A Metabolic Look at AMD
Disclaimer: None of what I’ve written below should be considered medical advice. It’s all just for education and furthering discussion with your well selected doctor. Generally, the research I’ve found shows positive results with small groups often of only animal models and only suggests the need for larger placebo controlled studies.
When I was looking into cardiovascular disease recently, I found an article describing the vascular plaque related build up of drusen as the initial driver of age related macular degeneration (AMD), wet AMD seems to be when the body responds to the drusen and reduced nutrient and oxygen delivery with increases in vascular endothelial growth factor (VEGF) promoting vascular growth around or through the drusen which leaks and bulges distorting the retinal topology and sometimes damaging the retinal cells. Left untreated this will ultimately result in blindness. The current best practice for treating wet-AMD is to have regular injections of an anti-angiogenic VEGF inhibitor, something like bevacizumab or aflibercept. These work to slow or halt the damage, but they can be very expensive, have side effects and they do not reverse the condition. The good news is, the condition seems reversible and the root cause seems straightforward when we have a systems model of physiology that centers on stress, metabolism and their relationships to coagulation.
Drusen and Plaques
As noted above the formation of drusen turns out to be quite similar to the formation of artherosclerotic plaques.
“A key similarity between atherosclerotic plaque and drusen formation are the molecular components involved. Both types of deposit have a significant lipid component (including cholesterol and neutral fats) and mineral content, as described above. It has also been reported that drusen contains a number of proteins that are also common to atherosclerotic deposits.”
“Both AMD and atherosclerosis are associated with low grade inflammation in the respective affected tissues, and it has been proposed that soft tissue mineralization may be best conceptualized as a convergence of bone biology with inflammatory pathobiology .”
It seems clear that increases in viscosity and reductions in vessel diameter will more readily injure the vasculature by simple mechanical action resulting in deposits and further obstructed nutrient delivery. Local or systemic stress will effuse calcium into both the blood and extracellular matrix and initiate the coagulation cascade by the action of parathyroid hormone (PTH):
“Slight increase of PTH secretion would produce a mild state of hypercalcemia which would enhance many of the major stress responses such as muscle contraction and neuron activity. Also, a slight increase in PTH secretion would affect other stress responses such as blood clotting, enzyme activity, insulin output, and other hormone-target reactions.”
As chronic stress dampens metabolism the effects will show up as modern diseases and their associated plaques and inflammation. The mechanism will bias the blood towards activating the coagulation cascade. Calcium antagonists are known to reduce the risks of various cardiovascular diseases. That said, we do not want to avoid calcium, but to ensure it goes to the appropriate places.
”Calcium antagonists inhibit the effects of vasoconstrictor hormones such as angiotensin II at the level of vascular smooth muscle by reducing calcium inflow and facilitating the vasodilator effects of nitric oxide. Calcium antagonists reduce smooth muscle cell proliferation and atherosclerosis”
All of this should give a picture that drusen has a similar root cause to that of atherosclerosis and systemic stress can dramatically impact the expression of such plaques through increases in coagulability. Simultaneously, the increase in viscosity and decrease in vascular diameter will restrict the flow of oxygen and glucose. Essentially all types of stress will impact the vasculature including the retinal vasculature to some degree. The particular degree one organ or another is first to be affected is likely from a confluence of genetics, epigenetics, and life history.
It seems there are a number of genetic-determined macular degenerations which express much earlier in life than AMD. Yet, given the state of the modern environment, I wonder how much can be done with off the shelf options along with environment and lifestyle changes. For perspective, people suffering from Multiple Sclerosis (MS) can expect to lose 10 years of life expectancy with modern best practices, or be part of a small subset of those who follow a protocol pioneered by Dr. Terry Whals and have a reasonable chance of putting the condition into full remission. It’s not quite clear what is possible for many conditions with significant genetic factors. There are genetic variants that allow for minimal conversion of beta-carotene to vitamin A. This clearly genetic state would likely lead to retinal problems if eating a diet absent fat soluble vitamin A, yet one could also adjust their diet which has been previously adjust toward disease by culture. In some sense there is no clear distinction, ultimately all development including aging is genetic or programmed, and our environments never cease to play a role on how the program is expressed.
