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Metabolic rate comprises the consumption of fuel and oxygen (O₂), which produces carbon dioxide (CO₂), work, and heat. Food provides the metabolic fuel for humans, and typical energy consumption for a 70 kg adult man aged 30–59.9 years engaged in moderate daily activity is 2,750 kilocalories/day, 190 kJ/day, or 11.4 MJ (3,166.67 W-hours) (Food and Agriculture Organization of the United Nations, 2004). Oxygen consumption is proportional to the fuel consumed in aerobic metabolism, and a resting adult consumes about 3.5 mL O₂/kg/min (1 metabolic equivalent, MET) (Food and Agriculture Organization of the United Nations, 2004; Jetté et al., 1990). This rate can increase briefly to more than 10 METs during vigorous exercise (Jetté et al., 1990). Differing amounts of CO₂ are produced for each unit of O₂ consumed, depending on the proportion of fuel sources (fat, carbohydrate, or protein). Assuming humans sleep 7–8 h per 24-h day (∼30%), their metabolic rate is expected to be around 1.0 MET (Jetté et al., 1990). During waking hours, even quietly working humans will have a mean metabolic rate of 1.4 METs. (Jetté et al., 1990). Thus, daily energy consumption will average (30% x 1.0 METs) + (70% x 1.4 METs) = 1.3 METs.

We speculate that increasing the proportion of sleep time to 80% of the day will reduce the average metabolic rate: (80% x 1.0 METs) + (20% x 1.4 METs) = 1.1 METs. By itself, this change in the proportion of sleep time from 30% of the day to 80% of the day would afford a 20% reduction (from 1.3 to 1.1 METs) in total fuel and oxygen consumption each day (Figure 1A, B).

Anesthetic drugs can further reduce metabolic rate below quiet resting rates. We speculate that drug-induced sleep could allow metabolic rate to decline below 1.0 METs. For an individual who is sleeping 80% of the day, modest reductions in resting metabolic rate can provide significant savings in fuel and O₂ consumption. For example, a 20% reduction in resting metabolic rate from 1.0 METs to 0.8 METs would reduce average metabolic rate: (80% x 0.8 METs) + (20% x 1.4 METs) = 0.9 METs. Thus, the combination of prolonging sleep to 80% of the day and metabolic reduction of 20% during sleep, would reduce overall fuel and O₂ consumption by 30% (from 1.3 to 0.9 METs) (Figure 1C).

Reduction of temperature also decreases metabolic rate by slowing the chemical reactions throughout the body. We have measured a 5.2% reduction in O₂ consumption for each 1°C decrease in core body temperature in sedated healthy volunteers for whom drugs inhibited shivering (Flickinger et al., 2024). Similar reductions in cerebral metabolic rate have been reported under general anesthesia (Michenfelder and Milde, 1991). It is conceivable that reducing core body temperature would further decrease resting metabolic rate and could amplify the metabolic reduction provided by anesthetic drugs.

There are at least three important practical considerations for implementation of an anesthetic-induced reduction in metabolic rate as a spaceflight countermeasure. First, drug administration should be minimally invasive. Peripheral intravenous catheters used in hospital care have a failure rate of 4%–9% per day (Takahashi et al., 2020). While central venous catheters may have a lower failure rate of 0.3% per day, they are more complex to insert and have thrombotic and infectious complications (McManus et al., 2024). Maintaining intravenous catheters for long-duration spaceflight is impractical. Therefore, to avoid intravenous drugs, we sought an oral, mucosal or transcutaneous drug regimen. Second, mechanical support of respiration is complex and hazardous. Non-invasive ventilation can avoid invasive airway management, but it also has failure rates of 30%–70% when used for acute respiratory failure (Rolle et al., 2022), and over 20% incidence of adverse events when used for chronic respiratory conditions (Wilson et al., 2020). Therefore, we sought a drug that produces minimal respiratory depression. Third, constant sedation requires plans to manage urine, solid waste, and nutrition. In medical settings, catheters to manage these needs also have high failure rates and complications (Gomes et al., 2015). Therefore, we targeted a regimen that included some waking time during each 24-h period during which a participant could self-manage nutrition and excretion.

