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NAD+ Precursors, Glaucoma, and Wallerian Degeneration

nmn nad+ nmnat

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#1 warner

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Posted 14 November 2017 - 11:23 PM


Increasing Nampt to increase NMN and NAD likely has negative impact on glaucoma progression (axon degeneration) via increased levels of NMN.
 
A rise in NAD precursor NMN after injury promotes axon degeneration
 
Axon Degeneration:  Too Much NMN Is Actually Bad?
 
Nicotinamide for use in the treatment and prevention of ocular neurodegenerative disorder (e.g., glaucoma)

It is believed that gene therapy employing NAMPT will lead to axon cell toxicity, albeit elevating the NAD+ levels in the cells. NAMPT functions to convert NAM to NMN, which is then converted to NAD+. Intracellular NAD+ is a key molecule associated with axon degeneration. When NAD+ levels are low, axons rapidly degenerate. It is also established that following axonal injury in sciatic nerve axons, NMN accumulates rapidly. In this model axon degeneration, NMN levels rise within 12 hrs, followed by neural injury occurs at 36-hr following injury. Blocking the NMN producing enzyme NAMPT using FK866 potentially inhibits this axon degeneration, hinting that NMN is toxic to neurons. Axon degeneration appears to be NMN-dependent, and inhibiting the increase of NMN using FK866 protects against axon degeneration. In a zebrafish model of axon degeneration (two-photon- laser axotomy), FK866 potently delayed axon degeneration. In a cell culture model of neurite degeneration (superia cervical ganglion; SCG), rapidly clearing NMN (by overexpression of the bacterial enzyme NMN deamidase which converts NMN to NAMN) robustly protects from axon degeneration.
 
Accordingly, the present invention represents an unexpected finding that gene therapy employing NMNAT, unlike that of NAMPT, is effective in protecting ocular neurodegeneration.  Thus we chose Nmnatl over Nampt, as Nampt overexpression would drive the production of NMN, which, without proper clearance, is toxic to neurons.
...
Mice with the Wlds gene have delayed Wallerian [axonal] degeneration. The Wlds mutation is an autosomal-dominant mutation occurring in the mouse chromosome 4. The gene mutation is a naturally occurring 85-kb tandem triplication, resulting in a mutated region containing two associated genes: nicotinamide mononucleotide adenylyl transferase 1 (Nmnat-1) and ubiquitination factor e4b (Ube4b), and a linker region encoding 18 amino acids. The protein created localizes within the nucleus and is undetectable in axons.
 
The mutation appears to cause no harm to the mouse. The only known effect is that the Wallerian degeneration is delayed by up to three weeks on average after injury of a nerve. Recent studies suggest that the mutation protects axons by a poorly understood mechanism. While not wishing to be bound by any particular theory, it is likely that the Wld mutation leads to overexpression and/or improved localization of the Nmnat {e.g., Nmnat-1) protein and increased NAD synthesis.
 
Nicotinamide and WLDs Act Together to Prevent Neurodegeneration in Glaucoma
 
Vitamin B3 modulates micochondrial vulnerability and prevents glaucoma in aged mice
 
So we now have several lines of evidence indicating the danger to neurons of excessive NMN, but also the value of both NAM supplementation and Nmnat activation for raising NAD and protecting neurons (from either a precursor deficit, toxic levels of NMN, or a, perhaps age-related, Nmnat enzyme deficit).
 
That makes me wonder about the wisdom of throwing a lot of NR or NMN at the system (and at my glaucomatous eyes), both from the point of view of cost and potentially toxic consequences.  The recent experience of Lawrence, for example, exposed to very high doses of NMN, makes me wonder if there are isolated areas (brain, retina, etc.) of his body that could actually be damaged by high NMN, in spite of the apparent overall metabolic benefits.  And such damage might not be readily apparent, or even measurable until many years into long-term supplementation.  (Such studies should at least be monitoring, where possible, changes to neuronal tissue - for example, measuring retinal nerve fiber layer thickness - given the above results.)
 
So, interestingly, we have a new strategy, based on raising NAD levels, that appears to slow glaucoma progression (and probably other retina-related diseases), but all we needed was to supplement with NAM, not NR or NMN.  And, even if enzyme manipulation is needed, its Nmnat that worked (lowering NMN levels), not Nampt, which raises NMN levels.

Edited by Michael, 15 November 2017 - 10:22 PM.

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#2 Michael

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Posted 16 November 2017 - 12:05 AM

Additional relevant papers:

 

Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.

 

The confusing results on members of the "NAD+ metabolome" and biosynthetic machinery continues:

 

NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion

 

Overexpression of the NAD+ biosynthetic enzyme NMNAT1 leads to preservation of injured axons. While increased NAD+ or decreased NMN levels are thought to be critical to this process, the mechanism(s) of this axon protection remain obscure. Using steady-state and flux analysis of NAD+ metabolites in healthy and injured mouse dorsal root ganglion axons, we find that rather than altering NAD+ synthesis, NMNAT1 instead blocks the injury-induced, SARM1-dependent NAD+ consumption that is central to axon degeneration. ...


 

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To raise intracellular NMN levels we expressed the NMN biosynthetic enzyme NAMPT or applied nicotinamide riboside (NR) to neurons expressing NRK1, a nicotinamide riboside kinase that converts NR to NMN [after injury]

[Both of these] significantly increased both NMN and NADlevels ... [and] showed strong axon protection for 24 to 48 hr....

 

To reduce NMN levels we treated neurons with the NAMPT inhibitor FK866 or expressed E. coli NMN deamidase [after injury] ...... [FK866] led to a slow decline in both cellular NAD+ and NMN before the axons begin to fragment ... [and] provided modest protection,...

 

E. coli NMN deamidase ... reduc[ed] NAD+ levels to 11 ± 7% of control, [but] neurons showed no signs of cell death or axon degeneration, but instead displayed potent axonal protection (Figure 3c and Figure 3—source data 1) as previously reported (Di Stefano et al., 2015).

 

The protection afforded by NMN deamidase was equivalent to that observed in neurons expressing cytNMNAT1 (Figure 3c and Figure 3—source data 1), however baseline levels of NMN and NAD+ were normal in neurons expressing cytNMNAT1 ...

