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Shelly Albaum

Editor, Science of NAD

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  • Shelly Albaum

NAD Can Protect Eyes from AMD and Glaucoma

Updated: Feb 2


 

TL;DR: There is a lot of research exploring the role of NAD precursors and the two major neurodegenerative diseases of the eye, age-related macular degeneration (AMD) and glaucoma. Theory, plus animal models, and now clinical studies, strongly indicate that these two very common forms of blindness result from disruption of the NAD system, and that NAD precursors can keep the tissues healthy.


There is not a lot of research assessing which NAD precursors are going to be the most effective at keeping the retinal tissues healthy. Although clinical trials are being run with nicotinamide, there is reason to believe that in the end NAM is not going to be the winner. NR might be the better choice, but the studies that could show that have yet to be done.

 

Research implicates NAD levels in neurodegenerative eye diseases like glaucoma and age-related macular degeneration


The rest of your body requires NAD to maintain its operations and to heal itself, so it is no surprise that the same is true for your eyes. Indeed, the retina is one of the most energy demanding tissues, requiring a constant energy supply to keep working.


Nor is it any surprise that NAD levels are implicated in neurodegenerative diseases of the eye, since the same is true of neurodegenerative diseases elsewhere, like Parkinson's and Alzheimer's.




Age-related macular degeneration (AMD) degrades vision in the the center of the retina. AMD is the leading cause of blindness among the elderly, and there is no cure. Approximately 200 million people are affected.


Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs), which transmit visual signals from the retina. Glaucoma, too, is one of the most common neurodegenerative diseases worldwide, affecting approximately 80 million people, and there is no cure.



Ophthalmological researchers have been exploring the role of NAD and NAD precursors in eye diseases at least since 2005, when researchers reported that "NAD+ maintenance attenuates light induced photoreceptor degeneration." But that was just the beginning.


In 2010, they reported that "metabolic vulnerability" seems to be implicated in the nerve degeneration underlying glaucoma.


In 2016, researchers reported that NAD biosynthesis via the salvage pathway was essential for vision, and that retinal cells exposed to the kind of oxidative stress typical of AMD were protected by replenishing NAD.


In 2017, researchers reported that Vitamin B3 prevented glaucoma in 93% of mice. Vitamin B3 not only prevented glaucoma, but also worked as an intervention. The language used by the researchers bordered on exuberant: "The degree of protection afforded by administering this single molecule [vitamin B3] is unprecedented and unanticipated."


Targeting NAD through dietary vitamin B3 or gene therapy prevents IOP-induced metabolic dysfunction and glaucoma...Oral administration of the NAD+ precursor nicotinamide (vitamin B3)...was protective both prophylactically and as an intervention. On our highest dose, 93% of eyes did not develop glaucoma. This supports therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations...The degree of protection afforded by administering this single molecule is unprecedented and unanticipated.

-- Science, April 28, 2017


In 2018, researchers speculated that the cause of AMD was mitochondrial dysfunction in a thin layer of the retina called the retinal pigment epithelium, or RPE.


"Strong evidence from analysis of human donors with AMD supports the emerging hypothesis that defects in RPE mitochondria drives AMD pathology."

-- Investigative Opthalmology & Visual Science, June 1, 2018


Another study in 2018 found that NAD replenishment robustly protected mice from inherited glaucoma, and the researchers reiterated the excitement:


"The possibility that a simple dietary supplement can prevent neurodegeneration is an exciting prospect with broad implications for age-related diseases."

-- Communicative & Integrative Biology, January 19, 2018


In 2020, hot on the trail, researchers conceded that NAD metabolism had not gotten as much attention as it should have in the context of eye medicine, and they tried to put the pedal to the metal:


Herein, we discuss important findings in the field of NAD+ metabolism, with particular emphasis on the importance of the NAD+ biosynthesizing enzyme NAMPT, the related metabolism of NAD+ in the retina...With such rapid progress in this field, there have already been many excellent review articles about general NAD+ biology and its relevance to health and disease. However, none has focused, as we do in the current review, on the specific importance of NAD+ metabolism in ocular diseases, an area that has received comparatively less attention. (Emphasis added)

-- Oxidative Medicine and Cellular Longevity, May 11, 2020


Also in 2020, researchers went to work using NAD precursors to attempt to rescue mitochondria in AMD retinal cells. And it seemed to work.


Consistent with results from previous studies, NMN treatment improved mitochondrial function in primary retinal pigment epithelium cultured from age-related macular degeneration donors. NMN was taken up by the cells as shown by the increase in intracellular NAD + content. Furthermore, NMN was taken up by the mitochondria, albeit through an unidentified carrier, as shown by the improvement in mitochondrial function.

-- Redox Biology, July 1, 2020


Later in 2020, another set of researchers summarized the emerging research, declaring that there was now "compelling evidence that NAD+ supplementation would be a promising intervention" in glaucoma and AMD:


Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions...


