식단 바꾸기 - 황반변성 치료 논문 2020,,

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Nutrients. 2020 Sep; 12(9): 2862.

Published online 2020 Sep 18. doi: 10.3390/nu12092862

PMCID: PMC7551870

PMID: 32962100

Dietary Patterns, Carbohydrates, and Age-Related Eye Diseases

Sarah G. Francisco,1 Kelsey M. Smith,1,2 Gemma Aragonès,1 Elizabeth A. Whitcomb,1 Jasper Weinberg,1 Xuedi Wang,1 Eloy Bejarano,1,* Allen Taylor,1,2,3,* and Sheldon Rowan1,2,3,*

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Abstract

Over a third of older adults in the U.S. experience significant vision loss, which decreases independence and is a biomarker of decreased health span. As the global aging population is expanding, it is imperative to uncover strategies to increase health span and reduce the economic burden of this age-related disease. While there are some treatments available for age-related vision loss, such as surgical removal of cataracts, many causes of vision loss, such as dry age-related macular degeneration (AMD), remain poorly understood and no treatments are currently available. Therefore, it is necessary to better understand the factors that contribute to disease progression for age-related vision loss and to uncover methods for disease prevention. One such factor is the effect of diet on ocular diseases. There are many reviews regarding micronutrients and their effect on eye health. Here, we discuss the impact of dietary patterns on the incidence and progression of age-related eye diseases, namely AMD, cataracts, diabetic retinopathy, and glaucoma. Then, we focus on the specific role of dietary carbohydrates, first by outlining the physiological effects of carbohydrates on the body and then how these changes translate into eye and age-related ocular diseases. Finally, we discuss future directions of nutrition research as it relates to aging and vision loss, with a discussion of caloric restriction, intermittent fasting, drug interventions, and emerging randomized clinical trials. This is a rich field with the capacity to improve life quality for millions of people so they may live with clear vision for longer and avoid the high cost of vision-saving surgeries.

미국 노인의 3분의 1 이상이 심각한 시력 손실을 경험하며, 

이는 독립성을 떨어뜨리고 

건강 수명 감소의 바이오마커로 작용합니다. 

전 세계적으로 고령화 인구가 확대됨에 따라 건

강 수명을 늘리고 

노화 관련 질환으로 인한 경제적 부담을 줄이기 위한 전략을 모색하는 것이 시급합니다. 

백내장의 수술적 제거와 같은 노화 관련 시력 상실에 대한 일부 치료법이 있지만, 

건성 연령 관련 황반변성(AMD)과 같은 시력 상실의 많은 원인은 

아직 제대로 이해되지 않았고 

현재로서는 치료법이 없습니다. 

따라서 

노화와 관련된 시력 상실의 질병 진행에 기여하는 요인을 더 잘 이해하고 

질병 예방 방법을 밝혀내는 것이 필요합니다. 

이러한 요인 중 하나는 

식단이 안과 질환에 미치는 영향입니다. 

미량 영양소와 

눈 건강에 미치는 영향에 관한 많은 연구가 있습니다. 

여기에서는 

식이 패턴이 

연령 관련 안질환인 

황반변성, 

백내장, 

당뇨병성 망막증, 

녹내장의 발생과 진행에 미치는 영향에 대해 논의합니다. 

그런 다음 

탄수화물이 신체에 미치는 생리적 영향과 

이러한 변화가 눈과 노화 관련 안구 질환으로 이어지는 과정을 설명함으로써 

식이 탄수화물의 구체적인 역할에 초점을 맞춥니다. 

마지막으로 

칼로리 제한, 

간헐적 단식, 

약물 중재, 

새로운 무작위 임상시험에 대한 논의를 통해 

노화 및 시력 상실과 관련된 영양 연구의 미래 방향에 대해 논의합니다. 

이 분야는 수백만 명의 삶의 질을 개선하여 더 오랫동안 선명한 시력을 유지하고 시력 보존 수술의 고비용을 피할 수 있는 풍부한 잠재력을 가진 분야입니다.

Keywords: age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, dietary pattern, Mediterranean diet, glycemic index, caloric restriction, intermittent fasting

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1. Introduction

Vision loss is a pervasive health impairment affecting over 400 million people worldwide. Aging is a significant risk factor for several loss-of-vision eye diseases. As the global elderly population is growing, it is incumbent upon researchers to uncover mechanisms of ocular disease progression and identify strategies to prevent or slow these diseases. The four major age-related eye diseases are age-related macular degeneration (AMD), cataracts, diabetic retinopathy (DR), and glaucoma.

AMD is the leading cause of vision loss in industrialized countries with an estimated 196 million people between the ages of 30–97 affected by AMD around the world [1]. Broadly, AMD involves damage to the macula, an area of the retina necessary for high-acuity vision, and can lead to loss of central vision. AMD comes in two forms, “dry” AMD and “wet” AMD, with dry AMD accounting for the majority of cases. Dry AMD results from damage to the supporting cells of the retina called retinal pigmented epithelial cells (RPE) and is associated with a buildup of extracellular protein- and lipid-containing deposits called drusen. Wet AMD, while less common, is far more damaging as it is the result of aberrant angiogenesis with an increase in leaky blood vessels releasing fluid under the macula resulting in photoreceptor degeneration.

Cataract is the second most pervasive cause of age-related vision loss accounting for 51% of world blindness [2]. Cataract is the result of opacification in the lens of the eye that blurs and eventually obscures vision and is most commonly corrected with surgical removal of the cataract.

Diabetic retinopathy (DR) is the cause of vision impairment for an estimated 146 million people worldwide [3]. DR is a diabetic complication of the eye that is similar to wet AMD in that it involves damaged blood vessels in the retina that can cause blurred vision, floating spots, or blindness. High blood sugar as a result of diabetes can lead to damaged blood vessels in the inner retina, triggering these symptoms.

Glaucoma, the fourth major age-related eye disease, affects an estimated 76 million people across the globe. The mechanism(s) of disease progression of glaucoma are not well understood, but the result is a loss of peripheral vision from damage to the optic nerve and a measurable increase in intraocular pressure. Glaucoma is treated with drug therapy in the form of eye drops that reduce eye pressure, or laser treatment; however, these treatments cannot reverse or cure the disease.

Nutritional epidemiology has provided insights into the major age-related eye diseases, largely through observational studies, as well as some seminal randomized clinical trials (RCTs), most notably the Age Related Eye Disease Study (AREDS)1 and AREDS2 studies [4]. Multiple reviews indicate effects of individual food components through supplementation with whole foods, micronutrients, or macronutrients. AMD onset and progression are associated with low levels of carotenoids, antioxidant vitamins, and omega-3 fatty acids, and reduced intake of fruit, vegetables, and fish [5]. The AREDS studies demonstrated that high intake of vitamin A, vitamin, C, zinc, copper, and carotenoids could reduce the progression of AMD by approximately 25%. Age-related cataract has also been associated with vitamin and carotenoid status [6,7]. Although nutrients such as vitamins A, C, and E, lutein, zeaxanthin, and β-carotene were associated with reduced cataract risk in cohort studies, inconsistent results are reported in RCTs [8]. Observational cohort studies suggest that regular consumption of nitrate-rich leafy green vegetables is associated with reduced risk of glaucoma development [9]. There is also evidence that vitamins A and C are protective against glaucoma [10].

In this review, we eval‎uated the risk for age-related eye diseases from the perspective of dietary patterns, which take into account the effects of groups of various foods. Given the complexity of the nutrient interactions within dietary patterns, we anticipated that the eval‎uation of differences in dietary patterns will better inform about vision maintenance and health than supplementation with individual nutrients or single whole foods alone and could provide more effective dietary recommendations in the future.

시력 상실은 

전 세계 4억 명 이상의 사람들에게 영향을 미치는 만연한 건강 장애입니다. 

노화는 여러 가지 시력 상실 안질환의 중요한 위험 요인입니다. 전 세계적으로 노인 인구가 증가함에 따라 연구자들은 안과 질환의 진행 메커니즘을 밝히고 이러한 질환을 예방하거나 늦출 수 있는 전략을 모색해야 하는 과제를 안고 있습니다. 

노화와 관련된 4대 안과 질환은 

연령 관련 황반변성(AMD),

백내장,

당뇨망막병증(DR),

녹내장입니다.

AMD는 

선진국에서 시력 상실의 주요 원인으로, 

전 세계 30~97세 인구의 약 1억 9,600만 명이 AMD의 영향을 받는 것으로 추정됩니다[1]. 

일반적으로 

AMD는 시력 유지에 필요한 망막 부위인 황반이 손상되어 

중심 시력을 상실할 수 있습니다. 

AMD는 

"건성" AMD와 "습성" AMD의 두 가지 형태가 있으며, 

건성 AMD가 대부분의 경우를 차지합니다. 

건성 AMD는 

망막색소상피세포(RPE)라는 

망막의 지지 세포가 손상되어 발생하며 

드루젠이라고 하는 세포 외 단백질 및 지질 함유 침전물이 축적되는 것과 관련이 있습니다. 

드루젠 : 누런색의 지질, 단백질 등 세포찌거기 

습성 AMD는 

흔하지는 않지만 

황반 아래에서 액체를 방출하는 새는 혈관이 증가하여 

광수용체 변성을 초래하는 비정상적인 혈관 신생의 결과이므로 

훨씬 더 손상될 수 있습니다.



