Fish Oil Supplementation: No Impact On NAD
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- čas přidán 7. 09. 2024
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Thanks Michael. Fascinating to watch your experiments. And I love the short but frequent format
Thanks @generalbystander1631! Sometimes the videos will be longer, but not to fill time, only to tell the story.
the ceteris paribus is tricky, when it comes to nutrition. On the one hand, you increased DHA by sardines, but you also increased methionine well above your baseline (I guess). Since the salvage pathway and the meth/Hcys cycle are so closely rlated and directly linked, I strongly adjust that you increase methyl groups intake along with NAD, in order not to mess up Hcys... the de-methylation through NA>NAM>meNAM might be the main reason for the drop in Dunedin. Note that the K values for some enzymes change through the elevated presence of the involved metabolites
lol.. just suggested the same thing.. great minds think alike
This suggests he just needs less of sardines?
@@tommyortiz6623 from my little bit of food tracking I know, that 2 Cana of sardines + 3eggs a day brings you easily to 300 % of the RDA for methionine. This may not be a problem for its own, but if you start to boost NAD with precursors the you create a deficiency in avail methyl groups. Sardines are an incredible super food, and reducing is not a good idea. However, More chapel also takes NA...and therefore he needs to care about the methylation capacity.
@@michaelransom5841 ,😎 where are you based? in US?
Thank you for sharing your data and your experience. Would be nice to see a low dosage of NA that does not cause much flushing and hits the SWEET spot for NAD boost. Look forward to your next VID
Or people can just try doing more exercise. Exercise appears to be, the best way the for people to raise their NAD levels, and better than supplements. Exercise tends to improve lifespan and reduce disease levels in studies. For the most part, we can't say the same about Niacin. People clocking in at least 13,000 dailysteps had the highest NAD levels in one study. While I suppose that could be a chicken and egg thing, I don't think so based upon some of the papers below.
""All in all, the data accumulated thus far indicate that the effectiveness of exercise clearly exceeds that of NAD+ precursor supplementation, and exercise remains one of the most potent interventions against muscle and systemic aging.""
Sabina Chubanava, Jonas T. Treebak, Regular exercise effectively protects against the aging-associated decline in skeletal muscle NAD content, Experimental Gerontology, Volume 173, 2023. Also see: : NAD+ Levels Are Correlated with Physical Activity in Humans
This research confirms what has been long suspected, LifespanIO, by Arkadi Mazin, February 22, 2022 In a study published in Nature Aging, a group of scientists has shown that NAD+ levels are correlated not only with age but with physical activity, with elder athletes rivaling normal young adults
Janssens, G.E., Grevendonk, L., Perez, R.Z. et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nat Aging 2, 254-263 (2022). In this paper it was reported by a third party that NAD+ was more than doubled in muscle cells following ten weeks of resistance training, restoring levels in older people to that of college-aged individuals. Lamb DA, Moore JH, Mesquita PHC, Smith MA, Vann CG, Osburn SC, Fox CD, Lopez HL, Ziegenfuss TN, Huggins KW, Goodlett MD, Fruge AD, Kavazis AN, Young KC, Roberts MD.
Resistance training increases muscle NAD+ and NADH concentrations as well as NAMPT protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals. Aging (Albany NY). 2020
In this paper, it was reported that aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. (NAMPT provides the mechanism to recycle NAD in human metabolism so it is not depleted as much) . Incidentally, it was reported that HIIT did not increase NAMPT
de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, Larsen S, Brandauer J, Houmard JA, Treebak JT. Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle. Physiol Rep. 2019
@@jackbuaer3828
Thanks... it can take a lot of time digging this stuff up.
I think one of the main problems here is that most people would rather just be able to pop a pill than do exercise. Personally, I get a reasonable amount of exercise for my age but I absolutely hate resistance training. I see gyms as akin to torture chambers, just causing pain and discomfort with no joy or fun involved.
I think the trick is for people to try to find a way of exercising that they can actually enjoy. I enjoy hiking, cycling and swimming. For some, it may be competitive sports such as tennis or football. It also improves the chances of sticking with it.
