Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. Genetics plays a huge role in AMD. There are supplements specifically promoted for preventing AMD… BUT, for people with specific genes, supplements containing antioxidants might triple the risk of worsening AMD.
This article explains age-related macular degeneration, delves into the genetic risks, and then explains which supplements are likely to be protective and which may do more harm than good.
What causes macular degeneration?
Age-related macular degeneration (AMD) is caused by changes to the retina, which is the layer at the back of the eye which helps us to see. Specifically, the changes happen in the center of the retina known as the macula.
AMD is the leading cause of vision loss in older people. About 1 – 3% of Caucasians will end up suffering from advanced AMD, but it is less common in other population groups.
Macular degeneration causes a loss of central vision. It can start as a blurry spot in the middle of the field of vision, progressing to a dark spot. Straight lines may look distorted and colors may be darker or less vivid.
Wet and Dry Age-related macular degeneration:
There are two types of AMD – wet and dry:
Dry age-related macular degeneration is caused by metabolic end products collecting under the top layer of the retina.
- These buildups are called drusen.
- It leads to scarring and thinning of the retina.
- Dry AMD causes a gradual loss of central vision.
- Dry AMD is also called geographic atrophy
Wet age-related macular degeneration is caused by abnormal, leaky blood vessels growing into the retina, after the formation of the drusen.
- The abnormal blood vessels cause swelling or bleeding in the retina.
- Wet AMD is also called neovascular AMD, and occurs in about 10-20% of cases.
- Wet AMD usually is linked with a more rapid loss of vision, but in certain cases, it can be gradual.
- There are several new treatments that can slow the progression of wet AMD including injectable medications that decrease swelling and blood vessel formation.
This is often where the explanation of AMD ends in most articles… but stick with me here and I’ll explain why wet and dry AMD occurs and how genes & lifestyle come into play.
How the complement system genetic variants increase AMD risk:
Age-related macular degeneration is now known to be caused by an interaction between environmental factors (smoking, diet, lifestyle, toxicants) and genetic susceptibility.
Genetic studies from the early 2000’s pointed researchers in the direction of the complement system, which is part of our immune system.
The complement system enhances (or complements :-) the ability of antibodies and phagocytic cells to attack microbes — and also to clear out damaged cells.
The outermost layer of the retina is the retinal pigment epithelium. This layer is important for moving ions and nutrients (e.g. vitamin A, glucose) in and out of the layer that contains the photoreceptors needed for vision.
AMD originates from cell death in the photoreceptor and retinal pigment epithelium cells. This causes holes or dark spots in vision.[ref]
What causes cell death for the photoreceptors and/or epithelial cells?
The body has various ways of killing cells that it thinks are pathogenic. The complement system acts as one of the known ways in this process.
Activation of the complement system can occur in a variety of different ways including the lectin pathway (e.g. mannose-binding lectin), classical pathway, the alternative pathway, or through the intrinsic pathway (C3, C5).
Complement factor H (CHF) is an inhibitor or regulator of the complement cascade. Its role is to regulate the complement system so that it attacks pathogens instead of damaging your own cells. (Your own cells have complement factor H, but bacterial cell surfaces don’t.)
Activating the complement pathway results in the formation of something called a membrane attack complex, which causes the rupture of a cell membrane. Great when it is attacking a bacterial pathogen, not great when it happens to the retinal pigment epithelium cells.
So everything needs to be in balance here. While there are a variety of ways to activate the complement pathway, complement factor H keeps the complement system from being overly active.[ref]
Completely unique in the body, the retinal pigment epithelium has the ability to create and express a variety of different complement system proteins normally only created in the liver. Basically, the eye has something called ‘immune privilege’, meaning that the body’s normal immune response (via the bloodstream) is not very active there. Instead, the eye has its own separate immune response.
Back to AMD and the complement system:
A buildup of cellular oxidative stress, due to smoking or simply aging, causes an increased amount of oxidative stress and cellular debris. This causes inflammatory signaling to occur, activating the complement system.
Too much complement activation causes damage to the retina. Thus, excessive cellular stress increases inflammation and complement activation causing damage when the complement system becomes overly activated.
This over-activation can be due to not having enough of the ‘stop’ protein, called complement factor H. Additionally, complement factor H interacts with complement factor I, so low complement factor I can also be important in halting over-activation of the complement system. Or the over-activation can be due to variants that increase the natural activity of the complement system.
When retinal epithelial cells are destroyed, they can’t grow back. At least not very quickly or easily. So the key is to keep the oxidative stress in retinal cells at a lower level, thus preventing the complement cascade from being activated in the eye.
