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All About SIRT1: Activators, Inhibitors, Genes

Written by Joe Cohen, BS | Reviewed by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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I’ve wanted to write a post about SIRT1/NAD+ for a while – and the recent release of our post on CIRS/mold is the perfect occasion to finally write it up.

Given that many modern ailments have NAD+/SIRT1 disturbances as a root cause, this important topic certainly deserves its own post!

What is SIRT1?

SIRT1 is a protein that removes acetyl groups from other proteins – and it requires NAD+ to function.

So SIRT1 is kind of like the car and NAD+ is like the gas – you need both of them together in order for them to work effectively.

The Importance of SIRT1

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

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 [1].

SIRT1 (and PGC-1a) also make you more sensitive to T3 [2], 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) [3].

Resveratrol and SIRT1 make you more sensitive to vitamin D – it potentiates the vitamin D receptor (VDR) [4, 5].

SIRT1 inhibits IGF-1 [6].

SIRT1 inhibits mTOR [7].

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 [8].

SIRT1 probably overall increases adiponectin release from fat cells. It decreases adiponectin by decreasing PPAR gamma in these cells [9], however, it increases adiponectin by increasing Foxo1 [10, 11, 12].

A reduction in SIRT 1 and SIRT 3 enzymes leads 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 the 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.

Molecular Pathways Activated by SIRT1:

SIRT1 causes the activation (by deacetylation) PPAR-alpha, PGC-1a, LXR [13], MAO-A, FOXOs – FOXO1a, Foxo3 [14], UCP2, FGF-21 [15], PXR (overall increase production/activity) [16, 17]. FXR (deacetylation allows to bind with RXR-a, DNA binding, and transactivation activity) [18] – can also inhibit FXR [19].

Deacetylation of Androgen Receptors and Estrogen Receptor-a by SIRT1 causes these hormones to have less cancer growth properties [20].

SIRT1 deacetylates and inhibits NF-kB, STAT3, and MMP9 [21]. SIRT1 deacetylation degrades PER2 [22].

SIRT1 Deacetylates the following other proteins not listed: Hif-1α, Hif-2a, HSF1, Bax, Ku70, b-catenin, E2F1, Myc, TORC2, SREBP, PER2, CLOCK [23].

SIRT1 and The Circadian Rhythm

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 [24] and is produced by CLOCK and BMAL1.

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 (25).

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 levels may 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 [26].

SIRT1 increased the cytokine TNF (in response to LPS), IL-6 and IL-8 in the tissue of patients with rheumatoid arthritis [27].

SIRT1 decreases Nrf2-related gene production since acetylation allows Nrf2 to bind to DNA better and produce antioxidant genes [28].

SIRT1 decreases beta cell proliferation in the pancreas (GLP-1 blocks SIRT1 deacetylation of FoxO1) [29]. 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 [30].

SIRT1 can contribute to cancer by inhibiting DNA repair enzymes (including p53, BRCA1&2, Ku70) and the apoptosis proteins [31].

Specifically, SIRT1 deacetylates p53, which decreases its ability to function as an anti-tumor protein [32].

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 [33].

SIRT1 overproduction can impair liver regeneration to a degree [19].

More SIRT1 in CD4+ cells increases Lupus risk [34, 35].

How to Activate SIRT1

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

DHA

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 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) [36].

DHA decreases macrophage inflammation and inhibits Nf-kB via increasing SIRT1 in macrophages (DHA decreases inflammation via other mechanisms as well) [37]. DHA decreases COX-2 inflammation and insulin resistance also through SIRT1 (in colon cells) [38].

DHA increases SIRT1 in the hippocampus and reverses the 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) [39].

DHA supplementation is effective in reversing the reduction of sirt1 levels in rats with mild traumatic brain injury [40].

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

Cold, forskolin, and adrenaline increase SIRT1 activity by increasing cyclic AMP and this is independent of NAD+ levels [41, 42].

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.

Lifestyle:

Diet:

  • Fish/DHA
  • Fructose – In the liver, fructose increased SIRT1 production and activity [45]
  • Extra Virgin Olive Oil [46]

Supplements:

Drugs:

  • Metformin – increases SIRT1 production and activity [68]

Pathways:

  • Adrenaline [41, 42]
  • Hydrogen Peroxide [63]
  • Hydrogen Sulfide [69]
  • PDE5 inhibitors [44]
  • PON1 [63], BMAL1 [70], Other: FOXO3a, c-Myc, PARP inhibition

How to Increase NAD+, Which Activates SIRT1

  • Fasting [71]
  • Calorie restriction [71]
  • Exercise [71]
  • Saunas [72]
  • Nicotinamide Riboside [47]
  • Ketosis/β-hydroxybutyrate [73]
  • Fructose [45]
  • AMPK activation [74] – AMPK increases SIRT1 activity by increasing cellular NAD+levels (increases NAMPT [68]). SIRT1 activation also stimulates fatty acid oxidation and indirectly activates AMPK.
  • Pau Darco/Beta Lapachone [59]
  • Oxaloacetate [75]
  • Malic acid [76]
  • Resveratrol [77]
  • Apigenin [77]
  • Leucine [77]
  • Niacinamide – low doses [78]
  • Lithium inhibits mir-34a, which inhibits NAMPT, the enzyme that makes NAD+ [79, 80] So lithium should technically increase NAMPT and NAD+ by taking the breaks away from its production.
  • Succinic acid, to a lower degree than malic acid [81]
  • Tryptophan and Aspartic acid are fuel for NAD+ [82], but we usually get enough dietary amino acids if you eat adequate protein.

SIRT1 Inhibitors

SIRT1 Genes

The variation rs12778366 is found in the SIRT1 gene. About 80% of the global population has “TT”, while 18% have CT.

It’s thought that the C allele causes increased gene production of SIRT1 [90].

People with the C allele have an almost 30% reduced risk of dying during an 18-year follow-up study in the general population [91, 92].

TT was at a higher risk for diabetes [93].

People with a C allele had better glucose tolerance indicated by 0.34 mmol/l lower glucose levels [92]. Obese people with the C allele especially had better glucose tolerance [90].

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About the Author

Joe Cohen, BS

Joe Cohen won the genetic lottery of bad genes. As a kid, he suffered from inflammation, brain fog, fatigue, digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional and alternative medicine.Frustrated by the lack of good information and tools, Joe decided to embark on a journey of self-experimentation and self-learning to improve his health--something that has since become known as “biohacking”. With thousands of experiments and pubmed articles under his belt, Joe founded SelfHacked, the resource that was missing when he needed it. SelfHacked now gets millions of monthly readers.Joe is a thriving entrepreneur, author and speaker. He is the CEO of SelfHacked, SelfDecode and LabTestAnalyzer.His mission is to help people gain access to the most up-to-date, unbiased, and science-based ways to optimize their health.
Joe has been studying health sciences for 17 years and has read over 30,000 PubMed articles. He's given consultations to over 1000 people who have sought his health advice. After completing the pre-med requirements at university, he founded SelfHacked because he wanted to make a big impact in improving global health. He's written hundreds of science posts, multiple books on improving health, and speaks at various health conferences. He's keen on building a brain-trust of top scientists who will improve the level of accuracy of health content on the web. He's also founded SelfDecode and LabTestAnalyzer, popular genetic and lab software tools to improve health.

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