Macular Degeneration

Macular Degeneration: A Comprehensive Reference in Nutritional and Natural-Health Context

1. Definition, Presentation, and Body Systems Involved

What Is Macular Degeneration?

Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. AMD is a progressively deteriorating eye condition primarily impacting the macula, the central portion of the retina responsible for high-acuity vision.

AMD is the leading cause of permanent, irreversible, central blindness — causing a scotoma in the central visual field that makes reading and writing, stereoscopic vision, and recognition of colours and details impossible — in patients over the age of 50 in industrialized European and North American countries.

Clinical Staging and Presentation

Clinically, AMD is characterized as being in an early stage to late stage and initially affects the macula, which is the center of the retina. Soft drusen and/or pigmentary abnormalities are clinically visible symptoms of early AMD. Clinically used classification systems for assessing severity of the non-sight-threatening earlier stages usually categorize AMD according to drusen size: medium-sized drusen are classified as 'early' AMD and large drusen are classified as 'intermediate' AMD.

Late (or advanced) AMD occurs in two distinct forms, and visual loss is caused by the "geographic atrophic" death of photoreceptors and retinal pigment epithelium (RPE) cells — the so-called dry AMD — or by formation of the choroidal neovascular membrane (CNV), as a result of pathological angiogenesis — the so-called exudative or wet AMD.

Neovascular AMD, sometimes known as "wet" AMD, is an advanced type of AMD characterized by choroidal neovascularization (CNV), in which newly created blood vessels leak into the retina, producing distortion and fast loss of vision. The onset of the disease typically becomes apparent in its late manifestation, presenting in two primary forms; the first, geographic atrophy, is the most prevalent variant, characterized by a slow progression and primarily associated with the loss of photoreceptors and RPE cells.

Body Systems and Structures Involved

The pathology of AMD is characterized by degenerative changes affecting the outer retina (photoreceptors), RPE, Bruch's membrane (BrM), and the choriocapillaris. The RPE is a central element in the pathogenesis of AMD.

The retina is the only neural tissue in the body that is exposed to direct sunlight, which favors the oxidation of lipids and is toxic for the photoreceptors. The retina consumes proportionally more oxygen than other tissues, generating free radicals that are toxic to retinal cells. The RPE is essential to countering oxidative stress in the retina.

At the cellular and molecular level, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time.

The immune system is centrally implicated. Once the subretinal region becomes chronically inflamed, the drusen operate as inflammatory centers that recruit macrophages and microglia to the area. The complement system plays a significant role in this process. Hypoxia, as well as hyperactivity of the complement system, together with the inflammatory process, leads to disturbances in the pro/antiangiogenic balance and RPE cells' overexpression of proangiogenic vascular endothelial growth factor (VEGF), which plays a key role in the pathogenesis of wet AMD.

Gut microbiota and epigenetics may also play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions.

2. Contributing and Associated Factors

Non-Modifiable Risk Factors

AMD is a complex degenerative and progressive disease of multifactorial etiology, in which advanced age and its related physiological cell apoptosis and tissue involution, and genetic predisposition, are the strongest risk factors.

Evidence for strong genetic involvement in AMD susceptibility came from familial aggregation studies and twin studies. The heritability of late AMD is estimated to be up to 71%, which is higher than most complex age-related diseases, for example coronary artery disease. Currently, 52 gene variants within 34 loci have been significantly associated with AMD. Two well-studied major genes are complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2).

Genetic studies have strongly supported a relationship between the alternative complement cascade, in particular the common H402 variant in Complement Factor H (CFH), and development of AMD. Both a biologic serum marker of inflammation as well as genetic factors in the inflammatory pathway (CFH) and another pathway (ARMS2/HTRA1) are related to AMD.

Family history of AMD is a consistent risk factor for AMD. The analysis of a systematic review including 18 studies found that older age and male gender significantly increase the risk of developing AMD.

Modifiable Risk Factors

AMD is regarded as a multifactorial disease comprising a complex interplay between ageing, genetic susceptibility and environmental risk factors. The most consistent modifiable risk factors are smoking and diet, and variants in CFH and ARMS2–HTRA1 confer the highest risk of AMD.

Smoking: Smoking and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Cigarette smoke is thought to contribute to AMD pathobiology through the creation of free radicals and direct activation of the complement cascade. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression.

