With the rapid growth of middle-aged and older adult populations, the prevalence of common age-related eye diseases has increased, including cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD), which are the main causes of progressive and irreversible vision loss in aging populations worldwide (1–3). Globally, 285 million people have moderate to severe visual impairment or blindness, of whom 65% of the visually impaired and 82% of all blind people are aged 50 or older (4). In the United States, the prevalence of most eye diseases increases with age among individuals aged ≥50 years, and such diseases impose a substantial socioeconomic burden (5). Furthermore, age-related eye diseases can reduce the quality of life of older adults and independently increase their mortality (6–8). Because of their overall health implications, age-related eye diseases are a major health concern among middle-aged and older adults, and new strategies for preventing or delaying disease progression must be identified.

Studies have reported that the cells of the tissues of the eyes are sensitive to oxidative stress, triggering and exacerbating age-related ocular abnormalities (9). Carotenoids are a group of common natural antioxidants and fat-soluble phytochemicals that are synthesized only by specific microorganisms and plants (10, 11). To the best of our knowledge, α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin account for more than 95% of the carotenoids in circulation (11, 12). Because ocular carotenoids absorb light in the visible light region, they protect the retina and lens from the potential photochemical damage caused by light exposure (13, 14). Carotenoids can also suppress the free radicals produced by complex physiological reactions, thereby protecting the eyes from the effects of oxidative stress, cell apoptosis, mitochondrial dysfunction, and inflammation (13). Several previous studies have reported that dietary carotenoid supplementation had a potential beneficial association with reduced risk of cataract, preserved macular health in glaucoma and promoted retinal health, and improved visual function in diabetic retinopathy (15–18). In addition, the Age-Related Eye Diseases Study (AREDS) Research Group demonstrated that dietary lutein/zeaxanthin supplementation was significantly associated with late AMD progression and can serve as an appropriate replacement for beta carotene, which increased the risk of lung cancer (19, 20).

To date, the majority of previous studies have focused on the association between dietary carotenoid intake and eye diseases (21, 22), whereas epidemiological evidence regarding the relationship between serum carotenoid concentrations and the risk of age-related eye diseases remains limited. Serum concentrations provide a direct measure of absorbed, metabolically processed carotenoids, reflecting interindividual differences in digestion, absorption, and metabolism that dietary assessments cannot capture. A cross-sectional study demonstrated that a higher concentration of serum α-carotene is associated with a lower risk of diabetic retinopathy (23). Furthermore, higher blood concentrations of α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin are associated with a lower risk of cataract among individuals aged ≥50 years (24). A case–control study reported that higher serum concentrations of carotenoids, particularly zeaxanthin and lycopene, were associated with a lower likelihood of developing exudative AMD in an older Chinese population (25). Notably, most of the aforementioned studies have mainly focused on the association between the serum carotenoid concentration and single eye diseases in Asian populations. To date, few studies have comprehensively explored the association between serum carotenoids and various age-related eye diseases among populations in the United States.

In the present population-based cross-sectional study, we examined the association of the serum carotenoid concentration with the risk of major age-related eye diseases, including cataract, glaucoma, diabetic retinopathy, and AMD, in a nationally representative sample of the middle-aged and older adult population in the United States.

The present study investigated the associations between the serum carotenoid concentration and the risk of major age-related eye diseases in a nationally representative sample of the middle-aged and older adult population in the United States. The findings indicated that higher serum concentrations of α-carotene, β-carotene, and lutein/zeaxanthin were negatively associated with the risk of cataracts; a higher serum concentration of β-cryptoxanthin was negatively associated with the risk of glaucoma; higher serum concentrations of β-carotene and β-cryptoxanthin were negatively associated with the risk of diabetic retinopathy; and a higher serum concentration of lycopene was negatively associated with the risk of AMD. In addition, we discovered that serum concentrations of α-carotene, β-carotene, β-cryptoxanthin, lycopene, and total carotenoids were inversely associated with the risk of any ocular disease, particularly among the female participants of the present study.

