Microgravity and Lymphatics: Why Space Programs Need Lymphedema Physiology Specialists

Introduction

Materials and Methods

This is a comprehensive narrative review of the past and current literature (2000–2021 through PubMed, Google Scholar, MEDLINE complete, and UpToDate) focusing on lymphatic physiology, endothelial glycocalyx layer, and microgravity. The review focuses on new evidence supporting the role and impact weightlessness has on the physiology of the body systems, through the lens of the glycocalyx and lymphatic system.

Results

Weightlessness, vacuum/hypobaria, extreme temperatures, initial launch accelerative forces, the weightlessness of being in an orbital plane and velocity elevated galactic cosmic radiation exposure, circadian disruption, and isolation/confinement are some of the unique conditions encountered in space travel. The body systems most impacted by microgravity are the cardiovascular, musculoskeletal, bone, metabolic, neurovestibular, and immunohematological. Microgravity and space radiation also have a crucial impact on oxidative stress in living organisms. To date, there is no research citing the impact of true “weightlessness” on human lymphatics and the GCX.

Discussion

Isaac Newton's comprehensive theory of gravity, published in 1687, holds that a universal force of attraction exists between all matter. Gravity is variable on Earth, from the depths of the oceans to the peaks of the tallest mountains, and its effects are dynamic. The average acceleration at the Earth's surface due to gravity is 9.8 m/s ² , but it differs slightly at the North and South poles, with diffusely scattered, smaller variations due to the Earth's nonperfect spherical shape. Geodesy is the discipline of measuring the shape and gravity fields of the Earth. Gravity variations on Earth are rarely noted by human perception unless at the extremes of depth or height. “Neo” (new) gravity therefore represents the impact of a new gravity exposure (dosing) when compared to a standard and constant 1 G (Earth gravity), where our bodies function optimally from a teleological aspect.

The head and neck are dependent upon gravity's effect for drainage of lymphatic, venous, and interstitial fluids (ISFs), while the body below the level of the shoulders is dependent upon distal to proximal flow against the effects of gravity. Guyton's principle of “suction theory” for clearing lymph from tissue includes the bellows effect of the chest wall and diaphragm, abdominal wall, and lower extremity musculature, dermal stretch upon the extensive network of dermal lymphatic collecting system and valved lymphangions, possessing both smooth muscle and cardiac-like striated muscle for propulsive activities.^1,2 The lymphangion is the fundamental physiologic unit of the lymphatic system. The head and neck are dependent upon gravity support for drainage. No valve exists in this lymphosomal distribution, and lymphangion regional variability in strength of contraction may exist, given the greater dependence upon “gravity assist” for drainage.

Gravity is as ubiquitous as water and oxygen. The impact of gravity is significant and interwoven within our biological function at a cellular level. Gravity has directly impacted the development and functionality of human physiology, anatomy, and function. The effects of gravity can be more readily appreciated at the gravitational extremes experienced during deep sea exploration, high-altitude mountaineering, and high-altitude flight. The Karman line (62 miles/100 km above sea level) is the boundary that separates Earth's atmosphere from “space.” This is the boundary where human physiology experiences notable change.

Weightlessness, vacuum/hypobaria, extreme temperatures, initial launch accelerative forces, the weightlessness of being in an orbital plane and velocity (17,500 miles/h, 5 miles/s), elevated galactic cosmic radiation exposure, and isolation/confinement are some of the unique conditions encountered in space travel. ³ Foundational research and publications by NASA, ESA (European Space Agency), JAXA (Japanese Space Agency), Russia, China, and others have detailed the complications experienced by astronauts, including, but not limited to the following:

Spaceflight-Associated Neuroocular Syndrome (SANS)

To venture beyond Earth effectively and safely, we need to understand and solve the biological and psychological challenges experienced in low Earth orbit (LEO), and the microgravity environment. The success of the privatization of space and the novel endeavor of “astrocivilians” and “space-cations” (authors' term) will be predicated on the development of preventative measures and countermeasures to manage the health challenges experienced outside the protective atmosphere of Earth.