백내장은 

전 세계 실명의 51%를 차지하는 

노화와 관련된 시력 상실의 두 번째로 널리 퍼진 원인입니다[2]. 

백내장은 

눈의 수정체가 혼탁해져 시야가 흐려지고 

결국에는 시야를 가리는 질환으로, 

백내장을 수술로 제거하는 것이 가장 일반적인 치료법입니다.



당뇨병성 망막증(DR)은 

전 세계적으로 약 1억 4,600만 명의 시력 장애를 일으키는 원인입니다[3]. 

DR은 

망막의 혈관이 손상되어 

시야 흐림, 떠다니는 반점 또는 실명을 유발할 수 있다는 점에서 

습성 AMD와 유사한 눈의 당뇨병 합병증입니다. 

당뇨병으로 인한 고혈당은 

망막 안쪽의 혈관을 손상시켜 이러한 증상을 유발할 수 있습니다.



노화와 관련된 네 번째 주요 안과 질환인 녹내장은

 전 세계적으로 약 7,600만 명의 사람들에게 영향을 미칩니다. 

녹내장의 질병 진행 메커니즘은 잘 알려져 있지 않지만, 

시신경 손상으로 인한 말초 시력 상실과 

안압의 측정 가능한 상승이 

그 결과입니다. 

녹내장은 안압을 낮추는 안약 형태의 약물 요법이나 

레이저 치료로 치료하지만, 

이러한 치료로는 질병을 되돌리거나 완치할 수 없습니다.



영양 역학은 

주로 관찰 연구와 일부 중요한 무작위 임상시험(RCT)을 통해 

주요 연령 관련 안질환에 대한 통찰력을 제공했으며, 

특히 연령 관련 안질환 연구(AREDS)1 및 AREDS2 연구[4]가 대표적입니다. 

여러 연구에 따르면 

전체 식품, 

미량 영양소 또는 다량 영양소 보충을 통해 

개별 식품 성분의 효과를 확인할 수 있습니다. 

AMD 발병 및 진행은 

카로티노이드, 

항산화 비타민, 

오메가-3 지방산의 낮은 수치와 과일, 채소, 생선 섭취 감소와 관련이 있습니다[5]. 

AREDS 연구에 따르면 

비타민 A, 

비타민 C,

아연, 구리,

카로티노이드를 많이 섭취하면

AMD의 진행을 약 25% 줄일 수 있는 것으로 나타났습니다.

노화 관련 백내장도

비타민 및 카로티노이드 상태와 관련이 있습니다[6,7].

비타민 A, C, E, 루테인, 제아잔틴, 베타카로틴과 같은 영양소는

코호트 연구에서 백내장 위험 감소와 관련이 있지만,

RCT에서는 일관되지 않은 결과가 보고되고 있습니다 [8].

관찰 코호트 연구에 따르면

질산염이 풍부한 잎이 많은 녹색 채소를 정기적으로 섭취하는 것이

녹내장 발병 위험 감소와 관련이 있다고 합니다 [9].

비타민 A와 C가 녹내장을 예방한다는 증거도 있습니다 [10].

이 리뷰에서는 

다양한 식품군의 영향을 고려한 식이 패턴의 관점에서 

노화 관련 안과 질환의 위험을 평가했습니다. 

식이 패턴 내 영양소 상호 작용의 복잡성을 고려할 때, 

식이 패턴의 차이를 평가하면 개

별 영양소 또는 단일 식품만을 보충하는 것보다 

시력 유지 및 건강에 대한 정보를 더 잘 얻을 수 있으며 

향후 더 효과적인 식이 권장 사항을 제공할 수 있을 것으로 예상했습니다.

2. Dietary Patterns and Eye Disease

Traditionally, dietary patterns have been divided into prudent dietary patterns and western dietary patterns. These can be defined based on a food factor analysis from dietary survey data, using techniques like principal component analysis to determine correlations between foods that are eaten together, or can be based on scores of adherence to pre-specified dietary patterns. These methodologies have been used to eval‎uate the major age-related eye diseases: AMD, cataract, glaucoma, and DR. For example, defined food intake patterns including prudent dietary patterns, the healthy eating index, and the Mediterranean diet have been related to risk for preval‎ence or progression of eye diseases in multiple cohorts. However, small differences in methodology likely contribute to some variation in findings using these metrics.

Cohort designs are discussed briefly alongside findings. In general, prospective cohorts have the least biased design, while case–control studies have the most. In all designs, dietary pattern studies have the common limitations that the defined pattern is not necessarily the one that the individual consumed throughout their relevant dietary histories. Human dietary intake is extremely complicated and cannot be determined through food-frequency questionnaires alone. There are also gene–nutrient interactions. Some studies have a sufficient number of genotyped individuals to determine if gene–diet interactions exist between dietary patterns for age-related ocular diseases. As an example, some studies discussed below eval‎uated the major gene variants associated with AMD, Complement Factor H (CFH), and ARMS2 [11]. CFH genotypes include alleles associated with highly increased risk for AMD, as well as alleles associated with lower risk for AMD. Figure 1 shows a graphical representation of the odds ratios presented in the text for AMD. The odds ratios below are presented as age-adjusted and/or sex-adjusted, but not fully multivariate adjusted. Non-significant associations have been largely omitted for clarity.

전통적으로 

식이 패턴은 신중한 식이 패턴과 서구식 식이 패턴으로 구분되어 왔습니다. 

이는 함께 섭취하는 식품 간의 상관관계를 파악하기 위해 주

성분 분석과 같은 기술을 사용하여 

식이 조사 데이터의 식품 요인 분석을 기반으로 정의하거나 

미리 지정된 식이 패턴을 준수하는 점수를 기반으로 정의할 수 있습니다. 

이러한 방법론은 

주요 노화 관련 안과 질환을 평가하는 데 사용되었습니다: 

AMD, 백내장, 녹내장 및 DR. 

예를 들어, 

신중한 식습관, 

건강한 식습관 지수, 

지중해식 식단을 포함한 정의된 음식 섭취 패턴은 

여러 코호트에서 안질환의 유병률 또는 

진행 위험과 관련이 있는 것으로 나타났습니다. 

그러나 방법론의 작은 차이로 인해 이러한 지표를 사용한 결과에는 약간의 차이가 있을 수 있습니다.



코호트 설계는 연구 결과와 함께 간략하게 설명합니다. 일반적으로 전향적 코호트는 편향성이 가장 적은 반면, 사례 대조군 연구는 편향성이 가장 높습니다. 모든 설계에서 식이 패턴 연구는 정의된 패턴이 반드시 개인이 관련 식이 이력을 통해 섭취한 것과 일치하지 않는다는 공통적인 한계가 있습니다. 인간의 식이 섭취는 매우 복잡하기 때문에 음식 빈도 설문조사만으로는 파악할 수 없습니다. 유전자-영양소 상호작용도 있습니다. 일부 연구에서는 노화와 관련된 안과 질환의 식이 패턴 사이에 유전자-식이 상호작용이 존재하는지 확인하기 위해 충분한 수의 유전자형을 가진 개인을 대상으로 진행되었습니다. 예를 들어, 아래에서 설명하는 일부 연구에서는 AMD, 보체 인자 H(CFH) 및 ARMS2와 관련된 주요 유전자 변이를 평가했습니다 [11]. CFH 유전자형에는 AMD 위험을 크게 높이는 대립유전자뿐만 아니라 AMD 위험을 낮추는 대립유전자도 포함됩니다. 그림 1은 AMD에 대한 본문에 제시된 확률 비율을 그래픽으로 표현한 것입니다. 아래의 오즈비는 연령 조정 및/또는 성별 조정으로 표시되었지만 완전한 다변량 조정은 아닙니다. 명확성을 위해 유의미하지 않은 연관성은 대부분 생략되었습니다.

Figure 1

Odds ratios or relative risk ratios for age-related macular degeneration (AMD) from studies described in text (Section 2.1, Section 2.2, Section 2.3, Section 2.4).

2.1. Prudent Dietary Patterns and AMD

One of the first studies to eval‎uate association of AMD with dietary patterns was a factor analysis study of the American clinical AREDS cohort. Chiu et al. defined two major American dietary patterns and eight minor American dietary patterns. They referred to the prudent dietary pattern as the Oriental diet pattern, which consisted of the following food groups in order of importance: dark-yellow vegetables, cruciferous vegetables, green leafy vegetables, legumes, fruits, other vegetables, whole grains, tomatoes, fish and other seafood, rice, poultry, soup, and low-fat dairy products. Adherence to the Oriental diet pattern was associated with decreased risk of early AMD (OR = 0.74 (95% CI: 0.59–0.91); Ptrend = 0.01) and late AMD (OR = 0.38 (95% CI: 0.27–0.54); Ptrend < 0.0001) [12]. Three additional minor dietary patterns that partially overlapped with the Oriental dietary pattern were associated with decreased risk of advanced AMD: breakfast pattern (OR = 0.60 (95% CI: 0.44–0.82); Ptrend = 0.004) characterized by cold breakfast cereals, fruit juices, whole grains, and fruit; Caribbean dietary pattern (OR = 0.64 (95% CI: 0.47–0.89); Ptrend = 0.009) characterized by organ meats, poultry, fish and seafood, rice, and low-fat dairy; and peanut pattern (OR = 0.64 (95% CI: 0.46–0.89); Ptrend = 0.03) characterized by peanuts, snacks, high-fat dairy, sweets, and desserts [13].

