Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight

Abstract

Space flight exerts a specific conglomerate of stressors on humans that can modulate the immune system. The mechanism remains to be elucidated and the consequences for cosmonauts in the long term are unclear. Most of the current research stems from short-term spaceflights as well as pre- and post-flight analyses due to operational limitations. Immune function of 12 cosmonauts participating in a long-duration (>140 days) spaceflight mission was monitored pre-, post-, and on two time-points in-flight. While the classical markers for stress such as cortisol in saliva where not significantly altered, blood concentrations of the endocannabinoid system (ECS) were found to be highly increased in-flight indicating a biological stress response. Moreover, subjects showed a significant rise in white blood cell counts. Neutrophils, monocytes and B cells increased by 50% whereas NK cells dropped by nearly 60% shortly after landing. Analysis of blood smears showed that lymphocyte percentages, though unchanged pre- and post-flight were elevated in-flight. Functional tests on the ground revealed stable cellular glutathione levels, unaltered baseline and stimulated ROS release in neutrophils but an increased shedding of L-selectin post-flight. In vitro stimulation of whole blood samples with fungal antigen showed a highly amplified TNF and IL-1β response. Furthermore, a significant reduction in CD4 + CD25 + CD27 low regulatory T cells was observed post-flight but returned to normal levels after one month. Concomitantly, high in-flight levels of regulatory cytokines TGF-β, IL-10 and IL-1ra dropped rapidly after return to Earth. Finally, we observed a shift in the CD8 + T cell repertoire toward CD8 + memory cells that lasted even one month after return to Earth. Conclusion: Long-duration spaceflight triggered a sustained stress dependent release of endocannabinoids combined with an aberrant immune activation mimicking features of people at risk for inflammation related diseases. These effects persisted in part 30 days after return to Earth. The currently available repertoire of in-flight testing as well as the post-flight observation periods need to be expanded to tackle the underlying mechanism for and consequences of these immune changes in order to develop corresponding mitigation strategies based on a personalized approach for future interplanetary space explorations.

Neutrophil-to-Lymphocyte Ratio: A Biomarker to Monitor the Immune Status of Astronauts

“…However, since MPO gene expression was elevated in HU mice blood, this suggests the potential for myelocyte/immature neutrophil infiltration and may also serve as a biomarker for elevated inflammation during spaceflight. To our knowledge no measurements have been recorded for elevated immature neutrophils in blood circulation in-flight; however, elevated neutrophils were identified in blood from 9 of 16 astronauts at landing (6,76,77). As compared to the rodent spaceflight results (in-flight day 14), elevated neutrophils were also observed at days 14 and 30 of HU in mice ( Figures 4C and 5A), suggesting the physical effects of fluid-shifting experienced during spaceflight and HU may stimulate the release of neutrophils into circulation; however this requires further investigation.…”

“…In humans, GLR was elevated at 180-days in-flight, suggesting prolonged exposure to spaceflight caused leukocyte differential changes. This change in immune differentials may be in response to elevated inflammation experienced in-flight (4,6,12), since elevated, chronic inflammation is often coupled with immune dysfunction and disease development (13,19,20,(67)(68)(69)(70). Therefore, monitoring distinct biomarkers, such as elevated NLR, can determine when countermeasures can intervene to avert immune dysfunction, promote immune recovery, and prevent disease development.…”

“…For instance, physiological aging occurs significantly faster as a result of spaceflight, when measured by muscle wasting, loss of bone density, and immune dysfunction (1,2). Processes regulated by redox imbalance may contribute to these adverse outcomes (3)(4)(5)(6)(7)(8)(9). Redox imbalance results from a disproportionate increase in reactive oxygen species (ROS) produced by the mitochondria (10) compared to antioxidants in the cell.…”

“…Although, elevated human NLR (>3.53) (27) has been implicated in clinical settings to identify heightened inflammation (18), this biomarker has not yet been recognized for spaceflight-induced inflammation. Spaceflight raises circulating white blood cell (WBC) counts, primarily granulocytes, may reduce lymphocyte counts (12,28,29), and impairs immune cell functions (6,12,30,31). Although, the spaceflight environment elevates circulating blood granulocytes counts in astronauts (29), the underlying molecular mechanisms remain elusive.…”

Spaceflight-Associated Immune System Modifications

“…This thymus involution and changes in the development and response of immune cells are also observed when the gravitational force is altered, as illustrated by the reactivation of latent viruses in astronauts and the elderly. In addition, a recent study suggests that long-term spaceflight could induce an increase in inflammation as in the elderly (inflammaging), which could increase the risk of allergies or autoimmune diseases in astronauts [80]. Finally, aging is accompanied by changes in antibody production similar to those observed in flight.…”