Space: The Next Frontier in Physical Medicine and Rehabilitation — Part 3

By Luke Brane, MD

This is the second part of a three-part series on Aerospace Medicine.

The four members of NASA’s SpaceX Crew-1 flight are seen seated in the Crew Dragon spacecraft during training. From left to right are NASA astronauts Shannon Walker, Victor Glover, and Mike Hopkins, and JAXA astronaut Soichi Noguchi. Credit: SpaceX

We have looked at the broad overview regarding the recent trajectory of human space exploration and its implications for health effects on the astronaut. From a physical medicine and rehabilitation standpoint, we have also explored some of the issues which cross over nicely into the PM&R wheelhouse and discussed how an approach informed by the function-based concepts in PM&R can be utilized to preserve the health of those living and working in space. In this third article, we will explore more of the future directions of how space medicine and PM&R might intersect as the new movement into space continues to grow. These topics will include some of the possible avenues for addressing human physiologic decrements via optimized exercise, pharmacology, and engineering. While such futuristic musings can easily drift into the realm of science fiction, we will stick more closely to those investigations that have preliminary science being conducted or that have antecedents in projects that have been previously explored, but for whatever reason were not pursued to full viability.

Unlike the prior two articles, this one involves some degree of conjecture about the future direction of spaceflight, but also alludes to potential benefits for terrestrial medicine. Disclaimer: The author is not an engineer, or a rocket scientist, but the concepts explained should not require formal training in either for the arguments to be sound and understandable. Instead, we approach these considerations as physicians from the medical and biological side.

As we move into this new era of space exploration there are several features that stand out as salient when choosing how to keep astronauts fit, healthy, and mission-capable. First, the missions are going to be longer, likely with fewer supply options, smaller spacecraft (when compared to current missions aboard the International Space Station (ISS)), and travel much farther away, hampering resupply and creating the psychological pressure of reduced communication options and isolation. These considerable pressures combine to present compounding constraints on the countermeasures that can be deployed. First, mass and volume are at a premium — a countermeasure (CM) might work well, but if it entails inordinate volume, or is very heavy, or requires complex components that may break or need repairs, then it may not be a viable countermeasure.

Just like in terrestrial rehabilitation medicine, good space medicine does not rely on just one approach to counter acquired dysfunction and preserve ability. It is vital that a multipronged approach with some redundancy and synergistic effects be employed. In rehab medicine, we often tend to patients recovering from severe illness and debility. If we focused on getting these patients up and walking again, but neglected to consider how they are to safely dress, bathe, or toilet themselves, we have not achieved the goals of making them any more independent or safe when they are on their own. In PM&R, we do not just focus on physical mobility, but on nutrition, sleep, cognitive tasks, and strategies that foster adaptation when met with novel situations, so that our patients can be as safe and independent as possible. A similar approach is even more critical in deep space. Creating an effective exercise CM program is wonderful, but if the equipment breaks or the astronaut sustains an injury that prevents exercise for a period of time, there must be other options for preserving function and limiting health decrements.

Exercise is the bread and butter of PM&R, and as with anyone here on Earth, it will always be a vital part of an astronaut’s health. However, on a long-duration mission, exercise can be the difference between success and failure, in the long term, and even life and death. Passing out from orthostatic hypotension shortly after stepping off the landing vehicle as the first human on Mars would be a terrible way to make one’s mark on history. Not to mention that falling down in a space suit could be potentially life-threatening, depending on the type of damage the suit sustains, or injury incurred. Therefore, preventing the causes of these falls is strategically paramount to the success of the mission. Exercise protocols will be the backbone of the countermeasure response that will protect against such adverse events and contribute to a successful mission, but they likely will not be sufficient on their own.

The question, as we look toward the future — can we make it better? Is it possible to make the exercise more effective, or decrease the need for so much of it? What other regimens can be employed in conjunction?

Exercise countermeasures

Over the years, since the Apollo missions, much has been explored regarding exercise as a countermeasure against the decrements seen in microgravity (µG). Accordingly, a better understanding of how to do that effectively and efficiently has slowly progressed from elastic cord-based exercise, through cycle-ergometers, to a treadmill with bungies holding the runner to it, and on to the Advanced Resistive Exercise Device (ARED), capable of mimicking many different weight lifting exercises in µG. Yet, it is not just the pieces of equipment that matter, but how they are used. Recent research has shown that exercise CM protocols that utilize a high intensity interval training strategy (HIIT), are just as effective at preserving muscle and bone, while requiring considerably less time and ultimately fewer calories.1,2 Additional research in high impact plyometrics using a clever “jump-sled” device has yielded promising results for protecting bone density and preserving muscle, but also for the neuromuscular coordination that is so key to a safe gait pattern.3

Applying a similar process for selecting the most effective exercises can serve to inform terrestrial-based exercise rehabilitation programs and refine their efficacy.

