The eye is a very delicate and complex biological organ with precise and integrated light-sensitive and visual processing functions. At the same time, the eye is richly vascularised and has a wide distribution of nerves, leading to an increased demand for oxygen and the consequent production of metabolic products , and a greater sensitivity to oxygen radical attack. In addition, other factors such as lighting, the nature of the work involved, time, distance and habits can further aggravate the eye and lead to various forms of discomfort and visual fatigue symptoms, such as blurred vision, that affect people's normal visual function . Visual fatigue, also known as eye strain, is common in people who use electronic devices regularly or have incorrect eye habits .
The main causes of visual fatigue are related to structural damage or reduced function of the outer corneal surface and the retina at the base of the eye [24
]. The main mechanisms by which polyunsaturated fatty acids alleviate visual fatigue are detailed in Figure 1
Figure 1. The main mechanism of PUFAs in relieving asthenopia. AMD = age-related macular degeneration; MMP-9 = matrix metalloproteinase-9; NPD1 = neuroprotection D1; IL-1β = interleukin-1β; IL-6 = interleukin-6; TNF-α = tumor necrosis factor-α; AA = arachidonic acid; NF-κB = nuclear factor kappa-B; ROS = reactive oxygen species; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; LA = linoleic acid.
2. Polyunsaturated Fatty Acids Improve Damaged Eye Surfaces and Act as Visual Fatigue Relievers
The corneal surface of the eye is rich in sensory nerves, an important refractive medium and key to maintaining ocular surface homeostasis [23
]. However, the ocular surface is highly exposed to the outside world and environmental stimuli of bright light and oxygen often damage the structure and function of the cornea, resulting in reduced tear volume, increased corneal sensitivity [23
] and further dry eye, which can lead to a range of episodes of visual fatigue symptoms such as photophobia and blurred vision.ω-3 polyunsaturated fatty acids and ω-6 polyunsaturated fatty acids are important components of cellular phospholipid membranes and are thought to be essential for maintaining cellular function . It has been reported that intake of ω-3 polyunsaturated fatty acids may affect the neural structure of the cornea and have an important role in corneal health [87
].Dietary supplementation with LA and GLA of omega-6 polyunsaturated fatty acids has also been shown to promote ocular surface tear production and reduce dry eye after refractive keratectomy [88
], thereby alleviating episodes of visual fatigue.Currently, most studies support that high levels of omega-3 polyunsaturated fatty acids are negatively associated with the development of dry eye, while high omega-6:omega-3 ratios are positively associated with the frequent occurrence of dry eye and ocular discomfort [90
]. Clinical studies have shown that omega-3 polyunsaturated fatty acids can reduce ocular surface inflammation in dry eye populations [91
], thereby effectively reducing visual fatigue. Meanwhile, a double-blind clinical trial found that continuous oral administration of omega-3 polyunsaturated fatty acids (360 mg/d EPA + 240 mg/d DHA) for 30 d significantly reduced tear evaporation and increased ocular surface tear production in patients with dry eye, effectively relieving dry eye and eye discomfort [93
]. In addition, oral administration of ω-3 PUFAs significantly improved the reduction in tear osmolarity and TBUT scores in the dry eye population, suggesting that ω-3 PUFAs improved the intrinsic stability of the tear film. The data show that matrix metalloproteinase-9 (MMP-9) is a protein hydrolase that induces inflammatory cytokines and inflammatory responses in the ocular surface and plays an important role in dry eye and ocular surface diseases [94
]. This trial also showed that oral administration of ω-3 polyunsaturated fatty acids significantly reduced MMP-9 and Ocular Surface Disease Index (OSDI) scores. This supports the idea that ω-3 PUFAs reduce hyperosmotic stress in the ocular surface epithelium, while directly reducing ocular surface inflammation [95