Genetic variants that increase the risk of age-related macular degeneration:
The heritability of AMD is fairly high – estimated to be as high as 70% for advanced AMD.[ref][ref] Thus genetics (along with lifestyle) plays an important role in the susceptibility and progression of macular degeneration.
Keep in mind when reading through any study or article about genetics and AMD that the studies are talking about increased (or decreased) relative risk. If the lifetime risk for a Caucasian who is elderly is 2% or 1 in 50, then doubling that risk makes it 1 in 25.
CFH gene: codes for complement factor H, the ‘stop’ that regulates the activation of the complement system.
Check your genetic data for rs1061170 Y402H (23andMe v4, v5; AncestryDNA):
- T/T: not at an increased risk for AMD
- C/T: increased risk for AMD
- C/C: increased risk for AMD (most common genotype in many population groups)[ref]
Members: Your genotype for rs1061170 is —.
Check your genetic data for rs1410996 (23andMe v4, v5; AncestryDNA):
- G/G: lower risk of AMD
- A/G: typical risk of AMD (most common genotype in many populations)
- A/A: increased risk of AMD[ref]
Members: Your genotype for rs1410996 is —.
Check your genetic data for rs800292 I62V (23andMe v4, v5; AncestryDNA):
- A/A: decreased risk of macular degeneration
- A/G: typical risk of macular degeneration
- G/G: increased risk of macular degeneration (most common genotype in many population groups)[ref]
Members: Your genotype for rs800292 is —.
*Note that some studies show that carrying the risk alleles for both of the above two variants is additive. This means that carrying rs1410996 A/A and rs800292 G/G had a 4-fold increase in relative risk when compared to the G/G and A/A (less common) genotypes.[ref]
Protective CFH variant:
Check your genetic data for rs10922109 (23andMe v5)
- C/C: typical or higher risk (depending on how you look at it)
- A/C: decreased risk of AMD
- A/A: increased factor H, significantly decreased risk of AMD even with above risk variants[ref][ref] reduced drusen formation[ref]
Members: Your genotype for rs10922109 is —.
CFI gene: this codes for a protein that works together with complement factor H to also put the brakes on the complement system
Check your genetic data for rs10033900 (23andMe v4, v5; AncestryDNA):
- C/C: typical risk or lower risk depending on the study
- C/T: typical risk
- T/T: increased risk in Chinese population[ref]
Members: Your genotype for rs10033900 is —.
C3 gene: codes for a part of the complement system
Check your genetic data for rs147859257 (23andMe v5; AncestryDNA):
- T/T: typical
- G/T: increased risk of AMD (rare)
- G/G: increased risk of AMD (rare)[ref]
Members: Your genotype for rs147859257 is —.
ARMS2 / HTRA1 gene:
Check your genetic data for rs10490924 (23andMe v4, v5; AncestryDNA):
- G/G: not at an increased risk for AMD (or at a decreased risk, depending on the study)[ref]
- G/T: typical or somewhat increased risk for AMD (most common genotype)
- T/T: increased risk for AMD compared to G allele (up to a 2-fold increase in likelihood depending on the study)[ref] **see Lifehacks section, antioxidants
Members: Your genotype for rs10490924 is —.
Protective against macular degeneration:
LIPC gene: codes for hepatic lipase
Check your genetic data for rs10468017 (23andMe v4, v5; AncestryDNA):
- T/T: half the risk of AMD (both wet and dry)[ref]
- C/T: somewhat reduced risk of AMD
- C/C: normal risk of AMD
Members: Your genotype for rs10468017 is —.
Check your genetic data for rs9332739 (23andMe v4, v5; AncestryDNA):
- C/C: half the risk of AMD[ref]
- C/G: reduced risk of AMD
- G/G: normal risk of AMD
Members: Your genotype for rs9332739 is —.
Check your genetic data for rs547154 (23andMe v4, v5; AncestryDNA):
- T/T: half the risk of AMD[ref]
- G/T: reduced risk of AMD
- G/G: normal risk of AMD
Members: Your genotype for rs547154 is —.
Check your genetic data for rs4151667 (23andMe v4, v5):
- A/A: half the risk of AMD[ref]
- A/T: reduced risk of AMD
- T/T: normal risk of AMD
Members: Your genotype for rs4151667 is —.
Check your genetic data for rs641153 (23andMe v4, v5):
Members: Your genotype for rs641153 is —.
If genetics plays such a big role, is there anything you can do about AMD?