 

Similarly, SARM1-deficient neurons had baseline levels of NMN, NAD+, NaMN, and NaAD that were equivalent to those of wildtype neurons. From these studies, it is clear that robust axonal protection can be observed in neurons that maintain low levels of NMN and NAD+ (NMN deamidase), normal levels of NMN and NAD+ (cytNMNAT1 or SARM1 knockout), or high levels of NMN and NAD+ (NAMPT or NRK1 + NR). ...

 

In cells expressing the strongly axoprotective cytNMNAT1, axonal NAD+ and NMN were comparable to baseline levels in uninjured axons of control neurons and these metabolite levels did not change after axotomy. Expression of NMN deamidase reduced axonal NAD+ and NMN compared with control axons, and these metabolite levels did not change after axotomy. In contrast, axons from neurons expressing NAMPT had high levels of both NAD+ and NMN at baseline and at six hours after axotomy. In axons from neurons expressing NRK1 and treated with NR there was a dramatic increase of NAD+ and NMN levels at baseline. After injury, these axons showed a robust decrease in NAD+ but further increases in NMN ..., yet these axons were strongly protected from degeneration (>48 hr). These results demonstrate that even within injured axons, elevated levels of NMN do not promote axon degeneration but rather can be compatible with robust axonal protection. ...

 

Hence, we sought to determine whether maintaining low NMN levels is necessary for the axoprotective function of NMN deamidase. We approached this problem by attempting to maintain normal NMN levels in neurons expressing E. coli NMN deamidase [which, again, breaks NMN down to NaMN]] ... utiliz[ing] an enzyme from Francisella tularensis called NMN synthetase that catalyzes the conversion of NaMN to NMN (i.e., the reverse of the reaction catalyzed by E. coli NMN deamidase) ... [T]he normal NMN deamidase-catalyzed reductions in NMN and NAD+ as well as the increases in NaMN and NaAD are largely abolished (Figure 3a,b and Figure 3—source data 1). Furthermore, the addition of the NMN precursor NR to neurons co-expressing F. tularensis NMN synthetase and E. coli NMN deamidase raised axonal NMN well above control levels (Figure 3a and Figure 3—source data 1). Despite this elevation in NMN levels under these conditions, NMN deamidase continued to provide robust axon protection ... [P]rotection of injured axons did not correlate with levels of NAD+, NaMN, or NaAD. Hence, neither a reduction in NMN nor the accumulation of NaMN/NaAD is necessary for NMN deamidase mediated axonal protection. These findings are inconsistent with the hypothesis that the axonal NMN level is a driver of axon degeneration.

 

[These studies show that] protection of injured axons did not correlate with levels of NAD+, NaMN, or NaAD. Hence, neither a reduction in NMN nor the accumulation of NaMN/NaAD is necessary for NMN deamidase mediated axonal protection. These findings are inconsistent with the hypothesis that the axonal NMN level is a driver of axon degeneration. ...

 

following axotomy, axonal NAD+ levels decline. This decline could be due to loss of NAD+ biosynthesis ... and/or to an increase in NAD degradation  ... To analyze NAD+ flux following injury, D4-Nam was added at the time of axotomy. In axotomized axons, steady-state NAD+ levels declined as previously reported. We now show that this is due to a large increase in the NAD+ consumption rate ... Surprisingly, in the first two hours after injury, there was also a modest increase in NAD+ biosynthesis .... This is likely due to the activation of NAMPT ... [as] The decline in NAD+ relieves feedback inhibition [on NAMPT] and results in increased NAMPT activity ...

 

[Still.] total NAD+ declined due to the larger increase in the NAD+ consumption rate (Figure 4a). After two hours post-axotomy, heavy NAD+ [from newly-synthesized, N4-Nam-derived NAD+ produced after injury] declined at the same rate as light NAD+ [recycled from pre-injury NAD+ pool], indicating a complete loss of NAD+ biosynthesis, likely due to loss of the labile NMNAT2 in the severed axon ...

 

We hypothesized that SARM1 may be required for this injury-dependent increase in NAD+ consumption because we previously demonstrated that SARM1 is required for the steady-state loss of NAD+ following injury in vivo and that SARM1 activation in primary cultured neurons leads to NAD+ degradation. [We confirmed this] ... The overexpression of NAMPT, which leads to modest axon protection, did not block injury-induced SARM1-dependent NAD+ consumption. In contrast, expression of either cytNMNAT1 or NMN deamidase completely eliminated SARM1-dependent NAD+ consumption after axotomy (Figure 4b and Figure 4—source data 1). This is a striking result that likely explains the profound axoprotective effects of overexpressing either NMNAT or NMN deamidase —both block the ability of SARM1 to trigger NAD+ degradation following axotomy. Loss of SARM1 or gain of NMNAT or NMN deamidase all lead to profound and long-lasting axonal protection following injury, and all three block NAD+ degradation following injury.

 

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#3 warner

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Posted 16 November 2017 - 03:34 AM

[from Michael's reference]  Finally, mutations in both NMNAT enzymes and NMN deamidase that destroy their enzymatic activity also block their axon protective capabilities (Araki et al., 2004, Sasaki et al., 2009b, Di Stefano et al., 2015). This strongly suggests that metabolites whose levels are altered by NMNAT and/or NMN deamidase activity regulate SARM1 function.  NMN was such a candidate metabolite because it is a substrate for both NMNAT enzymes and NMN deamidase; however, our studies show that NMN levels do not regulate NAD+ loss and axon degeneration, both SARM1-induced activities. Further investigations to identify other cellular metabolites modulated by NMNAT or NMN deamidase may help elucidate the mechanism of SARM1 regulation and axonal degeneration...    These studies support the hypothesis that SARM1-dependent NAD+ consumption is the central biochemical event in the axonal degeneration program. Further, they explain the phenotype of the wlds mutant mouse as one caused by the continued inhibition of SARM1 by the longer-lived Wlds protein that compensates for the loss of NMNAT2. Finally, these findings suggest that inhibitors of SARM1 or agents that boost NAD+ synthesis are likely to be valuable approaches for blocking axonal degeneration in the injured or diseased nervous system.

 

Okay, so the way I read this is that the glaucoma researchers (Williams et al.) are on the right track, pushing cheap NAM or finding ways to activate Nmnat, but that they missed the role of SARM1 in all of this.  Furthermore, they mistakenly assumed that promoting higher NMN levels (via Nampt or NR or NMN supplementation) might further neuron destruction, when in fact such strategies provide modest protection (by maintaining NAD levels in the face of rising SARM1), although not as protective as higher Nmnat activity (as with Wlds mutation).