], thereby effectively reducing visual fatigue and ocular discomfort. At the same time, a growing body of evidence confirms that combined supplementation with omega-6 polyunsaturated fatty acids and omega-3 polyunsaturated fatty acids has a more significant effect on improving ocular surface health and relieving ocular surface dryness than single supplementation with omega-3 polyunsaturated fatty acids. An animal study showed that combined supplementation with ω-3 polyunsaturated fatty acids and ω-6 polyunsaturated fatty acids (EPA+DHA and GLA) significantly improved elevated intraocular pressure (IOP) and further prevented IOP-induced retinal cell structure and glial cell activation in rats compared to single supplementation with polyunsaturated fatty acids (EPA and DHA or GLA) [96
]. In a double-blind, randomised and controlled trial, 138 patients with dry eye were given capsules of a supplement enriched with omega-3 PUFAs and omega-6 PUFAs, vitamins and zinc, three times daily for three months. The results showed that supplementation enriched with omega-3 PUFAs and omega-6 PUFAs significantly reduced the expression of human leukocyte antigen-DR (HLA-DR), an inflammatory marker of the conjunctival epithelium, in the dry eye population, and that dry eye discomfort was improved [97
In summary, oral administration of polyunsaturated fatty acids, particularly ω-3 polyunsaturated fatty acids with DHA and EPA, may have the effect of improving tear film stability and tear volume, reducing the amount of MMP-9 expression on the ocular surface and decreasing the degree of inflammation, thus providing relief from visual fatigue. In addition, combined supplementation of omega-6 polyunsaturated fatty acids with omega-3 polyunsaturated fatty acids showed better ocular surface improvement compared to single supplementation of omega-3 polyunsaturated fatty acids, suggesting that rationed intake of omega-3 polyunsaturated fatty acids with omega-6 polyunsaturated fatty acids is more beneficial in aiding eye health.
3. PUFAs Improve Damaged Eye Fundus and Relieve Visual Fatigue
Polyunsaturated fatty acids are one of the most important components in maintaining the homeostasis of the retina and promoting its healthy development [98
]. The retina is rich in several polyunsaturated fatty acids, such as DHA and AA, the former of which is important for the survival of photoreceptor cells [19
] and promotes the survival of rat retinal photoreceptors in vitro and under oxidative stress by activating the ERK/MAPK signalling pathway [99
]. Alternatively, it selectively protects photoreceptors from oxidative stress by regulating the levels of Bcl-2 family pro- and anti-apoptotic proteins [100
]. In addition, DHA can exert cytoprotective, anti-inflammatory and pro-survival repair signals on photoreceptors through the conversion of 1-lipoxygenase-1 to neuroprotective D15 (NPD1), which in turn further induces anti-apoptotic and inhibits pro-apoptotic proteins. In addition, a significant decrease in DHA and a significant increase in the ω-6/ω-3 ratio were observed in the eyes of retina-damaged mice [19
]. This reflects the fundamental and important role of DHA in the retina. In contrast, AA metabolism of arachidonic acid (including prostaglandins, coagulants, leukotrienes and lipoxygenases) is associated with activation of inflammatory pathways and regulation of microglia [101，102，103
Dietary supplementation routes for polyunsaturated fatty acids are particularly important as the body does not synthesize enough omega-3 polyunsaturated fatty acids to sustain all the vital activities of the organism [104
]. Dietary supplementation with omega-3 polyunsaturated fatty acids has been reported to be effective in preventing retinal damage, thereby furthering its effect on visual fatigue. Flaxseed oil rich in ω-3 polyunsaturated fatty acids has been reported to protect visual function by activating Nrf2-HO-1 signalling and down-regulating NF-κB p65 expression to reduce visible light-induced oxidative stress and retinal inflammatory damage [105
]. The clinical study further confirmed that in 30 individuals with visual fatigue, after 101 d of supplementation with flaxseed oil softgels, the symptoms of visual fatigue were significantly reduced, and the persistence of visual acuity in both eyes was 70.3%, with an overall effective rate of 51%, a significant difference, confirming that dietary supplementation with ω-3 PUFAs can effectively relieve visual fatigue [106
]. Fuminori et al. [28