We planned a three-phase study to 1) test the dosing and metabolic effects of a non-intravenous A2AR agonist for light sedation during a 6-h laboratory visit; 2) assess the degree of metabolic reduction achieved by our selected drug over a 24-h laboratory visit; and 3) evaluate the tolerability and feasibility of the protocol, as well as the ability to reduce metabolic rate and increase sleep time to 80% over five experimental days. The primary outcome for these experiments is the change in metabolic rate during the intervention relative to baseline. We measure the baseline resting metabolic rate in each participant prior to initiation of the drug, and then observe the change in metabolic rate over time following drug administration. We collect an array of physiologic data as well as blood samples for pharmacokinetic analysis. Participants complete serial psychophysiological batteries. We use performance and non-invasive muscle composition measures to assess changes in muscle health and function.

In Phase 1 and Phase 2 experiments, we measure O₂ consumption and CO₂ production captured via canopy (during rest) or facemask (during exercise) using a Parvo TrueOne 2400 metabolic cart (Parvo Medics, Salt Lake City, UT, United States). The difference between ambient and exhaled CO₂ and O₂ values allows calculation of oxygen consumption (VO₂), CO₂ production (VCO₂), respiratory exchange ratio, and total energy expenditure (de and Weir, 1948). In Phase 3, we measure changes in metabolic rate using both serial indirect calorimetry assessments via the Parvo metabolic cart as well as the gold-standard doubly labeled water method.

Additional physiologic measurements include electrocardiogram, respiratory rate, pulse plethysmography, blood pressure, and core temperature. We use an ingested telemetry capsule (eCelsius, BodyCap, Herouville Saint-Claire, France) to continuously capture gastrointestinal core temperature. In Phase 1 experiments we examined heat flux from the body surface using one-cm² sensors on the forehead, torso, arm and leg; we collected respiratory rate using a circumferential chest belt; and we used bioreactance to measure cardiac stroke volume and estimate cardiac output. We simplified our array of physiologic sensors and monitoring for longer Phase 2 and Phase 3 experiments for subject comfort, and focused on collecting continuous electrocardiogram, pulse plethysmography, and core temperature with serial blood pressure measurements.

We measure changes in muscle composition using electrical impedance myography (EIM, Myolex device, Myolex, Boston, MA, United States), a non-invasive method to measure muscle fiber consistency based on the properties of electrical impedance and capacitance that can be altered by free water, connective tissue, and fat (Sanchez and Rutkove, 2017; Rutkove and Sanchez, 2019). EIM allows us to evaluate changes in muscle composition over time and is highly reproducible. Previously, EIM has been employed to measure changes in muscle composition and health in neurodegenerative diseases like amyotrophic lateral sclerosis (Tarulli et al., 2009), and has been used in rats to measure changes induced by partial weight-bearing and hindlimb suspension models of atrophy that simulate weightlessness-induced muscle changes, (Mortreux et al., 2018),^, (Mortreux et al.),^, (Mortreux et al., 2019a; Semple et al., 2020), as well as in mice in low earth orbit (Sung et al.). Presently, we are using EIM as a virtual muscle biopsy (Mortreux et al., 2019b) in Phase 2 and Phase 3 experiments to track changes in muscle groups highly susceptible to unloading/disuse atrophy: Tibialis Anterior, Gastrocnemius, Quadriceps Femoris, Biceps Brachii. For our experiments, EIM is obtained prior to drug initiation and again prior to exercise at Time 23-h post drug initiation.

We also conduct functional strength assessments measuring changes in isokinetic muscle strength and mean power (e.g., changes in peak torque and concentric/eccentric velocity) to assess muscle health and function for Phase 2 and Phase 3 experiments. Grip strength, considered the simplest strength test and a vital sign of health to follow over time, is obtained at baseline (using a Jamar dynamometer, Chicago, IL, United States) and at the end of each drug administration period in Phase 1, 2, and 3 experiments.

During the 5-day protocols, we collect plasma and urine samples to measure changes in creatinine kinase M, nitrogen, 3-methylhistidine, glucose, and ketones as surrogates for catabolic or anabolic states. We hypothesize that the increased proportion of low activity time, combined with reduced caloric intake, could result in a catabolic state.

Finally, we employ a suite of computer-based psychometric tests to assess attention, memory, information processing, and fine motor skills (Joggle Research, Seattle, WA, United States) (Basner et al., 2015) as well as multidomain performance under increased task load (Multiple Attribute Test Battery-II). (Hart, 2006).

