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I’ve wanted to talk about SIRT1/NAD+ for a while, but I finally was forced to during the CIRS/mold post.

Given that most of the modern ailments have NAD+/SIRT1 disturbances as a root cause, this deserves its own post.

What is SIRT1?

SIRT1 is a protein or vehicle that requires NAD+ to function.  SIRT1 take acetyl groups off of proteins.  So SIRT1 is kind of like the gun and NAD+ is like the bullet.  You need both to work effectively.

The Importance of SIRT1


SIRT enzymes “turn off” certain genes that promote aging, such as those involved in inflammation, in fat synthesis and storage, and in blood sugar management (R).

When proteins are undergoing stress, acetyl groups are added to proteins as a response to changes induced by inflammation and oxidation.

Sirtuins (like SIRT1) remove these acetyl groups to keep the protein in service longer than usual, while simultaneously stabilizing the charge state of the carbon backbone in protein to resist any further changes in their shape. This allows your cellular proteins to live longer and you can save energy on other processes.

Excessive blue light is capable of loosening cytochrome c from the mitochondria, which makes the electron flow less efficient. Red light causes tight binding to remain to cytochrome c in mitochondria and this allows electrons to continue to flow normally to oxygen, which lowers free radical production per oxygen molecule.

SIRT1 powerfully reverses leptin resistance (R).

SIRT1 (and PGC-1a) also make you more sensitive to T3 (R), which is also a problem in CFS – indicated by the fact that people feel cold and have symptoms of low T3 (symptoms that are worse than their numbers reveal).

SIRT1 increases estrogen function (estrogen receptor signaling) (R),

Resveratrol and SIRT1 make you more sensitive to vitamin D – it potentiates the vitamin D receptor (VDR) (R, R2).

SIRT1 inhibits IGF-1 (R).

SIRT1 inhibits mTOR (R).

SIRT1 protects you from nitric oxide.  Nitric oxide is damaging but it can also be good.  When you have good SIRT1 levels and activity, nitric oxide will stimulate DNA repair genes (via deacetylation of FoxO1).  Otherwise, nitric oxide will stimulate genes that will cause the cell to self-destruct (R).

SIRT1 probably overall increases adiponectin release from fat cells.  (It decreases adiponectin by decreasing PPAR gamma in these cells (R), however, it increases adiponectin by increasing Foxo1 (R, R2, R3).)

How Sirt1 Affects Age-Related Physiology, source:

How Sirt1 Affects Age-Related Physiology, source:

A reduction in SIRT 1 and SIRT 3 enzymes lead to:

  • Neurodegeneration in the brain,
  • Vascular inflammation, producing damage to blood vessels that can result in stroke or heart attack,
  • Increased fat storage in the liver, which can lead to fatty liver disease (NAFLD),
  • Increased fat production and deposition in white adipose tissue, the primary fat storage form found in dangerous belly fat,
  • Insulin resistance, preventing cells from appropriately removing glucose from blood, producing higher blood sugar levels and leading directly to metabolic syndrome,
  • Fatigue, loss of muscle strength, and fatty infiltration of muscles resulting in reduced fatty acid oxidation (“burning”), thereby depriving muscles of their normal sources of energy.


SIRT1 causes the activation (by deacetylation) PPAR-alpha, PGC-1a, LXR (R), MAO-A, FOXOs -FOXO1a,Foxo3 (R), UCP2FGF-21 (R), PXR (overall increase production/activity) (R, R2).  FXR (deacetylation allows to bind with RXR-a, DNA binding, and transactivation activity) (R) – can also inhibit FXR (R)…

Deacetylation of Androgen Receptors and Estrogen Receptor-a by SIRT1 causes these hormones to have less cancer growth properties (R).

SIRT1 deacetylates and inhibits NF-kB, STAT3, and MMP9 (R). SIRT1 deacetylation degrades PER2 (R).