For space travel and/or exploration of any form, it is important to understand the impact of microgravity on lymphatic function. The authors' collective expertise has led them to hypothesize that the key to solving many biological and physiological problems associated with extreme environments resides within the response and adaptation of the lymphatic system and the endothelial glycocalyx. Preventative measures and countermeasures (devices, physiological and pharmacological) will be developed to support human physiology from the sea floor to outer space during the current renaissance of lymphatic medicine and surgery, and the rapidly expanding research into and clinical applications of GCX management. To do this, however, we must first understand the impact microgravity has on the lymphatic GCX architecture and physiology.

The body systems most impacted by microgravity are the cardiovascular, musculoskeletal, bone, metabolic, neurovestibular, and immunohematological. ³ Microgravity and space radiation also have a crucial impact on oxidative stress in living organisms. ⁴ Oxidative stress is involved in the aging process, and is pivotal to the development of cardiovascular diseases, all of which have been observed in the Apollo lunar astronauts. ⁵ During spaceflight, astronauts face three phases of physiological adaptation induced by changing gravity: (1) initial adaption upon entry to microgravity, (2) changes after prolonged exposure to microgravity, and (3) readaptation to 1 G or “normal” gravity on Earth upon return. ³

To date, there is limited research citing the impact of true “weightlessness” on human lymphatics and the GCX. Given the significant interrelationships within the cardiovascular system of the lymphatics and the GCX, we can begin to surmise the impact and adaptations during microgravity exposure. The changes are known as “cardiovascular deconditioning,” and begin exclusively with a fluid shift induced by microgravity.^6–8 This fluid shift is followed by a decrease in circulatory blood volume, cardiac size, aerobic capacity, and postflight orthostatic intolerance. ³ Body systems should be looked at as interdependent and interconnected, not siloed, as the systems must work in unison to achieve homeostasis, whether subjected to hydrostatic pressures in the ocean, 1 G on land, or “weightlessness.”

On Earth, body fluid compartments are maintained and balanced by the nano-scaled architectural integration of the endothelial glycocalyx and lymphatic system, which work in accord with gravity, respiration, and muscle contraction. The GCX is a carbohydrate-rich matrix composed of proteoglycans, glycoproteins, and glycosaminoglycans, abutting the luminal side of endothelial cells of all blood and lymphatic vessels. This GCX acts like a molecular sieve, regulating fluid and macromolecule movement from the vessels into the subglycocalyx space and interstitial spaces.^9–16 Redistribution of fluid volume and solutes between plasma and interstitial tissue is determined by complex physiological interactions among transport mechanisms in the microvasculature. ¹⁷

Along the length of the capillary, there is a diminishing net filtration through the capillary bed with no resorption at its venous end, except under extreme conditions.^15,18 This is a revision to the theory initially proposed by Starling regarding hydrostatic and oncotic forces that govern transcapillary fluid exchange. The GCX acts as a permeability barrier, preventing movement of proteins and fluid back into the venous end of the capillary. Thus, all fluid and macromolecules that exit the blood capillaries must be removed from the interstitium by the lymphatic capillaries alone.^10–12,15 Research has shown that enzymes can degrade the glycocalyx, whereas inflammation can induce shedding of the layer.^14–19

This may potentially be important considering the stressors astronauts experience upon launch, and upon exposure to the extreme environment of space, with the resulting impact and changes on their biology and physiology. This was evidenced in the NASA Twins Study where data were collected over 25 months looking at physiologic, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data. ²⁰ Data were compared between identical twins, one who remained on Earth and the other in space.

Although some biological functions were not significantly impacted by spaceflight, there were compelling changes noted during the spaceflight period, with eventual return to the preflight state. Such changes included telomere length, gene regulation, gut microbiome composition, body weight, carotid artery dimensions, choroidal and retinal thickness, and serum metabolites. ²⁰ Additional changes were noted with the stress of returning to Earth as well as persistent changes observed after returning to Earth for 6 months. These data would be interesting to look at through the lens of the GCX and lymphatic system with respect to regulation and/or dysregulation and the potential interplay with the noted changes.

