Apigenin: An Alternative Way of Boosting NAD+

    At the recent Ending Age-Related Diseases 2021 online conference, Dr. Eric Verdin of the Buck Institute gave a talk in which he described the mechanism behind the well-known drop in NAD+ with age, for which lots of anti-aging folks are spending significant $ taking NR or NMN, with very limited results in humans.  Verdin attributed the NAD+ loss to a rise with age of an enzyme called CD38, which destroys the NAD+, removing it from the normal cycle.  It turns out that the readily available flavonoid Apignin is an inhibitor of CD38.

    Therefore, there is leak in the NAD+ bucket.  Instead of loading up with NAD+ precursors like NR and NMN that don't really fix the leak, I suggest talking a daily dose of Apigenin.  Swanson sells 90 x 50 mg Apigenin capsules for $8.76, (or you can just eat a lot of parsley.)

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  • One step further they found last year 

    "Here, we show that pro-inflammatory M1-like macrophages accumulate in visceral white adipose tissue and liver. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels.

    We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells induce the macrophages to proliferate and express CD38

    https://pubmed.ncbi.nlm.nih.gov/33199924/

    So if you kill off the senescent cells in your fat and liver it should help lower cd38 and boost NAD too.

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  •     Yes, Verdin made the point that senescent cells produce CD38 as a part of SASP.

        One other point: apparently Resveratrol    2 enhances the anti-CD38 effects of Apigenin.

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    • JGC Yeah, I imagine he should know since Dr verdin is one of the authors of the study I posted talking about.

      Did he recommend senolytics or apigenin as the solution?

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    • Fred Cloud JGC

      When Apigenin is Co-administrated with resveratrol the  plasmalevel of Apigenin  increase 2,39 fold. (at least in mice).

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663613/

       

      The amount that is absorbed is very low so there is a real need for methods that enhances absorption even more. 

      https://pubmed.ncbi.nlm.nih.gov/16407641/

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      • JGC
      • JGC
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      Fred Cloud 

          Dr. Verdin did mention senolytics as a suppressor of CD38, but it isn't clear if accumulation of senescent cells is the only reason that CD38 increases with age.  He did not specifically mention Apigenin, but he pointed out that there are chemical suppressors of CD38.  (I note that Apigenin is only one of the CD38 suppressors, but most of the alternatives are unavailable or are prescription only.) 

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      • JGC
      • JGC
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      Staffan Olsson 

          All flavonoids have bioavailability problems because they are not very soluble in water and are broken down by digestion before they can be absorbed.  Perhaps Life Extension can be persuaded to apply to Apigenin their technique for shielding flavonoids from being quickly broken down by coating micro-particles with galactomannan fibers from fenugreek seeds,  LE already applies the technique to Curcumin, Fisetin, and Quercetin, and they claim increases in bioavailability of up to x80.

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    • JGC I wonder if piperine can have any effect on the absorption of Apigenin. I have not found any research at all about piperine and apigenin. 

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      • JGC
      • JGC
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      Staffan Olsson 

          I think piperine enhancement should work for Apigenin, since it suppresses digestive enzymes that break down flavonoids.

          I found a paper that makes this statement about its bioavailabiliy: "Apigenin taken orally is systemically absorbed and recirculated by enterohepatic and local intestinal pathways. Its bioavailability is in the region of 30%. Once absorbed from the oral route it reaches maximal circulating concentration (Cmax) after a time (Tmax) of 0.5–2.5h, with an elimination half-life (T1/2) averaging 2.52 ± 0.56h."

          However, they go on to estimate the daily human dose that would be required to treat certain types of cancer by using Apigenin to upregulate CD36, and they conclude that a dose of about 4.2 grams would be needed.  That's a much larger dose than is provided by a 50 mg Swanson capsule.  It is not clear if suppressing CD38 would require the same dose level as upregulating CD36.

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    • JGC It looks like there are apigenin nano-formulations in use in medical research. (The last two sections in this paper from 2021 mentions a few.) 

       

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017783/

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  • @JGC  Are you taking Apigenin and if so, what dose?

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      • JGC
      • JGC
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      Kaptain Asia 

          I take 50 mg/day, i.e, one capsule of Apigenin.  However, that's just the Swanson "serving size".  There's no data that I know of on how much Apigenin it takes to effectively suppress CD38.  I note that I also take 100 mg/day of Life Extension's Resveratrol in the trans- form, which should help (see above).

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    •   JGC Have you considered taking both the NMN  along with the apigenin? Should give you great synergy. People do respond to NMN so it cant be completely useless by itself, but it certainly would help to prevent the body from wasting it. I am in an NMN group and people take 1,000 NMN everyday, I wonder how much of that is getting wasted by cd38? Perhaps you would only need half the dose or perhaps less, who knows. I guess you would have to experiment and see how you feel.

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      • JGC
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      Fred Cloud 

          NMN and Apigenin are certainly not mutually exclusive.  In fact, taking both is probably a good idea.  I just wish there was a good way of monitoring the NAD+ level, so we were not flying blind.

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    • @JGC  yeah, well there are tests you can take to measure your levels, but if you can feel a boost or notice some effect at a certain doseage of NMN you should be able to compare and dial it in.

      https://www.longevity.technology/jinfiniti-testing-your-nad-levels-at-home-and-beyond/

      https://alivebyscience.com/product/ic-nad-test/

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  • Apigenin is already pretty cheap but it can also be purchased in bulk from Liftmode. They are suggesting 250mg per serving, up to 3 times per day for its calming effect. They state:  "In terms of general dosing, studies have shown Apigenin is most effective and safe in doses ranging from 200 mg to 1500 mg." They do note that possible toxicity has been show in mice at dosage of 100mg/kg. My plan is to take a daily 50mg/day capsule along with 50mg resveratrol and 5mg Bioperine. 

