SIRT1

SIRT enzymes œturn 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, SIRT1 adds acetyl groups 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. SIRT1 powerfully helps metabolic issues that cause diabesity.

SIRT1 also make you more sensitive to Thyroid hormones (R) and  more sensitive to vitamin D (R, R2).

SIRT1 inhibits pathways involved in aging (IGF-1 (R) mTOR (R).)

SIRT1 protects you from oxidative stress.

SIRT1 regulates the strength (amplitude) and the duration of your natural biological rhythms.

A reduction in SIRT 1 and SIRT 3 enzymes lead to (R):

• 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 (œburning), thereby depriving muscles of their normal sources of energy.

Read/Fix: NAD+ and SIRT1: Their Role In Chronic Health Issues.

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.

SIRT enzymes œturn 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).

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).) A reduction in SIRT 1 and SIRT 3 enzymes lead to (R):

• 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 (œburning), thereby depriving muscles of their normal sources of energy.

Technical: SIRT1 causes the activation (by deacetylation) PPAR-alpha, PGC-1a, LXR (R), MAO-A, FOXOs -FOXO1a,Foxo3 (R), UCP2, FGF-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-1, Hif-2a, HSF1, Bax, Ku70, b-catenin, E2F1, Myc, TORC2, SREBP, PER2, CLOCK (R).

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.

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 ROR³t), 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)

Top Ways to increase SIRT1:

• DHA (R)
• Cold (R, R2)
• Exercise (R)
• Nicotinamide Riboside
• Fructose from raw honey or fruit.  In liver, fructose increased SIRT1 production and activity (R),
• Forskolin (R, R2)
• Extra Virgin Olive Oil (R),
• Tea (R),
• Vinegar
• PQQ (R)