The glycocalyx has been linked to numerous pathologies and mechanisms, including vascular permeability, inflammation, atherosclerosis, and diabetes.^11,21–25 The fact that the GCX can shed in response to a variety of stimuli, such as inflammation, ischemia reperfusion, sepsis, trauma, and prolonged immobility, highlights the importance of its role in fluid regulation, as edema and fluid shifts are often evident in these situations.^10,14,16,26 In addition, the GCX has an antithrombotic effect and plays a significant role in reducing oxidative stress.^26,27 This further supports the authors' hypothesis that the GCX is a potential key regulator of bodily systems when exposed to microgravity, given the health challenges and physiologic paradoxes experienced by past and current astronauts with respect to fluid shifts and cardiovascular health.

In microgravity, with removal of the gravitational pressure gradient, blood pressure is reduced below the level of the heart, and elevated above the level of the heart. This resembles what happens when someone is tilted head-down on Earth. This position results in resorption of fluid from the interstitial tissues in the lower body, and a filtration of fluid into the interstitial tissues in the upper body. This shift manifests as “puffy face (or head), bird leg syndrome,” where the leg volume decreases by 1 L, whereas the forehead subcutaneous tissue thickens by 7% compared to preflight. ³

When astronauts enter the microgravity environment of LEO, body fluids move from the lower body to the thorax. The cephalad fluid shift causes an increase in venous return and stroke volume. Furthermore, on the first day of microgravity exposure, urine volume does not increase; however, the circulatory blood volume decreases by 17%, likely due to the shift of water from the intravascular to interstitial spaces and ultimately to the intracellular space, ³ a paradox previously described by Norsk. ⁸

We hypothesize that this may be due to GCX thinning or shedding, loss of the permeability barrier capacity, and a subsequent overload on the lymphatics primarily due to reduced microshear of the microvasculature. This is compounded in the glymphatics (lymphatics within the central nervous system), which may not function properly in microgravity (further research is needed in this area), and may contribute to other symptoms and manifestations, such as SANS, headaches, and nasal congestion. In the absence of a normal 1 G environment, the typical muscular and respiratory contractions that support lymphatic and venous flow are disrupted, and this appears to be especially evidenced in the lymphatics of the head, neck, and brain.

Furthermore, these fluid shifts result in an increase in the intraocular pressure (potentially contributing to SANS development as part of the multihit theory) as well as morphological alterations in the central nervous system.^3,7 The pulmonary capillary blood volume increases almost 25%, and intraocular pressure has been noted to double in some individuals. ⁷ Cardiovascular and fluid balance adaptation is gradual; symptoms (facial edema, nasal congestion, papilledema, headaches, and jugular vein dilatation) begin to appear within 1–5 days of arriving in LEO and may dissipate during a period of adaptability within the initial 2 weeks of spaceflight.^6,28–31

According to Diedrich et al, the reduced blood volume after adaptation to microgravity is due to “(1) a negative balance of decreased fluid intake and smaller reduction of urine output; (2) fast fluid shifts from the intravascular to interstitial spaces as a result of lower transmural pressure after reduced compression of all tissue by gravitational forces, especially of the thorax cage; and (3) fluid shifts from the intravascular to muscle interstitial spaces because of lower muscle tone required to maintain body posture, and the attenuated diuresis during space flight is due to increased retention after stress-mediated sympathetic activation during the initial phase of space flight.” ³² These adaptations may be linked to dysfunction in the GCX and lymphatics; research is needed in this area for correlation.

Upon returning to 1 G on Earth, astronauts experience orthostatic intolerance for up to 1–2 weeks. Circulatory blood volume reduction and attenuated vasoconstriction are the main factors for orthostatic intolerance and are believed to be the main reason for symptoms.^6,8 Salt loading and fluid loading have been used as countermeasures. The dysregulation of the GCX (whether degradation or shedding) and lymphatic overload potentially contributes to this intolerance, although more research is needed, as this has not been explored to date. GCX shedding may contribute to the low systemic vascular resistance and orthostasis. Interestingly, the 7 days required for this intolerance to resolve approximates the time required for GCX restoration.