Pharmacologic countermeasures

As is already the case with current astronauts, future populations will likely use pharmaceuticals to offset some of the harmful effects of the space environment. Currently, most of the pharmacology has been focused on preserving bone density, yet muscle preservation research is not far behind.

One of the promising areas of ongoing research in muscle atrophy mitigation relies on the fact that muscle anabolic and catabolic states have a “gatekeeper” mechanism in the regulatory protein called myostatin. When myostatin is upregulated, the muscle enters a state of catabolism, breaking down actin and myosin protein and mobilizing their substrates. When myostatin is suppressed, the reverse is true: a state of anabolism is maintained, muscle protein is preserved, with additional muscle protein laid down. This is a simplistic view of the process, but suffice it to say that animals with a defective gene for myostatin show dramatic muscle hypertrophy and functional strength, even in the absence of the traditional stimuli that would drive the anabolic process, like exercise. This evolutionary adaptation that allows animals to “trim down” any excess muscle that is not being used regularly, (as muscle is very metabolically expensive to maintain), backfires in the uG environment, where much of the astronaut’s muscles are not under load for a large majority of their day. Consequently, the catabolic process kicks in to “conserve” unused muscle and limit the additional metabolic demand. With myostatin inhibition, this process can be halted, and the muscle theoretically preserved, even when not being stimulated by loading to be maintained. A drug that addressed this concern could also be incredibly useful for the bed-bound and critically ill populations who see that same dramatic 17–24% drop in muscle cross-sectional area within the first couple weeks and experience an even more rapid decline in functional strength performance. Myostatin inhibition is being tested in humans currently for preservation of muscle mass in certain types of muscular dystrophy and other muscle wasting diseases, but it is still in early days. Additionally, the ISS recently had some genetically modified visitors in the form of myostatin double knock-out mice. These muscular murines display global muscle hypertrophy irrespective of normal anabolic stimuli. A cohort of these mice were studied as they experienced a period of prolonged uG on the ISS, as well as wild type mice who were given myostatin inhibitors. Those mice who were genetic knockouts, or who were given myostatin inhibitors, had preserved muscle mass and bone density that was not significantly different from their control counterparts on Earth. In fact, compared with WT controls on Earth, the myostatin inhibitor-treated group had greater muscle hypertrophy after the flight, despite the µG environment. This could provide a very real and accessible avenue for muscle preservation as a pharmacologic countermeasure.4 This is not only a boon to the astronaut’s need to preserve function and strength, but also to the terrestrial patient battling critical illness myopathy or other muscle destroying states of disease.

There is also reasonable promise in using other anabolic promoting hormones such as anabolic steroids or their precursors. This approach is not a new idea; medicine uses drugs like Oxandrolone for staving off muscle catalysis in severe burn patients and other specific scenarios. The degree to which anabolic steroids work to promote muscle growth is understood well enough to know they are effective, but there are significant trade-offs and risk profiles associated with most of these drugs, especially when employed over the long term. The potential for future applications lies in refining their use, diminishing the side-effect profile, and extracting from them the clear benefit we would see in muscle and bone preservation, while minimizing the harmful side effects. Recently, promising data showed that low-dose cycled testosterone used in conjunction with a modern NASA exercise protocol was more effective than the exercise alone in promoting lean body mass growth and maintaining bone mineral density (BMD) in a 70 day head down bed rest trial.5

Addressing the immediate environment as a way to protect health and function

Now, let us shift gears a bit from what we can do to alter the human component via direct human countermeasures, to what else can be altered in the spaceflight environment to preserve function and ward off decrement.