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#4 sthira

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Posted 24 November 2017 - 01:55 PM

Interestingly, my (normal tension) glaucoma is not really a "disease" as much as it is a genetic predisposition to lower retinal and optic nerve head perfusion. In other words, under normal conditions, if I eat right, sleep right, etc., then there is no progression since perfusion is adequate. However, that's an impossible standard to meet, and the purposely elevated NAM is there to protect me from unplanned episodes of reduced perfusion...


Just curious, why is it an impossible standard to "eat right, sleep right, etc.," if you believe these may help nudge you away from a genetic propensity toward glaucoma progression? I realize glaucoma has no adequately available prevention beyond basics (regular comprehensive eye exams; knowing family history; moderate exercise; prescribed eyedrops to reduce pressure; eye protection from injury risk...").

Have you checked in with your optometrist's opinion about your NAM+NR protocol?

(Personally, I'm currently taking 1000 mg of NAM during the night [time of greatest glaucoma risk], split into two 500 mg doses to deal with its one hour half-life, plus 250 mg of NR during day, figuring I'm getting both skin cancer and glaucoma protection from such dosing.)


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#5 warner

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Posted 24 November 2017 - 04:26 PM

Just curious, why is it an impossible standard to "eat right, sleep right, etc.," if you believe these may help nudge you away from a genetic propensity toward glaucoma progression? I realize glaucoma has no adequately available prevention beyond basics (regular comprehensive eye exams; knowing family history; moderate exercise; prescribed eyedrops to reduce pressure; eye protection from injury risk...").


Have you checked in with your optometrist's opinion about your NAM+NR protocol?

Optometrists and retina or glaucoma specialists (in my experience) know far less about this NAD stuff than most of us on these forums.  In general, I think most medical practitioners are more like technicians than scientists, applying known solutions to known problems, and spending only a few minutes of time with each patient.  Even when they have an interest in such things as NAD et al., they aren't interested in the risk (legal consequences) of experimentation.  So I tend to avoid discussion of supplements with them, although I did present my optometrist with a pile of NAM/glaucoma papers to read when we last met, which I may regret going forward (since the combination of their less informed opinions + risk aversion can be dangerous to one's health).  In the end, what I've found is that it pays to figure things out for yourself (i.e., literature + self-testing), and use the medical system as one of many tools to optimize health.  In the case of NAM, I'm betting that any risk of taking 1g/d will be quite small compared to the potential benefits (and we have the skin cancer and glaucoma studies to support that).

 

For people with normal tension glaucoma (i.e., with normal IOPs), the "disease" appears to be largely an issue of susceptibility to reduced perfusion (blood flow).  I have a complex model worked out showing the interrelationship of a multitude of factors affecting perfusion, and how they play into the glaucoma risk.  I've done my best to address all of these factors via food, supplements, behavior changes, etc.  However, I'm still left relatively more vulnerable (compared to those w/o NTG) to random events and variations (especially at night).  So the purpose of the NAM (in my model) is to help address that noise which is difficult to control.

 

An alternative approach, in my case, would be to use a surgical technique to drive my IOP a few mm Hg lower, thereby enhancing perfusion, and reducing vulnerability.  But, for NTG, high IOP is not the direct cause of the disease, and the mice in the glaucoma studies were protected from glaucoma progression in spite of rising IOP with age.  So it seems smarter to take the NAM and perhaps avoid the need for surgery, although I may eventually end up doing both (or at least switch to one of the newer drops that reduce IOP further).

 

Another aspect to this is that I'm willing to make small mistakes if the payoff is useful knowledge, although that does mean keeping up with the latest literature, and doing a lot of self-monitoring, which most people are (understandably) not capable of or interested in doing.  But the alternative is to put yourself at the mercy of a medical system that can be both powerful and dangerously ill-informed.  imho


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#6 warner

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Posted 28 November 2017 - 03:55 PM

Michael found this additional link to Williams/John glaucoma research:

https://www.research..._mouse_glaucoma

 

To present additional evidence for nicotinamide-mediated protection, we include here results from axon counting and optic

nerve head analyses. These data demonstrate that nicotinamide-treated nerves that show no nerve damage are as
healthy as non-glaucomatous age-matched controls in terms of their cross sectional area, axon number, and
general morphology, without obvious glial changes (Fig. 1). Nicotinamide-treated eyes were also protected
from the remodeling and atrophy of the optic nerve head that produces optic nerve cupping, a characteristic feature
of human glaucoma (Fig. 2). ...
 
The genes encoding the cellular machinery that drive NAD production from NAM are expressed in retinal ganglion cells (Nampt,
Nmnat1, Nmnat2,andNmnat3) however, transcript abundance of NRK genes (Nmrk1, Nmrk2) that produce NAD from NR are only
lowly expressed in retinal ganglion cells. Since age-dependent changes in gene expression may modulate glaucoma susceptibil-
ity, we have assessed the effects of aging on genes impacting NAD levels. Importantly, there are age-dependent declines in the
expression of Nmnat2 and Nampt, and an age-dependent increase in Nadk (whose encoded enzyme converts NAD to NADP)
within retinal ganglion cells (Fig. 3B). Nmnat2 is the only NAD-related transcript that we observed to decline in both an age- and
IOP- dependent manner (Fig. 3C). All these changes are prevented by nicotinamide treatment.

Also, we have this excellent exchange between Williams/John and other glaucoma researchers from the mid-2017

International Glaucoma Review:

http://www.e-igr.com...x.php?issue=183

or full issue download (pages 11 to 24):  http://www.e-igr.com...ue=183&type=pdf

in which they note in passing that:

 

Nicotinamide effectively raised NAD(total) levels in other systems, and was potent at raising NAD(total) in D2 [mice] retinas by about 3-fold.

So, again, all that seems to support the case that, with respect to glaucoma, and perhaps other retinal diseases, low-cost NAM may prove to be as effective as NR (or NMN) in preventing or slowing retinal disease that is tied to (locally) declining NAD levels.