A similar approach was taken by the Melbourne Collaborative Cohort study, a longitudinal cohort primarily focused on eval‎uating diet and lifestyle in cancer prevention. Amirul Islam et al. identified six dietary patterns associated with early or late AMD [14]. They found that one pattern (factor 6), characterized by grains, fish, steamed or boiled chicken, vegetables, and nuts protected against late AMD (OR = 0.49 (95% CI: 0.28–0.87); Ptrend = 0.008). Dietary patterns that consisted of fruits, vegetables, or salads did not have statistically significant associations with early or late AMD; there were no dietary patterns with significant associations with early AMD.

The Rotterdam Eye study was a prospective population cohort from the Netherlands. Using baseline dietary data, de Koning-Backus et al. defined nine dietary patterns from within a prudent diet and associated each with incident AMD. They found that one of those patterns (pattern 9) was associated with protection against incident AMD (OR = 0.56 (95% CI: 0.35–0.89)). This pattern included consuming vegetables (≥200 g/day), fruits (2×/day), and fish (2×/week) [15]. Surprisingly, other dietary patterns that included vegetables, fruits, and fish, but were constrained by intake levels of other foods like eggs, poultry, meats, or potatoes, did not reach statistical significance, suggesting that there may be negative off-sets from certain foods associated with a western dietary pattern.

Not all prudent dietary patterns have shown protective associations against AMD. A smaller study of the Irish Nun Eye Study identified a healthy dietary pattern containing fruits, vegetables, oily fish, nuts, and several other foods, but did not identify associations with AMD for any of their dietary patterns [16]. Notably, the healthy dietary pattern also included red meat and pizza, suggesting that, like in the Rotterdam Eye study dietary pattern analysis, protection from AMD may have as much to do with what is not consumed, as what is consumed. A prospective study from the ARIC (Atherosclerosis Risk in Communities) cohort identified a prudent dietary pattern and although the prudent dietary pattern showed a protective effect on late AMD, similar in magnitude to the studies above, it did not reach statistical significance (OR = 0.51 (95% CI: 0.22–1.18); Ptrend = 0.054) [17].

AMD와 

식이 패턴의 연관성을 평가한 최초의 연구 중 하나는 

미국 임상 AREDS 코호트를 대상으로 한 요인 분석 연구였습니다. 

Chiu 등은 두 가지 주요 미국식 식이 패턴과 여덟 가지 미국식 식이 패턴을 정의했습니다. 

그들은 신중한 식이 패턴을 동양식 식이 패턴이라고 불렀는데, 

이는 암황색 채소, 십자화과 채소, 녹색 잎 채소, 콩류, 과일, 기타 채소, 통곡물, 토마토, 생선 및 기타 해산물, 쌀, 가금류, 수프, 저지방 유제품 등의 식품군으로 구성됩니다. 동양식 식단 패턴을 준수하는 것은 초기 AMD(OR = 0.74 (95% CI: 0.59-0.91); Ptrend = 0.01) 및 후기 AMD(OR = 0.38 (95% CI: 0.27-0.54); Ptrend < 0.0001) [12] 위험 감소와 관련이 있는 것으로 나타났습니다. 

차가운 아침 시리얼, 과일 주스, 통곡물, 과일로 특징지어지는 아침 식사 패턴(OR = 0.60 (95% CI: 0.44-0.82); Ptrend = 0.004), 카리브식 식이 패턴(OR = 0. 64 (95% CI: 0.47-0.89); Ptrend = 0.009) 내장육, 가금류, 생선 및 해산물, 쌀, 저지방 유제품; 땅콩, 스낵, 고지방 유제품, 과자 및 디저트가 특징인 땅콩 패턴 (OR = 0.64 (95% CI: 0.46-0.89); Ptrend = 0.03) [13].



암 예방을 위한 식단과 생활습관 평가에 주로 초점을 맞춘 종단 코호트 연구인 멜버른 협력 코호트 연구에서도 비슷한 접근 방식을 취했습니다. 아미룰 이슬람 등은 초기 또는 후기 AMD와 관련된 6가지 식이 패턴을 확인했습니다[14]. 

연구진은 

곡물, 생선, 찜 또는 삶은 닭고기, 채소, 견과류가 특징인 

한 가지 패턴(요인 6)이 

후기 AMD를 예방한다는 사실을 발견했습니다(OR = 0.49 (95% CI: 0.28-0.87); Ptrend = 0.008). 

과일, 채소 또는 샐러드로 구성된 식이 패턴은 

초기 또는 후기 AMD와 통계적으로 유의미한 연관성이 없었으며, 초기 AMD와 유의미한 연관성이 있는 식이 패턴은 없었습니다.



로테르담 아이 연구는 네덜란드의 전향적 인구 코호트 연구였습니다. 드 코닝-백쿠스 박사 등은 기준 식이 데이터를 사용하여 신중한 식단 내에서 9가지 식이 패턴을 정의하고 각각의 패턴을 AMD 발병과 연관시켰습니다. 연구진은 이러한 패턴 중 하나(패턴 9)가 발병성 AMD 예방과 관련이 있다는 사실을 발견했습니다(OR = 0.56 (95% CI: 0.35-0.89)). 이 패턴에는 채소(≥200g/일), 과일(2회/일), 생선(2회/주) 섭취가 포함되었습니다[15]. 놀랍게도 채소, 과일, 생선을 포함하지만 계란, 가금류, 육류, 감자 등 다른 식품의 섭취량에 제약을 받는 다른 식이 패턴은 통계적 유의성에 도달하지 못해 서구식 식이 패턴과 관련된 특정 식품의 부정적인 오프셋이 있을 수 있음을 시사했습니다.



모든 신중한 식이 패턴이 AMD를 예방하는 연관성을 보인 것은 아닙니다. 아일랜드 수녀 눈 연구에 대한 소규모 연구에서는 과일, 채소, 기름진 생선, 견과류 및 기타 여러 식품을 포함하는 건강한 식이 패턴을 확인했지만, 해당 식이 패턴에서 AMD와의 연관성을 확인하지는 못했습니다 [16]. 특히, 건강한 식이 패턴에는 붉은 육류와 피자도 포함되어 있어 로테르담 아이 연구 식이 패턴 분석에서와 마찬가지로 AMD로부터의 보호는 섭취하는 것만큼이나 섭취하지 않는 것과도 관련이 있을 수 있음을 시사합니다. ARIC(지역사회 죽상경화증 위험) 코호트의 전향적 연구에서 신중한 식이 패턴을 확인했으며, 신중한 식이 패턴이 위의 연구와 비슷한 규모의 후기 AMD에 대한 보호 효과를 보였지만 통계적 유의성에 도달하지는 못했습니다(OR = 0.51 (95% CI: 0.22-1.18); Ptrend = 0.054) [17].

2.2. Mediterranean Diet and AMD

The Mediterranean diet (MeDi) has been one of the most extensively studied dietary patterns and has been linked to improved health span, weight maintenance, and reduced chronic disease [18,19]. The MeDi resembles the prudent dietary patterns described above, but has additional emphasis placed on regular consumption of olive oil, nuts, legumes, and fish and seafood. Several different approaches to assessing adherence to MeDi exist, including a score called the alternative MeDi score. All are based on extensive dietary questionnaire data. It can be difficult to directly compare studies that use different methodologies because of differences in how MeDi adherences are determined. Nevertheless, it is impressive that, to date, MeDi adherence has been consistently associated with protection against AMD in different geographic cohorts that have very different baseline dietary preferences.

Two prospective European cohort studies, the Rotterdam study from the Netherlands and the Alienor study from France, termed the EYE-RISK consortium, have eval‎uated associations between MeDi scores and AMD. Merle et al. reported that in both cohorts individually and combined, high adherence to MeDi, as assessed by the 9-point European-based MeDi score (mediSCORE > 6), was associated with reduced incidence of dry AMD (OR = 0.59 (95% CI: 0.37–0.95); Ptrend = 0.04) [20]. They eval‎uated the type of advanced AMD separately, and only dry AMD maintained a significant protective association (OR = 0.42 (95% CI: 0.2–0.9); Ptrend = 0.04). The association with wet AMD was of a similar magnitude, but did not reach statistical significance, perhaps due to a smaller number of cases. No gene–diet interaction between MeDi and the CFH risk allele (Y402H: rs1061170) was observed.

Case–control studies have been widely used to eval‎uate MeDi scores and AMD. The Coimbra Eye Study eval‎uated the association between MeDi adherence and risk of AMD in two Portuguese populations using the 9-item mediSCORE [21] and found that mediSCOREs > 6 were associated with protection from AMD (OR = 0.73 (95% CI: 0.58–0.93)). A nested subset of the Coimbra Eye Study was similarly analyzed and showed a very similar protection for any AMD (OR = 0.62 (95% CI: 0.38–0.97)) [22].

