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You have full access to this article via your institution. Download PDF INTRODUCTION Spaceflight is associated with several physiological changes in the human body, including changes in

ocular health [1]. One such change after long-duration spaceflight (LDSF) is spaceflight-associated neuro-ocular syndrome (SANS). SANS is characterized by imaging and clinical findings

including hyperopic refractive error shift, optic disc edema, choroidal folds [2], and posterior globe flattening [3]. Although SANS serves as one of the largest potential physiologic and

pathologic barriers to future crewed interplanetary LDSF by the National Aeronautics and Space Administration (NASA), the underlying mechanism of SANS remains ill defined [4]. However,

oxidative stress has been proposed as one of the contributory mechanisms underlying SANS [5]. In this article, we will focus on the ocular oxidative biomarker changes during spaceflight and

its implications for ocular health. OXIDATIVE STRESS AND THE EYE Spaceflight-induced oxidative stress may cause some of the visual abnormalities in astronauts including SANS. The body’s

antioxidant defense mechanisms may be overwhelmed in microgravity conditions, causing oxidative damage to tissues, including the eyes. Oxidative stress occurs when there is an imbalance

between the production of reactive oxygen species (ROS) and antioxidant defenses in the body [6]. ROS are molecules that have the potential to damage cellular components, such as

deoxyribonucleic acid (DNA), proteins, and lipids. Antioxidants are molecules that protect the body from oxidative damage by neutralizing ROS. The eye is particularly vulnerable to oxidative

stress due to its high metabolic rate and exposure to environmental stressors, such as light and oxygen [7]. Oxidative stress has been implicated in several ocular diseases, such as

age-related macular degeneration (AMD), cataracts, and glaucoma [6]. Mao et al. [8] examined the effects of spaceflight on mitochondrial function and oxidative stress in mice reported that

exposure to the spaceflight environment caused mitochondrial dysfunction and increased oxidative stress. The expression of genes related to mitochondrial function, as well as alterations in

the levels of antioxidants and markers of oxidative damage, was seen in the study mice [8]. This included significant elevations in the levels of 4-hydroxynonenal (4-HNE) protein (an

oxidative marker for lipid peroxidation) in the retina following spaceflight, as well as noticeable changes in the genes involved with a mitochondria-associated apoptotic pathway in mouse

ocular tissue following spaceflight when compared to ground-control mice [8]. ANTIOXIDANT THERAPY To mitigate the effects of ocular oxidative biomarker changes and preserve astronauts’

ocular health during spaceflight, several preventive measures and future research directions can be considered. For instance, exploring the effectiveness of antioxidant supplementation

regimens to counteract oxidative stress and mitigate ocular biomarker changes in astronauts is a potential avenue for future research. Antioxidants are molecules that protect the body from

oxidative damage by neutralizing ROS [9]. Several antioxidants have been studied for their potential to prevent or treat diseases associated with oxidative stress [9]. These antioxidants

include vitamins C and E, carotenoids, and flavonoids [9]. Vitamin E is a fat-soluble antioxidant that has been shown to protect against oxidative damage in the eye [10]. Vitamin E is found

in high concentrations in the lipid-rich membranes of the retina and plays a critical role in protecting these membranes from oxidative damage [11]. Carotenoids are pigments found in plants

that have antioxidant properties [12]. Lutein and zeaxanthin are two carotenoids that are found in high concentrations in the macula, which is the part of the retina responsible for central

vision [13]. Lutein and zeaxanthin are hypothesized to protect against oxidative damage in the macula and may help prevent or delay the onset of AMD [6]. Flavonoids are a group of

plant-derived compounds that have antioxidant properties [14]. Several flavonoids, such as quercetin and rutin have been shown to protect against oxidative damage in the eye [15]. Flavonoids

have also been shown to improve blood flow to the eye, which may help prevent or treat ocular diseases associated with reduced blood flow, such as glaucoma [16]. In a study by Luxton et al.