We propose increasing NAD+ as a putative effective therapeutic strategy for both glaucoma and AMD...NAD+ is a key molecule in healthy neurons and plays central role in cellular bioenergetics. Its age-related depletion affects the biological coping mechanisms associated with inflammation, oxidative stress, and accumulation of damaged molecules. All these alterations are intrinsically linked to retinal degenerative pathologies, such as glaucoma and AMD, and with compelling evidence that NAD+ supplementation would be a promising intervention in these diseases...This review focuses on the shared pathophysiological mechanisms of glaucoma and AMD and the potential role that NAD+ may play in their mitigation. (Emphasis added)

-- Nutrients, September 19, 2020


More studies were run, and in 2022 one group reported not only that an NAD precursor strongly prevented cell loss in the retinal pigment epithelium of AMD, but that it did so by preventing the oxidative damage that would normally have occurred without the maintenance of mitochondrial function, and that the NAD precursor did this by enabling SIRT1's protective effect.


(NMN) strongly ameliorated retinal pigment epithelium senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling.

-- Oxidative Medicine and Cellular Longevity, July 18, 2022


Other groups of researchers in 2022 further elaborated on the emerging understanding of the diseases, for both AMD and glaucoma. In AMD, inflammation caused NAD declines, and the NAD declines resulted in additional inflammation, leading to a positive feedback cycle that eventually flooded retinal cells with destructive reactive oxygen species. In glaucoma, too, the drop in NAD levels is where it starts.


In AMD, the over-expression of NAD+-consuming enzymes in macrophages leads to declining of NAD+ concentrations in the microenvironment. This phenomenon triggers the activation of inflammatory pathways in macrophages, positive feedback aggregation of inflammatory cells and accumulation of reactive oxygen species (ROS).

-- Mechanisms of Ageing and Development, November 23, 2022


In animal models of glaucoma, the capacity to maintain retinal nicotinamide adenine dinucleotide (NAD) pools declines early during disease pathogenesis. Treatment with nicotinamide, an NAD precursor through the NAD salvage pathway, robustly protects against neurodegeneration in a number of glaucoma models and improves vision in existing glaucoma patients....

-- Acta Neuropathologica Communications, January 22, 2023


Another group of researchers summed it up best, observing that although the various diseases of the retina look different, they all seem to start from mitochondrial dysfunction, oxidative stress, inflammation, or the ability to clear waste material from metabolic reactions, and all of these causes, in turn, are linked to the bioavailability of NAD+.


Despite the diversity of insults that can affect the retina, there are several common pathogenic mechanisms that may permit a unified therapy: mitochondrial dysfunction, oxidative stress, inflammation, and the inability to clear waste material from metabolic reactions. These are all mechanistically linked by the bioavailability of NAD+, either to insufficient production or over-consumption by NAD-consuming enzymes (e.g., SIRTs and PARPs). Given this, we propose increasing NAD+ as a putative effective therapeutic strategy for both glaucoma and AMD. (Emphasis added)

-- Nutrients, September 19, 2020


Human clinical studies were initiated, and reports from both Phase 1 and Phase 2 tests were published in 2020 and 2021. Both were positive.


A phase 1 human clinical trial with nicotinamide:

...A trend for improved visual field mean deviation was observed with 27% improving ≥1 dB on nicotinamide and fewer deteriorating (4%) compared to placebo (P = .02). Nicotinamide supplementation can improve inner retinal function in glaucoma.

-- Clinical and Experimental Ophthalmology, July 28, 2020


A larger, Phase 2 clinical trial tested ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization) in 32 participants (21 from the intervention group and 11 from the placebo group):


A combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression.

-- JAMA Ophthalmology, November 18, 2021


So the story here for NAD precursors and neurodegenerative eye diseases like glaucoma and age-related macular degeneration is very good. Theory shows that NAD depletion is a problem, and that NAD replenishment might help. Animal tests show compelling evidence that NAD replenishment does help. And early tests in humans seem to confirm that result.


Part 2 -- So What's Missing?


But there are important questions yet to be answered. For starters, although the early human tests are promising -- 27% saw improvement in the Phase 1 study, and the Phase 2 test group was about 3x as likely to improve compared to the placebo group -- they are not quite the compelling results seen in mice, where we saw that 93% of eyes did not contract glaucoma.


What's up with that?


Well, it could just be that mice are different from humans, and especially that animal models are different from sick humans. Or maybe the human study was shorter in duration, or there were not enough participants. Certainly even modest improvements would be welcome.


But there's something else, too.


The studies so far have mostly used NAM or NMN. There haven't been any that I am aware of with nicotinamide riboside (NR). And it's not clear why.


The very first study we looked at, from 2005, used NAM to replenish, and most of the researchers in eye medicine have been barking up that same tree, Each citing the prior studies.