An American clinical cohort consisting of patients from the AREDS1 and AREDS2 trials has also been scored for association of MeDi with advanced AMD using the alternative MeDi score (aMeDi), designed for U.S. populations. These studies demonstrated that MeDi not only protects against late AMD, but also that it can interact with a particular risk allele of the CFH alternative complement inhibitor (Y402H: rs1061170). Merle et al. showed that aMeDi scores > 6 were associated with protection from advanced AMD (OR = 0.74 (95% CI: 0.61–0.90), Ptrend = 0.005) [23]. They also described a gene–diet interaction between the non-risk allele of CFH (Y402) and aMeDi score > 6 (P = 0.04), wherein individuals with two copies of the risk allele of CFH (Y420H) were not protected from advanced AMD by high adherence to MeDi. These findings were expanded recently by Keenan et al., who used aMeDi scores to eval‎uate the combined AREDS1 and AREDS2 cohorts [24]. This study replicated the protective effect of MeDi on late AMD (OR = 0.78 (95% CI: 0.71–0.85); Ptrend < 0.0001), and further defined enhanced protection against dry forms of AMD compared with wet forms of AMD. In particular, individuals within the AREDS2 cohort did not show a significant protective effect of high aMeDi scores on wet AMD. Keenan et al. replicated the interaction between a CFH risk allele and MeDi and expanded these findings by eval‎uating separately a protective allele of CFH (rs10922109) and found a gene–diet interaction (P = 0.01), wherein only individuals containing at least one protective CFH allele were protected against advanced AMD by MeDi. The Keenan et al. study, as well as a follow-up study from Merle et al., found that MeDi was associated with delayed progression of drusen to large drusen size, indicating that one protective impact of MeDi may be mediated directly in the eye on drusenogenesis [24,25].

Other cohorts have eval‎uated advanced AMD relationships to MeDi. In the European Eye Study, Hogg et al. found that adherence to MeDi, as measured using a mediSCORE > 6 similar to the Coimbra studies, led to reduced wet AMD (OR = 0.53 (95% CI: 0.27–1.04); Ptrend = 0.01), without an interaction with the CFH risk allele (Y402H: rs1061170) (P = 0.89) [26]. No significant associations were found for early AMD. Hogg et al. also reported a weak trend between MeDi and large drusen (P = 0.05). It is curious that the European cohorts have not found interactions between MeDi and the CFH risk allele, as reported in the U.S. AREDS study. One possible explanation is that the AREDS study already enrolled patients with intermediate AMD and might have had an overabundance of the CFH risk allele. A second possibility suggested by Keenan et al. is that the relevant allele is the CFH protective allele, which was likely present in those lacking the CFH risk allele [24]. A gene–diet interaction between the risk allele of CFH and fish intake, a critical protective component of MeDi, may explain the MeDi–CFH genetic interactions [11,24].

While the associations between MeDi and late AMD have been well-replicated, the relationship between MeDi and early AMD is less clear. In an analysis of the CAREDS (Carotenoids in Age-related Eye Disease Study) cohort, using the aMeDi score cutoffs, Mares et al. reported a significant protective effect of MeDi on early AMD (OR = 0.34 (95% CI: 0.08–0.96); Ptrend = 0.046), but noted that only 53 women in their cohort fit the 6-9 aMeDi score cutoff [27]. Determining whether MeDi can prevent incident AMD will likely require several new cohort studies from different geographical regions, and potentially different, geographically relevant scoring systems for MeDi.

지중해식 식단(MeDi)은 가장 광범위하게 연구된 식단 패턴 중 하나이며 건강 수명, 체중 유지, 만성 질환 감소와 관련이 있는 것으로 알려져 있습니다[18,19]. MeDi는 위에서 설명한 신중한 식단 패턴과 유사하지만 올리브 오일, 견과류, 콩류, 생선 및 해산물을 규칙적으로 섭취하는 것을 추가로 강조합니다. MeDi 준수 여부를 평가하는 여러 가지 접근 방식이 존재하며, 여기에는 대체 MeDi 점수라는 점수가 포함됩니다. 모두 광범위한 식단 설문 데이터를 기반으로 합니다. MeDi 준수 여부를 판단하는 방법의 차이로 인해 서로 다른 방법론을 사용하는 연구를 직접 비교하기는 어려울 수 있습니다. 그럼에도 불구하고, 현재까지 기준 식단 선호도가 매우 다른 여러 지역 코호트에서 MeDi 준수 여부가 AMD 예방과 일관되게 연관되어 있다는 점은 인상적입니다.



두 개의 전향적 유럽 코호트 연구인 네덜란드의 로테르담 연구와 프랑스의 Alienor 연구(EYE-RISK 컨소시엄)는 MeDi 점수와 AMD 사이의 연관성을 평가했습니다. Merle 등은 두 코호트에서 개별적으로나 통합적으로, 9점 유럽 기반 MeDi 점수(mediSCORE > 6)로 평가한 MeDi의 높은 순응도가 건성 AMD 발생 감소와 관련이 있다고 보고했습니다(OR = 0.59 (95% CI: 0.37-0.95); Ptrend = 0.04) [20]. 연구진은 진행성 AMD 유형을 별도로 평가했으며 건성 AMD만 유의미한 보호 연관성을 유지했습니다(OR = 0.42 (95% CI: 0.2-0.9); Ptrend = 0.04). 습성 AMD와의 연관성은 비슷한 수준이었지만 사례 수가 적어서인지 통계적 유의성에 도달하지 못했습니다. MeDi와 CFH 위험 대립유전자(Y402H: rs1061170) 간에는 유전자-식이 상호작용이 관찰되지 않았습니다.



사례 대조 연구는 MeDi 점수와 AMD를 평가하는 데 널리 사용되어 왔습니다. 코임브라 아이 연구에서는 9개 항목으로 구성된 mediSCORE [21]를 사용하여 두 명의 포르투갈 인구 집단에서 MeDi 준수와 AMD 위험 간의 연관성을 평가한 결과, mediSCORE가 6점 이상인 경우 AMD로부터의 보호와 관련이 있는 것으로 나타났습니다(OR = 0.73 (95% CI: 0.58-0.93)). 코임브라 아이 연구의 중첩된 하위 집합도 유사하게 분석되었으며, 모든 AMD에 대해 매우 유사한 보호 효과를 보였습니다(OR = 0.62 (95% CI: 0.38-0.97)). [22].



AREDS1 및 AREDS2 시험의 환자로 구성된 미국 임상 코호트에서도 미국 인구를 대상으로 설계된 대체 MeDi 점수(aMeDi)를 사용하여 MeDi와 진행성 AMD의 연관성을 점수화했습니다. 이 연구에서는 MeDi가 후기 AMD를 예방할 뿐만 아니라 CFH 대체 보체 억제제의 특정 위험 대립유전자(Y402H: rs1061170)와 상호작용할 수 있음을 입증했습니다. Merle 등의 연구에 따르면 aMeDi 점수가 6점 이상이면 진행성 AMD로부터의 보호와 관련이 있습니다(OR = 0.74 (95% CI: 0.61-0.90), Ptrend = 0.005) [23]. 또한 연구진은 CFH의 비위험 대립유전자(Y402)와 aMeDi 점수 > 6(P = 0.04) 사이의 유전자-식이 상호작용을 설명했는데, CFH의 위험 대립유전자(Y420H)를 2개 보유한 개인은 MeDi에 대한 높은 순응도를 통해 진행된 AMD로부터 보호받지 못했습니다. 이러한 연구 결과는 최근 Keenan 등이 aMeDi 점수를 사용하여 AREDS1 및 AREDS2 코호트를 통합 평가한 연구로 확장되었습니다[24]. 이 연구에서는 후기 AMD에 대한 MeDi의 보호 효과를 재현했으며(OR = 0.78 (95% CI: 0.71-0.85); Ptrend < 0.0001), 습성 AMD에 비해 건성 AMD에 대한 보호 효과가 더욱 강화된 것으로 정의했습니다. 특히 AREDS2 코호트에 속한 개인은 습성 AMD에 대해 높은 aMeDi 점수가 유의미한 보호 효과를 보이지 않았습니다. Keenan 등은 CFH 위험 대립유전자와 MeDi 간의 상호작용을 재현하고 CFH의 보호 대립유전자(rs10922109)를 별도로 평가하여 이러한 결과를 확장한 결과, 유전자-식이 상호작용(P = 0.01)을 발견했으며, 보호 CFH 대립유전자를 하나 이상 보유한 개인만이 MeDi를 통해 진행된 AMD로부터 보호되는 것으로 나타났습니다. Keenan 등의 연구와 Merle 등의 후속 연구에 따르면 MeDi는 드루젠이 큰 드루젠 크기로 진행되는 것을 지연시키는 것과 관련이 있으며, 이는 MeDi의 보호 효과가 눈에서 드루젠 발생에 직접 매개될 수 있음을 나타냅니다[24,25].



다른 코호트에서는 진행된 AMD와 MeDi의 관계를 평가했습니다. 유럽 눈 연구에서 Hogg 등은 Coimbra 연구와 유사한 mediSCORE > 6을 사용하여 측정한 결과, MeDi를 준수할 경우 CFH 위험 대립유전자(Y402H: rs1061170)와의 상호작용 없이 습성 AMD가 감소(OR = 0.53 (95% CI: 0.27-1.04); Ptrend = 0.01)[26](P = 0.89) 한다는 사실을 발견했습니다. 초기 AMD에 대해서는 유의미한 연관성이 발견되지 않았습니다. Hogg 등은 또한 MeDi와 큰 드루젠 사이의 약한 경향을 보고했습니다(P = 0.05). 미국 AREDS 연구에서 보고된 것처럼 유럽 코호트에서 MeDi와 CFH 위험 대립 유전자 간의 상호작용을 발견하지 못한 것은 의문입니다. 한 가지 가능한 설명은 AREDS 연구에 이미 중등도 AMD 환자가 등록되어 있어 CFH 위험 대립 유전자가 과도하게 많았을 수 있다는 것입니다. Keenan 등이 제안한 두 번째 가능성은 관련 대립 유전자가 CFH 보호 대립 유전자인데, 이는 CFH 위험 대립 유전자가 없는 사람들에게 존재했을 가능성이 높다는 것입니다 [24]. CFH의 위험 대립 유전자와 MeDi의 중요한 보호 요소인 생선 섭취 사이의 유전자-식이 상호작용은 MeDi-CFH 유전적 상호작용을 설명할 수 있습니다 [11,24].



