The Final Frontier: Toward Transformative Insights into the Pathophysiologic Adaptations to Microgravity with Molecular Imaging

We live in the age of accelerated space exploration. A major goal of these endeavors is in preparing humans for long-term habitation in space and sustainable existence on other celestial objects. The National Aeronautics and Space Administration, the international space agencies, and several private space corporations are actively working independently or collaboratively to develop the necessary technologies that will not only address these objectives but improve life on Earth. There have been many unmanned spacecrafts exploring our solar system successfully through flybys, in the orbits, or on the surface of celestial bodies. Human landing on Mars has been a dream for many decades, but it may become a reality within the next decade. However, many hurdles still need to be overcome, most notably the physiologic and psychologic issues confronted by the astronauts during the long journey to Mars and back to Earth. Lessons learned from the long duration of human habitation in the Mir space station and the International Space Station have been helpful to explore the pathophysiologic adaptations that occur in response to a microgravity environment. Understanding and mitigating the undesired effects of microgravity will be essential for healthy human habitation in space. This article reviews briefly these pathophysiologic adaptions and proposes how molecular imaging may provide transformative insights into the effects of microgravity on various organ systems.

In general, pathophysiologic adaptive changes in response to microgravity have been described as analogous to an accelerated aging process, with the potential emergence of some diseases (1,2). Organ-level alterations include cephalad fluid shift; the loss of muscle and bone mass; anemia; reduced immune function; variability in cardiovascular, gastrointestinal, renal, and hepatic functions; and the development of neuroocular syndrome. At the cellular level, diverse effects include changes in cellular behavior, cytoskeletal arrangement, cell aggregation, cell cycle regulation, and protein synthesis (3–5). Molecular imaging, particularly with PET, including total-body PET systems, and MRI, including combined PET/MRI systems, can compare the scans before and after space flights to characterize the physiologic and anatomic changes induced by short-term and long-term exposure to microgravity (6).

Extended space flight missions also affect brain structure and function (7). PET with appropriate radiotracers can assess changes in brain perfusion, blood volume, metabolism, and receptors (e.g., dopamine, μ-opiate, γ-aminobutyric acid, serotonin) (8). Correlation of the imaging data to clinical manifestations (e.g., space-related motion sickness, neuropsychiatric signs and symptoms) will not only inform on precautions that may be necessary to mitigate the observed alterations but also expand our knowledge on the brain’s adaptive mechanisms.

In the cardiovascular physiology domain, PET and MRI can provide valuable quantitative information on numerous physiologic parameters, including coronary arterial flow; shear stress; and myocardial perfusion, metabolism, and sympathetic innervation (9,10). Echocardiography can be performed before the space flight, onboard the spacecraft, and after the space flight to assess changes in ventricular volumes, ejection fraction, myocardial contractility, and valvular function (11).

In the pulmonary system, weightlessness reduces the normal earthbound ventilation and perfusion inequality in the lung zones. There are also nonclinical impactful changes in the lung mechanics and volumes. Despite the increased pulmonary capillary blood volume, there is no development of pulmonary interstitial edema. PET with appropriate radiotracers can be useful in assessing the physiologic consequences of microgravity on physiologic parameters such as vascular permeability and diffusing capacity.

Microgravity also affects gastrointestinal motility and absorption. These alterations can have important effects on the astronaut’s nutritional status and bioavailability of oral drugs (12). Potential variations in gastrointestinal enzymes, gut bacteria, and hepatocellular metabolism and function are additional essential parameters that require investigation. PET with suitable radiotracers can assess intestinal absorption rate, various enzymatic availabilities and activities, and hepatic functions, such as fatty acid β-oxidation activity and the glucose–glycogen cascade metabolism.

The renal system is also affected by microgravity. There is renal adaptation to the cephalad fluid shift and increased central compartment volume. There may be an increased risk of urolithiasis related to hypercalciuria and changes in urine pH and volume (13). Imaging assessments of renal blood flow, glomerular filtration rate, tubular function, and renal electrolyte management can shed light on the renal adjustments that occur in a microgravity environment.

Significant changes in musculoskeletal physiology caused by microgravity have long been recognized. A loss of up to 10% of muscle mass has been observed after short space missions. There may also be damage to muscle fibers and neuromuscular junctions. Moreover, there is bone loss, with the emergence of microgravity-induced osteoporosis. There are countermeasures with appropriate exercise regimens aboard the spacecraft that aid to mitigate the musculoskeletal loss (14). Molecular imaging at both the cellular and the organ levels may provide insights into the mechanistic processes that may be involved (e.g., functionality of osteoblasts and osteoclasts, alterations in muscle metabolism, neuromuscular viability and function) (15).