Cardiovascular and Metabolic Factors: This updated meta-analysis highlights the significance of modifiable risk factors for AMD, including smoking, hypertension, cardiovascular diseases, and diabetes. Although a number of studies have shown a link between cardiovascular risk factors and AMD, the roles of hypertension, atherosclerosis, high BMI, diabetes mellitus, higher plasma fibrinogen, and hyperlipidaemia remain equivocal owing to inconsistent findings.

Solar and Light Exposure: Available data indicate that long-term occupational solar radiation exposure, in particular for its blue-light component, is associated with macular degeneration in outdoor workers. Sunlight exposure has been hypothesized to be associated with AMD; interestingly, sunlight was not a consistent risk factor across studies.

Body Mass Index: Increasing age, BMI, and current smoking were significantly associated with an increased risk of AMD in a study also evaluating genotypic factors. However, other factors such as sex, body mass index (BMI) and education are less often associated with AMD progression than smoking and age.

Gene–Environment Interactions: Various diet–gene–lifestyle interactions have been reported to be associated with advanced AMD, including associations between the CFH Y402H genotype and body mass index as well as the Mediterranean diet. Effects of interactions between the ARMS2/HTRA1 gene and dietary omega-3 fatty acid intake, and between complement component 3 (C3) R102G and folate intake, have also been reported for progression to geographic atrophy.

3. Nutrients, Herbs, and Natural Ingredients

3a. The AREDS and AREDS2 Landmark Trials

The most robust nutritional evidence base for AMD comes from two large randomized clinical trials conducted by the U.S. National Eye Institute (NEI): the Age-Related Eye Disease Study (AREDS, begun 1996) and its successor AREDS2 (begun 2006).

The original AREDS study showed that a dietary supplement formulation (500 mg vitamin C, 400 international units vitamin E, 2 mg copper, 80 mg zinc, and 15 mg beta-carotene) could significantly slow the progression of AMD from moderate to late disease.

The investigators found that participants who had been assigned to the antioxidants plus zinc plus copper formulation in the trial were 25–30% less likely to develop advanced AMD than those who had originally been assigned to placebo. Among participants at the highest risk for AMD, 34% who had taken the AREDS formula progressed to advanced AMD, compared to 44% who had taken the placebo.

For those study participants who had either no AMD or early AMD, the nutrients did not provide an apparent benefit.

A Cochrane systematic review found: Over half the participants (3,640) were randomised in one trial (AREDS in the USA), which found a beneficial effect of antioxidant (beta-carotene, vitamin C and vitamin E) and zinc supplementation on progression to advanced AMD (adjusted odds ratio 0.68, 95% confidence interval 0.53 to 0.87) over an average of 6.3 years. Overall, the strength of the evidence was considered moderate.

NEI launched AREDS2 in 2006 to test if adding omega-3 fatty acids or lutein plus zeaxanthin would make the AREDS formula more effective. AREDS2 evaluated the additional effects of lutein, zeaxanthin, and omega-3 long-chain polyunsaturated fatty acids in 4,203 participants at high risk for advanced AMD.

In the AREDS2 trial, adding omega-3 fatty acids or lutein plus zeaxanthin to the AREDS formula had no additional overall effect on the risk of advanced AMD. However, subgroup findings were notable: in the AREDS2 trial, the participants who benefited most from taking lutein plus zeaxanthin were those who did not get much of these nutrients in their diet. Within this group, those who received lutein/zeaxanthin supplements had a 26% reduced risk of developing advanced AMD compared with those who did not receive the supplements.

After 10 years, the group originally assigned to receive lutein/zeaxanthin had an additional 20% reduced risk of progression to late AMD. Results of this epidemiologic follow-up study of the AREDS2 clinical trial suggest a beneficial association of lutein/zeaxanthin that persisted throughout the 10-year follow-up study. In addition, the results indicate that this is a safe supplement, with no increased risk of developing lung cancer.

3b. Lutein and Zeaxanthin

Traditional Context

Lutein and zeaxanthin are dietary xanthophyll carotenoids found naturally in green leafy vegetables such as spinach and kale, and in egg yolks. They were not historically used in the context of a formal herbal or botanical tradition but were consumed as part of traditional plant-rich diets across cultures worldwide. Their specific relevance to eye health emerged from scientific research in the late 20th century.

