Can the Nrf2 Antioxidant Help with Eye Diseases? Macular Degeneration, Glaucoma, Cataracts & Diabetic Retinopathy

Oxidative stress may be at the root of many eye diseases. The body depends on a careful balance between oxidants and antioxidants. When that balance is disrupted, delicate tissues in the eye can be damaged. In this article, we will focus on an important antioxidant defense system called the Keap1-Nrf2-ARE pathway, abbreviated as NRF2. We will also look at how this system may relate to major eye diseases, including age-related macular degeneration, cataracts, diabetic retinopathy, and glaucoma—conditions that together account for many cases of vision loss and blindness worldwide.

Oxidative Stress and the Keap 1-Nrf2-ARE Pathways

Free radicals, such as reactive oxygen species (ROS), are oxidants produced as by-products of aerobic metabolism. In addition to the natural metabolic production of ROS, environmental sources such as light, smoking, and exposure to or intake of heavy metals also contribute to increased ROS burden. ¹ 

Oxidative stress can denature lipids and proteins, and fragment DNA and RNA. This damages cells, causing them to malfunction and possibly die prematurely.

The Keap1-Nrf2-ARE pathways play a critical role in regulating a comprehensive and protective antioxidant response and are upregulated during oxidative stress. ² It establishes a sequence of events that ultimately protects the cell from oxidative injury by enabling antioxidants to bind to free radicals, thereby neutralizing them. These free radical-fighting enzymes include SOD1, catalase, GSH (glutathione), and Trx. Since the depletion of GSH is directly correlated to oxidative injury and cell death via apoptosis, Nrf2 thus serves as an important link between cell survival and antioxidant gene expression. ³

Inflammation and Free Radicals

When oxidative free radicals accumulate, they can increase the activity of pro-inflammatory genes and trigger inflammatory responses. ⁴ In turn, inflammation can intensify oxidative stress, creating a harmful cycle in which oxidation and inflammation continue to fuel one another.  ⁵

Oxidative Stress and Nrf2 in Ocular Diseases

The eye is a prominent target of oxidative stress. It is continuously exposed to various oxidative conditions, such as photo-oxidation, ionizing radiation, smoke, and various forms of pollutants.  The retina, in particular, is at high risk due to its high metabolic activity involved in processing light for vision. The retina contains unusually high levels of polyunsaturated fatty acids compared with other tissues in the body. These fats are especially prone to free radical damage, making the retina more vulnerable to oxidative stress.

The combination of these factors renders it vulnerable to the injurious actions of oxidants such as ROS. As a result, oxidative stress has been associated with many ocular disorders, notably age-related macular degeneration (AMD), glaucoma, cataract, and diabetic retinopathy (DR). ⁶

Aged-Related Macular Degeneration (AMD) and Nrf2

AMD is often linked to deterioration of central vision, blurriness, and, in advanced cases, permanent vision loss. Drusen are extracellular deposits of debris that accumulate between the RPE (retinal pigment epithelium) and Bruch’s membrane, a feature of dry AMD. Those with dry AMD are also at risk of it turning into wet AMD, which is more acute and can result in rapid vision loss if not treated. The dry form, characterized by geographic atrophy, is more prevalent, affecting 90% of AMD patients. ⁷ Approximately 10% of dry AMD can turn to wet AMD.

Aging is one of the main risk factors for AMD, and ongoing oxidative stress is thought to play a significant role in its development and progression. Several factors have been linked to a higher risk of AMD, including sunlight and UV exposure, cigarette smoke, complement factor H polymorphisms, a high-fat diet, and low intake of antioxidant-rich foods. ⁸ 

The effects of oxidation on retinal proteins may contribute to drusen formation. Another hallmark of AMD is the accumulation of lipofuscin in RPE cells. Lipofuscin, also called “age pigment,” is often considered a symbol of aging. ^9  10 Lipofuscin granules accumulate in the RPE over time. Age-dependent accumulation of lipofuscin may cause RPE damage and is thereby associated with AMD pathogenesis.