Microgravity induces major changes in endocrine, hematologic, and immune homeostasis. The hormonal variations may lead to profound effects on human physiology during and after long space flights. Anemia and a decline in immune system function are two well-recognized effects. These observations may be partially caused by systemic hormonal effects or related to the direct influence of microgravity and relatively high radiation exposure in space to bone marrow cellularity and function. Immunosuppression may lead to increased susceptibility to infection and a propensity to the development of autoimmune diseases or cancer (16,17). Molecular imaging of immune cellular trafficking, differentiation, and function (e.g., T-cell lymphocytes, natural killer cells, cytokine production) and hormonal production and functionality will elucidate the underlying etiology for these alterations, which will need to be understood before countermeasures can be developed. Finally, across all physiologic systems, studies on the impact of microgravity and space radiation on gene expression and regulation will be relevant and critical. Studies on human cell lines exposed to microgravity have demonstrated effects on gene regulation, with the underexpression or overexpression of various genes (18–20). Molecular imaging may facilitate translation of these early investigations to an understanding of their impact on the whole human organism. Table 1 provides examples of how currently available PET agents could be used to decipher the physiologic adaptations to microgravity exposure.

TABLE 1.

Potential PET Agents for Assessing Physiologic System Adaptations to Microgravity

Physiologic system	Physiologic parameters and corresponding PET agents
Brain/central nervous system	Blood flow (15O-H2O), blood volume (15O-CO), glucose metabolism (18F-FDG), μ-opiate receptor (11C-carfentanil), γ-aminobutyric acid receptor (11C-methoxyprogabidic acid), D2 dopamine receptor (11C-raclopride)
Cardiovascular	Myocardial perfusion (15O-H2O, 13NH3, 18F-flurpiridaz), fatty acid metabolism (11C-palmitic acid), oxidative metabolism (11C-acetate), sympathetic innervation (18F-fluorodopamine), muscarinic receptor (11C-methylquinuclidinyl benzilate)
Pulmonary	Blood flow (15O-H2O), ventilation (13N2 gas), vascular permeability (68Ga-transferrin or 11C-methylalbumin), angiotensin-converting enzyme content (18F-fluorocaptopril)
Gastrointestinal/hepatic	Portal blood flow (15O-H2O), protein synthesis (11C-methionine), fatty acid β-oxidation (11C-octanoate), glucose metabolism (18F-FDG)
Renal	Blood flow (15O-H2O), oxygen consumption (11C-acetate), excretory function (68Ga-ethylenediaminetetraacetic acid,11C-para-aminobenzoic acid)
Musculoskeletal	Osteoblastic activity (18F-NaF), glucose metabolism (18F-FDG), protein metabolism (11C-methionine)
Endocrine/hematologic/ immune	Somatostatin receptor (68Ga-DOTATATE), androgen receptor (18F-fluorodihydrotestosterone), estrogen receptor (18F-fluoroestradiol), norepinephrine transporter (124I-metaiodobenzylguanidine), immune cell migration (68Ga-vascular adhesion protein-1), tissue remodeling and inflammation (18F-fibroblast activation protein inhibitor), leukocyte trafficking (68Ga-pentixafor)
Gene expression (multisystem)	Reporter genes and reporter probes (e.g., the gene–probe pairs of herpes simplex virus type 1 thymidine kinase and 18F-FHPG and D2 dopamine receptor and 18F-FESP])

¹⁸F-FHPG = 9-[(3-¹⁸F-fluoro-1-hydroxy-2-propoxy)methyl]guanine; ¹⁸F-FESP = [3-(2′-[¹⁸F]-fluoroethyl)spiperone.

As interplanetary missions and prolonged human habitation in space become commonplace in the next decades, there is an urgent need to understand how microgravity affects human physiology. Such understanding paves the way for healthy and safe extended space missions. Molecular imaging has a proven record of achievements in the investigation of human pathophysiology on Earth and will certainly aid in unraveling the mysteries of physiologic adaptations to microgravity.

DISCLOSURE

Hossein Jadvar reports support from National Institutes of Health grant P30-CA 014089. No other potential conflict of interest relevant to this article was reported.