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)

The following transcription factors affect gene expression:

• NF-kappaB
• p53
• FOXO4
• NF-kappaB1
• C/EBPalpha
• FOXO1a
• FOXO1

Tissue specificity:

Widely expressed.

Induction:

Up-regulated by methyl methanesulfonate (MMS). In H293T cells by presence of rat calorie restriction (CR) serum.

Enzyme Regulation:

Inhibited by nicotinamide. Activated by resveratrol (3,5,4'-trihydroxy-trans-stilbene), butein (3,4,2',4'-tetrahydroxychalcone), piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene), Isoliquiritigenin (4,2',4'-trihydroxychalcone), fisetin (3,7,3',4'-tetrahydroxyflavone) and quercetin (3,5,7,3',4'-pentahydroxyflavone). MAPK8/JNK1 and RPS19BP1/AROS act as positive regulators of deacetylation activity. Negatively regulated by CCAR2.

Cofactor:

Binds 1 zinc ion per subunit.

Molecular Function:

• Core Promoter Sequence-Specific Dna Binding
• P53 Binding
• Transcription Corepressor Activity
• Histone Deacetylase Activity
• Protein C-Terminus Binding
• Transcription Factor Binding
• Nad-Dependent Histone Deacetylase Activity
• Deacetylase Activity
• Enzyme Binding
• Protein Deacetylase Activity
• Nad-Dependent Protein Deacetylase Activity
• Nuclear Hormone Receptor Binding
• Histone Binding
• Identical Protein Binding
• Hlh Domain Binding
• Bhlh Transcription Factor Binding
• Metal Ion Binding
• Nad-Dependent Histone Deacetylase Activity (H3-K9 Specific)
• Mitogen-Activated Protein Kinase Binding
• Nad+ Binding
• Keratin Filament Binding

Biological Processes:

• Single Strand Break Repair
• Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
• Chromatin Silencing At Rdna
• Pyrimidine Dimer Repair By Nucleotide-Excision Repair
• Dna Synthesis Involved In Dna Repair
• Angiogenesis
• Ovulation From Ovarian Follicle
• Cellular Glucose Homeostasis
• Positive Regulation Of Protein Phosphorylation
• Positive Regulation Of Endothelial Cell Proliferation
• Positive Regulation Of Adaptive Immune Response
• Dna Replication
• Dna Repair
• Chromatin Organization
• Chromatin Silencing
• Establishment Of Chromatin Silencing
• Maintenance Of Chromatin Silencing
• Methylation-Dependent Chromatin Silencing
• Transcription, Dna-Templated
• Rrna Processing
• Protein Deacetylation
• Triglyceride Mobilization
• Cellular Response To Dna Damage Stimulus
• Response To Oxidative Stress
• Spermatogenesis
• Regulation Of Mitotic Cell Cycle
• Muscle Organ Development
• Cell Aging
• Positive Regulation Of Cell Proliferation
• Cellular Response To Starvation
• Negative Regulation Of Gene Expression
• Positive Regulation Of Cholesterol Efflux
• Regulation Of Lipid Storage
• Regulation Of Glucose Metabolic Process
• Macrophage Cytokine Production
• Positive Regulation Of Phosphatidylinositol 3-Kinase Signaling
• Viral Process
• Positive Regulation Of Macroautophagy
• Protein Ubiquitination
• Histone Deacetylation
• Peptidyl-Lysine Acetylation
• Macrophage Differentiation
• Negative Regulation Of Cell Growth
• Negative Regulation Of Transforming Growth Factor Beta Receptor Signaling Pathway
• Negative Regulation Of Prostaglandin Biosynthetic Process
• Protein Destabilization
• Positive Regulation Of Chromatin Silencing
• Negative Regulation Of Tor Signaling
• Regulation Of Endodeoxyribonuclease Activity
• Negative Regulation Of Nf-Kappab Transcription Factor Activity
• Response To Insulin
• Circadian Regulation Of Gene Expression
• Regulation Of Protein Import Into Nucleus, Translocation
• Leptin-Mediated Signaling Pathway
• Regulation Of Smooth Muscle Cell Apoptotic Process
• Peptidyl-Lysine Deacetylation
• Cellular Triglyceride Homeostasis
• Regulation Of Peroxisome Proliferator Activated Receptor Signaling Pathway
• Regulation Of Cell Proliferation
• Negative Regulation Of Phosphorylation
• Response To Hydrogen Peroxide
• Behavioral Response To Starvation
• Cholesterol Homeostasis
• Intrinsic Apoptotic Signaling Pathway In Response To Dna Damage By P53 Class Mediator
• Positive Regulation Of Apoptotic Process
• Negative Regulation Of Apoptotic Process
• Negative Regulation Of I-Kappab Kinase/Nf-Kappab Signaling
• Proteasome-Mediated Ubiquitin-Dependent Protein Catabolic Process
• Positive Regulation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Process
• Negative Regulation Of Sequence-Specific Dna Binding Transcription Factor Activity
• Negative Regulation Of Dna Damage Response, Signal Transduction By P53 Class Mediator
• Response To Leptin
• Positive Regulation Of Mhc Class Ii Biosynthetic Process
• Negative Regulation Of Fat Cell Differentiation
• Positive Regulation Of Dna Repair
• Positive Regulation Of Angiogenesis
• Negative Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Positive Regulation Of Insulin Receptor Signaling Pathway
• White Fat Cell Differentiation
• Negative Regulation Of Helicase Activity
• Positive Regulation Of Histone H3-K9 Methylation
• Negative Regulation Of Protein Kinase B Signaling
• Fatty Acid Homeostasis
• Negative Regulation Of Androgen Receptor Signaling Pathway
• Cellular Response To Hydrogen Peroxide
• Regulation Of Bile Acid Biosynthetic Process
• Uv-Damage Excision Repair
• Histone H3 Deacetylation
• Cellular Response To Tumor Necrosis Factor
• Negative Regulation Of Histone H3-K14 Acetylation
• Cellular Response To Hypoxia
• Cellular Response To Ionizing Radiation
• Regulation Of Protein Serine/Threonine Kinase Activity
• Regulation Of Brown Fat Cell Differentiation
• Stress-Induced Premature Senescence
• Regulation Of Cellular Response To Heat
• Negative Regulation Of Neuron Death
• Negative Regulation Of Protein Acetylation
• Negative Regulation Of Intrinsic Apoptotic Signaling Pathway In Response To Dna Damage By P53 Class Mediator
• Negative Regulation Of Oxidative Stress-Induced Intrinsic Apoptotic Signaling Pathway
• Positive Regulation Of Endoplasmic Reticulum Stress-Induced Intrinsic Apoptotic Signaling Pathway
• Positive Regulation Of Adipose Tissue Development
• Positive Regulation Of Macrophage Apoptotic Process
• Negative Regulation Of Camp-Dependent Protein Kinase Activity
• Positive Regulation Of Camp-Dependent Protein Kinase Activity
• Negative Regulation Of Histone H4-K16 Acetylation
• Negative Regulation Of Cellular Response To Testosterone Stimulus
• Negative Regulation Of Peptidyl-Lysine Acetylation
• Negative Regulation Of Cellular Senescence
• Positive Regulation Of Cellular Senescence