] Continuous supplementation with omega-3 polyunsaturated fatty acids rich in omega-3 polyunsaturated fatty acids, specifically a combination preparation of fish oil (DHA 783 mg/d and EPA 162 mg/d), lingonberry extract (containing anthocyanins 59 mg/d) and lignan (17.5 mg/d), significantly improved symptoms in patients with visual fatigue for 4 consecutive weeks. Thus, there is a growing body of research supporting that increasing dietary levels of omega-3 polyunsaturated fatty acids can promote human health. Research also confirms that dietary supplementation with omega-3 polyunsaturated fatty acids is important in preventing or reducing eye inflammation, for example, supplementation with fish oil rich in DHA and EPA has been shown to reduce retinal damage in premature infants, thereby repairing impaired vision function in infants [107
]. In addition, the dietary supplementation route of fish oil is also effective in reducing the production of ROS and the release of pro-inflammatory factors, thereby effectively suppressing the levels of inflammatory factors in the retinal vascular endothelium . Clinical studies have also shown that 3 months of oral omega-3 (EPA and DHA) significantly inhibited the production of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in the blood of young and older women . Expression of pro-inflammatory factors, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) [108
]. In addition, a significant reduction in plasma production of IL-5β, IL-6 and TNF-α in C57BL/6 mice was observed in animal studies after 1-6 weeks of dietary supplementation with EPA + DHA or fish oil [109
In addition, ageing is accompanied by a decline in RPE cell viability, leading to a reduction in their antioxidant and self-healing capacity, making the retinal macula more susceptible to adverse reactions, leading to AMD, which further exacerbates visual fatigue [24
]. Epidemiological, clinical and experimental studies have shown that supplementation with omega-3 polyunsaturated fatty acids is negatively associated with AMD and that an increase in omega-6 polyunsaturated fatty acids increases this risk [112
]. Higher intakes of both EPA and DHA can help prevent or delay the onset of AMD in the medium term [113
Combined intake of omega-6 and omega-3 has been reported to significantly modulate the amount or ratio of PUFAs in the body, thereby reducing the extent of retinal damage [114，115
]. Dietary supplementation with DHA and EPA can effectively regulate the ratio of AA, DHA and EPA in the body [116
]. High levels of LA intake significantly reduce the risk of AMD; conversely, high levels of DHA intake are negatively associated with the risk of AMD [117
]. In addition, the EPA + DHA + GLA diet significantly reduced the activation of glial cells in rats with retinal damage compared to EPA + DHA or GLA supplementation alone, and was effective in protecting the structural integrity of the retina [96
]. These studies suggest that diets with different combinations of ω-3 and ω-6 PUFAs may be more helpful in improving damaged retinas than single ω-3 PUFAs or ω-6 PUFAs supplementation, suggesting that regulation of ω-3 PUFA levels and the ratio of ω-6/ω-3 PUFAs are important in retinal protective function. A stable ω-6/ω-3 ratio in the range of 1:1-4:1 has been reported to be an appropriate balance ratio in animal and human diets and more beneficial to the health of the organism [118
]. However, the optimal range of ω-6/ω-3 ratios has not been clearly reported in ocular studies.
In conclusion, oral supplementation with ω-3 polyunsaturated fatty acids, particularly DHA and EPA, is effective not only in reducing visual fatigue but also in improving dry eye [119
] or other adverse reactions that occur in the eye [120
]. These studies also suggest again that dietary supplementation with omega-3 polyunsaturated fatty acids can have an impact on visual fatigue through a variety of pathways, including antioxidant and anti-inflammatory as well as anti-apoptotic, and that the ratio of omega-3 polyunsaturated fatty acids to omega-6 polyunsaturated fatty acids intake is important for eye health and the degree of visual fatigue relief, but no studies appear to have been reported examining the optimal ratio of the two in terms of eye health. This may be a direction for future research. Table 1 summarises the mechanisms by which PUFAs improve the extent of ocular surface and fundus damage, and thus exert a visual fatigue-relieving effect.
Table 1. Mechanisms by which PUFAs reduce the extent of damage to the ocular surface and fundus, exerting their effects on the relief of visual fatigue.