Scientific Evidence

Like beta-carotene, lutein and zeaxanthin are antioxidants with activity in the retina. Previous studies have suggested that people who have diets rich in green, leafy vegetables — a good source of lutein and zeaxanthin — have a lower risk of developing AMD.

Formulations containing lutein and zeaxanthin and no beta-carotene had a reduction in developing advanced AMD by 18% compared to participants who took the AREDS2 formula with beta-carotene and no lutein or zeaxanthin. Beta-carotene was shown to compete with lutein and zeaxanthin, as individuals who took all three nutrients had lower levels of circulating lutein and zeaxanthin when compared to participants who took lutein and zeaxanthin without beta-carotene.

Evidence strength: Strong — supported by large-scale multicenter randomized controlled trials (AREDS2, n=4,203) with up to 10 years of follow-up from the NIH National Eye Institute.

3c. Zinc

Traditional Context

Zinc is an essential trace mineral present in high concentrations in the retina and choroid. Its presence in the retina has long been recognized through anatomical observations, but its specific supplementation for eye health was not part of classical botanical or herbal traditions. Oysters, red meat, and legumes are traditional dietary sources.

Scientific Evidence

Zinc was a core component of the original AREDS formula. In AREDS/AREDS2 trials, copper (as cupric oxide) was added to supplement formulas containing zinc. The goal was to reduce the risk of copper deficiency anemia, a condition associated with high levels of zinc intake.

The AREDS2 study showed that lowering the amount of zinc had no effect on AMD progression. The AREDS1 trial demonstrated benefit of zinc in combination with antioxidants; the independent contribution of zinc alone versus the combined formula is difficult to isolate from trial data. The included trials reported that hospitalisation for genito-urinary problems was more common in people taking zinc.

Evidence strength: Moderate to strong, primarily based on its role in the combination AREDS formula, with the individual contribution of zinc being harder to separate from the antioxidant components.

3d. Vitamins C and E

Traditional Context

Vitamins C and E are found widely in fruits, vegetables, nuts, and seeds. These nutrients have been part of traditional dietary guidance across many cultures, though not specifically formalized for ocular use in classical herbal monographs.

Scientific Evidence

Scientists found that people at high risk of developing advanced stages of AMD lowered their risk by about 25 percent when treated with a high-dose combination of vitamin C, vitamin E, beta-carotene, and zinc. These findings are drawn from AREDS report No. 8, a large randomized placebo-controlled clinical trial. The AREDS and AREDS2 studies demonstrated that supplements including vitamins C and E, beta-carotene, and zinc may reduce the progression to advanced AMD in some patients by 25% over five years. This is one of the few nutritional supplements known to have a beneficial effect in any eye disease.

There is an increased risk of lung cancer in smokers associated with beta-carotene supplements. Therefore, AREDS2 investigators excluded current smokers from receiving the formulation containing beta-carotene.

Evidence strength: Moderate to strong for slowing progression in those with intermediate to advanced AMD; combination formula only. Vitamins C and E alone have not been evaluated as rigorously in isolation for AMD.

3e. Omega-3 Fatty Acids (DHA and EPA)

Traditional Context

Fish and fish oils have been consumed medicinally in many coastal cultures for general health. In Northern European and Japanese traditional diets, oily fish such as mackerel, herring, and salmon formed core components. However, their use specifically for macular health was not historically articulated in formal traditional medicine systems; this association is a product of modern epidemiological research.

Scientific Evidence

Docosahexaenoic acid (DHA) is the most abundant retinal omega-3 component and is produced by RPE and retinal cells. Moreover, RPE delivers DHA from the systemic microcirculation to the photoreceptors. LC-PUFA metabolites can influence inflammation by producing either pro-inflammatory (omega-6 PUFAs) or anti-inflammatory (omega-3 PUFAs) fatty acids.

A meta-analysis showed that high intake of omega-3 LCPUFAs, DHA, and EPA, as well as the simultaneous intake of DHA and EPA, lowered the risk of overall AMD. However, the picture from clinical trials is more nuanced. In the AREDS2 trial, adding omega-3 fatty acids to the AREDS formula had no additional overall effect on the risk of advanced AMD.