MeDi와 후기 AMD 사이의 연관성은 잘 재현되었지만, MeDi와 초기 AMD 사이의 관계는 덜 명확합니다. Mares 등은 aMeDi 점수 컷오프를 사용한 CAREDS(연령 관련 안과 질환 연구) 코호트 분석에서 초기 AMD에 대한 MeDi의 유의미한 보호 효과를 보고했지만(OR = 0.34 (95% CI: 0.08-0.96); Ptrend = 0.046), 해당 코호트에서 6-9 aMeDi 점수 컷오프에 맞는 여성은 53명에 불과하다고 지적했습니다 [27]. MeDi가 AMD 발병을 예방할 수 있는지 여부를 결정하려면 여러 지역에서 여러 개의 새로운 코호트 연구가 필요하며, 잠재적으로 지역적으로 다른 MeDi 점수 체계가 필요할 수 있습니다.

2.3. Healthy Eating Index and AMD

Many western populations show overall poor adherence to MeDi, but there are alternative defined dietary patterns that have been used to assess dietary relationships to health. One of those is the healthy eating index (HEI). Two studies have eval‎uated associations between early or late AMD and HEI scores. Montgomery et al. used the alternative HEI to assess its relationship to advanced AMD in a case–control study and found that it was protective (OR = 0.54 (95% CI: 0.30–0.99)) [28]. They also used the traditional HEI and found a protective effect that did not achieve statistical significance, possibly because of the relatively small size of the cohort (666 total). Aspects of the alternative HEI that may track better with AMD protection include components for trans-fat intake and a ratio of polyunsaturated fats to saturated fats. Mares et al. also used a modified HEI to examine relationships to early AMD, as they did above for MeDi, and found a protective association (OR = 0.54 (95% CI: 0.33–0.88), Ptrend = 0.01) [27]. These protective associations were also true when analyzed for large drusen, pigmentary abnormalities, or total AMD including late AMD.

2.4. Western Diet and AMD

The flipside of the healthy dietary patterns presented above as prudent dietary patterns, MeDis, or HEI is the western diet. Although categorized differently based on food frequency questionnaire data, the common features of western dietary pattern are higher intakes of red meat, saturated fats, highly processed foods, sweets and desserts, and sugar-sweetened beverages. Chiu et al. characterized such a western dietary pattern and showed a statistically significant association with early AMD (OR = 1.56 (95% CI: 1.18–2.06); Ptrend = 0.01) and late AMD (OR = 3.7 (95% CI: 2.31–5.92); Ptrend < 0.0001) [12]. Chiu et al. separately identified a minor dietary pattern, overlapping with the western dietary pattern, coined the steak pattern, with an emphasis on red meat, potatoes, gravies, and butter or margarine, that was associated with late AMD risk (OR = 1.73 (95% CI: 1.24–2.41); Ptrend = 0.02) [13].

Using a similar factor analysis approach to dietary patterns, Amirul Islam et al. characterized a red meat dietary pattern (Factor 4) that also included processed fish, eggs, and low intake of whole wheat or rye bread [14]. The red meat dietary pattern was associated with increased risk for late, but not early, AMD (OR = 1.46 (95% CI: 1.0–2.17). Their factor analysis also identified a separate subset of the typical western dietary pattern containing mostly processed foods (Factor 5) that did not associate with any AMD. However, Factor 5 also included foods like peanuts, tea, and dairy that have been associated with protection from AMD, suggesting that potentially harmful foods in the dietary pattern could be counterbalanced by the intake of beneficial foods.

As described above, prospective studies are powerful designs for dietary pattern analysis. Dighe et al., using the ARIC cohort, eval‎uated dietary patterns with risk for AMD among 1278 individuals, and identified major prudent and western dietary patterns [17]. Individuals that adhered to a western diet were at increased risk for advanced, but not early, AMD (OR = 3.44 (95% CI: 1.33–8.87); Ptrend = 0.014). The findings from Dighe et al. and Amirul Islam et al. that the Western diet patterns were only associated with late, but not early, AMD seem to be at odds with the Chiu et al. findings. In the AREDS cohort, individuals were enrolled based on having intermediate AMD present in at least one eye; therefore, the individuals in this study may be at increased risk of early AMD in the other eye. Prospective studies using healthy individuals at baseline are therefore better suited for the eval‎uation of early AMD.

2.5. Cataract and Dietary Patterns

Age-related cataract is the most preval‎ent condition associated with vision impairment and blindness in older adults worldwide [29]. Although it can be treated surgically, this is cost-prohibitive in many developing nations, where there are insufficient numbers of surgeons to meet the challenge. Prevention through lifestyle intervention may be the only viable treatment option. It is therefore important to determine whether dietary patterns impact cataract preval‎ence or progression. A role for nutrition in cataract formation has been widely assumed based on findings that micronutrient status is strongly associated with cataract risk (reviewed in [6,8]). However, supplementation studies, most of which were short term, have largely failed, suggesting that either longer term intervention trials are required and/or multiple dietary components may be involved in cataract formation. Micronutrient or vitamin status may be acting as a surrogate for diet quality.

Given the emphasis on phytochemical-rich foods in MeDi, it is hypothesized that adherence to MeDi might delay cataractogenesis. Garcia-Layana eval‎uated the incidence of cataract surgery from the landmark PREDIMED (Prevención con Dieta Mediterránea) clinical study, where 5802 men and women were randomized to a MeDi supplemented with extra-virgin olive oil, a MeDi supplemented with mixed nuts, or a low-fat control diet that conformed to the American Heart Association (7272 Greenville Avenue, Dallas, Texas) guidelines [30]. There was no difference in the incidence of cataract surgery (a surrogate for advanced cataract formation) in any of the diet groups. Nevertheless, since cataracts can be present for long periods of time before surgical removal is necessitated, the study was not designed to test whether MeDi could affect earlier steps in cataractogenesis. Further, the control arm was a different kind of healthy diet. A comparison against a western diet in a prospective cohort might still reveal important roles for MeDi in cataract prevention or a role for western diet in cataract promotion.

The HEI has also been eval‎uated as a potentially beneficial dietary pattern for cataract prevention. Moeller et al. eval‎uated HEI scores in a subset of the Nurses’ Health Study prospective cohort study [31]. They found that adherence to the HEI was associated with reduced preval‎ence of nuclear cataract (OR = 0.44 (95% CI: 0.26–0.76); Ptrend = 0.001). Interestingly, another indicator of dietary pattern at that time, the recommended food score (RFS) did not show any relationship to nuclear cataract. The authors pointed out that the RFS correlated better with dietary variety than dietary pattern.

Mares et al., using hybrid cross-sectional and prospective data from the CAREDS prospective study and the WHI (Women’s Health Initiative) observational study, eval‎uated associations between nuclear cataract and two versions of the HEI, HEI-1995 and HEI-2005 [32]. They found that adherence to HEI-1995 was protective for nuclear cataract (OR = 0.57 (95% CI: 0.4–0.81); Ptrend = 0.01), whereas adherence to the HEI-2005 was not. This discrepancy was resolved by the finding that the highest quintile of adherence to HEI-2005 also had the highest intake of oils, an independent co-variate for nuclear cataract.

A prospective cohort study eval‎uated an Australian HEI to determine whether adherence to healthy dietary patterns would affect the incidence of nuclear, cortical, or posterior subcapsular cataract within the Blue Mountains Eye Study [33]. Tan et al. found marginally non-significant decreased risk of incident nuclear cataract associated with each unit increase in total HEI score (OR = 0.95 (95% CI: 0.87–1.01); Ptrend = 0.08). No association was evident between increased total HEI score and incident cortical or posterior subcapsular cataract.

Smaller studies have also suggested the protective effects of adherence to HEIs on cataracts. Ghanavati et al. utilized a case–control study in Iran and assessed the association of cataract with HEI [34]. They found that all categories of HEI were protective against cataract except for the lowest quartile (OR = 0.19 (95% CI: 0.09–0.4); Ptrend < 0.01). These data speak more to the detrimental effect of a poor diet on cataractogenesis than protection from healthy dietary pattern. Indeed, a follow-up study performing factor analysis on the dietary data to extract nutrient patterns identified two unhealthy nutrient patterns, one termed a sodium pattern that also contained high amounts of carbohydrates and proteins (OR = 1.97 (95% CI: 1.09–3.96)), and the other termed a fatty acid pattern that included trans fats, and thus a surrogate for processed meats and foods (OR = 1.94 (95%CI: 1.1–3.86)) [35].

2.6. Glaucoma and Dietary Patterns

The predominant risk factor for glaucoma is age, and there is not yet a well-established nutrient or food association with glaucoma and a very small number of studies have rigorously tested dietary patterns as risk factors for glaucoma. A systematic review found that some micronutrients like selenium and iron may be associated with increased risk for glaucoma, while components of dark-green leafy vegetables, specifically glutathione, flavonoids, and nitric oxide, were significantly associated with decreased risk for glaucoma [36]. The disparate effects of nutrients that synergize within a given dietary pattern may explain the lack of clear associations between dietary patterns and glaucoma.