Absolutely! Knowing your genetic risk can help you determine which diet and lifestyle changes you can make at a younger age in order to prevent AMD.
The AREDS2 trial looked at the effect of supplementing with specific antioxidants, vitamins, and minerals in preventing the progression of AMD. Overall, the trial showed some success, reducing progression by 19%.[ref]
The AREDS2 trial supplement contained:
- 80 mg zinc
- 2 mg copper
- 500 mg vitamin C
- 400 IU vitamin E
- 10 mg lutein
- 2 mg zeaxanthin
While you will often see an AREDS2 supplement suggested for preventing macular degeneration, that may not be the right approach for everyone.
Antioxidant supplements may make AMD worse for people with ARMS2 variants: One study found that for people who carry the ARMS2 risk allele, there was a deleterious response – a worsening of macular degeneration – in people who took antioxidant supplements (vitamins E, C, lutein, and zeaxanthin). For people with the ARMS2 variants, zinc supplement alone was beneficial.[ref] One question here is whether is it is one specific antioxidant, such as vitamin E, that causes people with the ARMS2 risk allele to be at a greater risk.
Other studies, though, don’t show that antioxidants are harmful, necessarily, for people with the ARMS2 variants — but they do back up the idea that zinc is most helpful.[ref]
Antioxidant supplements help with CFH variants: For patients with no ARMS2 variants but with CFH variants antioxidant supplements (along with adequate zinc) decreased the progression of AMD.[ref][ref]
Why is lutein always included in AMD supplements? Lutein is a carotenoid and found in high amounts in the macula. It acts to protect the eye against cataracts, and it is retained in the retina for a period of time (months). Within the retina, it can act to scavenge reactive oxygen species and as an anti-inflammatory.[ref]
Foods that are very high in lutein and zeaxanthin include kale, spinach, green peas, summer squash, and pumpkin. Egg yolks from pasture-raised chickens are also a great source. Carotenoids are best absorbed when eaten with some fat.[ref]
Targeting mitochondrial health:
The retinal pigment epithelial cells need to create a lot of ATP for powering our vision. The photoreceptors use glycolysis for ATP production, but within the retinal pigment epithelium, many mitochondria are needed for producing ATP through the electron transport chain. Thus, the mitochondrial health of the eye is thought to be important.[ref][ref]
When mitochondria aren’t working efficiently, they produce a lot of reactive oxygen species (ROS). High ROS levels then cause oxidative damage to the cell.
NAC: N-acetylcysteine is often used as an antioxidant to boost mitochondrial function through increasing glutathione. Cell studies show NAC boosts ATP production in retinal pigment epithelial cells.[ref][ref] Human trials are needed for AMD, but NAC has been studied extensively for its antioxidant properties and has a good safety profile.[ref]
Rapamycin is of interest due to its ability to increase autophagy (or mitophagy) which can clear out damaged mitochondria and stimulate the production of healthy mitochondria. A recent cell-based trial showed that rapamycin does increase autophagy and helps with mitochondrial function in retinal pigment epithelial cells.[ref] Mouse studies also show some promise here.[ref] Human clinical trials are needed to determine if rapamycin would be effective. (Learn more about rapamycin)
NMN or NR: Increasing NAD+ in a cell is another way to target mitochondrial health. Cell studies in retinal pigment epithelial cells show a lot of promise here, but long-term human trials are needed to know for sure if NR or NMN will work for preventing AMD.[ref][ref][ref] (Learn all about NAD+)
In addition to age, other factors such as cigarette smoking, UV and blue light exposure, being female, lighter colored eyes, cardiovascular disease, and obesity can all increase the risk of AMD.[ref]
Smoking: One genetic study points out that the link between the ARMS2 variant and AMD is particularly risky for smokers or former smokers.[ref]
Cataract surgery: A number of studies have looked at the link between cataract surgery and an increased risk of macular degeneration. Most of the large studies find no increase in risk from cataract surgery.[ref][ref] There are a couple of early studies, though, that did find a link between cataract surgery and late AMD.[ref] Questions remain here as to whether it is the surgery that caused a link to AMD vs. lifestyle factors that increase both cataracts and AMD.
Related Genes and Topics:
CYP1A1: Detoxifying Cigarette Smoke and Estrogen
Genetic variants in the CYP1A1 gene are linked to a number of different health conditions, including an increased risk for estrogen-related cancers and increased risk for lung cancer in smokers.
Circadian Rhythms: Genes at the Core of Our Internal Clocks
Circadian rhythms are the natural biological rhythms that shape our biology. Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours. This is driven by our master ‘clock’ genes.