Both prospective and Mendelian randomization analyses suggest omega-3 and DHA may protect against AMD, supporting the need for further clinical trials to test their effectiveness in AMD prevention and treatment. Epidemiologic studies and clinical trials have reported inconsistent findings regarding omega-3 fatty acids' protective role in AMD.

Studies suggest that omega-3 PUFAs, particularly DHA and EPA, might provide protection against AMD, highlighting the necessity for additional clinical trials to evaluate their efficacy in the prevention and treatment of AMD.

Evidence strength: Preliminary to moderate. Observational and meta-analytic evidence is suggestive; the major RCT (AREDS2) did not confirm benefit when omega-3 supplements were added to the AREDS formula. The relationship between dietary (versus supplemental) omega-3 intake and AMD risk may differ. Further trials are needed.

3f. Saffron (Crocus sativus)

Traditional Use

When traditional medicines were earlier practiced, saffron was used as a treatment for conditions such as cancerous tumours and depression. It has a long history in Persian, Indian Ayurvedic, and Mediterranean traditional medicine systems as a general tonic and treatment for a variety of ailments. Its application specifically to retinal or macular conditions is not part of classical herbal use; this emerged from modern pharmacological investigation.

Scientific Evidence

Chemical analysis of saffron has identified that it includes antioxidant carotenoids such as crocin and crocetin. Saffron has been found to protect human eyes from damaging effects of bright light and has shown a beneficial effect in human individuals suffering from early AMD.

Falsini et al., in a randomized, double-blind, placebo-controlled study, showed that three months of dietary saffron supplementation significantly improved the focal-ERG-estimated retinal flicker sensitivity in early AMD patients. Daily supplementation of 20 mg/d saffron for 90 days resulted in statistically significant improvements, compared to a placebo control, in the macular fERG parameters (amplitude and modulation threshold) of patients with early AMD. These post-supplementation changes in the macular fERG reflected a beneficial effect on macular function, as they were associated with a small but significant increase in average Snellen visual acuity.

Among medicinal plants, saffron improves visual function at safe doses far below the lethal dose, as multiple clinical trials show. However, results from one study indicated that orally consuming 20 mg/day of saffron for three months may induce a short-term and significant improvement of retinal function in early stages of AMD. However, these beneficial effects disappear after cessation of consumption of saffron-containing pills.

Evidence strength: Preliminary but promising. A small number of randomized placebo-controlled trials in early AMD have reported beneficial electrophysiological and functional outcomes, though studies are small in size and further replication is needed.

3g. Bilberry (Vaccinium myrtillus) and Berry Anthocyanins

Traditional Use

Bilberry (Vaccinium myrtillus) has a long history of use in European folk medicine, particularly in Northern and Eastern Europe. It was traditionally used for diarrhea, urinary tract conditions, and, notably, vision improvement — including reports of improved night vision during World War II among RAF pilots. The berries and their extracts were consumed or prepared as decoctions and tinctures. Bilberry fruit extract is believed to have anti-angiogenic properties that may help decrease blood-vessel leakage in AMD and diabetic retinopathy. Bilberry contains high concentrations of the antioxidant resveratrol and chemical compounds known as anthocyanosides that are said to maintain rhodopsin levels, the purple pigment used by the rods in the eye for night vision.

Scientific Evidence

Preclinical studies and limited clinical trials indicate that compounds from berries like bilberry, aronia, wolfberry, and black currant can mitigate oxidative stress, reduce inflammation, and enhance visual function, thereby slowing AMD progression.

In the RPE, bilberry extracts reduced hydrogen-peroxide-induced reactive oxygen intermediate (ROI) generation by a glutathione-S-transferase-pi-dependent effect. Bilberry and blackcurrant anthocyanins also inhibit inflammatory responses of transcription factor nuclear factor-κ-B, an effect that was also confirmed in a placebo-controlled clinical trial in healthy subjects.

Anthocyanins from bilberries and black currants have low bioavailability due to rapid metabolism and excretion. Significant challenges remain in translating these findings into clinical practice. The low bioavailability of many berry-derived phytochemicals limits their effectiveness in vivo, necessitating further research into advanced delivery methods to enhance absorption and stability.