Not everyone, though. In 2016, another group found that they could rescue vision from retinal degeneration using NMN. Since then, other researchers has been barking up that tree.


But what you do not find in the research is a thorough review of the five NAD precursors -- Tryp, NA, NAM, NR, and NMN -- a comparison of how they work, and an analysis of which ones might be the most promising for the treatment of neurodegenerative disorders of the eye.


Ophthalmologic researchers through 2022 focused on just two of the precursors -- Nicotinamide (NAM) and Nicotinamide Mononucleotide (NMN). I have seen no studies comparing, or even considering, whether the experimental results would vary depending on which precursor was used.


Instead, what we have seen are cursory brush-offs like this from a review written in 2020, which was reasonably enthusiastic about the prospects for nicotinamide and glaucoma:


NMN and NR are well tolerated as well, but the effects of long-term chronic administration are yet to be assessed fully in humans.

-- Nutrients, September 19, 2020


That's not false, but even at the time that was written in 2020, the safety of NR in humans had in fact been extensively studied, and the research then, as now, suggests that NR is actually more safe than nicotinamide, rather than less safe, in humans, at high doses. The brush-off sentence sounds more like an attempt to placate Reviewer #2, less like an attempt to seriously consider whether the choice of NAD precursor might matter in the context of these diseases.


But at least these researchers took the time to blow off the alternatives. Most of the other studies don't even mention NR.


But all that is water under the bridge.


There is still time, and now very good reason, to seriously consider how the various precursors might work in the context of eye diseases. And a new study published less than two weeks ago in the January 2023 issue of Acta Neuropathologica Communications, attempts to do exactly that.


The new study noted that although NAD replenishment robustly prevented glaucoma in animal models, there really had not been enough work done to understand how NAD biosynthesis worked in eye tissues, and specifically whether the nicotinamide (NAM) that was being tested could even be used by the target cell types, and even if so, whether that capability became impaired as the disease progressed:


A major finding has been that the capacity to maintain nicotinamide adenine dinucleotide (NAD, an essential metabolite in neurons) declines in the retina in an age-dependent manner and renders retinal ganglion cells susceptible to neurodegeneration. Preventing NAD depletion via administration of nicotinamide (a precursor to NAD through the NAD salvage pathway) robustly prevents glaucoma in multiple animal models. Supporting a hypothesis in which age-related, pathogenically low NAD leads to glaucoma susceptibility, glaucoma patients have been demonstrated to have systemically low levels of nicotinamide (in sera) and recent preliminary clinical trials have demonstrated that oral nicotinamide can improve visual function in existing glaucoma patients. This has initiated a large scale, multicenter randomized controlled trial (RCT) exploring nicotinamide for glaucoma prevention which is taking place in Sweden, Australia, Singapore, and the UK. Even though these preliminary studies have been successful and RCTs are now on-going, it is currently unknown if the target neurons in the retina contain or express the enzymatic machinery to utilize nicotinamide in its current form, and how this might change during glaucoma pathogenesis.

-- Acta Neuropathologica Communications, January 22, 2023


What the researchers discovered was that how eyes synthesize NAD is complicated. Although the retina seemed to favor NAM, tissues in other parts of the eye favored NA and NR. Moreover, the ability to synthesize NAD from NAM declined with age and with disease progression.


NAD production is an ideal target for neuroprotection in glaucoma and other age-related ophthalmic diseases...While the retina favors the NAD-salvage pathway, the anterior chamber favors the Preiss-Handler pathway and nicotinamide riboside as an alternative substrate to the NAD-salvage pathway...There is down-regulation of Nmnat2 in rodent RGCs in both an age- and disease-dependent manner...Our finding that NAMPT, NMNAT1, and NMNAT2 labelling decreases in the inner retina with severe disease might limit this NAD synthesis in more severe glaucoma patients, however, these enzymes remain detectable at 32%, 49%, and 46% respectively...[Therefore], the ability to [synthesize NAD from NAM] is maintained, but the capacity to do so may be lower in glaucoma.

-- Acta Neuropathologica Communications, January 22, 2023


The researchers took this as good news that NAMPT was present in retinal tissue, and therefore could synthesize NAD from NAM. And although they noted that NAMPT gets downregulated with age, and then further again with disease -- the NAM pathways was reduced by two-thirds! -- they guessed there would still be enough NAMPT present to make a difference.


I don't think that is an improper conclusion. But if it is the right answer, then it is the right answer to the wrong question. The question should not be whether NAM will work at all. The question should be whether we are barking up the wrong tree, and a different precursor will work even better.


Researchers who are experts in metabolism crossed this bridge many years ago, realizing that the NAMPT salvage pathway was downregulated in conditions of age and stress, and that therefore nicotinamide riboside was more likely to be effective because it bypassed the NAMPT step. That's kind of the whole point of NR.