SIRT1 Deacetylates the following other proteins not listed: Hif-1α, Hif-2a, HSF1, Bax, Ku70, b-catenin, E2F1, Myc, TORC2, SREBP, PER2, CLOCK (R).

Pasted Graphic 10

SIRT1 and The Circadian Rhythm

Chang and Guarente GA

Not taking care of your circadian rhythm properly is also a root cause of chronic health issues because your circadian rhythm gets deregulated (mainly by not enough sun in the day and too much artificial lighting at night).

The enzyme that makes NAD+ (NAMPT) is under circadian control (R) and is produced by CLOCK and BMAL1 (R).

When your circadian rhythm isn’t working, NAD+ levels are not regulated properly and that means SIRT1 (and SIRT3) isn’t either regulated properly since NAD+ is needed to activate SIRT1&3.

SIRT1 regulates the strength (amplitude) and the duration of circadian gene expression in the retina by removing acetyl groups from key circadian clock regulators, such as BMAL1 and PER2.

In aged mice, SIRT1 levels in the SCN (circadian command center) are decreased, as are those of BMAL1 and PER2, causing a longer circadian period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 have similar effects to these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging (R).

We start getting to feedback loops, where not taking care of your circadian rhythm, hypoxia, excess carbs and energy imbalance go on to cause an even more deregulated system and you get lower levels of SIRT1.

This is why ALL CFS sufferers that I’ve seen have a messed up circadian rhythm/SCN.

Negatives of SIRT1

The way to look at these negatives is:

  1. Most of the time, biology deals with tradeoffs.
  2.  SIRT1 effects are tissue dependent.  So even though SIRT1 level might correlate in one tissue to another, the levels are different.
  3. The cellular environment matters.  If SIRT1 is high AND you have certain other genes switched on, then SIRT1 will matter.  Otherwise, it won’t.  I see this with many other pathways.
  4. SIRT1 is supposed to be cycled in a circadian manner.  Chronically high levels could produce a different effect.

Recent studies show that SIRT1 can increase Th17 cells (by deacetylating RORγt), which are inflammatory.  Inhibition of SIRT1 suppresses multiple sclerosis (R).

SIRT1 increased the cytokine TNF (in response to LPS), IL-6 and IL-8 in the tissue of patients with rheumatoid arthritis (R).

SIRT1 decreases Nrf2-related gene production since acetylation allows Nrf2 to bind to DNA better and produce antioxidant genes (R).

SIRT1 decreases beta cell proliferation in the pancreas (GLP-1 blocks SIRT1 deacetylation of FoxO1) (R).  Beta cells release insulin, so reduced beta cells can contribute to diabetes, but SIRT1 has many other anti-diabetic actions.

SIRT1 inhibition with nicotinamide is being investigated as an anti-tumor agent because SIRT1 promotes cell survival over apoptosis, which can increase cancer in some ways and also block the ability of chemotherapy to kill cancer (R).

SIRT1 can contribute to cancer by inhibiting DNA repair enzymes (including p53, BRCA1&2, Ku70) and the apoptosis proteins (R).

Specifically, SIRT1 deacetylates p53, which decreases its ability to function as an anti-tumor protein (R).

Since SIRT1 lowers IGF-1 and its receptors, it can cause some downsides to less IGF-1, including less neuroprotection and more likely for your neurons to die (R).

SIRT1 overproduction can impair liver regeneration to a degree (R).

More SIRT1 in CD4+ cells increases Lupus risk (R, R2)

How to Increase SIRT1

Anything that increases NAD+, will increase SIRT1 activity.  So I won’t list the ones listed above.


According to Kruse, SIRT1 and NAD+ provide that fine control through the special properties of DHA.

Increasing DHA is the best way to increase SIRT1 (R) because it works together with it to modulate the immune system and improve your mitochondria.

DHA increases SIRT1 in the blood vessels, which increase Nitric Oxide (eNOS) (R).