Evidence strength: Preliminary. Most evidence is from preclinical (in vitro and animal) studies. Clinical trial data in AMD populations specifically are limited. Bioavailability is a recognized challenge.

3h. Ginkgo Biloba

Traditional Use

Ginkgo biloba is a traditional Chinese medicine extracted from the leaves of the maidenhair tree. The main indication in Chinese medicine is to treat circulatory problems. It has been used for thousands of years in East Asian medicine for memory support and cardiovascular function.

Scientific Evidence

Ginkgo biloba extract contains a wide variety of constituents, but the main action appears to be mediated via the antioxidant properties of flavonoids and terpenoids.

Ginkgo biloba extract is a popular herbal medicine. A Cochrane review found only two trials. One compared ginkgo extract with placebo but had only 10 patients per arm followed for 6 months; in both groups, vision was reported to improve but the ginkgo group was reported to have improved more. The other trial compared two doses of ginkgo and found no significant differences. There is insufficient evidence for the use of ginkgo biloba in AMD.

Evidence strength: Insufficient. The very limited number of small, short-duration trials precludes conclusions about efficacy in AMD.

3i. Resveratrol

Traditional Use

Resveratrol is a biologically active plant polyphenolic compound commonly found in grapes' skin and seeds, red wine, Japanese knotweed (Polygonum cuspidatum), blueberries, cranberries, bilberries, cocoa, pistachios, and peanuts. Grapes and red wine have been used medicinally in Mediterranean and European cultures for centuries, though resveratrol as a specific compound was not identified until the modern era.

Scientific Evidence

In vitro and in vivo (animal model) experimental studies have provided evidence for the biological effects of resveratrol on numerous pathways including oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, pro-survival pathways, and angiogenesis that are implicated in the pathogenesis of AMD.

Results demonstrated that treatment with different resveratrol formulations improved cell viability and decreased reactive oxygen species generation in AMD patient cell lines. Although further studies are required, this novel study established positive effects of over-the-counter resveratrol supplements in macular degeneration patient cybrid cell lines in vitro.

In a small clinical trial (n=50), fifty naïve and previously untreated patients suffering from wet AMD were randomly assigned in two subgroups of 25 patients each. All participants were treated with monthly intravitreal injections of aflibercept, while in one group the patients also received daily resveratrol oral supplement. Over the 12-month period, a similar number of injections was applied in both groups. A statistically significant difference was detected in the mean change from baseline values of contrast sensitivity in favour of the patients treated with resveratrol supplements. The resveratrol oral supplement is a complementary treatment in cases of wet AMD, highlighting its effectiveness in improving patients' quality-of-life status.

Evidence strength: Preliminary. Most evidence is from in vitro and animal studies. The available clinical trial is small and used resveratrol as an adjunct to standard therapy, not as a primary intervention. Further research is needed.

3j. Curcumin (Curcuma longa)

Traditional Use

Curcumin is the primary bioactive polyphenol in turmeric (Curcuma longa), a rhizomatous plant native to South and Southeast Asia. Turmeric has been used for over 4,000 years in Ayurvedic and traditional Chinese medicine as an anti-inflammatory and digestive agent. It was applied to wounds and used for liver conditions, but was not historically associated with retinal or macular conditions specifically.

Scientific Evidence

The use of curcumin in AMD was investigated on cellular models, demonstrating a decreased apoptosis of retinal pigmented epithelial cells and a reduction of inflammatory markers. So far, the use of curcumin has been limited by poor bioavailability.

A curcumin supplement consisting of 95% curcuminoids, AREDS2 components, astaxanthin and resveratrol, in combination with intravitreal injection of anti-VEGF, was shown to improve functional outcomes in a retrospective case-control study. Curcuma, used in an adjuvant setting, would be necessary to reduce the need for ongoing injection therapy. However, recall bias occurs most often in case-control studies; these studies may prove an association, but they do not demonstrate causation. Despite promising findings, further evidence is needed to evaluate the impact of curcuma in human clinical trials of AMD. A lack of clinical trials evaluating the safety and efficacy of the adjuvant setting can be a point of concern for evidence-based research in alternative medicine.

Evidence strength: Very preliminary. Cellular and retrospective study data only. Significant bioavailability limitations. No high-quality RCTs in AMD populations available as of current literature.