2.7. Diabetic Retinopathy and Dietary Patterns

Diabetic retinopathy (DR) is a microvascular complication of diabetes that is associated with increased age, increased duration of diabetes, and worsened control of hyperglycemia. A large body of literature has concerned itself with the relationships between nutrients, diet, and dietary patterns and control of diabetes [37]. Treatments that improve diabetes should lower the progression to DR. Nevertheless, a relatively few studies have tested whether adherence to healthy or unhealthy dietary patterns alter the incidence of DR, as assessed ophthalmologically.

Adherence to MeDi has been shown to prevent diabetes, as eval‎uated within the PREDIMED randomized clinical trial [38]. It was thus logical to determine whether DR might be similarly prevented. In a post-hoc analysis of the PREDIMED trial, Díaz-López et al. assessed whether individuals that consumed a MeDi containing olive oil or nuts were protected from developing DR [39]. The analysis was limited to individuals with type 2 diabetes. Comparing MeDi with the control diet, there was a significant reduction in incident DR (OR = 0.59 (95% CI: 0.37–0.95)). A further comparison of the MeDi supplemented with extra-virgin olive oil had a similar protective effect on DR (OR = 0.57 (95% CI: 0.33–0.98)), while the MeDi supplemented with nuts had a non-significant risk reduction (OR = 0.62 (95% CI: 0.34–1.11)) for DR. As this study was a post-hoc analysis of a randomized clinical trial, future studies are required that eval‎uate incident DR from a prospective cohort to confirm‎ these findings.

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3. Physiological Effects of Dietary Carbohydrates

Each of the dietary patterns outlined above includes varying ratios of macronutrients from whole food sources. Although exploring associations of disease with dietary patterns rather than individual nutrients may better reflect the effects of the human diet, it may also still be useful to apply a reductionist approach and eval‎uate the effect of individual nutrients on the physiology and mechanisms of pathogenesis. Carbohydrates vary greatly in structure and function and have wide-ranging physiological effects outside of the eye. Here, we discuss the effects of different carbohydrates on the body and how these changes lead to downstream effects in the eye. Given that the eye is distal from the sites of digestion and absorption of carbohydrates, contextualizing the eye effects with mediating factors, such as gut microbiome changes and inflammation, can inform our thinking regarding eye health outcomes.

3.1. Physiological Effects of Hyperglycemia

The physiological effects of dietary carbohydrates are dependent upon the structure and composition of the carbohydrate as well as host characteristics including gut microbiome composition and genetics. The structure of the carbohydrate determines the rate of monosaccharide release and absorption. Simple sugars and highly branched starches, such as those found in refined flour, are rapidly digested and absorbed, resulting in a quick and substantial increase in blood glucose concentration, mirrored by a rise in insulin [40]. Frequent consumption of rapidly digested carbohydrates can lead to insulin resistance and eventual exhaustion of the pancreas’ ability to maintain glucose homeostasis, leading to chronically elevated blood glucose, which has far ranging effects including increased gut permeability [41], chronic systemic inflammation and oxidative stress [42], and increased protein damage due to advanced glycation end products (AGEs) [43,44], which have been associated with many diseases including retinopathy.

The eye is particularly vulnerable to damage from direct and indirect effects of chronically elevated blood glucose due in part to its limited capacity for cellular turnover, limited roles for glucose transporters, and the high metabolic activity of the retina. Hyperglycemia has been clearly associated with DR, AMD, and cataracts [45]. There are multiple co-occurring pathways by which hyperglycemia can lead specifically to eye disease. Glucose entry into the retina is mediated by glucose transporter 1 via facilitated diffusion, and elevated blood glucose leads to increased cellular glucose in the eye [46]. This increase in cellular glucose can result in cell damage and apoptosis via an accumulation of AGEs [47], increased metabolism leading to reactive oxygen species accumulation and decreased glutathione, and protein kinase C activation leading to immune hyperactivity [45]. Additionally, aberrant vasculature present in retinopathy can be induced by AGEs and protein kinase C activation [45]. Finally, the effects of hyperglycemia on eye health may be mediated by systemic health conditions including dyslipidemia, which is associated with the formation of deleterious lipid droplets in the eye [48], as well as chronic low-grade inflammation, which triggers immune hyperactivity in retinal cells [49].

3.2. Dietary Fiber, Gut Microbiome, and Inflammation

Replacing rapidly digested starch with resistant starches, which humans have limited capacity to digest, has been shown to attenuate the rise in blood glucose following the meal and prevent the long-term negative health outcomes of a high carbohydrate diet [50]. Research from our group has found that replacing a rapidly digested starch with resistant starch can arrest or reverse the development of retinal lesions and photoreceptor layer thinning in the eyes of aged mice [44,51,52].

As the rate of digestion of resistant starch can be slower than the rate of transit through the small intestine, a portion passes into the large intestine, leading this carbohydrate to be classified as a dietary fiber [53]. Dietary fibers are a diverse class of carbohydrates with wide-ranging physiological effects. By increasing bulk and viscosity, dietary fibers slow the digestion and absorption of nutrients such as monosaccharides and fatty acids and improve bowel movement regularity. Through decreased calorie absorption, increased dietary fiber can reduce and prevent obesity and associated disease [54].

Additionally, dietary fibers provide metabolic substrate for commensal bacteria in the colon, which then produce short-chain fatty acids (SCFAs). SCFAs have effects throughout the body, including improved gut epithelium integrity, decreased appetite, altered fatty acid synthesis, and decreased systemic inflammation [55]. Increasing the substrate available to carbohydrate-utilizing bacteria increases their ability to out-compete pathogens and bacteria that produce harmful metabolites such as trimethylamine [56], which has been linked to cardiovascular disease [57]. Finally, some dietary fibers, such as arabinoxylan found in whole wheat, contain potent antioxidants [58], which further alter the gut microbiome [56], reduce intestinal oxidative stress [58], and may reduce systemic oxidative stress [59], an established pathoetiologic mechanism for cardiometabolic disease and retinopathy.

In addition to the physiological effects of SCFAs, the gut microbiome can affect multiple pathways implicated in eye disease. Increased gut permeability, which can be a result of intestinal inflammation and/or hyperglycemia, allows the translocation of microbial products, which can bind receptors in the eye and signal ocular inflammation [60]. Additionally, microbial metabolites may cross the blood–retina barrier and act as signaling molecules in the eye. Multiple molecules produced in the gut, including serotonin, have been associated with eye disease severity [44]. Finally, the gut microbiome can indirectly affect eye health by affecting mediators such as insulin sensitivity and adiposity.

Dietary carbohydrate content and composition are major determinants of gut microbiome function [61]. Consequently, these factors are likely important mediators of the effects of dietary patterns on gut microbiome composition and downstream health outcomes. A western diet, characterized by low fiber intake and high simple sugar and starch content, results in increased gut permeability and microbial translocation, increased intestinal inflammation, and decreased resilience to enteric infections [62]. A Mediterranean diet, which includes increased consumption of produce, nuts, and legumes, promotes the proliferation of bacteria associated with several beneficial changes in gut microbiome function, including increased SCFA production and decreased secondary bile acids and inflammatory markers [63].

3.3. High Glycemic Diet and Age-Related Eye Diseases

As thoroughly reviewed previously, advanced glycation end products (AGEs), the result of non-enzymatic addition of sugars and their metabolites to proteins and their subsequent toxic accumulation, have been implicated in a wide variety of age-related diseases, including ocular diseases such as AMD, cataract, and DR [64,65,66]. These cytotoxic AGE accumulations occur in individuals with high blood glucose levels, including individuals with diabetes or pre-diabetes with chronic hyperglycemia. Additionally, high glycemic diets, whether measured by glycemic index or glycemic load are associated with eye disease progression, including AMD and cataract, as measured in case–control studies and epidemiological analyses [64,67,68,69,70,71]. A recent case–control study demonstrated a significant, direct relationship between daily glycemic index, glycemic load, and insulin load on cataract risk [67]. These studies highlight the importance of dietary carbohydrate source and structure in eye disease progression and prevention.

Many animal studies have been done to model eye disease progression in a high glycemic (HG) context and to recapitulate the ameliorative effects of a low glycemic (LG) diet. AMD-like features, namely, RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degradation, were observed in male C57BL/6J mice fed an HG diet [44]. These AMD features were not seen in the group that was fed an LG diet and importantly, the intervention with the LG diet from the starting HG-fed animals improved eye outcomes compared with HG-fed throughout, indicating that dietary intervention with changes in carbohydrate content directly affects eye outcomes.

The high glycemic diet models a western diet that is high in rapidly digested starch, but there are several other models of unhealthy western diets, including a high fat diet commonly used in obesity studies as well as an extreme western diet model using a high fat/high sugar diet. In a mouse model of glaucoma using induced intraocular pressure by injecting endotoxin-free saline, mice fed a high fat/high sucrose diet were more susceptible to damage to retinal ganglion cells under increased intraocular pressure [72]. The damage measured was used as a measure of glaucoma in these animals and this susceptibility in the high fat/high sucrose diet group was not improved with exercise, suggesting that this type of dietary change is severely detrimental and cannot be compensated by other aspects of a healthy lifestyle. The diet used in this study was an extreme model of unhealthy eating, the equivalent of consuming “fast food” with high fat content paired with high sugar, soda-like drinks. In the Nrf2 knockout mouse, a model of age-related macular degeneration, HG diet induced more severe AMD features that were ameliorated with LG diet, underscoring the strong effects of diet over a genetic factor in disease progression [51].