The retinal pigment epithelium, or RPE, is a layer of pigmented cells that works closely with the outer segments of the photoreceptors. The RPE is involved in many functions of the retina, including vitamin A metabolism, choriocapillaris maintenance, immunity, heat exchange, and forming part of the outer blood-retina barrier (BRB). Most importantly, RPE is primarily responsible for phagocytosing photoreceptor outer segments, thereby promoting photoreceptor health. ¹¹  Phagocytosis is the process of removing waste in the retina as well as other parts of the body.  It acts as a crucial first line of defense in the immune system and plays a vital role in maintaining tissue health.

Ongoing exposure to UV and blue light contributes to oxidative stress and can damage photoreceptor cells in the retina.

Essential Nutrients for ARMD

Curcumin, a compound found in turmeric, has also shown multiple antioxidative and anti-inflammatory properties in RPE cells. It protects against both acrolein- and light-induced damage. ¹²

Alpha-tocopherol, the most biologically active form of vitamin E, helps protect the RPE from oxidative damage.  Tocopherol accelerates Nrf2 activation and increases the expression of multiple other antioxidant enzymes. α-tocopherol repairs mitochondrial dysfunction, a contributor to AMD pathogenesis, and restores redox balance in RPE cells. ¹³

Zinc is also an established vitamin with antioxidant properties. Zinc reestablishes GSH levels in the RPE to 70% of preinjury level by activating Nrf2, which in turn promotes GSH synthesis. ¹⁴

GSH is a crucial small-molecule antioxidant that can directly scavenge free radicals

As we age, chronic oxidative stress from factors such as UV light, cigarette smoke, and weakened antioxidant enzyme activity can place added strain on the retina. Over time, this can speed up photoreceptor damage and cell death, contribute to drusen formation, and increase inflammation.  ¹⁵

Cataracts

There are three main types of cataracts: subcapsular, cortical, and nuclear cataracts. Aging and oxidative stress are the common denominators in the development of all three types of cataracts. Corticosteroid use, diabetes, and certain lifestyle factors can raise the risk of cataract formation. These factors include poor nutrition, sunlight exposure, smoking, and alcohol consumption. ¹⁶

To maintain a clear pathway for light to reach the retina, the lens must be a flexible, transparent, and biconvex structure. ¹⁷ These are composed of the lens capsule, epithelium, and fibers. The lens itself has no connective tissue, blood vessels, or nerves. ¹⁸

Despite chronic exposure to UV light, the lens, compared to other tissues, has an effective antioxidant system to combat oxidative stress, including GSH and high levels of enzymes that support GSH’s ability to scavenge free radicals.

When GSH levels start to deplete with age, especially in the nucleus of the lens, protein oxidation can lead to protein aggregation, decreased crystallin, protein solubility abnormalities, and an overall yellowing of the lens. ¹⁹  This process can lead to nuclear cataracts, the most common type of cataract. Oxidative stress is a major contributor to nuclear cataracts, causing proteins to accumulate in the lens and leading to the characteristic yellowing.

Nrf2 is the major antioxidant in the lens. Decline of Nrf2 under aging and oxidative stress conditions can lead to reduced levels of cytoprotective antioxidant enzymes and may contribute to cataract formation. ²⁰ Diets high in sugar can cause diabetic complications, inhibit Nrf2, and promote demethylation. This process can alter arginine and lysine residues in lens proteins, causing proteins to clump together and encouraging the formation of advanced glycation end products. ²¹ Glycation occurs when sugars bind to proteins in the eyes and throughout the body, contributing to age-related tissue changes. Antioxidants such as glutathione, or GSH, help counter this process.

Vitamin deficiency has also been attributed to cataract formation. ²² Acetyl-l-carnitine demonstrated antiapoptotic abilities and decreased ER stress by stimulating Nrf2 and several of its phase II antioxidants, including GSH, catalase, SOD, and glutathione peroxidase. ²³ Antiapoptotic refers to properties, mechanisms, or substances that prevent or inhibit apoptosis (programmed cell death).