#7 warner

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Posted 16 December 2017 - 03:14 PM

UPDATE:  As described above, I had been taking 1000 mg NAM each night (2 doses of 500 mg each) to reduce glaucoma progression, based upon ground-breaking research with mice.  In addition to the glaucoma research, I had been encouraged by the use of NAM to grow new RPE (retinal pigment epithelium - the critical retinal cell layer between the photoreceptors and underlying choroidal blood vessels) from stem cells, as well as the use of NAM to normalize and enhance growth of existing RPE, with the latter forming the basis of this patent application:

 

Methods for inhibiting or reversing epiretinal membrane formation

http://www.freshpate...20150148383.php

 

NAM Ameliorates Disease Phenotypes in a Human iPSC Model of AMD

https://www.ncbi.nlm...pubmed/28132833

 

That recent work has been quite encouraging, pointing to NAM as a cheap way to slow both glaucoma and AMD (Age-related Macular Degeneration).  HOWEVER, as one might have expected, throwing a lot of NAM at oneself can have a lot of complex effects.  And in response to the above work, Westenskow recently explored some of the effects such NAM treatment might produce, including its effect on VEGF production by RPE cells,

 

Nicotinamide:  a novel treatment for age-related macular degeneration?

https://www.ncbi.nlm...les/PMC5676191/

 

The observation that VEGF-A is suppressed by nicotinamide is the most difficult to interpret, especially since we do not know if the patients involved in this study had wet or dry AMD. If the patients had wet AMD, reducing VEGF might be beneficial, but reducing VEGF below threshold levels in dry AMD patients can exacerbate disease progression. In primates, single intravitreal injections of VEGF antagonists transiently defenestrate and induce vessel occlusion in the choriocapillaris (29).In mice, we showed that single anti-VEGF injections promote complement accumulation around retinal capillary beds that predispose them to vaso-obliteration (30), and genetic ablation of Vegfa in adult murine RPE results in severe choriocapillaris drop-out and profound cone dysfunction three and seven days-post-induction respectively (17,31). Finally, chronic anti-VEGF injections can cause GA [geographic atrophy] in wet AMD patients (32). Therefore, if validated for human use, nicotinamide might be best employed as a therapy for wet AMD; however, care must be taken to not cause GA in wet AMD patients by over-antagonizing VEGF and causing damage to ocular vascular networks.

 

In other words, NAM reduces the VEGF production by RPE cells that is vital to maintaining a healthy choroid (i.e., by that route it may actually increase AMD risk).  Moreover, we know that NAM reduces SIRT1 activation, which can affect VEGF production throughout the body.  In this light, taking a lot of NAM may create risks on a par with those associated with taking too much of an anti-VEGF drug.

 

So, in light of the above, and encouraged by recent NR research results, I've stopped taking the 1000 mg of NAM at night, and upped my daytime NR dosage from 250 to 375 mg (3x125).


Edited by warner, 16 December 2017 - 03:24 PM.

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#8 warner

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Posted 08 February 2018 - 03:32 AM

UPDATE:  After 2 months taking just 375 mg/d NR, I've returned to taking 250 mg/d NR plus the overnight 1000 mg/d NAM as two doses of 500 mg NAM at about 11 PM and 2:30 AM (to maintain NAM blood levels equivalent to those in the rodent studies that prevented glaucoma progression - as described in previous posts).

 

I did this after seeing some visual field loss during those 2 month on only 375 mg/d NR.  Upon returning to the 1000 mg/d nightly NAM, I appear to have gotten back most of the vision loss, but it will be awhile before I'm certain of that (another month or so).

 

In general, having tried 3 types of B3 (NA, NAM, NR) while monitoring visual field results over several years, my conclusion at this point is that NA (nicotinic acid) reduces visual field response, NR does not protect me from visual field losses (or, worse, it adds to them, like NA), but nightly NAM (nicotinamide) stabilizes visual fields, slowing glaucoma progression.  And while its true that a reduction in visual field response does not necessarily indicate neuron damage (for example, retinal edema [fluid accumulation] caused by NA might produce apparent visual field losses w/o damaging neurons directly), at this point I still feel most confident using NAM nightly for protection (vs. NR or NA).  (And am setting aside concern about RPE effects noted in last post, figuring that these will be limited by just nightly use of NAM.)

 

In another month or so, I'll return with a summary of the related data after getting a better handle on the NAM effects.  But I thought I should speak up now in case any glaucoma patients were following this thread and were interested in my latest results.


Edited by warner, 08 February 2018 - 03:36 AM.

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#9 stefan_001

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Posted 08 February 2018 - 07:41 AM

Would the timing of the supplementation have influence? So taking 500mg NR or NA for overnight? Reason I am asking is that the NAD+ levels drop strongly in the night and perhaps thats the time degradation occurs.



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#10 warner

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Posted 08 February 2018 - 03:40 PM

Would the timing of the supplementation have influence? So taking 500mg NR or NA for overnight? Reason I am asking is that the NAD+ levels drop strongly in the night and perhaps thats the time degradation occurs.

Yes, most glaucomatous progression/risk likely happens at night, with higher IOPs and lower blood pressure reducing perfusion while also increasing the translaminar pressure gradient (leading to lamina cribrosa damage).  With that in mind, I first tried taking 250 mg NR at night (125 mg @ 11 PM and 2:30 AM), but was unable to sustain that since it caused insomnia.  I then tried just 125 mg NR at 2:30 AM, but that just kept we awake for the second half of the night.  Also, we got into a big discussion up here about not letting NR wreck one's circadian rhythm, so that too made me wary of taking NR at night.  And we also had evidence by then that the increased NAD levels from NR persisted throughout the day, so perhaps nighttime (vs. daytime) NR was not necessary.

 

However, I then found that I had lost some visual field response (a few % of vision) during the year or so that I had been on 250 mg NR.  The underlying cause of this loss was likely a period of extreme exertion that had occurred about 4 years before, damaging an area of the optic disk rim, which then took years to play out as nerve fiber layer loss and eventual vision loss (a common timeframe for glaucoma progression).  So, in other words, I had created a region of nerve fiber that had become susceptible to further degradation, but the 250 mg NR did not stop that degradation from proceeding.  (Although perhaps nothing would have stopped this.)

 

Encouraged by the recent rodent studies showing NAM stopping glaucoma progression, I then added the nighttime NAM and found that that appeared to stop vision loss (actually gained a bit).  After about 6 months of that, I then ran into the reservation that NAM may be inhibiting release of VEGF by RPE cells, thereby disrupting proper functioning of the underlying choroid, so I stopped the NAM and upped the total NR to 375 mg, figuring that might help with overnight protection.  However, the result of that change, over just 2 months, was a measurable reduction in visual field response.

 

So, you can see how that experience has made me skeptical of the use of NR to prevent glaucoma progression, while encouraged by the use of NAM taken at night (although I'm still taking 250 mg NR during day).