DHA decreases macrophage inflammation and inhibits Nf-kB via increasing SIRT1 in macrophages (DHA decreases inflammation via other mechanisms as well) (R). DHA decreases COX-2 inflammation and insulin resistance also through SIRT1 (in colon cells) (R).

DHA increases SIRT1 in the hippocampus and reverses cognitive decline in a bunch of disease states.  Several epidemiological studies have shown that low blood DHA levels are associated with cognitive deficits in healthy elderly subjects and also in patients suffering from neurodegenerative disorders. Additionally, DHA enhances performance in learning and memory tasks in aged animals, and it also improves cerebral blood flow (which is lacking in CFS sufferers) (R).

DHA supplementation is effective in reversing the reduction of sirt1 levels in rats with mild traumatic brain injury (R).

Ideally, you want to get DHA from fish, but supplements are certainly better than nothing. I use them a little in addition to a lot of seafood.

Cyclic AMP and SIRT1


Cold, forskolin and adrenaline increase SIRT1 activity by increasing cyclic AMP and this is independent of NAD+ levels (RR2).

We evolved to have this as a more rapid way to activate metabolism than by slowly increasing NAD+ levels.  There are many other benefits to these as well.

Top Ways to increase SIRT1:




  • Fish/DHA (R)
  • Fructose – In liver, fructose increased SIRT1 production and activity (R)
  • Extra Virgin Olive Oil (R)



  • Metformin – increases SIRT1 production and activity (R)


How to Increase NAD+, Which Increases SIRT1 Activity

SIRT1 Inhibitors

SIRT1 23andme Genes

SelfDecode is the best gene analyzer around and helps you interpret your genetics from 23andme and ancestry

Order your 23andme to see what alleles you have.

About 80% of the global population has “TT”, while 18% have CT…11% of the alleles are C.

It’s thought that the C allele causes increased gene production of SIRT1 (R).

People with the C allele have an almost 30% reduced risk of dying during an 18-year follow-up study in the general population (RR2).

TT was at a higher risk for diabetes (R).

People with a C allele had better glucose tolerance indicated by 0.34 mmol/l lower glucose levels (R).  Obese people with the C allele especially had better glucose tolerance (R).

Further Reading:

These are some comprehensive articles about SIRT1:

Health Tools I Wish I Had When I Was Sick

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That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
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  • Matthew

    Fantastic article Joe 🙂

    As someone who deals with such issues, I would like to emphasise the point that SIRT1 activation upregulates the MAO-A enzyme in the brain. MAO-A is critical in the breakdown of monoamines, such as serotonin, dopamine and histamine. Therefore, natural SIRT1 activators, as listed here, may well prove neurologically beneficial for those dealing with excess levels of monoamines.

  • Michelle Madsen

    Joe, two questions, do you believe in NAD supplements like Niagen (oral availability)? Second this observation, I have 3 times taken Niagen by itself…wicked headache which lasted 2 days each time – adequate break between trials for washout so I am certain. BUT I had previously taken Elysium Basis product, with is NR + the Pterostilbene component, no headache. I also routinely get a headache from Phosphatidylserine also, which is also a multi-day recovery event. any thoughts?

  • Phil Alcoceli

    The problem with Niagen being short lived on the duration of its effects is solved by Life Extensions’ “Optimized NAD+ Cell Regenerator with Resveratrol”. If you want even better effects combine it with their “Liver Efficiency” supplement which increases SOD. Take one of each once a day away from food. Best of health to you!

  • Albert Radulescu

    I study medical nutrition in London and this website is gold, amazing !!!

  • th
  • David Bathalovski

    I took H2 tablets with Niagen powder, oh my goodness. I can walk, talk, and have become a BRAND again. Saved my life after I took Cipro which lead to an explosion in my mercury levels. I was Cipro toxic and metal toxic. I am back. My brain is back.

  • john seville

    In reading Vince Giuliano’s blog, his experience and observation in using NR or any other means of increasing NAD+ is transient at best, lasting only 2 weeks for him and apparently this also appears common to many reviews on sites such as Amazon from users of Niagen etc. As a user yourself of these compounds what is your opinion and any methods you believe would allow someone to continue to reap the rewards of increased NAD+ past an iniitial surge. Thanks in advance!