Although the causes of age-related eye diseases are complex and multifactorial, oxidative stress is widely recognized as a common factor that contributes to the development of age-related eye diseases in middle-aged and older adults (31, 32). The eyes are particularly vulnerable to oxidative stress due to factors such as direct exposure to ultraviolet light, a high content of mitochondria, and high metabolic activity (2, 33). Studies have demonstrated that reactive oxygen species (ROS) can cause cataracts by damaging cell membrane fibers and crystalline proteins (34). The complex non-enzymatic and enzymatic antioxidant system in the lens can scavenge ROS for preserving lens proteins, whereas the weakening of this antioxidant defense system can cause damage to lens molecules and disrupt their repair mechanisms (35). Furthermore, in several studies examining the superoxide dismutase-knockdown mouse model, mice with lower levels of antioxidants were reported to exhibit higher ROS levels; these mice also displayed various AMD characteristics, including drusen, thickened Bruch’s membrane, and choroidal neovascularization (36–38). Oxidative stress has been speculated to be involved in diabetic retinopathy. For example, studies have demonstrated that oxidative stress can alter the blood–retinal barrier and increase vascular permeability, which are the most prominent characteristics of diabetic retinopathy (39). Therefore, antioxidants may alleviate diabetic retinopathy. A study reported that the long-term administration of antioxidants inhibited the development of early-stage diabetic retinopathy in diabetic rats (40).

A growing body of evidence suggests that carotenoids have antioxidant effects and that higher circulating concentrations of carotenoids are associated with lower risks of various oxidative stress–related chronic diseases, such as diabetes, hypertension, and non-alcoholic fatty liver disease (11, 26, 41, 42). Because carotenoids may be involved in cellular signaling pathways related to inflammation and oxidative stress, they may inhibit oxidative stress and inflammation (43). However, to date, no systematic evaluation has examined the associations between the serum concentrations of various carotenoids and the development of age-related eye diseases, and most studies have mainly focused on single eye diseases. A meta-analysis of observational studies indicated that the serum concentration of β-carotene was associated with a reduced risk of cataracts (44). Similarly, inverse associations were observed between the serum concentrations of α-carotene, lutein, and zeaxanthin and the risk of cataracts (45), corresponding to our findings. To the best of our knowledge, no study has evaluated the associations between serum concentrations of carotenoids and the risk of glaucoma. Only one study reported that the dietary intake of α-carotene, β-carotene, or lutein/zeaxanthin was associated with a decreased risk of glaucoma among older African-American women. The present study also identified negative associations between the serum concentration of α-carotene and the risk of glaucoma among female participants (46). Regarding the associations between the serum concentrations of carotenoids and the risk of diabetic retinopathy, a study reported that the plasma levels of carotenoids, including α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin, were lower in individuals with diabetic retinopathy than in those without diabetic retinopathy (47). Similar to our findings, the results of a cross-sectional study conducted in a Chinese population indicated that a higher serum concentration of β-carotene is associated with a lower risk of diabetic retinopathy, suggesting that β-carotene plays a protective role against diabetic retinopathy (23). Furthermore, in a matched case–control study of 164 patients with AMD, higher concentrations of carotenoids, including β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin, were revealed to be inversely associated with the risk of AMD (48). Our study also revealed an inverse association between the serum concentration of lycopene and the risk of AMD.

The results of the present study suggested that serum concentrations of α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein/zeaxanthin, and total carotenoids were associated with a decreased risk of any ocular disease among the female participants. By contrast, no association was identified between the serum concentrations of carotenoids and the risk of any ocular disease among the male participants. While this finding is intriguing, the underlying mechanisms remain uncertain and should be interpreted with caution. A possible explanation for this phenomenon is that relative to men, women are typically more sensitive to oxidative stress and tend to exhibit higher levels of oxidative stress (49–51). In particular, for postmenopausal women, the lack of estrogen often leads to increased oxidative stress (52). In addition, women may have a higher risk of age-related eye diseases than men because of various socioeconomic factors and the effects of estrogen withdrawal during menopause (4). In addition, the stronger inverse associations observed in women may reflect estrogen’s modulation of carotenoid metabolism and absorption. For instance, scavenger receptor class B member 1 (SR-B1) is a multiligand receptor that facilitates the uptake of cholesteryl esters from high-density lipoproteins (HDLs) and the transport of carotenoids. Its expression is transcriptionally upregulated by estrogen through the direct binding of estrogen receptors to estrogen response elements (EREs) in its promoter (53). This is supported by our supplementary analysis showing lower carotenoid levels in female participants compared to male participants (54). However, it is important to note that these explanations remain hypothetical. Residual confounding by unmeasured socioeconomic or lifestyle factors. Therefore, our results should be seen as generating a hypothesis that warrants further investigation in studies designed specifically to explore causal mechanisms behind sex differences in carotenoid metabolism and ocular protection.