 

With respect to NA (niacin, nicotinic acid), the problem is that it is associated with retinal edema (pockets of fluid in the retina, and/or subclinical increases of retinal fluid that decrease visual field response).  The current speculation is that niacin interferes with Muller cell operation...

 

https://www.ncbi.nlm...les/PMC4458328/

"The second and the most reliable hypothesis supports that the niacin has a direct toxic effect on Müller cells, without disruption of the blood-retinal-barrier. Alterations in cellular metabolism cause intracellular fluid increase and swelling of these cells, with secondary formation of cysts between the glial spaces. After the discontinuation of niacin therapy, there is a complete regeneration of the Müller cells and their normal function."

 

Fortunately, there is no evidence that NAM has such an effect (i.e., no evidence of retinal edema associated with NAM), and I personally found no evidence that either NAM or NR had any effect on my retinal fluid levels, whereas NA definitely reduces my visual field response, likely due to subclinical fluid accumulation.  So NA use is probably not a good idea, day or night, wrt retinal effects.


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#11 warner

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Posted 08 February 2018 - 04:23 PM

Human trials of NAM on the way...

Nicotinamide shows promise as neuroprotective treatment for glaucoma

 

wrt NR vs. NAM, as discussed before, it may be the case that, in body locations where the main issue is lack of NAD precursor, that NAM works as well as any other precursor, but with fewer side effects, and/or lower cost.  And perhaps this lack of precursor is the main problem for glaucoma (at night) and skin cancer risk, where NAM's benefits are now well-supported.


Edited by warner, 08 February 2018 - 04:29 PM.

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#12 Harkijn

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Posted 08 February 2018 - 05:51 PM

Human trials of NAM on the way...

Nicotinamide shows promise as neuroprotective treatment for glaucoma

 

with fewer side effects, and/or lower cost.  

 

The researchers warn against presently available NAM. They say it is their future formulation that will be safe and effective, based on their clinical trials. Low cost? Not very likely, but I genuinely hope for you that the price will be lower than that of the NAD+precursors  available now.



#13 warner

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Posted 08 February 2018 - 07:43 PM

The researchers warn against presently available NAM. They say it is their future formulation that will be safe and effective, based on their clinical trials. Low cost? Not very likely, but I genuinely hope for you that the price will be lower than that of the NAD+precursors  available now.

Given its short blood half-life, and the need to take a second dose in the middle of the night to maintain the mouse-like levels, one obvious ploy will be to develop a timed-release form taken just once before bed, and using whatever dosage has been approved for that purpose, thereby justifying a special formulation and labeling for which a supplier will try to justify a much higher price.

 

However, I wouldn't worry about the "presently available NAM", and many of us older folks get up in middle of night for other reasons.  Thus it's unlikely that I'll be buying their special formulations -- similar to the AREDS2 formulas for AMD prevention - way overpriced, not optimal, and better done by supplementing components based on the actual research.

 

I'm going to contact one of the researchers, but not because of their bogus concern about NAM, but rather because I'd like them to include testing of nighttime-only NAM, with that potentially being the most effective way to get the biggest bang per dose.  But I suspect they are going to spend a long time with these human trials, given how they can't purposely (ethically) accelerate glaucoma progression in subjects, and how slow that progression can be in humans.  Also, the delay between optic disk trauma, nerve fiber loss, and vision loss can be many years, making it hard to understand cause and effect, even without introducing NAM treatment.  So we are probably looking at large numbers of glaucoma patients, split into controls and various NAM doses, watched by traditional means for many years.  And if they're not careful to include nighttime testing, they might miss when it is that NAM has the biggest impact, and end up with mediocre results and/or completely bogus NAM doses based on daytime dosing.


Edited by warner, 08 February 2018 - 07:49 PM.

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#14 Harkijn

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Posted 08 February 2018 - 07:54 PM

I'm going to contact one of the researchers, but not because of their bogus concern about NAM, but rather because I'd like them to include testing of nighttime-only NAM, with that potentially being the most effective way to get the biggest bang per dose.  But I suspect they are going to spend a long time with these human trials, given how they can't purposely (ethically) accelerate glaucoma progression in subjects, and how slow that progression can be in humans.  Also, the delay between optic disk trauma, nerve fiber loss, and vision loss can be many years, making it hard to understand cause and effect, even without introducing NAM treatment.  So we are probably looking at large numbers of glaucoma patients, split into controls and various NAM doses, watched by traditional means for many years.  And if they're not careful to include nighttime testing, they might miss when it is that NAM has the biggest impact, and end up with mediocre results and/or completely bogus NAM doses based on daytime dosing.

 

 

 

Yes, I hope they show flexibility and cooperation in this! Please keep us posted about this issue that is so complicated (involving high blood pressure and many other factors.)



#15 warner

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Posted 08 February 2018 - 08:37 PM

OK, I've sent an email to Dr. Liebmann summarizing my experience with the B3s, and concern that they include testing of nighttime-only NAM dosing.  We'll see what happens with that.  :)  Generally, I'm not very optimistic about such matters (i.e., the ability of the medical profession to act scientifically), and end up making my own decisions based on a combination of evidence sources.

 

btw, wrt this idea of using NAM as an NAD precursor, note that the mass/day comparisons we discuss are misleading due to molecular weight differences between the B3s.  For example, the molar ratio of NAM to NR that I'm currently taking is actually about,

 

((1000 mg/d) / 122 g/m) / ((250 mg/d) / 255 g/m) = 8.4 : 1

 

Moreover, the NAM is taken only at night when it is likely most needed.  So it is easy to imagine chemistry at the optic disk rim that is much more impacted (for better or worse) by the big nightly NAM doses than the distant, smaller, daytime NR doses.


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#16 warner

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Posted 20 February 2018 - 03:12 PM

UPDATE:  This plot, which I'll describe further in following post, presents the results of 10 years (120 months) of visual field count (VFC) results that include experiments with three types of B3 supplementation:  NA = niacin, NR = nicotinamide riboside, and NAM = nicotinamide.  The horizontal error bars denote the length of each treatment, and the vertical bars denote the average deviation of measurements.  The size of the squares (RE = right eye) or diamonds (LE = left eye) roughly indicate the total number of measurements made during each treatment, ranging from just 6 (the 375 mg NR treatment - halted after just 2 months due to significant vision loss) to many hundreds (the central "No B3" treatment).