It is well known that astronauts generally have decreased sleep length on mission despite allowance for 8-h rest cycles (Dijk et al., 2001; Jones et al., 2022; Stampi, 1994). Astronauts demonstrate desynchronization of hormonal and activity rhythms from the artificially prescribed circadian schedule during space flight, resulting in cumulative sleep deprivation (Dijk et al., 2001). Hence, sleep medications are the second most commonly used medications during low earth orbit missions. (Dijk et al., 2001; Barger et al., 2014) We chose to maintain a 24-h earth-based cycle but alter the rest period by increasing rest time to 20-h with 4 hours of activity for our Phase 2 and 3 proof-of-concept ground-based studies. This choice allowed us to maximize potential metabolic reduction during the rest time while minimizing overall alterations in the 24-h earth-based cycle. It also simplified scheduling of laboratory activities. Because any quasi-torpor intervention could dramatically disrupt many circadian rhythms, alternative rest:activity ratios and total times should be investigated. For example, Mars has a 24.6-h day and synchronizing to the destination clock might optimize crew performance and wellbeing. Alternatively, longer rest:activity cycles, such as 30 or 36 h, might maximize metabolic savings.

Longer sleep durations have positive effects on astronaut neurobehavioral functioning in low earth orbit missions, (Dijk et al., 2001; Jones et al., 2022) yet too much sleep may indeed be detrimental to astronaut wellbeing or perceptions thereof. We hypothesize that longer durations of rest will reduce the opportunities for crew conflict and dysphoria from confinement on long-duration space missions in cramped quarters, in addition to reducing consumable requirements. However, extensive cognitive and psychological testing will need to be performed to determine whether a prolonged sleep strategy truly provides psychological benefit. Furthermore, sleep architecture is known to be altered during low earth orbit missions (Dijk et al., 2001; Koller et al., 2021; Monk et al., 1998) and it is unknown if a sedation-induced prolonged sleep countermeasure strategy affects sleep architecture. We are collecting limited electroencephalographic data during the 5-day protocols, but longer-term monitoring is necessary for more robust assessments of sleep architecture. This highlights a critical knowledge gap to our protocol and any similar countermeasure strategy.

Exercise is presently the main approach to reduce muscle atrophy that occurs due to unloading of the body during low earth orbit space missions. Aerobic exercise is the primary countermeasure for protection from aerobic deconditioning (measured by pre-flight to post-flight changes in maximal oxygen consumption, VO_2max). Yet appreciable declines in VO_2max and general aerobic conditioning still occur and knowledge gaps regarding optimization of exercise protocols for long-duration space missions remain (Rivas et al., 2023). Additionally, aerobic exercise is metabolically demanding and it is unknown how it might impact the metabolic reduction desired during a quasi-torpor state. Resistance exercise training, which is used to minimize muscle atrophy and preserve muscle strength and quality (Rivas et al., 2023), also attenuates VO_2max losses as well as muscle atrophy in ground-based bed rest analogs and during space flight (Ploutz-Snyder et al., 2018; Stremel et al., 1976; Engelke et al., 1998; Greenleaf et al., 1989). Therefore, designing a less metabolically expensive protocol focused on resistance exercise could protect muscle architecture and function as well as reduce the decline in VO_2max during long-duration space missions. We developed a specific exercise protocol (Table 1) built around devices with small physical footprints, and we are monitoring the metabolic cost of this protocol during our trials. The flywheel and the isometric ball used in this protocol conform to the space restrictions expected on Artemis and Mars missions. Comparing the muscle-preserving efficacy of this metabolically less-costly protocol to current aerobic protocols will be an important future study.