One of the leading candidates for causing the dramatic national and global rise of AMD is the extreme increase in the use and ingestion of polyunsaturated oils. The name “age related macular degeneration” exists as such because it is predominantly seen in older adults. It happens to be associated with diabetes, cardiovascular disease, smoking and omega-6 fats in the diet and was rarely eaten in previous generations. This is a disease of modern civilization with an explosion of cases almost perfectly correlated with a given region’s adoption of “heart healthy” polyunsaturated vegetable oils. Both Dr. Raymond Peat and Dr. Knobbe suggest the pre-eminent role that polyunsaturated fats play in the progression of AMD.
“Light and stress, especially with excess iron, damage the retina when the cells contain too much PUFA, since these fats react with light and free radicals.” ~ Dr. Ray Peat
“If vegetable oil consumption plays a substantial role in atherosclerosis and heart disease via the production of oxidized-LDL, and AMD is characterized by vascular occlusion (atherosclerosis) of the choriocapillaris, which nourishes the outer retina and photoreceptors, shouldn’t this be a major risk factor for AMD as well? Many studies suggest this would be true.”
~ Dr. Chris Knobbe
In a previous discussion, I described how polyunsaturated fats are one of the environment's primary signals of impending winter. Winter in temperate regions requires a lower metabolism, higher blood sugar, more viscous blood, and a larger reserve of calories for potential famine. I see the dramatic overconsumption of polyunsaturated fats pushing our physiology to over-express winter-ready phenotypes.
Retinal Metabolism:
The retina is composed of neurons and neurons are some of the most metabolically active cells in the body. Like all neurons, they rely almost exclusively on glucose for metabolism.
“it is becoming more evident that the metabolic needs of the neural retina profoundly influence the vascular network that supplies oxygen and nutrients”
The neurons in the retina are very energy intensive requiring steady supplies of oxygen and glucose, but as we’ve said above stress will constrict the vasculature and reduce the flow rate of blood reducing the supply to the retina. Eventually, drusen forms locally as the vasculature is injured and the immune system insufficiently manages the plaques. Perhaps that is simply a function of ease of access, a function of blood flow. This can technically be from either local or systemic stress, but it is likely both. The tissue response to oxygen deprivation is to then excrete VEGF to bring blood vessels into the area; however, these vessels take up space and in doing so disturb the important geometry of the macula. The new vessels tend to also be leaky which is a significant risk of more macular damage from ruptures or bleeds.
“SPN, [ A chinese herb] also prevented hypoxia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy in vivo. These results indicate that SPN ameliorates retinal neovascularization through inhibition of HIF-1α/VEGF signaling pathway.”
Blocking bleeds by blocking VEGF with a pharmaceutical or other compound seems of critical importance to triage the condition. However, reducing the local stress, increasing vasodilation while also increasing macular metabolism and nutrient access seem more likely to address the root cause. The evidence above led me to look into the same nutrients, resveratrol and menaquinone, that seem useful for removing sclerotic plaques in the cardiovascular system more broadly.
As noted above, the vascular endothelial growth factor, also known as vascular permeability factor, is secreted in response to cellular hypoxia as well as a response to estrogen and progestins. This is likely why women are twice as likely to suffer from AMD.
Relatedly, in healthy tissue plaques and related particles are metabolized or moved by macrophages of the immune system. This fact had me look at astragalus, cycloastragenol and melatonin and find likely benefits for AMD. The case study with TA-65 (cycloastrogenol) recovered about 1 diopter per subject. It’s critical role in the immune system as well as its aromatase inhibiting properties are likely important to zinc’s role in aiding eye health.
Niacinamide was a late find while writing this but has everything to do with supporting oxidative metabolism. It seems to potentially do everything needed and is one of the cheapest substances on the list. It’s molecular sibling, nicotinamide mononucleotide (NMN) is one of the most promising anti-aging substances, so I would suggest both as very promising candidates for AMD.