The present study has several strengths. First, we comprehensively assessed the associations between the serum concentrations of various carotenoids and the risk of various age-related eye diseases, including cataract, glaucoma, diabetic retinopathy, and AMD. Notably, our study is the first to explore the dose–response relationship between the serum concentrations of various carotenoids and the risk of any ocular disease. Second, because we used data from the National Health and Nutrition Examination Survey, which is a nationally representative database, our findings can be generalized to the community-dwelling population in the United States. Third, our analyses were adjusted for an extensive set of confounders, including socioeconomic and health factors. Finally, serum carotenoid levels provide a more robust and biologically relevant measure than dietary intake estimates for studying age-related eye diseases. Unlike questionnaire-based dietary data, serum concentrations objectively reflect bioavailable carotenoid exposure, integrating absorption efficiency, metabolic variation, and contributions from both diet and supplements. Crucially, they exhibit stronger physiological plausibility for antioxidant protection in ocular tissues and, in our analyses, remained independently associated with disease risk even after adjustment for dietary intake, highlighting their value as a superior biomarker in nutritional ophthalmology research.

Nonetheless, the present study still has several limitations. First, because of the cross-sectional design of our study, we could not explore the causal relationship between the serum concentrations of the studied carotenoids and the development of age-related eye diseases. Second, the cohort consisted predominantly of non-Hispanic White participants, with underrepresented groups comprising a smaller proportion, which limits the generalizability of our findings. Third, our study is limited by the classification of diabetic retinopathy within the NHANES database, which did not separately identify proliferative diabetic retinopathy (PDR). Consequently, our analysis was restricted to non-proliferative stages, potentially diluting the observed effect sizes and preventing an assessment of whether higher carotenoid levels are associated with a reduced risk of progressing to sight-threatening PDR. This may result in a conservative underestimation of the true protective association. Fourth, cataract and glaucoma were defined based on self-reported data obtained during a personal interview. This method does not allow differentiation between primary open-angle glaucoma (POAG) and ocular hypertension (OHT). Since OHT is not associated with the optic nerve damage characteristic of POAG, this misclassification likely biases the observed associations toward null, thereby potentially underestimating the relationship between carotenoid levels and neurodegenerative glaucomatous pathology. Future prospective studies should incorporate detailed clinical assessments, such as optic nerve head imaging, visual field testing, to improve diagnostic accuracy and better distinguish between glaucoma subtypes. Fifth, due to constraints in the NHANES dataset, we did not exclude participants with non-age-related ocular conditions (e.g., uveitis and traumatic cataract) or a history of cataract surgery, which may introduce some potential for confounding. Furthermore, the findings of the present study could have been influenced by residual confounders, such as dietary supplementation (AREDS formulations, multivitamins) and medication use (statins, corticosteroids). Finally, the sample size of the present study was small because limited data were available, and the associations between the serum concentrations of several carotenoids and the development of age-related eye diseases approached statistical significance. Although the FDR correction was applied to mitigate the risk of false positives resulting from multiple comparisons, some significant findings may still be attributable to type I error. Therefore, our overall findings must be further verified through prospective studies with larger sample sizes.

Our study demonstrated that higher serum concentrations of carotenoids, particularly α-carotene, β-carotene, β-cryptoxanthin, and lycopene, were associated with a lower risk of age-related eye diseases. The present findings need to be verified in prospective studies with a larger sample size.