Diabetic Retinopathy

Diabetic retinopathy (DR) is the most common retinal vascular disease and the leading cause of new cases of blindness in adults. ²⁴ Diabetes alters the balance between the oxidant-antioxidant system by increasing ROS as well as compromising the antioxidant defense system. An increase in ROS is critical in the development of diabetic complications, specifically Diabetic retinopathy. ²⁵ The highly oxygenated environment of the retina, combined with the impaired redox homeostasis seen in diabetes, is a crucial prerequisite for the development of Diabetic retinopathy.

Additionally, hyperglycemia, hyperlipidemia, and inflammation are the three main metabolic abnormalities in diabetes, all of which generate ROS and induce oxidative stress. ²⁶

Diabetes skews the balance between oxidative stress and the antioxidant system. 

In the retina, Nrf2 acts as a cytoprotective mechanism in response to oxidative stress. ²⁷  Elevated states of glucose in diabetes decrease the protection offered by Nrf2.

Glaucoma

Glaucoma refers to a group of eye diseases involving damage to the optic nerve and retina. Although the exact causes are not fully understood, elevated intraocular pressure, or IOP, is considered a major risk factor. This pressure often rises when aqueous humor does not drain properly from the eye.

Clinical research increasingly suggests that oxidative stress may contribute to glaucomatous nerve damage. Oxidative damage has been found in the trabecular meshwork, or TM, of patients with glaucoma. ²⁸ Other research has linked oxidative DNA damage in the TM with higher average IOP and visual field loss. ²⁹ Oxidative damage has also been detected in the aqueous humor of glaucoma patients. ³⁰

Oxidative stress is demonstrated not only in the TM but also in the retina. Studies show that depletion of Nrf2 aggravates RGC death induced by optic nerve injury. ³¹

Nrf2-protective nutrients include quercetin, curcumin, and a number of natural products, such as synthetic triterpenoids, salvianolic acids, and sulforaphane. They have been identified as potent activators of Nrf2.

Nutrients in Food that Promote Nrf2

Nutrients and dietary phytochemicals promote Nrf2 activation (which releases and regulates cellular antioxidant responses), assisted by preventing its degradation. Key compounds include sulforaphane (from cruciferous vegetables including broccoli, Brussels sprouts, cabbage, watercress, and kale), curcumin (turmeric), and polyphenols/flavonoids (found in berries, tea, and citrus). ³²

Suggested Supplements Consider

Dr. Grossman’s Complete Eye Formula 2oz (oral spray)

Dr. Grossman’s Meso Plus Formula with Astaxanthin – 90 vcaps (3-month supply)

Advanced Eye & Vision Support Formula (whole food) 60 vcaps

ReVision Formula (wild-crafted herbal formula) 2 oz – based on classic Chinese medicine Liver tonic formula to help support healthy circulation and blood flow throughout the eyes and body.

Dr. Grossman’s Blood Vessel Control Formula 2oz – helps reduce the risk of unwanted blood vessel growth, supports healthy circulation, reduces inflammation, and more.

Dr. Grossman’s Bilberry/Ginkgo Combination 2oz (60ml) – helps support healthy circulation, and strengthens blood vessels and capillaries.

Dr. Grossman’s Whole Food Organic Superfood Multi-Vitamin 120 Vcaps – whole food, organic, GMO free multivitamin.

Dr. Grossman’s Premium Turmeric Vcaps (Organic)

H2 Elite Molecular Hydrogen 60 tabs

NMN Wonderfeel Capsul 60 vegcaps – helps protect ganglion cells in the retina and optic nerves from damage, reduces inflammation, supports the immune system.

Supplement Packages

AMD Package 1 (3-month supply)

Brain and Memory Support Package 1

Retinal Circulation Package

Recommended Books

Natural Eye Care: Your Guide to Healthy Vision and Healing

Natural Brain Support: Your Guide to Preventing and Treating Alzheimer’s, Dementia, and Other Related Diseases Naturally

Natural Parkinson’s Support: Your Guide to Preventing and Managing Parkinson’s