Potential Steps Toward Agency:
How would I individually aim for recovery if it was my diagnosis? I would “over do it” and see if I could induce reversal, then perhaps reduce to a manageable set of critical supplements or drugs. Trying to balance cost with efficacy I would start with Zinc, Selenium, Niacinamide and Red light (3-5mins/day). After 1 month or 6 weeks add in resveratrol, NMN, the K vitamins and vitamin D. If the budget fits add cycloastragenol and melatonin. Wait maybe 3 months with that stack. Probably follow with a SIRT 6 activator. Improvement or not then consider peptides and all other options as you like really. Nightly epitalon would probably be my first choice because it will work on many/all other physiologic systems. Too much selenium might be the highest risk of the bunch, keep the daily dose at recommended. Red light and or resveratrol should be started early in the effort because their mechanisms involve increasing vasodilation and reducing blood viscosity through eNOS production. In list form:
Limit chronic physiologic stressors especially from omega-6 fats and other anti-nutrients
Red light
Resveratrol, menaquinone-4 and menaquinone-7. All of these need to be taken with fat for absorption. This is likely part of the reason for the limited results from the AREDS 2 trial. They also seem to have only used 30mgs of resveratrol within their formulations and no menaquinone. Anti-aging folk usually aim for 1 gram daily of resveratrol. 5mg mk4 and whatever I can find in an mk7 capsule.
Niacinamide and NMN - 1 gram daily of each. I’m already taking NMN
All the usual suspects for vision: lutein, retinol (real Vitamin-A) only if I can metabolize it, zinc, selenium, zeaxanthin & astaxanthin
Cycloastragenol 10mg/evening and melatonin 1-2mgs/evening (older folks can increase the melatonin. Larger doses will make one drowsy but we eventually adjust.
Some combination of stress reducing compounds: astragalus, magnesium threonate, ashwagandha, l-theanine, apigenin and probably cannabis/cannabidiol
Cannabis might fit into the above - I’ve seen studies of it boosting melatonin, and it turns out to allow for increased calories without increasing weight
Take supplemental thyroid and increase calories from animal/dairy protein and healthy fruit/dairy sugars - this is fundamentally how to reduce local hypoxia. It is very likely that the thyroid tissue needs to re-grow from persistent stress catabolism.
Increase other endothelial nitric oxide promoters: beet powder, sildenafil
Sirt6 activators - the eye strongly expresses SIRT6 when healthy
TRIIM protocol: Metformin, HGH or precursors, DHEA, Zinc & Vitamin D - this protocol was built to regrow the thymus, the thymus is like the source of the immune system. The protocol is likely to also directly aid in retinal healing, but immune function increase could be expected to help remove the drusen.
Various combinations of retinal and systemic peptides will likely be helpful
Substance specific notes and references:
Nicotinamide & NMN:
“ we discover that nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins and inflammatory and complement factors while upregulating nucleosome, ribosome, and chromatin-modifying genes.”
Nicotinamide: a novel treatment for age-related macular degeneration?
“iPSC-derived RPE cells from age-related macular degeneration patients express increased levels of pro-inflammatory factors that can be normalized by the anti-aging drug nicotinamide.”
“Nicotinamide (NAM), a vitamin B3 derivative with anti-oxidant and anti-inflammatory properties (Maiese et al., 2009), can restore cognition in AD mice (Green et al., 2008) and is in clinical trial for AD (NCT00580931). Here we show that NAM can significantly inhibit the production of AMD-related proteins including drusen proteins, and markedly repress key genes in the complement and inflammatory pathways as well as improve RPE survival.”
Nicotinic acid inhibits angiogenesis likely through cytoskeleton remodeling
Resveratrol:
I found evidence for resveratrol which seems very suggestive of its ability to prompt reversal of wet-AMD which is consistent with its ability to do the same for arteriosclerosis.