  • Leo

    Main differences in Nicotinamide vs Nicotinamide riboside? One suppresses SIRT1 at high dosage and the other one doesn’t?

    1. Joseph M. Cohen

      Yup, nicotinamide suppresses

  • Dylan

    Do you think taking leptin mimicing agents (stimulants/bromocriptine etc.) would nullify the modulatory effect eating/fasting has on NAD+?

  • ky
    Still not sure of association between sirt1 expression and hif-1,2 expression.
    Perhaps, because the relationship does not specify the concentration of oxygens.
    See this study.
    It somewhat mentions about how nrf2 responds to the oxygen insufficiency.
    Also, we have known that mTor signalling depends on hypoxic condtion and exposure time.
    You can see DAF-2 related genes modulate the lifespans of C. elegan (
    And, this seems to be related to stress response pathways with oxygen availability.
    Of course, hypoxic response can be bad in moderate to severe situation, and I don’t think that low oxygen level is good in a common sense. However, it is suggested to mention about the dose(oxygen saturation) given in experiments to better understand hormetic shape.

    1. Joseph M. Cohen


      1. ky

        Hi, I look through the detail of above mentioned paper to figure out relation between sirt1 and hif, and found out there is not clear mechanism of co-relation, yet too complex.
        You mentioned about ratio of NAD+/NADH, but it is not the only factor to influence the level of sirt1 expression.
        “Although most hypoxia/pyridine nucleotide studies examined total NAD+ or NADH levels rather than free NAD+ or NADH levels or ratios, which are the relevant molecular species for NAD+/NADH-regulated enzymes such as Sirt1, it is nevertheless unlikely that a major change in direction of the cellular redox state during hypoxia would occur if free NAD+/free NADH ratios were calculated. Therefore, an alternative mechanism for activation of Sirt1 during hypoxia, besides changes in redox state and pyridine nucleotide levels/ratios, must exist” (, Rui C, Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner)
        Author mentions some possible pathways to explain mechanisms, but it is still unclear.
        I am not sure if this study extends to normal cell lines. (The study was performed in carcinoma cell lines, which have telomerase activities while most normal cells do not have).
        Do you know any papers regarding how sirt1 and hypoxic are related in normall cells?

      2. ky

        I also found p53(tumor supressor, senescence inducer) level is decreased in mild hypoxia while increase in severe hypoxia. But, these studies was also performed in carcinoma cell lines. Can it be applied to normal cells?

  • Dan

    Hi my names is Dan. I have found your info very helpful. I have been taking a product with Niagen in it at 250 mgs per serving. At first I felt great then after a few weeks I feel a little depressed. Not sure if it is too much dopamine being produced which can cause depression. Have you heard anyone relay this specific side effect?. I also take prelox, curcumin, PS, Feel a little shaky too. Maybe too much other neurotransmitters being produced. Will cut back on dose. I have CFS and a therapy called LENS therapy has made an enormous difference and I believe it will soon cure me. I have had CFS for 30 years and nothing has made such a difference with measurable and steady improvement. Helps to dis-entrain a stress pattern in your brain which causes slow EEG wave patterns that causes your central nervous system to go awry. Chronic or unrelenting stress either emotional ,physical or due to illness is usually how most people with CFS first become ill. I know this is how I first became ill. Check it out and look into it more. I will keep you posted on my future progress.

    1. Joseph M. Cohen

      Depression isn’t from Niagen…

    2. brycemfsellers

      Hi dan can u give us an update on how ur doing with lens therapy? i also did lens neurofeedback and found it very helpful!

    3. Tara

      Hi Dan,
      You should look into IV NAD therapy. I know The NAD Treatment Center in San Diego has treated patients before with CFS with great success. Wish you the best of luck!