I remember visiting a Fun Park, as a young adult, that had a place called "The Fun House". After spending an hour or two in there, I came out hot and exhausted, though I didn't go in there to exercise. It had a spinning disk, big rotating tubes, ropes, rope nets, all kinds of fun things to play in and all of them required using physical energy. I burnt a ton of calories, just having fun.
We need more of that kind of thing.
even 50mg gives intense flushing, no way around it unfortunately but the flushing goes away after daily use for a long time once tolerance develops, whether this means it still boosts NAD+ after tolerance develops is an open question.
@@pariodeusex I concur, regarding the tolerance, but now that I'm getting 500 mg twice a day, the flushing is still there after months of supplementation. And that's good. Sure, it tingles and itches a bit, but the dilation of small blood vessels is good at least for the skin, and if it works also in the brain, then all the better, especially if we take other supplements at the same time, since it should help these supplements reach corners of the body it normally wouldn't.
Thanks Doc.
You just have to wonder how well the pace aging clock translates into real life when niacin for such a small period can have such a major change.
Metabolism is fine-tuned for physiological amounts of nutrients. I supplemented with 600 mg of NA/day, which doesn't seem like much, but it's 15x normal intake.I don't doubt the validity of the test.
@@conqueragingordietrying1797 my thoughts are that if niacin can affect the epigenome and this the PACE measurement, and then reducing niacin can then reset it, doesn’t it imply that what it’s measuring is transient ? maybe a great experiment for you would be to eat junk food for a month .. get a tridiagnistic test then clean up and retest …
Great research. Good on ya Michael 👍
Thanks @aljosarojac8575!
Thanks
Thanks for your support, @helenmckay3260!
Thanks!
Thanks for your support, @christianravera6768!
Thanks again.
It is recommended that you take NA with TMG. NA depletes methyl groups in the body, and TMG is a good supplement for methyl groups. The lack of methyl may be the reason of your epigenetic pace of aging becoming worse.
There are many ways to increase methyl donors, it doesn't have to only be TMG.
Fascinating video. Thank you for the information.
I take D3 and K2 together along with a multi magnesium. I also take omega-3 fish oil and MCT oil along with my NAD plus of 500 mg. I do take other vitamins as well like hyaluronic acid, multi collagen, and NAC. I also take pycnogenol because the reviews look good, and the human trials looked very promising. Any thoughts would be greatly appreciated, and I am only interested in your opinion in my research to make sure that I am giving myself the best possible chance for anti-aging and staying healthy Thank you kindly my friend.
Excellent… as always .. thank you.
Thanks @jp7357!
Please, keep on going man...finding a way to hit nad levels will help A LOT(Really a lot) of people.
Thanks
@roblim1767, there's no quit in my game!
Will it be impressive if I get to the 1000 mg/d NMN-induced NAD level (39um) with a low NA dose (60 - 150mg/d)? I think that's possible...
You are welcome!
@@conqueragingordietrying1797
That mentality is what we need!
I think low dose of NA is a believe of Mercola too, and it makes sense.
Milk thistle increased NAD a lot in the liver of rats, perhaps it is an indication of some good effect in humans.
Cinnamon leaves have a large amount of NMN, perhaps it is a more bioavailable form, there is no shortage of options for us to try. Let's get it on.
EPA and DHA require Lysophosphatidylcholine as a carrier to cross the blood brain barrier to be of any lasting use or benefit.
The goal was to impact blood intracellular NAD levels, that's a different story
Since you went through the De Nova NAD Synthesis Pathway, increasing individual parts of the pathway without any effect, is the only other hypothesis that you have to do some combination of supplementation to target multiple parts of the pathway at once? For example, there’s not a block or deficiency in one part of the pathway, but in multiple parts of the pathway? Or is there another plausible hypothesis?
Hey @MichaelSpivey, that's a definite possibility, but alternatively, if there are no blocks, tryptophan, on its own, either at 1 or 2g/d, should've made an impact on NAD, but it didn't
I think he said there are multiple blocks and you are just trying to fix only one with no result.