In the practice of PM&R there is a key concept regarding the functional capacity of patients in their own environment. Of course, we aim to give the patient as much physical functionality as we can during inpatient rehabilitation, followed by subsequent outpatient therapies and follow-up visits, but there can come a time when the patient has reached certain limitations that we cannot overcome with rehab alone. Consider the newly paraplegic patient: after a spinal cord injury (SCI) at say, T10 with a complete cord injury, the patient will often have a stay in an acute inpatient rehabilitation facility where they will focus on strengthening and adaptive strategies that allow them the greatest degree of independence. While this can mean that a patient may achieve independence at a ‘modified level,’ they can bathe and dress themselves, they can handle all their activities of daily living, like locomotion via wheelchair, toileting, cooking, feeding, etc.; they still must be able to do this in their native environment at home. If they are then discharged to a house with stairs and tall counters, or narrow bathroom doors too small for their chair and no way to transfer into the shower, then despite all the function gained from rehab, they are no longer “functional,” in that environment. Therefore, the next thing to do after rehabbing the patient to as highly functional as we can get them, is to modify their personal environment to accommodate their functional capacity. The same concept can be applied to the spaceflight environment. We send up astronauts who are in peak physical condition, screened for any medical issues that might interfere with the success of the mission. They are extensively exercised and utilize a plethora of countermeasures to mitigate the detrimental effects of µG, yet still it takes its toll, and it is unclear whether this strategy will hold up to multiyear exposures, such as a journey to Mars. The next task is to adapt the environment for such a pursuit.

The current paradigm of spaceflight is, to a large degree, a product of the original space race. As mentioned in our first article, prior space exploration programs were tied to achieving the greatest possible accomplishment as quickly as possible, with little focus on (or knowledge of) creating a sustainable presence in space. Therefore, the spacecraft designs reflected this, optimized for short stays in µG, with flight directly out of a gravity well, and the necessary design features for the high-risk descent back through the atmosphere after achieving orbital velocity. These constraints drastically limited the possible engineering approaches that could be used to build a more human-friendly environment in space. More on this concept shortly.

When space stations were first flown, the consequences of long-term µG exposure were still poorly understood. Additionally, the longest duration mission prior to those stations was only measured in weeks. Still, the constraints of the launch vehicles and the complexity of just surviving in space were enough to limit design options to bare necessities where mass and volume were always at a premium. With the construction of the ISS, and its subsequent continuous inhabitation — now ongoing for 20 years — we have, of necessity, learned a great deal more about what it takes to make a human-habitable niche off-planet.

Adapting the space environment to humans

So, what does it mean to adapt the space environment to meet the human needs?

It nearly all comes down to gravity, or the lack of it. As discussed in the second article, the µG of the spaceflight environment seems to set off a cascade of decrements that affect every measurable part of the human system. Prolonged µG exposure even behaves as a model for accelerated aging. Gravity, or rather the acceleration component of it as experienced by human tissue, is what will make or break human space flight and long-term human space habitation. We humans need to be able to create a viable analog to gravity, and it needs to be constant and portable — this is a physiologic necessity at the present stage of the game. When it all is said and done, the part of gravity we need is the effect of the constant acceleration in one direction. On the surface of Earth, that acceleration is 9.8m/s², which is helpfully provided by Earth’s mass and our proximity to it. There are basically two approaches to recreating this acceleration without using a massive object, based on the laws of physics as we currently understand them. The first approach would be to create constant acceleration in one direction at 9.8m/s². This would allow the occupant of a spacecraft to feel exactly as though they were standing up in a room on Earth. Earth-like “gravity” would appear to be intact as long as the constant uni-directional acceleration was maintained. This is, of course, provided the spacecraft was oriented like a building with the top of the building pointing in the direction of travel and the decks arrayed like floors in the building. The experience would be indistinguishable from gravity on Earth, so long as the acceleration was maintained. Or, if the acceleration decreased to say 3.71m/s², the occupant would experience gravity comparable to Mars. This “gravity” would, naturally, disappear entirely if the ship stopped accelerating. This is bound to happen with today’s technology, as we cannot maintain such an incredible acceleration with our current chemical rockets for more than a few 10’s of minutes at most. At which point, you resume µG, until the ship accelerates again or decelerates. Continuous propulsion of this type is considerably beyond our present technological abilities, but its invention would completely change the calculus to the same degree that crossing the Atlantic Ocean in a wooden sailing ship would compare to crossing it in a modern jet airliner. The time difference is comparable when discussing a mission to Mars. Today’s technology would take between 6–9 months to reach Mars, where the vast majority of that time would be spent coasting between planets in a µG environment. Contrast that with a constant 1G acceleration (from an as-of-yet-undeveloped) form of propulsion, where you accelerate toward your destination for half of the journey, then flip and decelerate for the remaining half. It would take about 2 or 3 days to reach Mars and would be experienced under a full 1G load the whole time.