And that's why most studies involving other neurodegenerative diseases like Alzheimer's, Parkinson's, ALS, and Ataxia, are using NR or NMN. NR enters cells directly and bypasses the rate-limiting step that can reduce NAM's effectiveness. NMN simply delivers NR to cells, and thus fundamentally works in the same way (the difference being how much NR is delivered to cells by NMN versus how much NR is delivered to cells by administering NR directly).


Even skin researchers trying to protect against skin cancer, who have seen good results with nicotinamide, and who are not dealing with a neurodegenerative condition, are guessing that NR and NMN will work even better than NAM:


Research into cellular metabolism and aging suggests that NR and NMN can lead to greater increases in NAD+ vs NAM. NR and NMN are safe and well-tolerated and are consequently currently undergoing investigation as agents able to protect against age-associated disease caused by NAD+ depletion. We hypothesize that oral supplementation with NR or NMN may lead to greater reductions in KC than NAM....recent work using animal models has shown that both NR and NMN supplementation can mitigate DNA damage, improve cellular metabolic function, and reduce age-associated disease more effectively than NAM supplementation.

-- Journal of Drugs and Dermatology, October 1, 2022


Did the eye researchers not get the memo?


Actually, this kind of confusion makes sense, because the problem of (1) neurodegeneration, (2) in the eye, (3) due to metabolic dysfunction, (4) involving mitochondria, is deeply interdisciplinary. The metabolism experts do not have specialized knowledge about eyes, and the eye experts do not have specialized knowledge about metabolism. Now would be a good time for some NAD metabolism experts to join some of these eye research teams.


In the meantime, we are left to guess whether the eye researchers who are seeing good results from nicotinamide would see better results from NR. The reasons I suspect they would seem quite strong:


First, we know that NR can enter the target cells and bypass the NAMPT step, using the NR Kinase 1 pathway. The Acta Neuropathologica article noted that all the salvage biosynthesis pathway enzymes were well-expressed except for NRK2, which suggests that NRK1 was adequately present. In order to get to NAD, two hurdles must be cleared: first NAMPT, then NMNAT. For all we know NMNAT is a problem, too, but even if so, clearing the NAMPT hurdle, when we know it is downregulated by both age and disease, can only be a benefit.


Second, we also know that with oral NR supplementation, some of that will get delivered to tissues as NR, some will get delivered as NAM, and some will get delivered as NA or NAR (NAD precursors associated with the Preiss-Handler pathway). In other words, NR activates at least three NAD biosynthetic pathways, including the one relied on by NAM. Having three chances to replenish NAD is going to be better than only having one chance, especially if the one chance you are counting on is known to be downregulated, and at least one of the other pathways is also present and not downregulated. I have a deep-dive in case you want to read more about how NR becomes bioavailable via multiple pathways.


Third, although the eye researchers reckon NAM to be proven safe at high doses, that's not really how the studies read. Here, eye researchers say that NAM at 3 grams, or even up to 9 grams, is safe with only minor side effects:


Chronic intake of 3 g/day of NAM is well tolerated with side effects (mostly gastric minor disturbance) only in a small percentage of patients. In classic studies from the 1950s and onwards, long-term higher doses of NAM at >9 g/day have been reported with minimal side effects (Emphasis added)

-- Nutrients, September 19, 2020


I don't think that's accurate. The researchers fail to note that at such high doses NAM has been shown to cause liver damage, kidney damage, and suppression of protective processes relying on PARPs and SIRTs. You can read here a list of problems with NAM.


The effect on SIRTs will be especially important for retinal conditions, though, because one of the studies we just reviewed, which showed that NMN protected against AMD, found that protection of retinal cells by NMN depended on the action of SIRT1.


Nicotinamide mononucleotide (NMN) strongly ameliorated retinal pigment epithelium senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. (Emphasis added)

-- Oxidative Medicine and Cellular Longevity, July 18, 2022


If you must seriously overdose on NAM in order to make up for the downregulated NAMPT pathway, and that high dose gets the NAM through, but depresses the SIRT1 activity that was a primary purpose of the supplement, then it's not going to work as well. Maybe that's what we are seeing in the early clinical trials with NAM, if I am correctly reading those outcomes as good but not great.


Conclusion


There is a lot of research exploring the role of NAD precursors and the two major neurodegenerative diseases of the eye, age-related macular degeneration (AMD) and glaucoma. Theory, plus animal models, and now clinical studies are all indicating that these two very common forms of blindness result from disruption of the NAD system, and that NAD precursors can keep the tissues healthy.


There is not a lot of research assessing which NAD precursors are going to be the most effective at keeping the tissues healthy. Although clinical trials are being run with nicotinamide, there is reason to believe that in the end NAM is not going to be the winner. NR might be the better choice, but the studies that could show that have yet to be done.

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