What happens if you try everything at once?
And then may be remove one by one to see which ones are essential…
Darnit! NOT the result I wanted. Try again!
Joking apart, kudos again for stating the result in the title, instead of ckickbaiting.👍
I do find that fish oil lowers my triglycerides
I didn't measure TGs on the same day, so I don't know if that's true for me
Better take astraxanthin and flaxseed oil or algea oil
i tried higher flax (see the video before this one in the NAD playlist), but that didn't impact NAD
Why would you expect astaxanthin to impact NAD?
Great video, have you tried niacinamide/nicotinamide to see if it has the same effect as niacin since it is non flushing. Dr Nichola Conlon includes it in her supplement to increase NAD?
Thanks @danprism, I haven't, because NAM raises homocysteine (which is already too high) more than NA. I'm currently on 60mg of supplemental NA, and there's no flush. I'm sending blood for NAD analysis tomorrow-we'll see if that dose can increase NAD (or not).
Then, the argument is to increase methyl donors (i.e. TMG, which didn't work for me), and I'm currently on B12 + choline. I think it's funny that Nichola's company is happy to recommend everyone buy her product, but they haven't partnered with a NAD testing company, which would probably be best for business (for everyone involved).
Maybe we are disappointed a little to early. Even if not raising NAD+ levels, the stimulation of QAPRT activity by any of the ways you tested could lead to lowering of toxic quinolinic acid which would be a benefit on its own.
Unfortunately, the iollo kit doesn't yet include quinolinate, so I agree!
Is there a video or page on the website where Michael’s whole protocol is described, such as what is his diet, exercise and supplement regime?
I can’t find a singular video which covers the basic protocol and I’ve checked his website which just seems to list the videos in chronological order
Hey @jamieclarke321, not yet. Going through the playlists can be helpful for that until then...
@@conqueragingordietrying1797 thanks Micheal, I look forward to hearing about your whole regime in the future! In the meantime I will watch more videos 👍
Did the extra fish oil affect any other markers that you tracked?
I sent blood for metabolomic analysis on that day, too, so we'll see
Nicotinic acid is bad for methylation
Does Krill oil take the same verdict as well?
Seems like a good plan - low dose nicotinic acid. btw I reckon that fish oil comes from salmon that is sold everywhere and the salmon are farmed in water tanks where they are fed with corn that has zero omega 3 so fish oil is also zero omega 3. Someone tell me I'm wrong....? I use algae generated omega 3 but it always contains vitamin E which I don't want and who knows if there is any DHA in it..
You've probably ruled this out in your previous steps but could it be that you're still too young for QAPRT to be sufficiently impacted through aging and so maybe your de novo pathway is already firing on all cylinders? Maybe the de novo pathway is just a back-up or auxilliary one and not meant to compete with the Salvage pathway in a younger individual (I consider you young because I'm older :) ). Sorry if that's a silly thing to say and you've already covered it. The NA/Priess-Handler pathway shares a couple of enzymatic steps with the Tryptophan/De Novo pathway so it will be interesting to see how that might figure into your results.
BTW, your channel is youtube at its best.
That's a definite possibility-I've ruled it out only because of many experiments aimed at its optimization , but without success!
It's not a backup pathway-tryptophan content in the diet is far greater than niacin (~1g of tryptophan/d vs 15 mg of niacin).
NA increases NAD, but possibly by too much (as we saw in the last video).
Thyroxine vid eagerly anticipated!
It's on the to-do list, later vs sooner unfortunately
Hmm.. I'm curious to know how nicotinic acid could have negatively impacted your DunedinPACE biomarkers.... Is it something that was a direct result of NA interfering with something? Was it its effect on blood glucose levels due to it's effects on glycemic control, possibly due to rebound effect? Was it due to an increase in CD38? or perhaps a build up of NAM in excess of NAMPT, thereby putting pressure on the clearance pathway, consuming methyl groups and raising homocysteine levels?... or was it just a coincidence and the cause was actually due to some outside variable such as a mild viral infection?