[17], the levels of several biomarkers in the blood and urine of astronauts before, during, and after spaceflight were measured. The results showed that the levels of

8-hydroxy-2’-deoxyguanosine (8-OHdG), a marker of DNA damage, were significantly increased during spaceflight compared to pre-flight levels and were highly correlated with telomere length

[17]. This is indicative of increased oxidative stress during spaceflight can potentially be one of the contributing factors for SANS development [17]. An experiment involving mice carried

out by Overbey et al. [18] revealed a number of different ways the retina is impacted during spaceflight [18]. Such changes include decreased retinal thickness, decline in the number of cone

photoreceptors, and an increase in oxidative stress. Furthermore, evidence for a rise in 4-hydroxynonenal (4-HNE), a marker of oxidative damage to the retina was noted to be elevated in

cone photoreceptors, retinal inner nuclear layer (INL), and ganglion cell layer (GCL) after spaceflight compared to terrestrial control mice [18]. Folate is a key player in oxidative

phosphorylation and adenosine triphosphate (ATP) production, an essential nutrient that is necessary for formate detoxification [19]. The accumulation of formate negatively impacts ATP

production, in turn causing optic nerve and mitochondrial injury, as well as intra-axonal swelling. An investigation by Zwart et al. suggested an association between SANS-related alterations

and the minor allele of methionine synthase reductase (MTRR) 66 as well as the major allele for serine hydroxymethyltransferase (SHMT1) [20]. Furthermore, a deficiency in B-vitamins such as

folate, riboflavin and B6 along with genetic changes elevated the likelihood of developing such alterations [20]. A later study by Zwart et al. investigating polymorphisms in 1-carbon

pathway metabolites, further found a link between folate status and HDTBR with carbon dioxide exposure (terrestrial analog to spaceflight) [21]. Implementing regular ocular screenings and

monitoring of astronauts’ ocular health using innovative screening technologies and biomarker assessments, will be essential to aid in early detection of ocular changes and prompt

intervention [22,23,24]. CONCLUSION Oxidative stress has been proposed as one of the mechanisms underlying SANS. As SANS serves as one of the largest barriers to future spaceflight, further

investigation of oxidative stress may provide further insight into effective countermeasures. Further research is needed to determine the efficacy of antioxidant therapy for preventing or

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study. Aerosp Med Hum Perform. 2022;93:800–5. Article  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * University College Dublin School of Medicine,

Belfield, Dublin, Ireland Mouayad Masalkhi * Michigan Medicine, University of Michigan, Ann Arbor, MI, USA Joshua Ong * Department of Ophthalmology, University of Cambridge, Cambridge, UK

Ethan Waisberg * Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA Andrew G. Lee * Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital,

Houston, TX, USA Andrew G. Lee * The Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA Andrew G. Lee * Departments of Ophthalmology, Neurology, and

Neurosurgery, Weill Cornell Medicine, New York, NY, USA Andrew G. Lee * Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX, USA Andrew G. Lee * University of

Texas MD Anderson Cancer Center, Houston, TX, USA Andrew G. Lee * Texas A&M College of Medicine, Houston, TX, USA Andrew G. Lee * Department of Ophthalmology, The University of Iowa

Hospitals and Clinics, Iowa City, IA, USA Andrew G. Lee Authors * Mouayad Masalkhi View author publications You can also search for this author inPubMed Google Scholar * Joshua Ong View

author publications You can also search for this author inPubMed Google Scholar * Ethan Waisberg View author publications You can also search for this author inPubMed Google Scholar * Andrew

G. Lee View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS MM: literature review and writing. JO: manuscript editing and review. EW:

manuscript editing and review. AGL: manuscript review. CORRESPONDING AUTHOR Correspondence to Mouayad Masalkhi. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

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PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Masalkhi, M., Ong, J., Waisberg, E. _et al._ Ocular oxidative changes and antioxidant therapy during spaceflight.

_Eye_ 38, 1034–1035 (2024). https://doi.org/10.1038/s41433-023-02841-0 Download citation * Received: 03 November 2023 * Revised: 06 November 2023 * Accepted: 10 November 2023 * Published: 24

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