Appropriate nutrition during long-duration space missions can also help to prevent muscle atrophy and ensure astronauts’ safety and mission success. Inadequate food and nutrition is one of the highest priority risks for the Human Research Program and is currently assessed as a 3x4 LxC risk, meaning that it has a High Likelihood of occurring (>1%), and High Consequences for both mission health and performance (e.g., death, severe reduction in performance), and for long term health (e.g., major impact on quality of life) (NASA Human Research Roadmap) Despite the existence of a standardized diet for moderately active adults (Baba et al., 2020), astronauts experience significant energy deficits resulting in weight loss (Matsumoto et al., 2011) as large as 5 kg per month (Stein et al., 1999), which can lead to reduced protein synthesis and loss of lean mass. This energy deficit is mainly caused by two factors: astronauts do not have a sufficient caloric intake (Stein and Blanc, 2011; Heer et al., 2000) and in-flight exercise countermeasures significantly increase total energy expenditure (Bergouignan et al., 2016). As plans develop for longer-term space missions, increased research is needed to optimize health and performance of astronauts and reduce health risks. (Smith et al., 2005; Smith and Zwart, 2021; Tang et al., 2021; NASA, 2020; Smith et al., 2021) Given that the loss of lean tissue often seen with space missions is associated with detriments to multiple organ systems (Smith et al., 2005; Smith and Zwart, 2021), it is critical that lean tissue be preserved as much as possible. Doing so requires that the exercise performed during space missions is fueled by ample energy and provision of the necessary macro- and micro-nutrients (Smith and Zwart, 2021). In addition to the recognized demands of long-duration space missions, the interaction of a quasi-torpor state with muscle mass and nutritional status remains unknown. For our Phase 1 and Phase 2 experiments we did not mandate a pre-study or on-study diet. However, for Phase 3 we are implementing a specific diet regimen designed to minimize glucose shifts and muscle catabolism during the prolonged sleep period while maximizing energy availability during the short awake period. Future studies will need to evaluate in more depth what the optimal timing and composition of nutrients is to support resting metabolic rate reduction and lessen muscle disuse atrophy, bone resorption, and other untoward catabolic events.

We have extensive clinical and laboratory experience with light to moderate external cooling (Moore et al., 2008; Sonder et al., 2018; Callaway et al., 2020; Callaway et al., 2015; Rittenberger et al., 2019; Flickinger et al., 2024; Hostler et al., 2009; Rittenberger et al., 2021). External cooling used in clinical applications, such as after cardiac arrest, reduces many physiologic processes and our hypothesis for this experimental series was that sedation plus active light external cooling would be synergistic and compounding to reduce overall metabolism. Our experiments to date have found that central body temperature slowly falls after sedation and causes a reduction in metabolism (Callaway et al., 2024). This is consistent with a loss of total body heat content after a reduction in heat production (Elmer and Callaway, 2023). An important observation from our trials is that we do not require very cold external cooling; contact of skin with circulating water at 20°C-25°C will remove enough heat to facilitate a 1-2°C decrease in core body temperature from baseline without causing discomfort (Callaway et al., 2024). It remains to be seen if there is a synergistic effect of hypothermia and sedation on metabolic reduction.

Several major areas require further investigation. Determining the optimal exercise strategy (including exercise type, timing, duration, and frequency of training) to minimize muscle atrophy and loss of strength incurred during both the quasi-torpor protocol and long-duration space missions is critical to ensure crew safety and wellbeing. The exercise strategy also needs to balance the metabolic cost of exercise with maintenance of muscle volume and strength. Equally as important, defining the optimal nutrition strategy (including meal composition, micronutrients and supplements, and timing of ingestion of proteins, carbohydrates, fats, and fluids) to reduce muscle catabolism and promote lean muscle mass maintenance, or even enhance muscle protein anabolism, is vital to success of the quasi-torpor strategy. We also need to understand the physiological and psychological effects of repeated bouts of prolonged sleep over a longer period, such as several weeks or months. Additionally, we need to evaluate the physiological effects of prolonged sleep and metabolic reduction in microgravity, including whether the quasi-torpor protocol reduces susceptibility to the effects of radiation or microgravity. Other physiologic effects also require scrutiny, such as the short and long-term consequences of prolonged sleep and dexmedetomidine on both in-protocol and post-protocol sleep and sleep architecture; and the safety, tolerance, withdrawal, and possible addiction profile for long-term dexmedetomidine administration. Microgravity and radiation may additionally affect the shelf-life of any drug, pharmacologic testing of any candidate drug will be necessary to ensure fidelity during long-duration space missions. For example, the terrestrial shelf-life of dexmedetomidine is 2 years for undiluted unopened vials, while the diluted shelf-life is 48-h at room temperature or 14-day at refrigerated temperatures; the current drug stability would not suffice for a round-trip to Mars (Marquis et al., 2017). Finally, many logistical hurdles must be resolved, including but not limited to whether astronauts can safely self-administer this protocol routinely, and if astronauts can perform emergency or mission critical tasks during and following this protocol.