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4. Future Directions for Nutrition and Age-Related Eye Diseases

Although nutrition research in the eye field has mainly focused on the contributions of macronutrients/micronutrients to eye health, there is an increasing interest in determining if other dietary parameters, such as how many or when calories are ingested, might impact the ocular function. Although not yet in clinical practice, a body of clinical evidence and data from animal models supports that dietary trends are potential approaches for the prevention and treatment of vision disorders.

4.1. Calorie Restriction and Ocular Diseases

Among the different interventions regarding dietary trends to slow down age-related functional decline, caloric restriction is the best studied strategy in the context of ocular diseases. Caloric restriction, which is defined by low intake of calories without undernutrition, has been shown to trigger anti-aging mechanisms by decreasing mTOR activity and IGF/insulin signaling and enhancing sirtuin activity [73]. The therapeutic benefit of caloric restriction has been explored in different eye-related disorders including cataract, AMD, dry eye disease, and corneal endothelial cell loss.

The best-documented caloric restriction-related studies in eye diseases are analyses of cataract onset and progression. Caloric restriction was shown to delay age-related cataract in different dark-eyed mouse and rat strains [74,75,76,77,78,79]. The molecular mechanism behind the protective effect mediated by caloric restriction remains unclear. Caloric restriction delays the age-related decline in proliferation capacity of lens epithelial cells [80,81], attenuates the shortening of telomeres [82], and lowers the aggregation of β- and γ-crystallins [83]. Caloric restriction’s protective benefit might be also due to enhanced tissue antioxidant capacity by retarding the age-related aggregation of crystallins [75,84]. However, the literature is inconclusive and lower levels of superoxide dismutase and no differences in primary antioxidants, such as ascorbate, were found in calorically restricted animals [76,78,79,84].

Caloric restriction also limits age-related dysfunction in retinal tissues. Caloric restriction attenuates inherent age-related loss of retinal ganglion cells and is also neuroprotective against ischemia [85,86]. Age-related photoreceptor cell death is attenuated in calorically restricted brown Norway rats [87,88]. In the neural retina of this rat strain, caloric restriction diminishes age-related protein insolubilization and blunts age-related decline in total soluble thiols [89,90]. However, the protective role of caloric restriction in photoreceptors is strain-dependent as it resulted in increased light-dependent photoreceptor cell death in the neural retina of Fischer 344 rats [87,88]. Caloric restriction also reduces the age-related accumulation of lipofuscin associated with RPE dysfunction in male Wistar rats [91]. In addition, although not statistically significant, calorically restricted rhesus monkeys had lower preval‎ence and severity of AMD-like ocular pathology [92].

노화와 관련된 기능 저하를 늦추기 위한 다양한 식이 요법 중 

안구 질환의 맥락에서 가장 많이 연구된 전략은 

칼로리 제한입니다. 

영양 부족 없이 칼로리를 적게 섭취하는

 칼로리 제한은 

mTOR 활성과 

IGF/인슐린 신호를 감소시키고 

시르투인 활동을 강화함으로써 

노화 방지 메커니즘을 촉발하는 것으로 나타났습니다 [73]. 

칼로리 제한의 치료 효과는 

백내장, AMD, 안구 건조증, 각막 내피 세포 손실 등 

다양한 눈 관련 질환에서 연구되어 왔습니다.



안구 질환에 대한 칼로리 제한 관련 연구 중 가장 잘 문서화된 것은 백내장 발병 및 진행에 대한 분석입니다. 열량 제한은 다양한 흑안 쥐와 쥐 실험군에서 노화 관련 백내장을 지연시키는 것으로 나타났습니다[74,75,76,77,78,79]. 칼로리 제한에 의해 매개되는 보호 효과의 분자 메커니즘은 아직 명확하지 않습니다. 

칼로리 제한은 

수정체 상피 세포의 노화와 관련된 

증식 능력 저하를 지연시키고[80,81], 

텔로미어의 단축을 늦추며[82],

 β- 및 γ-크리스탈린의 응집을 낮춥니다[83]. 

칼로리 제한의 보호 효과는 

노화와 관련된 크리스탈린의 응집을 지연시켜 

조직 항산화 능력을 강화하기 때문일 수도 있습니다[75,84]. 

그러나 문헌에 따르면 열량 제한 동물에서 수퍼옥사이드 디스뮤타아제 수치가 낮고 아스코르브산염과 같은 주요 항산화 물질의 차이가 발견되지 않았습니다[76,78,79,84].



칼로리 제한은 

또한 망막 조직의 노화 관련 기능 장애를 치료합니다. 

열량 제한은 

망막 신경절 세포의 고유한 노화 관련 손실을 줄이고 

허혈에 대한 신경 보호 효과도 있습니다 [85,86]. 

열량 제한을 받은 갈색 노르웨이 쥐에서

노화와 관련된 광수용체 세포 사멸이

줄어듭니다 [87,88].

이 쥐의 신경 망막에서 칼로리 제한은 노화와 관련된 단백질 불용화를 감소시키고 노화와 관련된 총 가용성 티올의 감소를 둔화시킵니다 [89,90]. 그러나 광수용체에서 칼로리 제한의 보호 역할은 피셔 344 쥐의 신경 망막에서 빛에 의존하는 광수용체 세포 사멸을 증가시켰기 때문에 균주에 따라 달라집니다[87,88]. 칼로리 제한은 또한 수컷 Wistar 쥐에서 RPE 기능 장애와 관련된 리포푸신의 연령 관련 축적을 감소시킵니다 [91]. 또한, 통계적으로 유의미하지는 않지만 열량을 제한한 붉은털원숭이는 AMD와 유사한 안구 병리의 유병률과 심각도가 낮았습니다[92].

4.2. Intermittent Fasting and Eye Diseases

In spite of data supporting a therapeutic role of caloric restriction on eye heath, the implementation of caloric nutrition as a disease prevention or treatment strategy is challenging due to its large impact on quality of life, especially in clinical settings, and recent research has sought ways to mimic the benefits of caloric restriction with less strict guidelines. One such strategy is intermittent fasting, which involves restricting food intake to specific periods of time followed by extended fasting. Alternate-day fasting for 6 months accelerated the recovery in inner retinal function following intraocular pressure challenge in C57BL/6J mice [93]. Additionally, every-other-day fasting showed a neuroprotective effect on glaucomatous pathology in EAAC1−/− mice, a mouse model of normal tension glaucoma, suppressing retinal ganglion cells and retinal degeneration without altering intraocular pressure [94]. The mechanisms behind the beneficial properties of fasting remain unclear, but several reports suggest that inducing autophagy through fasting improves retinal ganglion cell survival in animals subjected to ischemia [95]. In addition, intermittent fasting restructured the gut microbiota toward species that modulate the production of neuroprotective bile acids, preventing diabetic retinopathy [96].

눈 건강에 대한 열량 제한의 치료적 역할을 뒷받침하는 데이터에도 불구하고, 

특히 임상 환경에서 열량 제한이 삶의 질에 미치는 영향이 크기 때문에 

질병 예방 또는 치료 전략으로 열량 영양을 실행하는 것은 어려운 일이며, 

최근 연구에서는 

덜 엄격한 지침으로 

열량 제한의 이점을 모방하는 방법을 모색하고 있습니다. 

이러한 전략 중 하나는 

간헐적 단식으로, 

특정 기간 동안 음식 섭취를 제한한 후 

장시간 단식을 하는 것입니다. 

6개월 동안 

격일 단식을 시행한 결과, 

C57BL/6J 마우스에서 안압 도전 후 망막 내부 기능 회복이 빨라졌습니다[93]. 

또한, 

격일 단식은 

정상 긴장 녹내장의 마우스 모델인 EAAC1-/- 마우스에서 

녹내장 병리에 대한 신경 보호 효과를 보여 

안압 변화 없이 망막 신경절 세포와 망막 변성을 억제하는 것으로 나타났습니다 [94]. 

단식의 유익한 특성에 대한 메커니즘은 아직 명확하지 않지만, 

여러 보고에 따르면 

단식을 통해 

자가포식을 유도하면 

허혈을 받은 동물의 망막 신경절 세포 생존이 개선된다고 합니다 [95]. 

또한 

간헐적 단식은 

장내 미생물을 신경 보호 담즙산 생성을 조절하는 종으로 재구성하여 

당뇨병성 망막증을 예방합니다 [96].

4.3. Drug Interventions and Eye Diseases

While several pharmaceutical options have been eval‎uated for efficacy against age-related eye diseases, here, we focus on those that are widely applied for other metabolic disorders, such as diabetes, that may elicit similar effects as dietary changes. Diabetes and hyperglycemia are risk factors for several of the age-related eye diseases outlined above. Similarly, cardiovascular disease (CVD) is frequently a comorbidity for age-related pathologies. Therefore, efforts are currently underway to establish whether drugs used to treat these conditions additionally have beneficial eye outcomes.

Drugs for the treatment of diabetes have the potential to attenuate age-related vision loss through reducing hyperglycemia. Metformin, a common treatment for type 2 diabetes, is associated with decreased AMD incidence [97,98]. Additionally, metformin has been detected in the aqueous humor of diabetic patients taking the drug, but the association of metformin use and cataracts has not been eval‎uated [99]. Finally, long-term regular use of high-dose metformin is associated with reduced risk for glaucoma and reduced severity of DR [100,101,102].