I ask because the cause matters. If it was a direct cause of NA interfering with something, perhaps that can be mediated, or perhaps it demonstrates that another form of B3 such as NR or NMN might be a better approach after all.
If it's a result of it's effect on blood glucose through a rebound effect, maybe that can be managed through breaking the dose up into multiple doses throughout the day, or through diet management, timing the intake of carbs and fats to coincide with stages in the cycle.
However, If it's due to CD38 levels, or increases in NAM levels and the impact on the clearance pathway, then this is going to be true of anything that raises NAD+ levels, be it NMN, NR, NA, or otherwise... This is since these effects are downstream of NAD+, either as a direct effect of elevated NAD+, or due to levels becoming elevated as NAD+ degrades.
Determining if it's one of these last ones is particularly important, as it may demonstrate that there are additional interventions that are necessary if you are raising NAD+ levels, and if these are not taken, then the raise in NAD ,ay be more harmful than helpful.
Personally I strongly suspect this last one, although the effect on blood glucose levels may also play a role. This is because NAM clearance chews through a lot of methyl groups, which if insufficient additional methyl groups are provided, would cause issues with the methylation of the epigenome, leading directly to a negative effect on your epigenetic clock that would show up in tests like dunedinpace.
just something to think about.
Glucose levels were within my normal range with NA, nothing crazy there like DunedinPACE. I'm not sure what the mechanism is, outside of NAD potentially being too high, which argues against an increase for CD38.
@@conqueragingordietrying1797 increasing NAD+ would increase CD38 levels as well as it is the largest consumer of NAD+. In fact it has been argued that one possible reason for declining NAD+ levels as we age may be an attempt by the body to lower CD38 levels... although plausible, I haven't personally seen a lot of evidence for this, not to say that the evidence doesn't exist though.
That said you can easily check for this, either directly or indirectly by looking at total inflammatory markers.
I do genuinely suspect that the culprit is elevated NAD+ leading to elevated NAM in excess of NAMPT levels as it degrades, depleting your stores of methyl groups.. It Is one of the main known concerns with raising NAD levels, as known to directly effect the epigenetic methylation patterns, effectively speeding up the epigenetic clock. Given that this lines up perfectly with your test result.. as they say, when the shoe fits...
This makes a lot of sense…can u plz trll us more about the mechanism? Is it because of the large amounts of reduced NADH?
@@conqueragingordietrying1797 There are studies showing nicotinic acid can raise ROS/hydrogen peroxide in addition to consuming methyl groups and that should also be considered as a mechanism. Glutathione seems to be the major molecule dealing with H2O2 and if this is the relevant mechanism Glutathione may be low. Perhaps iollo can shed some light.
@@Always-xl9db While the ratio of NADH to NAD+ is a reflection of the cellular redox state and is crucial for many cellular processes, and elevated ratios of NADH to NAD+ is correlated with a number of negative health outcomes, this is unlikely to be the cause as both the mechanism doesn't quite fit, and elevated NADH levels are usually more of an indicator of some other pathology rather than the cause of the pathology.
the mechanism most likely responsible is the normal consequences of the degradation of NAD...
While it is true that NAD has the ability to cycle between it's oxidized NAD+ state and it's reduced NADH state, over time and under various conditions, NAD eventually degrades. This typically happens due to consumption by Sirtuins, PARPs, or CD38/CD157. when used and degraded in these processes, NAD is converted it to nicotinamide (NAM) and various other metabolites. It's this build up of NAM that is then responsible for the consumption of methyl groups.
If NAM levels increase to levels greater than can be cleared by NAMPT via the salvage pathway, it begins to suppress the activity of Sirtuins and Parps and must be cleared. This is where the clearance pathway comes in.
An enzyme named nicotinamide N-methyltransferase (NNMT) uses SAMe to methylate NAM and clear it by converting it into 1-methylnicotinamide (MeNAM) which then undergoes further metabolism in the liver before being excreted via the kidneys.
