. J. Nutr. 135, 437–443 (2005). creativecommons.org/licenses/by/4.0/. 38. Laughlin, M. S., Guilliams, M. E., Nieschwitz, B. A. & Hoellen, D. Functional Fitness Testing Results Following Long-Duration ISS Missions. Aerosp. Med. Hum. Perform. © The Author(s) 2023 86, A87–A91 (2015). Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 11
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