 

Attached File  10 yr B3 trials.jpg   119.52KB   3 downloads


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#17 warner

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Posted 20 February 2018 - 03:59 PM

(These posts assumes knowledge of previous posts regarding this topic.)

 

About VFCs.  The VFCs (visual field counts) are simply the total number out of 224 stimuli (flashes of light of varying intensity and position) seen as presented by the VisionField application.  Because we all have a blind spot in each eye (site of optic nerve head), no one will see all 224 of the stimuli, and my highest recorded VFCs near 170 are not that far from the response of a normal eye.  These VFCs are similar to the visual field index (VFI) which has been added to the Humphrey Field Analyzer (HFA) results in recent years, although the latter is a normalized value with increased weighting for central vision, so the values are not comparable, although they both give a general idea of overall visual response.  (Personally, I like the simplicity of my VFCs being a simple measure of the total number of seen stimuli.)

 

Visual field response is dependent on many factors such as overall brightness of display, surrounding brightness, time of day, distractions, mood, health, hunger, etc.  The HFA does a good job of controlling display issues (I have to be more careful to control screen and surrounding brightness), but is just as subject to all the other factors as my own VisionField testing.  Furthermore, I can easily overcome the variability of results by doing much more testing than is possible with HFA, where the latter would be done (at your eye doc's office) not more than once every few months (probably much less).  In fact, if I had relied on occasional HFA testing, it would have been impossible to generate results equivalent to those shown in the plot.

 

The restricted VFC scale (140 to 170) expands and highlights the range of VFCs measured during the 10 years.  You'll notice that the average deviation of these results (vertical error bars) decreased somewhat over time due to various improvements that I made in taking the test that reduced variability (more consistent mental concentration, nutrition, etc.).  There's more I could say about that, but let me just conclude this section by making the point that I'm confident that the mean VFCs and deviations associated with each treatment are good estimates of my visual field response during those times.


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#18 warner

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Posted 20 February 2018 - 04:25 PM

About RNFL.  Retinal Nerve Fiber Layer (RNFL) refers to the uppermost layer of the retina which contains the nerves connecting the photoreceptors to the optic nerve and brain.  The RNFL consists of both nerves and supporting tissue (other cell types and blood vessels) such that a decrease in RNFL usually precedes vision loss, presumably because, in most cases, the supporting tissue dies/degrades before the nerves die.  You can see examples of this in the plot, for both eyes, where some damage occurs (described below), followed by RNFL loss, and then, finally, corresponding vision loss (as measured by VFC decrease).

 

The "damage" done in glaucoma usually starts at the optic disk rim due to a difference in eye pressure (IOP) and blood (BP) or cerebrospinal fluid (CSF) pressure.  An increase in IOP relative to BP or CSF has two negative effects:  decreases perfusion (blood flow) to the eye, and increases structural stress near the optic disk rim (near lamina cribrosa).  This combined effect accelerates aging of the eye, especially at the disk rim, and also makes it more susceptible to trauma from certain physical activities.  In my case, extreme exertion (shown as attic and yard work in plot) damaged my already-weakened optic disk rims, as evidenced by OCTs at the time (fluid accumulation originating at the disk rims).  This eventually led to corresponding RNFL loss, and later vision loss (VFC drop).  (In other words, glaucoma progression can be episodic, rather than continuous, although it is difficult to see this given the long time lines involved, with vision loss being far removed from the disk damage event.)

 

So, in my case, we have a good reason to expect to see some vision loss in both eyes in recent years, and that confounds the NR and NAM testing in the sense that we won't be able to blame any vision loss on NR and NAM alone.  However, we may still be able to say something about whether NR or NAM increase or decrease the rate of such loss.  (Note too how much less useful these trials would have been if I had not been experiencing some RNFL loss.  Similarly, in the clinical studies, they can't actively increase RNFL loss, but they're still hoping to randomly have enough poorly controlled patients to see such loss for test purposes.)

 

(back after lunch to finish summarizing plot results)


Edited by warner, 20 February 2018 - 04:34 PM.

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#19 warner

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Posted 20 February 2018 - 07:52 PM

Tentative Conclusions from 10 years of B3 trials:

 

● daytime NA (red triangles) reduces VF response by a mechanism not involving RNFL loss

 

As discussed in a previous post, NA is known to increase retinal fluid levels, possibly due to its effect on Muller cells, which probably also accounts for its reduction of visual field response.  This is further supported by the fact that I found that dorzolamide drops and Avastin treatments, both known to reduce retinal fluid levels, increased visual field response.  In all cases (NA, dorzolamide, Avastin) these effects were reversible, at least for the relatively short duration times of their use, so probably have no effect on RNFL or long-term glaucoma progression (i.e., they just confuse VF/HFA measurements).

 

● daytime NA's VF reduction appears to be dose-dependent (> 62.5 mg/d)

 

250 mg/d NA had significantly greater suppression of VFC than 125 mg/d NA, and 62.5 mg/d NA and below had no effect (not shown).

 

● daytime NR does not prevent VF loss due to RNFL damage

 

In hindsight, the 250 mg/d NR (blue data) was started at a time when both eyes were susceptible to further vision loss from a past event that damaged a portion of the optic disk rim.  Unfortunately, we must conclude that NR does not prevent ensuing vision loss from such events (although it is possible that nothing can prevent such loss).

 

● daytime NR may accelerate VF loss due to RNFL damage

 

It may be coincidental, but nonetheless troubling that vision loss in both eyes did not begin until NR was started.  For example, did daytime NR create some sort of reactive nighttime deficiency that pushed already-weakened neurons over the edge, resulting in vision loss?  This also seems to be supported by the faster sequence of RNFL and vision loss in the RE during NR use, than in the LE during the period w/o NR use.

 

● daytime NR itself may be a cause of RNFL damage and/or VF loss

 

It's also possible that the observed vision loss may have never occurred w/o the use of NR, making NR use directly toxic to the already-weakened neurons.  That seems unlikely, but there is nothing in the data to discount this.  In fact, during the more recent 2 months of 375 mg/d NR (w/o NAM), additional visual loss occurred.  And the entire sequence of declining NR results (blue data) taken together makes me very skeptical about the wisdom of using daytime NR to slow glaucoma progression.  At best, daytime NR may make no difference to such progression, although nothing in the data directly supports that.