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  • Niacin as primary NAD booster? 

     

    https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30190-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS155041312030190X%3Fshowall%3Dtrue

     

    When I read this I think it might be a relevant strategy to focus in on niacin and apigenin as primary supplements to boost NAD levels. The resaerch is done on human patients with mitochondrial myopathies. It does not mean that we automatically can translate the results to humans without this condition. But there might be something in this approach. I remember that Nuchidos main product (time) to boost NAD levels use B3 and Apigenin:

     

    "Highlights

    -          Mitochondrial myopathy patients have NAD+ deficiency in muscle and blood

    -          Niacin is an efficient NAD+ booster in humans

    -          Niacin improves muscle strength and fatty liver in mitochondrial myopathy

    -          boosts muscle mitochondrial biogenesis and respiratory chain activity in humans

     

    Summary

    NAD+ is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD+ depletion occurs in patients with degenerative disorders and whether NAD+ repletion improves their symptoms has remained open. Here, we report systemic NAD+ deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD+-booster niacin, a vitamin B3 form (to 750–1,000 mg/day; clinicaltrials.gov NCT03973203) for patients and their matched controls for 10 or 4 months, respectively. Blood NAD+ increased in all subjects, up to 8-fold, and muscle NAD+ of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%. Our evidence indicates that blood analysis is useful in identifying NAD+ deficiency and points niacin to be an efficient NAD+ booster for treating mitochondrial myopathy.

    Context and Significance

    NAD+ is a molecule with important roles in regulating metabolism in our tissues. Its roles in the context of longevity, aging, and disease are under intense investigation, so far mainly in model organisms. However, the relevance of NAD+ levels for human disease progression has remained elusive. Here, researchers at the University of Helsinki report that mitochondrial muscle disease leads to low NAD+ levels in both blood and muscle. Importantly, they show that treatment with niacin, a vitamin B3 form and an NAD+ precursor, improves NAD+ levels, disease signs, and muscle metabolism in patients, also improving muscle strength and performance. These results indicate that NAD+ depletion occurs in human diseases, and its repletion is a potential therapy for mitochondrial myopathies."

     

     

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    • Staffan Olsson "In the healthy subjects, niacin did not increase muscle NAD+, despite the 5-fold increase in the blood. These results suggest that in healthy muscle the NAD+ amounts are close to the homeostatic maximum."

       

      It might be easy to increase levels of NAD+ in the blood of healthy subjects. But the increased levels of NAD+ in blood did not lead to increased levels in the target tissue (in this case the intracellular levels of NAD+ in muscle cells). 

       

      My question is:

      Will increased levels of NAD+ in the blood of ageing persons have meaningful effects in the ageing cells in the rest of the body? I wonder if anybody have knowledge of reasearch showing if/how increased blood levels of NAD+ affects different cells in the ageing human body?

       

      As they say in this paper. Therapeutic potential of boosting NAD+ in aging and age-related diseases - ScienceDirect 

      ..."what levels of NAD+ are to be associated with healthy aging and age-related diseases? In particular, it is of great relevance to elucidate organ and sub-cellular localisation as well levels of NAD+ in health and disease."...

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    • Staffan Olsson I just inject NAD+ directly that way you know for sure you are getting it.

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    • Fred Cloud But how do we know that NAD+ actually enters the human liver, muscles, brain, kidney etc?

       

      In other words how do we know that injected NAD+ can circulate in the body to be absorbed in different targettissues and where it can intervene in human cells so they are rejuvenated?

      After I posted my thoughts here, Brenner was kind enough to answere me in another media and he said in very short words that we are assuming (based on the results from animal studies) that oral NAD+ can reach target tissues. I quote ..."the expectation from mice is that liver NAD expands, heart NAD is corrected to normal if it’s down & many or all tissues increase NAD-dependent processes in response to oral NR — good question"

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    • Staffan Olsson So does that mean it raised it in mice therefore it is expected to raise it in humans, yet you are uncertain if it is does in humans?

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    • Fred Cloud Sinclair have used CD38 knockout mice. I think that is a good strategy to use. In other words inhibiting Cd38 in the cells. 

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  • My question from the beginning was:  how do we know that increased NAD+ in the blood will cause increased NAD+ levels in the target cells in the healthy ageing human body. Now I know that we act on the results from mice. 

     

    The paper I posted a Link to was a human study (Brenner was one of the contributers) they found that increased levels of NAD+ in the blood of Patients with severly low NAD+ in their muscles had a normalizing effect on the levels of NAD+ in the patients muscles. 

     

    But in the healthy controls with normal levels of NAD+ in their muscles already from the beginning,  even a dramatically increased level of NAD+ in the blood did nothing to increase the NAD+ levels in the muscle cells.

    This result made me curious about how effective an intervention with increased NAD+ in blood actually is? And I asked myself uf we have human studies that show total body rejuvination after boosting NAD+ in the blood?

    So will increased NAD+ in the blood of healthy persons with normal NAD+ Levels be a rejuvenating intervention? Now I know ( from Brenner) that, based on results from mice, we assume it does. 

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