As NNMT uses SAMe, this reduce the availability of SAMe for other methylation reactions, including DNA methylation, the mechanism by which the epigenetic clock works. This also drives up homocysteine levels as SAMe losses it's methyl group, which converts it to S-adenosylhomocysteine (SAH) and subsequently homocysteine
The epigenetic clock refers to specific methylation patterns on DNA that correlate with age. As an individual grows older, certain CpG sites (regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide) on the DNA gain or lose methyl groups. Changes in the availability or activity of molecules involved in the methylation process can disrupt these patterns, potentially accelerating the rate at which the epigenetic clock ticks.
hope that all makes sense.
Cheers!
Danke!
Do you think higher blood NAD translate to higher NAD in other parts of the body?
Thanks for your support, @livintnet!
@@livintnet That's tough to say, as we'd need liver and muscle biopsies, for example.
But, I've been sending blood for metabolomic analysis on the same day as NAD testing, which can help address that question.
❤my friend why you did not try nicotinamide to increase NAD+ ??
NAM raises homocysteine more than NA, so I've avoided NAM (for now) because homocysteine is currently a weak spot.
@@conqueragingordietrying1797 i think plasma homocystine levels can be decreased by folic acid+B12 supplementation
That should mix with NAM daily intake👍🏻
@conqueragingordietrying1797 also why you didn't use niacinamide instead of naicn
Niacinamide is one of the precursors to NAD+, and therefore, supplementation can increase levels.
You are assuming that the bio clocks are accurate. I remember other variables you talked such as grip strength, HRV, heart rate and especially Vo2 max (not sure if you did something on the subject) that are related to longevity. However none of these variables are in any clocks. If none of those variables are included in clocks, how can you be sure of the different strategies with supplements? Maybe we are still learning on the different pathways of our biology.
There's no published reason to think that the Horvath and DunedinPACE are inaccurate
Did you look at fish oil and other bio markers or just NAD?
I sent blood for iollo's metabolomic analysis on the same day, waiting on results...
would also been interesting to see the lowest dose possible that increases NAD without messing up liver enzymes, currently on 50mg daily NA pill plus some more from diet, I don't want to go higher if can help it for this reason, I also take the CD 38 inhibitor apigenin, I wonder if increasing NAD may up-regulate CD 38 for homeostatic reasons which would be counter productive, jury's still out if increasing feed stock or reducing breakdown is best way to keep NAD levels high or if both required.
Liver enzmes were 21 each on 600 mg supplemental niacin, so that's not an issue in my case
We'll see if ~50mg NA makes an impact on NAD within the next few weeks, tesing on Monday
The only way to know if apigenin and everything else is impacting NAD is to measure it
Inhibiting CD38 will certainly raise NAD. It will also help to feed any cancer cells that pop up and be real boost for a tumor. Not sure about that helping longevity.
The safest way to reduce CD38 is by inducing apoptosis to clear out defective cells. Or use a senolytic.
@@antonystringfellow5152 most evidence shows it suppresses tumor growth rather than enhances it> Pub Med Id: 30875872 (figure 4) although human trials are lacking either way.
Do you track heavy metals? I like sardines but I'm afraid of the heavy metal burden.
Not yet, but I might, sooner vs later. I've held off based on the assumption that heavy metal toxicity would show up in terms of other biomarkers, like elevated inflammation or reduced kidney function. No evidence for that, yet...
@@conqueragingordietrying1797 I asked because in an old Joe Rogan episode he said he had elevated mercury from daily sardines and it quickly resolved after he stopped eating them.
Edit: it was arsenic. czcams.com/video/qdTr7gI2WI0/video.htmlsi=doEV8SycMahxwIBq
Why not try and lower CD-38 to help raise NAD? You made a video about CD-38 getting in the way when trying to raise NAD. Apigenin for instance.
Also I wonder, could your relatively high epigenetic age be linked to your low NAD? IIRC, in one of the charts you presented in a previous video NAD is involved in making AKG, which demetylates the DNA.