 

● nighttime NAM appears to stabilize VF response (time will tell)

● nighttime NAM partially recovers VF losses after daytime NR-only use

 

As described previously, the 1000 mg/d (2 x 500 mg at night) NAM dosage is meant to approximate the rodent dosage found to prevent glaucoma progression.  So far, the NAM data (magenta) appears to support this, apparently stopping VF loss, and even recovering VF losses caused by NR-alone treatment.  Note that this nighttime NAM is being taken along with daytime 250 mg/d NR, so it may be that whatever harm is done at night as a result of the daytime NR is being offset by the NAM.  Going forward, my inclination is to stick with the current regime to continue testing the hypothesis that nightly NAM can stabilize glaucoma (i.e., to gather more evidence for the effectiveness of NAM treatment).


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#20 warner

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Posted 20 February 2018 - 08:30 PM

Going forward (final plot-related post).  A big problem I see in the glaucoma world is that the only hammer (treatment) they have (IOP reduction) makes everything look like a nail (inadequate IOP control).  For someone with NTG (normal tension glaucoma) like myself, however, there are many things related to blood perfusion that can accelerate glaucoma progression, including inadequate nutrition, low blood pressure, or simply being too cold at night.  Moreover, these other factors affect lots of other disease risks (dementia for example), which won't be helped one bit by measures to control IOP (eye pressure).

 

So that's why I'm much more interested in controlling glaucoma progression with improvements to general health, along with modest IOP reduction and management, rather than just using dramatic IOP reduction that only benefits my eyes.  (Note too that such IOP reduction probably has no effect on the risk to already ["baked-in"] damaged rim tissue from extreme exertion events.)  And with nightly NAM, I may have an additional tool to reduce progression, especially given the finding from the rodent studies that NAM prevented progression in spite of rising IOPs with age (i.e., it doesn't do its magic by reducing IOP, and works in spite of rising IOP).

 

Another way of putting this is that I'm willing to sacrifice a few percent of vision to learn something that will more effectively protect both my future vision and overall health.  NA was a bust.  NR was good bet that doesn't seem to work (for glaucoma).  NAM looks like the best bet.  But if I lose much more vision, then I'd likely turn next to more dramatic IOP reduction methods.


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#21 MikeDC

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Posted 20 February 2018 - 08:35 PM

Your results have no credibility what so ever. You don't just lose and gain vision at will. 


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#22 warner

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Posted 20 February 2018 - 11:39 PM

Your results have no credibility what so ever. You don't just lose and gain vision at will. 

Since someone actually thought that was a "good point", I guess I should address this. :)

 

There are 3 general ways in which your ability to see details such as the light stimuli in the VF or HFA programs can be affected:

 

1. General mental variations, such as mood, attentiveness, effects of hunger, distractions, etc., as well as local lighting conditions.  Use of both the VF and HFA programs is affected by these factors, creating uncertainty/imprecision in results that can only be overcome by either better control of all these factors, and/or by taking enough measurements.

 

2. Anything that interferes with or modifies the light getting to your photoreceptors deep within the retina.  That could be anything from a physical obstruction like a cataract, to the edema/fluid produced by NA within the retina.  Such effects are often reversible, but, with respect to NA, for example, we simply don't know if long-term use of NA contributes to photoreceptor or nerve fiber damage in addition to its immediate effect on visual field response.

 

3. Finally, things that directly affect the operation of photoreceptors and the connecting nerve fibers.  And in this case, it's reasonable to think that photoreceptors and connecting nerves can be in varying states of stress, affecting their performance to varying degrees (i.e., at varying distances from the cliff of total destruction).  Thus, the effects of minor stress, producing minor visual field losses, may be reversible, while more severe stress might be irreversible, ultimately resulting in permanent vision loss (by loss of nerve fiber and photoreceptors).

 

So, the fact is, you're "losing and gaining vision" all the time, and it's easy to do this "at will" (close your eyes).  The question is whether, for someone with glaucoma, their progressive vision loss, some of which becomes permanent, can be modified by B3 supplementation.  Due to the nature of the disease, this will likely depend on the B3's interaction with nerves near the optic disk rim.  Can the B3 save those near destruction?  Can it prevent others from progressing toward destruction?  Can it improve the performance of those that are stressed, thereby improving visual field response?  My results take us a little ways further toward answering such questions, and NR does not seem (to me) to be a very good bet at this point (for purposes of glaucoma control).


Edited by warner, 20 February 2018 - 11:40 PM.

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#23 HempOil

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Posted 05 March 2018 - 05:37 PM

Hi Warner,

 

Where did you derive your 1000mg/d dose of NAM? I found the following passage in an article from the authors of the original mouse study:

 

"In our studies, the lowest dose used (nicotinamide low dose; NAM Lo ) is equivalent to ~2.7 g/day for a 60 kg human (the human dose equivalent is based on a mouse dose of 550 mg/kg/d 65 ). At this dose structural and functional changes were prevented and the overall neural protection was robust, despite no impact on IOP elevation. The highest dose that we tested (nicotinamide high dose; NAM Hi , 2000 mg/kg/d) is equivalent to ~9.8 g/day for a 60 kg human and was extremely protective against glaucoma."

 



#24 Slobec

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Posted 08 March 2018 - 12:56 PM

If you are taking higher dose of NAD precursors take some betaine with it   http://www.freewebs....cin_therapy.pdf


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#25 Harkijn

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Posted 16 March 2018 - 04:50 PM

We will know more about NR and eye functioning when the study below will be completed. As always frustrating that such a small scale project will take such a long time to finish:

https://clinicaltria...how/NCT03432871



#26 Slobec

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Posted 17 March 2018 - 11:52 AM

We will know more about NR and eye functioning when the study below will be completed. As always frustrating that such a small scale project will take such a long time to finish:

https://clinicaltria...how/NCT03432871

 

https://www.ncbi.nlm...pubmed/28209901

https://www.ncbi.nlm...pubmed/29497468


Edited by Slobec, 17 March 2018 - 11:54 AM.

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#27 warner

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Posted 22 March 2018 - 10:32 PM

Hi Warner,

 

Where did you derive your 1000mg/d dose of NAM? I found the following passage in an article from the authors of the original mouse study:

 

"In our studies, the lowest dose used (nicotinamide low dose; NAM Lo ) is equivalent to ~2.7 g/day for a 60 kg human (the human dose equivalent is based on a mouse dose of 550 mg/kg/d 65 ). At this dose structural and functional changes were prevented and the overall neural protection was robust, despite no impact on IOP elevation. The highest dose that we tested (nicotinamide high dose; NAM Hi , 2000 mg/kg/d) is equivalent to ~9.8 g/day for a 60 kg human and was extremely protective against glaucoma."