More research is needed to investigate this to determine if a correlation truly exists versus just coincidence. According to Potter et al, it can take 5–7 days for the GCX to endogenously restore itself to its native thickness in vivo. ¹⁹ Although more in vitro and in vivo research are needed to support this hypothesis, it does suggest a connection to the health and integrity of the GCX. If measures can be implemented to protect the GCX and support the lymphatics before microgravity exposure, it may be possible to reduce the cardiovascular impact, SANS development, and negative immunomodulation during spaceflight. Such measures may involve nutritional supplementation, pharmacotherapy, physiological devices, modified complete decongestive therapy, and other countermeasures yet to be developed.

A Review into the Effects of Microgravity on the Lymphatics and Body Systems

The venous and lymphatic systems are interdependent. Nutrient-rich plasma of the blood moves out of the arterial side of the blood capillaries to nourish and bathe cells in the interstitial tissues. The lymphatic system absorbs nearly 100% of this ISF, also known as initial lymph, filtering it through lymph nodes and returning it back into the bloodstream by way of the veins.

Once absorbed into lymphatic capillaries, lymph coalesces in larger collecting vessels, and is propelled against gravity toward the heart through lymphangions. These bulbous, contractile units give these vessels the appearance of a string of pearls. The wall of the lymphangion is made up of smooth muscle that contracts in response to filling with lymph, and one-way valves prevent lymph backflow during the contractions. In conjunction with intrinsic contractility of lymphatic vessels, active contraction of skeletal muscles surrounding vessels enhances mobilization of lymph through the deep lymphatic system. In tandem, the muscle contractions facilitate flow through the deep veins. Contraction of the calf muscle is pivotal in moving blood through the deep veins back toward the heart, and this mechanism of action is known as the “calf muscle pump.”

When standing in Earth's gravitational field, the mean arterial pressure at the level of the head is 70 mmHg, compared to 200 mmHg at the level of the feet. Venous pressures at the feet are about 100 mmHg while standing, and 30 mmHg while walking, because of the calf muscle pump.^33,34 Under normal physiologic conditions, gravity enhances the resistive force against the ball of the foot during toe-off in gait, resulting in strong contractions of the calf muscle, which aids in both venous and lymphatic return. In addition, gravity provides resistive forces for leg movements during walking, which helps to keep blood and lymph circulating through the leg vasculature toward the heart.

In pathophysiologic states, gravity impairs the movement of blood and lymph toward the heart and exacerbates swelling of the legs. In the United States, the most common cause of chronic lymphedema of the legs is Chronic Venous Insufficiency, called phlebolymphedema. ³⁵ Ambulatory venous hypertension results in pooling and engorgement of leg veins, and higher pressures in the venous end of the blood capillary bed. These elevated venous pressures result in ultrafiltration of fluid into the interstitial space. This excess fluid can overwhelm a healthy lymphatic system, resulting in a dynamic insufficiency. Where the lymphatic system cannot keep up with these new demands, swelling is evident in the legs. Over time, lymphatic dysfunction can progress from a dynamic to a mechanical insufficiency, leading to a mechanical lymphatic failure (damaged lymphatic system), which can lead to the disease of lymphedema.

The lymphatic system recycles proteins, removes cellular waste, and provides immune protection for the tissues. Lymph stasis in the legs can result in accumulation of waste and proteins that lead to chronic swelling, inflammation, thickening of the tissues, and diminished immune response. While phlebolymphedema is a common vascular pathology observed in normal gravitational fields on Earth, microgravity is an abnormal gravitational field that leads to pathology in an otherwise healthy vascular system. What is observed in space is the inverse of phlebolymphedema on Earth.