“Resveratrol is known as an anti-aging, anti-cancer, anti-diabetic, neuroprotective and cardioprotective agent that acts by modulating various physiological processes, including oxidative stress, cell proliferation, apoptosis, inflammation, metastasis and angiogenesis”
“resveratrol-based nutritional supplementation on three octogenarians with AMD observed a short-term effect similar to that found with anti-VEGF treatment including anatomical restoration of retinal structure, improved RPE function, and a suggested improved choroidal blood flow. In another recent study, Richer et al. reported broad bilateral improvements in ocular structure and function in three patients with AMD over a long-term follow-up of two to three years suggesting its efficacy in AMD”
Of course, I don’t expect double blind placebo controlled trials of resveratrol or any non patentable substances because there is essentially no incentive to fund one. Even Dr. Sinclair who discovered resveratrol’s SIRT1 activation and uses it daily himself is putting much of his efforts into patentable chemicals and gene treatments including one of those that treats retinal conditions.
New Highlights of Resveratrol: A Review of Properties against Ocular Diseases
Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases
Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase
Of Vanishing Retinal Drusen and Oxysterols
Small molecules, taken orally, such as resveratrol (RV) and zeaxanthin (Z), resolve retinal drusen and amyloid protein, yet few clinicians are aware of this molecular, biochemical progress against the major degenerative disease(s) of ageing.
Resveratrol and Ophthalmic Diseases
Many studies have investigated the effects of resveratrol within the eye and its related disorders. Similar to the effects observed in other diseases, such as cancer, heart and neurodegenerative diseases (discussed above) the major biological actions on the eye include: anti-oxidative, anti-apoptotic, anti-tumorogenic, anti-inflammatory, anti-angiogenic and vasodilation. Studies investigating these effects and their potential role in the progression of eye diseases including glaucoma, cataract, age-related macular degeneration and diabetic retinopathy have been described in this section.
Vitamin K2
I think of vitamin K2 as the calcium management hormone. All the evidence I found for menaquinone (K2) is simply related to its criticality in vascular health with no mention of AMD. Dr. Knobbe has a similar expectation with vitamin K2 for the treatment and reversal of AMD. K2 takes calcium from the vascular system and puts it back into bone, and other appropriate tissues. While it is known to support proper coagulation, it is arguably more important at preventing inappropriate coagulation. It is important to note that I am talking about the K2 versions: menaquinone-4 (mk4) and menaquinone-7(mk7) which each have subtly different effects. Mk7 seems to be the most potent for removing calcium, but I suggest both should be taken consistently.
“Vitamin K deficiency results in inadequate activation of MGP, which greatly impairs the process of calcium removal and increases the risk of calcification of the blood vessels.”
“Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification.”
Breathwork, stress reduction and CO2 increases:
Macular Degeneration Symptoms + 6 Natural Treatments
Stress and Alterations in Bones: An Interdisciplinary Perspective
ACUTE MENTAL STRESS AND HEMOSTASIS: WHEN PHYSIOLOGY BECOMES VASCULAR HARM
Rebreathing into a bag increases human retinal macular blood velocity.
The study above is fascinating and I believe substantiating the effect of increase carbon dioxide on cerebral blood flow: “At the end of restricted breathing (RB), mean systolic brachial arterial pressure and heart rate were significantly increased [and] the RB produces a large increase in macular leucocyte velocity, suggesting an increase in blood flow.”
From my point of view this finding can be used to support the effect of thyroid, and various increases of carbon dioxide in the system such as drinking baking soda and doing other types of restricted breathing. It also seems likely that reduced CO2 and thyroid from stress play a role in the retinal pathology.
Specnuezhenide (SPN), one of the main ingredients of Chinese medicine "Nü-zhen-zi", has anti-angiogenic and vision improvement effects.
Thyroid - T4 seems contra-indicated:
Study cautions the increase of T4 which is what most modern MDs use. The causal structure could be wrong in this study. For example, those who don’t convert T4 to T3 will have low metabolisms and high T4. In that scenario, high T4 would not indicate hyerthyroid as the paper suggests. The study below suggests that an anti-thyroid medication increases the risk of more neovascularization.