I calculated a similar human equivalent to the low (but effective) mouse dose of about 3 g/d NAM.  However, since most glaucoma damage likely happens at night with rising IOP and falling BP, I'm using just 1/3 of the 3 g/d NAM to protect my eyes during those 8 hours (and taking 250 mg NR during daytime hours).  This 1 g/d also matches the amount that provided some protection from non-melanoma skin cancers, and is also effective in suppressing my moderate back acne (the risk of which also appears to be raised at night).  Splitting the 1 g/d into 2 x 500 mg taken a few hours apart during the night then ensures better peak blood levels throughout the night (based on research I did into NAM half-life - the numbers are in previous posts).

 

Interestingly, some of the kinetics research found that higher doses of NAM greatly increased its half-life, probably due to methyl donor depletion (not a good thing), so taking just 1 g/d for a limited period, when it matters most, is probably smart in that respect too.


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#28 jimsmith

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Posted 25 March 2018 - 08:08 PM

UPDATE:  This plot, which I'll describe further in following post, presents the results of 10 years (120 months) of visual field count (VFC) results that include experiments with three types of B3 supplementation:  NA = niacin, NR = nicotinamide riboside, and NAM = nicotinamide.  The horizontal error bars denote the length of each treatment, and the vertical bars denote the average deviation of measurements.  The size of the squares (RE = right eye) or diamonds (LE = left eye) roughly indicate the total number of measurements made during each treatment, ranging from just 6 (the 375 mg NR treatment - halted after just 2 months due to significant vision loss) to many hundreds (the central "No B3" treatment).

 

attachicon.gif 10 yr B3 trials.jpg

 

You had 6 visual field measurements during the 2 months on 375mg/day of NR? Is that 6 per eye? How do you manage to have so many visual field tests? Please describe the visual field testing method. Even better, can you post some of the actual visual field reports for some of these periods? It sounds like you have hundreds of visual field test reports and I suspect you cannot post all those here, although if it is possible that would make your case history much more compelling. Thank you.


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#29 warner

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Posted 26 March 2018 - 12:56 PM

 

UPDATE:  This plot, which I'll describe further in following post, presents the results of 10 years (120 months) of visual field count (VFC) results that include experiments with three types of B3 supplementation:  NA = niacin, NR = nicotinamide riboside, and NAM = nicotinamide.  The horizontal error bars denote the length of each treatment, and the vertical bars denote the average deviation of measurements.  The size of the squares (RE = right eye) or diamonds (LE = left eye) roughly indicate the total number of measurements made during each treatment, ranging from just 6 (the 375 mg NR treatment - halted after just 2 months due to significant vision loss) to many hundreds (the central "No B3" treatment).

 

attachicon.gif 10 yr B3 trials.jpg

 

You had 6 visual field measurements during the 2 months on 375mg/day of NR? Is that 6 per eye? How do you manage to have so many visual field tests? Please describe the visual field testing method. Even better, can you post some of the actual visual field reports for some of these periods? It sounds like you have hundreds of visual field test reports and I suspect you cannot post all those here, although if it is possible that would make your case history much more compelling. Thank you.

 

Post #17 in this thread describes the visual field testing.

 

One issue with home testing is that one has a harder time controlling head position (compared to using Humphrey's device), but that is less of an issue for total visual field count (VFC), in same way that the overall VFI is more precise than measures that try to specify the exact location of vision loss.  And by taking more measurements (something easily done at home), even the VFC imprecision can be overcome.  So I have very high confidence in the mean VFC results -- the real question being, since I was not conducting a fully controlled experiment, whether some other, unrecognized factors contributed to the lower VFCs when on NR alone.  But that's the nature of self-study, and one has to judge the relative merit of such results as best as one can, adding that to the larger pile of information.  As noted before, at this point, I'm more confident, in agreement with the mice studies, that nighttime NAM is protective, but somewhat skeptical about the value of daytime NR wrt protection from glaucoma progression.



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#30 jimsmith

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Posted 26 March 2018 - 08:32 PM

Post #17 in this thread describes the visual field testing.

 

 

One issue with home testing is that one has a harder time controlling head position (compared to using Humphrey's device), but that is less of an issue for total visual field count (VFC), in same way that the overall VFI is more precise than measures that try to specify the exact location of vision loss.  And by taking more measurements (something easily done at home), even the VFC imprecision can be overcome.  So I have very high confidence in the mean VFC results -- the real question being, since I was not conducting a fully controlled experiment, whether some other, unrecognized factors contributed to the lower VFCs when on NR alone.  But that's the nature of self-study, and one has to judge the relative merit of such results as best as one can, adding that to the larger pile of information.  As noted before, at this point, I'm more confident, in agreement with the mice studies, that nighttime NAM is protective, but somewhat skeptical about the value of daytime NR wrt protection from glaucoma progression.

 

 

I went back and re-read post #17. Can you describe the software you are using for visual field testing and the computer monitor you use? Do you do your testing at the same time of the day? If it is daytime, how do you control ambient light?

 

In regard to your post #19, do you have any data regarding RNFL loss in months ~100 to 120? If you are experiencing RNFL loss on NR, I do not think VFC would rebound the way your results show. So one tentative conclusion would be that NR reduces VF response in a manner similar to NA, and that this is independent of RNFL loss (exactly as it was around month 30-35 when you were on NA). Have you considered that possibility? Do you have RNFL results to confirm or refute this hypothesis?

 

It's possible to interpret your VFC data as indicating that none of NA, NR or NAM are helpful to your vision as measured by this test. I could further read this data as saying that both NR and NA suppress your VFC count in a dose-dependent manner while NAM appears to cause somewhat less suppression.

 

In addition to the RNFL data, you need a period with "no B3" again to paint a better picture of the treatment effect. A "no B3" period of 6-12 months would seem appropriate. After that, maybe you could do two trials with B3. One would involve B3 only and the second would incorporate the suggestion from post #24 to use methyl donors along with B3. The idea behind adding methyl donors is that insufficient methylation capacity in the RGC's might explain your reduced VFC during each B3 trial.

 

Looking forward to your response.


Edited by jimsmith, 26 March 2018 - 09:19 PM.






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