  • Kyle

    Have you ever thought of having Steve Fowkes on for an interview. He seems to be incredibly knowledgable about supplements and chemistry. He also seems to be very willing to help people out.

    He gets into NADH in this article and states:”The natural production of NADH (in the absence of alcohol) depends on lipoic acid, thiamine and riboflavin. Since lipoic acid and thiamine contain sulfur which may become bound to acetaldehyde, I wonder whether the use of alcohol compromises the very energy pathways it stimulates.” What are your thoughts on this?

    1. Joseph M. Cohen

      I interviewed him a few months ago. Will publish.

    2. Tara

      I know alcohol seriously impedes NAD recycling and production because it uses up a tremendous amount of NAD+ to metabolize ethanol. In fact, chronic alcohol use inhibits SIRT3, or maybe SIRT1, and enhances PARP1- which can signal cell death.

  • locosoroso

    thoughts on NAD+ IV Therapy?

    Just looking at the testimonial videos, people have had miraculous results. It is rather expensive at @ 10k however.

    1. Joseph M. Cohen

      Niagen gets absorbed well

  • Ole

    Forskolin does not raise cAMP in useful ways if it even does it at all consistently.

    1. Joseph M. Cohen

      Did you read your article?

      “The amount of forskolin generally talked about is too little to cause a significant elevation in brain cAMP levels

      6.25mg/kg forskolin subcutaneously increases cAMP levels about 33% in rat brains,[6] the human equivalent dose would be about 1mg/kg or 70mg for a 155lb individual. But unlike the typical forskolin+artichoke preparation, this forskolin was injected. 4mg orally isn’t anywhere near enough.”

      The pill I recommend is 95mg forskolin. You should start feeling the effects by 10mg.

      1. Ole

        Ah, makes sense. I looked at your iHerb recommended one which has 25mg since amazon doesn’t ship worldwide on nearly all products.

        I still think its a little inconclusive to say it does something when studies are done by injection on rats in doses that we probably dont know what would equal to oral in humans.

        How does it feel by the way? Most supps you recommend i have no clue what to look for in terms of effects.

        1. Joseph M. Cohen

          Nothing in my site is conclusive.

  • Jiri

    Joe, does molecular hydrogen increase NAD+/NADH ratio? As NAD+ is hydrogen acceptor, in process of glycolysis, its reduced form NADH2 “donates” 2H+ together with 2e- to the electron transport chain. NAD then becomes available to accept more hydrogens and continues the process of regeneration of NAD. So what about the ratio? Thanks a lot!

    1. Joseph M. Cohen

      Don’t know, good question.

  • Kyle

    sounds like the wim hoff method would be great for sirt1 and nadh.

  • wut

    Ive used NAD+ in the ranges 100-600mg on and off with meals and never felt anything until one day a few weeks ago i did 200mg with brain octane on empty stomach (ive never felt energy just mental clarity from brain octane so it didnt contribute i think) and i just had extreme energy and dramatic lack of social anxiety for hours upon hours. I couldnt sit still and i kept like having euphoric feelings from random radio music tapping my fingers to the beat etc. All unlike me. I did not consume any other supps and i had my usual meal earlier in the day.

    I have not been able to do this again with 200mg NAD+, higher dose doesnt do anything either. Why would this occur?

    Same thing with curcumin (longvida), rare use gives me euphoria and energy but daily use or frequent use does nothing. Best results was with 400mg and ive taken 2,5g at once with no noticeable effects several times.

    Im very anti placebo (give me MDMA and ill deny it does anything until it kicks in) so i didnt experience placebo effects.

    1. Tara

      Oral NAD is poorly absorbed, which might be the reason you didn’t feel anything. IV NAD therapy has the best absorption rate of NAD into the cells because you are able to get higher concentrations into the blood stream than oral supplementation.

      Are you looking to boost NAD levels for bio-hacking, or for a chronic condition?

  • Donna

    Thanks Joe! Brilliantly written and very helpful!

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