3k. Astaxanthin

Traditional Context

Astaxanthin is a ketocarotenoid found in microalgae, crustaceans, salmon, and trout. It has a history of dietary consumption through seafood in coastal cultures. Its targeted use for retinal protection is a modern development based on its potent antioxidant properties.

Scientific Evidence

Of particular interest are astaxanthin, EPA, and DHA, which have shown very promising effects thanks to their anti-inflammatory, anti-angiogenic, anti-vasoproliferative and neuroprotective properties. Astaxanthin has been studied in combination supplement formulas (see saffron and curcumin sections) including as part of a combination formula with lutein, zeaxanthin, and other antioxidants. A study included people with dry AMD, and found significantly better visual acuity in the supplement group (lutein, zeaxanthin, astaxanthin, zinc, copper, and antioxidant vitamins) after 24 months' follow-up compared with no supplementation.

Evidence strength: Preliminary to moderate. Astaxanthin is typically studied in combination formulas rather than in isolation for AMD, making its independent contribution difficult to determine. More dedicated RCTs are needed.

3l. Wolfberry / Goji Berry (Lycium barbarum)

Traditional Use

Lycium barbarum (wolfberry or goji berry) has been used in Traditional Chinese Medicine (TCM) for centuries, particularly for supporting liver and kidney organ systems and, notably, for improving vision and nourishing the eyes. It was consumed as dried berries in foods and decoctions.

Scientific Evidence

Carotenoids such as lutein and zeaxanthin found in wolfberries have higher bioavailability and effectively accumulate in retinal tissue, reducing the risk of AMD. The clinical efficacy of milk-based formulation designated as Lacto-Wolfberry and whole fruit of Lycium barbarum have been evaluated in randomized double-blinded placebo-controlled studies involving healthy elderly subjects and patients with neovascular AMD, respectively. The 90-day supplementation showed a striking ability to sustain visual function and delay macular degeneration associated with soft drusen and areas of hypopigmentation.

Evidence strength: Preliminary. Small, short-duration RCTs showing some functional and structural benefit. Likely partly attributable to its lutein and zeaxanthin content. Additional replication in larger trials is needed.

3m. Vitamin D

Scientific Evidence

Eighteen observational studies enrolling 75,294 patients were selected in a systematic review and meta-analysis. No significant differences were found, but there appears to exist a trend for late AMD among subjects with a serum 25(OH)D level below 50 nmol/L (odds ratio 1.8; 95% CI 1.00–3.24, P=0.05). There is no clear evidence of a definitive association between serum 25(OH)D and AMD risk, mainly due to heterogeneity in study procedures.

Evidence strength: Weak to insufficient. Available evidence from observational studies is heterogeneous and inconclusive. No large RCTs have been conducted on vitamin D supplementation specifically for AMD prevention or progression.

4. Dietary and Lifestyle Factors

Mediterranean Diet

A Mediterranean diet has been suggested to provide protective effects against AMD development and progression due to its antioxidant and anti-inflammatory properties. The Mediterranean diet, a nutritional pattern characterized by a high intake of fruits, vegetables, whole grains, legumes, nuts, and olive oil, along with moderate consumption of fish and poultry, has gained attention in AMD research.

Pooling data from the Rotterdam Study I and the Alienor Study, higher adherence to the Mediterranean diet was associated with a 41% reduced risk of incident advanced AMD. The AMD risk was reduced by 60% in subjects with high adherence to the Mediterranean diet compared to subjects with low adherence. in the Coimbra Eye Study.

The interaction between genetic risk and diet has been studied. Combined effects of having low adherence to the Mediterranean diet and high genetic risk score led to almost a 5-fold increase in the risk for AMD, compared to low genetic risk and high adherence to the Mediterranean diet.

Across disease stages, closer adherence to a Mediterranean diet is consistently associated with substantially slower AMD progression. In AREDS, individuals with early AMD who adhered more closely to a Mediterranean diet were significantly less likely to develop intermediate AMD.

Specific Dietary Components

Previous studies have established modifiable lifestyle factors associated with progression to advanced AMD: smoking, BMI, daily caloric intake, and a diet rich in green leafy vegetables and fish.

Dietary fat quality is of relevance. Genetics, age, and smoking history are well-accepted and major risk factors, but obesity, hypertension, dietary fat intake, and sunlight exposure have inconsistently been associated with the disease.