Hey @Battery-kf4vu, I'm already averaging 100 mg/d apigenin from fresh parsley, so it might not be a CD38 issue, unless that's not enough. I am considering supplementing with it, though, but won't until I see how 60 and possibly 100 mg of NA impact NAD.
I think you mean Horvath age? I don't have enough data for correlations with NAD yet, but that's on the to-do list.
AKG doesn't make NAD but helps with NAD/NADH balance. Only the NAD precursors, NR, NMN, NAM, NA, and tryptophan can increase the NAD pool, in contrast.
@@conqueragingordietrying1797 I take liposomal apigenin, perhaps it helps the NAD level I don't know.
Regarding AKG, I meant to say that NAD may help to make AKG in the Krebs cycle.
In the Krebs cycle, NAD converts isocitrate to oxalosuccinate. It is one step before the creation of AKG from oxalosuccinate. So NAD might indirectly increase AKG.
With CD38 you need to understand underlying cause for its increase as we age…. if you restore immune system, suppress viral and cancerous load - it will lower naturally…and for his age and health status it’s probably not a big factor regardless, for NAD decline
Another experiment, would NMN increase your Dunedin-Pace score? To me NMN increase NAD more than Nicotinamide, of the approx same amount (mmol), so perhaps it is more efficient.
1000 mg/d increased NAD to 39uM but DunedinPACE didn't go crazy (0.79), which suggests ~40uM as the upper limit (for me) for DunedinPACE. That's the goal with low-dose NA
@@conqueragingordietrying1797 I suspect that is due to absorption and transport issues with NMN... although the conversion pathway is more efficient than NA, there are definitely some issues with NMN absorption when taken orally. NA on the other hand is EXTREAMLY effectively absorbed. There is debate regarding how significant this is, and weather or not the additional conversion efficiency is enough to compensate for the reduced absorption, but based on your results, I'd venture to guess that NA is the more effective of the two at raising NAD levels for a giving oral dose.
I STRONGLY suspect that if you took enough NMN to raise you NAD levels to the same level as you did with your NA trial, you would likely see the same effect on your Dunedin score.
That said, it would be interesting to see what would happen if you raised your NAD levels to the same level as you did with your NA trial using a higher dose of NMN, and seeing if this has the same effect on your Dunedin score.... seems like it would be a quick way to determine if the score results were an effect of elevated NAD levels, or were specifically caused by the high NA intake levels independent of the effect on NAD levels.
What's about nicotinic acid vs. nicotinamide? Both are forms of niacin, but do they work through different pathways to increase NAD?
My homocysteine is already on the higher side, and NAM increases it more than NA, so I'm hesitant to use NAM, for now
@@conqueragingordietrying1797 rightfully so, your negative dunedin score is likely a result of NAM levels increasing as NAD degrades, putting pressure on the salvage pathway and chewing through a ton of methyl groups. That can do all sorts of damage to your epigenome.
How much is your homocysteine right now, if you don’t mind me asking?
I myself had considered high doses of NA for increasing NAD+.
But its effect on the blood fats seems to me being detrimental.
Chris Masterjohn, has talked about it, and how to possibly avoid its detrimental effect.
Nicolas Verhoeven on Physionic, has described how it does very clearly.
So I'm now trying NMN, currently at 2 weeks, and no noticeable effect, except on hair color. I should meassure the blood levels, but so far I don't.
There's much hype, but little research, about NMN.
But NR, and probably NMN too, has an effect of hair color. A beginning thin spot at the crown of the head seems to gone missing too. So, at least it does something!
Since it's a special kind of stem cells at the roots of the hair which gives color to the hair, it would be interesting to find out if NR and NMN has any effect on other stem cells too.
Hair color in two weeks?
NMN causes a higher ratio of NADH to NAD+ which is disastrous and can cause cancer. Be careful.
@@rredding ditto, also interested in this observation.
You reduced greying with NMN, and possibly increased thickness, is that what you're saying? And noticeably within two weeks? Do you have hairs that are darker at the roots, and white at the tips?