Microgravity Effects on Proximal Veins

In microgravity, the 2 L shift of fluid from the legs toward the head increases central venous pressure and pre-load of the heart, resulting in increased cardiac output. ³⁶ Volume sensors of the heart perceive this as a volume overload, resulting in an increased release of atrial natriuretic peptide, although no associated diuresis.^33,37 Measurements of central venous pressure demonstrated that the external jugular vein is continuously distended throughout the cardiac cycle in microgravity conditions. ³⁸ Furthermore, it was found that this pressure increased with G forces during launch, but decreased in microgravity after main engine cutoff, compared to Earth. With an increase in internal jugular vein pressure, the space traveler is exposed to constant cerebral venous congestion, with the potential to develop stagnant venous blood flow. ³⁸ This microgravity-induced proximal venous hypertension is coupled with ultrafiltration of fluid into the interstitial space, readily observable in swelling of the face, head, and neck. ³³

Microgravity Effects on Cervical Lymphatics

Normally, lymph drainage from the legs runs counter to the Earth's gravity through lymph nodes in the groin, and up the thoracic duct toward the terminus at the left venous angle, the juncture between the left internal jugular and subclavian vein. In contrast, gravity assists lymph flow from the brain, eyes, face, head, and neck, through cervical lymphatics, toward the venous angles on the right and left. In microgravity, however, this is inverted, disrupting the normal physiology.

On Earth, simulation of microgravity can be achieved by inverting the human body. Microgravity sensations of fluid displacement can be similarly experienced by hanging upside down, performing a sustained headstand or handstand, or using an inversion table (6-degree head down tilt is an established ground-based analog). Fourteen days of continuous head-down tail suspension (HDT) of rats was used to simulate microgravity to study its effects on active lymph pumping through cervical lymphatics. ³⁹

Results showed the diameter of the cervical lymph vessels was increased, with a compensatory increase in wall thickness by 42% after HDT. The distended, engorged lymphatic vessels exhibited lymphatic insufficiency, with a dramatic reduction of the contraction amplitude by an average of 84%, 80% inhibition of contraction frequency, and 83% inhibition of the ejection fraction. ³⁹ Impairments of the human cervical lymphatic system were dynamically visualized using in vivo near-infrared fluorescence imaging (NIRFLI). ⁴⁰ NIRFLI imaging showed that lymphatic drainage through cervical pathways is dependent upon gravity, and impaired under short-term HDT.

The cephalad fluid shifts in microgravity induce a proximal venous hypertension that, in turn, creates back pressure into the cervical lymphatics, which drain into the neck veins. During space travel, this impairment results in swelling in the face, head, and upper body. More problematic, these same cervical lymphatics have been visualized in vivo using MRI and found to be the drainage pathway for the brain and eyes.^41,42

Microgravity Effects on Meningeal Lymphatics

In 2017, Jamalian et al combined experimental measurements of contractile function and pressure generation with a previously validated mathematical model, and provided definitive evidence for the existence of “suction pressure” in collecting lymphatic vessels. ² These manifest as a transient drop in pressure downstream of the inlet valve following lymphangion contraction. This suction opens the inlet valve and is transmitted upstream, allowing fluid to be drawn in through initial lymphatics. The authors explained that positive transmural pressure is required for this suction, providing the energy required to reopen the vessel or, alternatively, external vessel tethering can serve the same purpose when the transmural pressure is negative.

In the peripheral lymphatics, the dense spider web-like network of lymphatic capillaries is tethered to the elastic fibers of the dermis. Anchoring filaments connect the skin's elastic fibers to the lymphatic capillary valves and wall. When swelling stretches the skin, these anchoring filaments expand the dermal lymphatic capillary lumen, and open wide the swinging tips of the lymph capillary valves, allowing lymph from the interstitial tissues to flow into the initial lymphatics. This lymphatic absorption is enhanced by a siphoning effect as well as the relative higher pressures in the edematous interstitial space. ² In the brain, to what are the lymphatic capillaries tethered? Recent evidence reveals a dense network of meningeal lymphatic capillaries that absorb lymph from the brain, and transport it toward the cervical collecting vessels and lymph nodes.

Aspelund et al studied the lymphatic vasculature of the mouse brain and found a lymphatic vessel network in the dura mater. ⁴³ They showed that dural lymphatic vessels absorb cerebral spinal fluid (CSF) from the adjacent subarachnoid space and brain ISF through the glymphatic system, transporting the lymph into deep cervical lymph nodes through foramina at the base of the skull. Furthermore, they showed that disruption of this lymphatic pathway resulted in impaired macromolecule clearance from the brain.