Smoking Cessation

Smoking is the most consistently identified modifiable environmental risk factor for AMD across the literature. Cigarette smoke is thought to contribute to AMD pathobiology through the creation of free radicals and direct activation of the complement cascade. Cessation of smoking is a primary lifestyle recommendation in every major AMD risk-reduction review.

Physical Activity

A combination of lifestyle behaviors such as the avoidance of smoking, physical activity, and the adoption of a healthy dietary pattern like the Mediterranean diet was associated with a lower prevalence of AMD.

Combined Lifestyle Effects

A combination of lifestyle behaviors — including the avoidance of smoking, physical activity, and adoption of a healthy dietary pattern like the Mediterranean diet — was associated with a lower prevalence of AMD. The adoption of these lifestyles may reduce the prevalence of the early stages of AMD and decrease the number of individuals who develop advanced AMD.

Research on gene–lifestyle interactions emphasizes that lifestyle factors operate within the context of genetic susceptibility. A 2006 case-control analysis reported strong susceptibility of the joint effects of the high-risk CFH Y402H (CC genotype) plus a higher BMI (OR = 5.9) or high-risk genotype plus smoking (OR = 10.2) on advanced AMD.

References

• Karger: Pathophysiology of Age-Related Macular Degeneration (Ophthalmic Research, 2022)
• PMC: Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment
• PMC: Recent Advances in AMD: Mitochondrial Dysfunction, Redox Signaling, and the Complement System
• PMC: AMD in the Aspect of Chronic Low-Grade Inflammation (Pathophysiological ParaInflammation)
• PMC: Risk Factors for AMD: Updated Systematic Review and Meta-Analysis (Medicine, 2025)
• PubMed: Clinical Risk Factors for AMD: A Systematic Review and Meta-Analysis
• PMC: Risk Factors for Progression of Age-Related Macular Degeneration
• PMC: Macular Degeneration and Occupational Risk Factors: A Systematic Review
• NIH National Eye Institute: AREDS/AREDS2 Clinical Trials
• NIH National Eye Institute: NIH Study Confirms Benefit of Supplements for Slowing AMD
• NIH National Eye Institute: Antioxidant Vitamins and Zinc Reduce Risk of Vision Loss from AMD
• PMC: Long-term Outcomes of Adding Lutein/Zeaxanthin and ω-3 Fatty Acids — AREDS2 Report 28
• PMC: Nutritional and Lifestyle Interventions for AMD: A Review
• PubMed: Antioxidant Vitamin and Mineral Supplements for Slowing the Progression of AMD (Cochrane)
• PMC: Omega-3 Fatty Acids for Preventing or Slowing the Progression of AMD (Cochrane)
• PMC: Implications of Fatty Acids for AMD: Evidence and Recommendations
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• NCBI Bookshelf: Nutritional Interventions in Dry AMD (Systematic Review)
• PMC: Medicinal Plants and Natural Products as Neuroprotective Agents in AMD
• PMC: A Longitudinal Follow-Up Study of Saffron Supplementation in Early AMD
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• PMC: Curcumin in Retinal Diseases: A Comprehensive Review from Bench to Bedside
• PMC: One-Year Outcomes of Resveratrol Supplement with Aflibercept versus Aflibercept Monotherapy in Wet AMD
• PMC: Role of Resveratrol in Transmitochondrial AMD RPE Cells
• PMC: Resveratrol and Ophthalmic Diseases
• MDPI Antioxidants: Berries and Their Active Compounds in Prevention of AMD (2024)
• PubMed: Serum Vitamin D and AMD: Systematic Review and Meta-Analysis
• PMC: Vitamin D and Age-Related Macular Degeneration
• PMC: The Role of Oral Supplementation for the Management of AMD: A Narrative Review
• PMC: Complement Factor H in AMD: Bridging Genetic Associations and Pathobiology
• PMC: C-Reactive Protein and CFH, ARMS2/HTRA1 Gene Variants Are Independently Associated with Risk of AMD
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• PMC: Age-Related Macular Degeneration (Nature Reviews, 2025)
• PMC: EPA and DHA: A Targeted Antioxidant Strategy to Counter Oxidative Stress in Retinopathy