The second option for creating our own gravity is much more feasible with today’s technology; in fact, we could do it right now with current engineering. That type of gravity-like acceleration would be created by rotation. This could be achieved by rotating a large wheel, or two opposing segments of equal mass. Inside the vehicle, the “floor” would be facing the outside of the circle described by the wheel or opposing segments and their ceiling facing the center of rotation. Using a wheel of sufficient size and with the correct rotational velocity, the centrifugal force created by this rotation would provide a verisimilitude of gravity that would be all but indistinguishable to the parts of our biology which so desperately need gravity to function properly over the long term. Admittedly, there are some limitations to this approach, namely, that it has not been done before on a large scale, so it would need considerable engineering development. Two, it would require construction on orbit, as the rotating structure of the necessary size, in conjunction with the rest of the vessel, could not fit inside any current or near-future spacecraft designs. The good news is we already have a decent idea that this will work to mitigate much of the medical issues that are seen with long-term µG exposure.

A form of this technology has already been tested in miniature on the ISS in experiments involving mice. They were housed in a special centrifuge cage that provided this rotational “gravity” force. Unsurprisingly, those mice that are housed in rotational gravity maintain their bone density and muscle volume, as well as cardiovascular fitness. They also did not show the dysregulation of their immune or endocrine systems that their µG -living control groups showed. In fact, their health was pretty much indistinguishable from the controls living back on Earth. 6

Since the 1960’s, NASA studied the effect of rotational forces on humans using various types of centrifuges, as well as data from inflight experiments. This research gives us some indication of the rotational speed and radius needed to sustain this type of centrifugal gravity, allowing for the generation of Earth-like-gravity centrifugal acceleration, without incurring a noxious neurovestibular response.

This concept is neither new nor outlandishly far-fetched. NASA had a program dedicated to exploring this technology for use aboard the ISS and possible long-haul spacecraft, called Nautilus X. This was a smaller torus that would rotate around a stationary module connected to the ISS, intended eventually to be adapted for use in long duration flights. This program was cancelled due to a shift in funding priorities, but the concepts and engineering were sound.

Ultimately, as we seek to understand the health and medical implications of human spaceflight and space habitation, it is more and more clear that it will require an amalgam of these previously vetted approaches in exercise along with development of some newer approaches, potentially more comprehensive ones. It will take a careful and measured approach with a data-driven, evidence-based practice to employ the most effective and efficient versions of these countermeasures. The most comprehensive discussed in this series in rotational gravity, as it all but eliminates the major negative features of long-term µG exposure. Yet, even with that accomplished, efficient exercise programs, nutrition and pharmaceutical approaches must be in place. If the apparatus creating the rotational gravity fails, or requires maintenance, it must be repaired while in µG. If the crew has neglected their physical training, their adaptation to the new (and unplanned) µG environment will be very poor indeed, as the earliest data from NASA showed that resistance to decrements in hemodynamics was directly related to pre-mission cardiovascular health.

Conclusion

The PM&R approach might be to say: “we have already improved the function of the astronaut as much as possible before putting them in this environment, now what must we do to modify the environment to extend this function?” The unequivocal answer is to simulate gravity. This one feature, if achieved in long-term human spaceflight, would negate a host of potentially catastrophic problems while giving humanity a literal toehold among the stars. When humans can live and work in space for prolonged periods, while preventing the myriad degradations and accelerated aging that accompanies µG exposure, we can really start to understand the concomitant environmental challenges. Eventually, there will be a desire to launch people into space who do not meet the rigorous and impressive standards of fitness and medical good fortune of our current astronauts. Whether because the most talented researchers in a particular field also happen to have medical issues, or to foster commercial offers of space tourism, simulated gravity will be crucial to the medical stability of humans in space. Augmented by thoughtful and efficient exercise protocols and pharmacologic support, humans will be able to pursue a healthy life off-planet where we can thrive.

1. English, K. L. et al. High intensity training during spaceflight: results from the NASA Sprint Study. npj Microgravity 6, (2020).

2. Laurens, C. et al. Revisiting the role of exercise countermeasure on the regulation of energy balance during space flight. Front. Physiol. 10, 1–14 (2019).

3. Koppelmans, V. et al. Exercise as potential countermeasure for the effects of 70 days of bed rest on cognitive and sensorimotor performance. Front. Syst. Neurosci. 9, 1–14 (2015).

4. Lee, S.-J. et al. Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight. Proc. Natl. Acad. Sci. 202014716 (2020) doi:10.1073/pnas.2014716117.

5. Ploutz-Snyder, L. L. et al. Exercise training mitigates multisystem deconditioning during bed rest. Med. Sci. Sports Exerc. 50, 1920–1928 (2018).

6. Tominari, T. et al. Hypergravity and microgravity exhibited reversal effects on the bone and muscle mass in mice. Sci. Rep. 9, 1–10 (2019).

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