Microgravity Effects on Brain Glymphatics

For many years, it was thought that there were no lymphatics in the central nervous system, which intuitively did not reconcile the high metabolic activity of the brain and its critical importance. In 2012, Iliff et al performed in vivo two-photon imaging of small fluorescent tracers in mice, and showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries, and that brain ISF is cleared along paravenous drainage pathways. ⁴⁴ Contractions of the heart propel nutrient-rich plasma upward into the cranial cavity, and pulsations in the arteries facilitate flow across the paravascular space. Like a living bridge, astrocyte end-feet span the gap between the arterial and venous side of this “glymphatic” system.

The glymphatic system is a macroscopic waste clearance system that uses perivascular channels to promote efficient elimination of soluble proteins and metabolites from the CNS. ⁴⁵ This system may also function to distribute nonwaste compounds (glucose, lipids, amino acids, and neurotransmitters) related to volume transmission in the brain. ⁴⁵ Astrocytes function as the controllers and monitors of fluids leaving the paravascular space that bathe the brain. As this fountain of fluid flushes the brain tissue, simultaneous pulsations of lymphangions induce a suctioning effect on the venous side of this hydraulic system, coupled with gravity-assisted movement of fluid toward the veins of the neck.

In mouse models, Iliff et al found that mice lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibited slowed CSF influx through this system, and a ∼70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. ⁴⁴ In addition, they found that fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, is transported along this route, and deletion of the AQP4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. ⁴⁴

In microgravity, the hemodynamics of brain glymphatics is disrupted. Like lymphedema on Earth, a space travelers' genetics, musculoskeletal dynamic anatomy, lymphovenous vasculature, risk factors, and medical history are some of many contributing factors potentially leading to chronic brain “glymphedema” (authors term), whether on a macroscopic or microscopic level. Glymphedema can present as a dynamic insufficiency of lymph flow that is transient, and can recover when re-entering Earth's gravitational field, or it could lead to accumulation of waste with inflammatory responses resulting in brain tissue changes like the chronic inflammation and fibrotic soft tissue changes commonly seen in the legs of patients with phlebolymphedema or in neurodegenerative diseases such as Alzheimer's. This may contribute to the development of SANS, along with other cognitive changes experienced during longer duration space flight.

Microgravity Effects on Sleep and Brain Bathing

On Earth, humans normally sleep lying down, often in a lateral position. This position in the Earth's gravitational field is believed to enhance bathing of the brain. While we sleep, the brain is actively processing information through synchronized bioelectric pulsations of neurons, and is bathed by a flushing of cerebral spinal and ISF. In rats, clearance of brain waste, including amyloid β, is most efficient in the lateral position, which mimics their natural sleeping position. ⁴⁶

In 2013, Xie et al studied metabolite clearance from live, adult mice. ⁴⁷ They showed that natural sleep is associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of CSF with ISF. In turn, convective fluxes of ISF increased the rate of amyloid β clearance during sleep. The enlarged interstitial space volume during deep-wave sleep lowers the overall resistance to paravascular inflow, resulting in a sharp increase in CSF-ISF exchange and convective transport of waste solutes toward paravascular spaces surrounding large caliber cerebral veins, for ultimate clearance through cervical lymphatic vessels. ⁴⁷

Space travelers are particularly susceptible to disruption of normal glymphatic drainage due to upended circadian rhythms and sleep disruption. Furthermore, it is difficult to achieve a sustained supine position for sleep in space. The International Space Station (ISS) circles the Earth at 17,130 mph, with a sunrise to sunset interval of a mere 90 minutes. As a result, astronauts experience 15–16 sunrises and sunsets every day aboard the ISS. ⁴⁸ The long-term effects on brain health from sleeping in microgravity environments with disrupted circadian rhythms are unknown.

Microgravity Effects on Eye Glymphatics

Like the glymphatic drainage of the brain, the eyes also have their own glymphatic pathways. In 2017, Mathieu et al presented the first evidence of a glymphatic pathway in the optic nerve. ⁴² CSF enters the optic nerve through spaces surrounding blood vessels, bordered by astrocytic end-feet, like the brain glymphatics.