Statins are used to treat high cholesterol in patients at risk for CVD and are one of the most preval‎ent prescriptions, with 28% of adults over 40 taking statins in 2012 [103]. Many diabetic and pre-diabetic patients take statins and are at risk for different age-related eye diseases, but the association of statin use and AMD is inconclusive [104,105]. Information surrounding statin use and cataracts is also inconclusive: of three meta-analyses of observational and randomized controlled trials for statins and cataracts, one reported reduced risk for cataract, one reported a mild increased risk, and the third was inconclusive [106,107,108]. Similarly, a recent retraction of a study analyzing glaucoma and statin use revealed that there was no decreased risk of primary open-angle glaucoma with statin use over 5 years (OR = 0.93 (95% CI: 0.75–1.15); Ptrend = 0.49) [109,110].

4.4. Randomized Controlled Clinical Trials

Observational studies are powerful but are limited by their inability to prove causation from association. RCTs are essential to move from research findings to clinical practice. The largest nutrition-based randomized controlled study in targeting age-related eye diseases was the AREDS study by the National Institutes of Health, which focused on micronutrient supplementation as an intervention strategy to analyze disease incidence and progression for AMD and cataracts [111]. While this study aimed to recommend supplements to prevent or slow AMD and cataract development, it is a model for future randomized controlled studies that may be done with macronutrient or dietary pattern recommendation as the previously described evidence suggests that making changes to these aspects of nutrition has more drastic effects on disease than micronutrient supplementation.

RCTs specifically investigating dietary patterns and age-related eye diseases have not yet been performed. Recently, the first study of this kind has been proposed for Australian patients with any form of AMD, with the intervention group to receive detailed dietary information as it relates to macular health as well as regular contact with a registered dietician, while the control group will receive generic nutrition advice [112]. Older adults with varying stages of AMD will be recruited, which will allow researchers to identify the most effective timing of dietary intervention to prevent disease progression. The recommendations given by the dietician will emphasize the consumption of vegetables, fruits, fish and nuts, or low glycemic index, all associated with improved eye outcomes [112].

There have also been several RCTs that explored the effect of dietary pattern on other health outcomes, and age-related eye diseases can be added as measured outcomes within these cohorts to analyze the long-term effects of diet on age-related vision loss in older adults. An example of such an approach is the post-hoc analysis of cataract surgery rates within the PREDIMED RCT, described above in Section 2.5 [30].

관찰 연구는 강력하지만 인과관계를 증명할 수 없다는 한계가 있습니다. 연구 결과를 임상으로 옮기기 위해서는 무작위 대조군 연구(RCT)가 필수적입니다. 

노화 관련 안과 질환을 대상으로 한 

가장 큰 규모의 영양 기반 무작위 대조 연구는 

미국 국립보건원의 AREDS 연구로, 

AMD와 백내장에 대한 질병 발생률과 진행을 분석하기 위한 개입 전략으로 

미량 영양소 보충에 초점을 맞췄습니다[111]. 

이 연구는 

AMD와 백내장 발병을 예방하거나 늦추기 위해 

보충제를 추천하는 것을 목표로 했지만, 

앞서 설명한 것처럼 영양의 이러한 측면에 변화를 주는 것이 

미량 영양소 보충보다 질병에 더 큰 영향을 미친다는 증거에 따라 

향후 다량 영양소 또는 

식이 패턴 추천으로 수행할 수 있는 무작위 대조 연구를 위한 모델입니다.

식이 패턴과 연령 관련 안구 질환을 구체적으로 조사한 RCT는 아직 수행되지 않았습니다. 최근에 모든 형태의 AMD를 가진 호주 환자를 대상으로 한 첫 번째 연구가 제안되었는데, 중재 그룹은 황반 건강과 관련된 자세한 식이 정보를 받고 등록 영양사와 정기적으로 연락하는 반면 대조 그룹은 일반적인 영양 조언을 받게 됩니다[112]. 다양한 단계의 AMD를 가진 고령자를 모집하여 연구자들이 질병 진행을 예방하기 위한 가장 효과적인 식이요법 개입 시기를 파악할 수 있도록 할 것입니다. 영양사가 제공하는 권장 사항에는 시력 개선과 관련된 채소, 과일, 생선, 견과류 또는 저혈당 지수의 섭취가 강조될 것입니다[112].



또한 식이 패턴이 다른 건강 결과에 미치는 영향을 탐구한 여러 RCT가 있으며, 이러한 코호트 내에서 연령 관련 안질환을 측정 결과로 추가하여 고령자의 연령 관련 시력 손실에 대한 식단의 장기적인 영향을 분석할 수 있습니다. 이러한 접근 방식의 예로는 위의 섹션 2.5 [30]에서 설명한 PREDIMED RCT 내 백내장 수술률의 사후 분석이 있습니다.

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5. Strengths, Limitations, and Outlook

Here, we outline many epidemiological studies analyzing the correlation between various dietary patterns, macronutrient contributions to diet, and eye disease outcomes. These studies have highlighted the effect of diet on age-related eye diseases, identified important dietary components, and formed the basis for the animal models that have shaped our understanding of the interrelatedness between diet and eye health. However, RCTs of dietary patterns are the essential next step to further our progress toward translating evidence to practice and preventing and treating age-related vision loss. Future RCTs of dietary patterns need to be performed in older adults and measure specific ocular outcomes, including incidence and progression of AMD, DR, cataract, and glaucoma. An emphasis should be placed on the prevention of early disease, which would have greater potential to extend the health span.

Although we discussed the role of dietary carbohydrates on age-related eye diseases, there is also likely an important role for dietary lipids and lipid composition in these diseases. For example, there is evidence suggesting that omega-3 fatty acids are protective against wet AMD [113], but more work is required with regard to lipids and age-related eye outcomes.

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6. Conclusions

A summary of the findings of this review are included in Figure 2. Based on our literature review of dietary patterns and age-related eye diseases, we found strong evidence about dietary patterns in regard to AMD and some in cataract, but there is surprisingly little conclusive evidence linking specific dietary patters with DR and glaucoma. Across studies looking at AMD progression, there are consensus findings that adherence to a prudent dietary pattern, the Mediterranean diet, and the healthy eating index all protect against AMD and that the western dietary pattern can accelerate AMD progression. In cataract, there is more evidence indicating that an unhealthy western dietary pattern accelerates cataractogenesis, but there is some evidence to suggest that dietary patterns such as the HEI may be protective against cataract progression. In order to best design future RCTs involving dietary pattern changes, animal models are important to uncovering the mechanisms that could explain human epidemiology. Animal models can then be used to implement whole dietary changes that are expected to benefit human participants in the future as exemplified here through mice fed a low or high glycemic diet. Information from animal studies can inform the future of nutrition and age-related eye disease research through RCTs that are specifically designed to analyze eye health outcomes.

이 검토 결과의 요약은 그림 2에 포함되어 있습니다. 식이 패턴과 연령 관련 안질환에 대한 문헌 검토 결과, AMD와 백내장 관련 식이 패턴에 대한 강력한 증거가 발견되었지만 특정 식이 패턴과 DR 및 녹내장을 연관시키는 결정적인 증거는 의외로 거의 없습니다. 

AMD 진행을 조사한 여러 연구에서 

신중한 식이 패턴, 

지중해식 식단, 

건강한 식습관 지수를 준수하면 

AMD를 예방할 수 있고 

서구식 식이 패턴은 

AMD 진행을 가속화할 수 있다는 공통된 결과가 있습니다. 

백내장의 경우 건강에 해로운 서구식 식이 패턴이 백내장 발생을 가속화한다는 증거가 더 많지만, HEI와 같은 식이 패턴이 백내장 진행을 예방할 수 있다는 증거도 일부 있습니다. 식이 패턴 변화와 관련된 향후 RCT를 가장 잘 설계하기 위해서는 동물 모델이 인간 역학을 설명할 수 있는 메커니즘을 밝히는 데 중요합니다. 동물 모델은 저혈당 또는 고혈당 식단을 먹인 쥐를 통해 예시된 것처럼 향후 인간 참가자에게 도움이 될 것으로 예상되는 전체 식이 변화를 구현하는 데 사용할 수 있습니다. 동물 연구에서 얻은 정보는 눈 건강 결과를 분석하기 위해 특별히 고안된 RCT를 통해 영양 및 노화 관련 안질환 연구의 미래에 정보를 제공할 수 있습니다.

Figure 2

Summary of findings linking dietary patterns or select dietary interventions to age-related eye disease. Abbreviations: CR, caloric restriction; IF, intermittent fasting; DR: diabetic retinopathy.

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Author Contributions

Writing–original draft preparation, S.G.F., K.M.S., G.A., E.A.W., J.W., X.W., E.B., A.T., S.R. Writing–review and editing, S.G.F., K.M.S., G.A., E.A.W., J.W., X.W., E.B., A.T., S.R. All authors have read and agreed to the published version of the manuscript.

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Funding

This research was funded by grants from NIH (RO1EY028559 and RO1EY026979 to AT), USDA (NIFA 2016–08885 to AT and SR and 8050-51000-089-01S to AT), Kamada (to AT), Thome Memorial Foundation (to AT), and BrightFocus Foundation (to SR), and a grant from the Human Nutrition Research Center on Aging (to EB). This material was based upon work supported by the U.S. Department of Agriculture—Agricultural Research Service (ARS), under Agreement No. 58-1950-4-003.

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Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript, or in the decision to publish the results.

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