Thyroid hormone and angiogenesis | Request PDF
Thyroid Hormone-Induced Angiogenesis
Red Light:
Optically Improved Mitochondrial Function Redeems Aged Human Visual Decline
Near Infrared (NIR) Light Therapy of Eye Diseases: A Review
Low-level laser therapy improves vision in patients with age-related macular degeneration
Declining eyesight improved by looking at deep red
Anti-diabetic anti-inflammatories
Antibiotic anti-inflammatories
“In addition to their well-known bacteriostatic properties, tetracyclines, especially doxycycline and minocycline, regulate inflammation, immunomodulation, cell proliferation, and angiogenesis. In particular, the anti-angiogenic properties of doxycycline—which have been recognized since the 1990s—have been shown to play a role in the treatment of pathologic angiogenesis”
Astaxanthin
Effects of astaxanthin on VEGF level and antioxidation in human aqueous humor: difference by sex “In conclusion, astaxanthin appears to affect O2 •- scavenging activity in the aqueous humor in females, and is likely to be involved in the control of VEGF levels in the anterior eye.”
Retinoids:
Results: The amount of cell-associated and secreted VEGF strongly decreased with retinoid concentration (e.g. 48, 69% inhibition at 0.1 microM all-trans-retinal and -retinoic acid, respectively, in the supernatants). In parallel, approximately 25% inhibition of VEGF mRNA expression was obtained in the presence of 0.01 microM all-trans-retinal.
“ Retinoic acid significantly prevented the development of hypoxia-induced retinal neovascularization and retinopathy in OIR mice and improved the functional recovery of retinal neurons downstream of photoreceptor cells as measured by focal electroretinography.”
TCM/Astragalus:
Overall, the TCM-based pharmaceutical composition is effective in treating wet AMD. Based on the animal model, its efficacy seems to be comparable to anti-VEGF agent Avastin.
Astragalus root extract was found to protect blood-retinal barrier in the OIR model mice through repairing the structure and morphology of retina, inhibiting ROS production, retinal cell apoptosis, as well as improving retinal vascular angiogenesis. Astragalus root extract was also found to decrease VEGF and HIF-1α expression, but enhance PEDF and IGF-1 expression in the OIR model mice, thereby protecting retinas in ROP. This study highlights that Astragalus root extract is able to suppress retinal cell apoptosis and repair damaged retinal neovascularization in ROP, which provides the basis for ROP therapy.
Evaluation of an oral telomerase activator for early age-related macular degeneration - a pilot study The macular function in the arm receiving the TA-65 showed significant improvement relative to the placebo control. The improvement was manifest at 6 months and was maintained at 1 year: macular threshold sensitivity (measured as average dB [logarithmic decibel scale of light attenuation]) improved 0.97 dB compared to placebo (P-value 0.02) and percent reduced thresholds lessened 8.2% compared to the placebo arm (P-value 0.04). 16mgs/day.
Melatonin:
We conclude that the daily use of 3 mg melatonin seems to protect the retina and to delay macular degeneration. No significant side effects were observed.
Melatonin Helps Macular Degeneration
Melatonin MZS Sleep Disorder & Reversal of Macular Degeneration 60 Count(Zinc, melatonin, selenium)
Peptides:
Russian Clinic: ANTIAGINGCLINIC
Peptides and the Eye Overview:
Neuroprotective Peptides in Retinal Disease
Epithalon:
Epitalon (Epithalamin): Potential Anti-Aging Compound
Peptide Bioregulators and Vision
SkQ1:
Peptide Axt107:
First patient dosed in AXT107 clinical trial for DME
Synthetic peptide outlasts macular degeneration med Eylea in animal models
Retinalamin
Visoluten:
Retina peptide (Visoluten®) - Antiaging Systems
Vasotide
https://www.eyeworld.org/article-novel-peptide-drug-for-treatment-of-retinal-diseases-on-the-horizon
Other:
New Treatments for Age-Related Macular Degeneration
ARTICLE Aging Eyes, Infant Eyes, and Excitable Tissues
Nutrients for the aging eye (AREDS) Nutrients of interest are vitamins C and E, β-carotene, zinc, lutein, zeaxanthin, and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid.
The role of blood viscosity in the development and progression of coronary artery disease