In 2020, Wang et al identified a glymphatic clearance route for fluid and wastes from the high metabolic activity of the retina and optic nerve. ⁴⁹ Amyloid β was cleared from the retina and vitreous through a pathway dependent on glial water channel AQP4, and driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal amyloid β was cleared through the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced efflux, whereas atropine, or raising intracranial pressure blocked efflux. ⁴⁹ Mathieu et al also determined CSF entry into the paravascular spaces of the optic nerve is size dependent. ⁴² These collective findings, combined with our terrestrial knowledge of lymphedema etiology and treatment, lend insight into the cause of, and potential countermeasures for SANS.

Our understanding of the altered hemodynamics and dynamic insufficiency of the lymphatic system in microgravity helps to explain the symptoms and etiology of SANS. The cephalad fluid shift in microgravity, and fluid congestion, affects perception by the special senses, including taste and smell. ⁴⁸ Vision is also affected. During and after missions on the ISS, some astronauts experience ophthalmic changes, including choroidal folds, optic disc edema, cotton-wool spots, globe flattening, and refraction changes.^50,51 Astronauts with ophthalmic issues also had significantly higher plasma concentrations of metabolites, which is also consistent with our understanding of lymphedema in many other parts of the body, and the potential genetic contribution to SANS through 1-carbon metabolic pathway abnormalities. This may also link back to glymphatic dysregulation induced by microgravity, which disrupts its ability to clear the brain/eyes of metabolites.

Conclusion

The Manhattan Project engaged the most brilliant minds of the day on U.S. soil to bring peace to a world at war, although it ultimately led to a transition realized as the Cold War. The Cold War race became defined by the “Space Race,” won by Sputnik launched from Russian soil, but owned and dominated by the United States in landing upon lunar soil, bestowing national pride upon the shoulders of 400,000 NASA employees and contractors.

As the ISS joined countries once pitted at polar ends of the Cold War, and the union of additional flag-bearing countries as significant participants, human dwell time outside of the atmospheric boundaries grew proportionately, as did risk exposure for risk-averse nations. Hence, the fertile soil and call for research grew as evidence of pathology from a variety of insults, including Galactic Cosmic radiation, genetic and epigenetic alterations, fluid shifts in microgravity, circadian rhythm alterations, microbiome shifts in human bodies, effects of confinement, and the ISS bulky skeletal confines, became harsh realities of the extreme environment.

Countermeasure development has become a strategic key resource to be allocated, with translatable improvement in outcomes aboard ISS and in the form of NASA spinoffs. As privatization of Earth's orbital exploration capacity rapidly expands, countermeasure development must hasten both in research, and with safe, consistent transparent applications. Early capable, paying “astrocivilians” must be readily risk aware, but LEO must become a durable safe zone for all, including para-astronauts. Like scaling Mount Everest, there will be no shortage of the adventuresome to wait in long lines for the ascent. The window to climb, like the window to launch, is for the brave of heart, body, mind, and soul.

The following question remains: who will compose the next peaceful “Manhattan team,” an entity focused on reverse engineering the domains of the lymphatics and glycocalyx, outside, and then within the scope of neogravity environments? The team is already present, although siloed, brilliant, although isolated from a more common “think tank.” To abide together, patiently seeking collaboration that excites the intelligence and awakens the soul to unbridled possibilities, is the recognized calling.

The potential outcomes are the distinct possibility of altering the pan-epidemics of diabetes, cardiovascular disease, immune dysfunction, and obesity, through new countermeasure development, fostered in an understanding of lymphatic and GCX function in neogravity. The spinoff could bring Moore's Law to health care, both in patient outcomes and economics. The realities of the revision of the classical Starling forces are fueled by the physical nature of GCX, and the innate restorative and regenerative properties of the lymphatic system. Neoclassical health care hangs in the balance and is now visible on the near horizon. A commanding knowledge and understanding of the lymphatic and GCX response and adaptation in LEO broaden and sharpen the global overview and vision for all humankind.