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Sirtuins: the 7 gatekeepers of health

Posted: Sat Nov 16, 2019 3:28 am
by Fred
The seven sirtuin genes, SIRT1 to SIRT7, have been called our "guardians of the genome" or "gatekeepers of health" since they are so instrumental in protecting us against the diseases of aging.

While resveratrol and fisetin and metformin and other sirtuin-activating compounds only activate SIRT1, NAD precursors like NMN have the potential to activate all seven of the sirtuins.


Here I would like to briefly just post how sirtuins protect us from the following pathologies:

1. Diabetes
2. Non-alcoholic fatty liver disease
3. Atherosclerosis
4. Alzheimer’s disease
5. Retinal degeneration
6. Depression


Re: How the 7 gatekeepers of health works

Posted: Sat Nov 16, 2019 3:29 am
by Fred
SIRT1 is important for promoting glucose-stimulated insulin secretion in pancreatic β-cells. Additionally, SIRT1 has a protective effect against insulin resistance in peripheral tissues, including adipose tissue, liver, and skeletal muscle.

These findings suggest that SIRT1 is important for glucose homeostasis and the prevention of type 2 diabetes. Whole-body Sirt1-overexpressing transgenic mice, when fed a high-fat diet (HFD), have shown improvements in glucose tolerance through reduction of hepatic glucose production.

Additionally, these mice do not show changes in body weight or composition. In the kidney of diabetic model mice, SIRT1 inhibits oxidative stress, which can lead to nephropathy, by induction of cyclooxygenase-2 (COX-2) expression.

It has also been shown that administration of NMN ameliorates glucose intolerance in HFD-induced type 2 diabetic mice, enhances hepatic insulin sensitivity, and restores oxidative stress gene expression, and inflammatory responses, partly through the activation of SIRT1.

Re: How the 7 gatekeepers of health works

Posted: Sat Nov 16, 2019 3:31 am
by Fred
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by steatosis of the liver and is linked with insulin resistance and metabolic syndrome. Studies have observed a reduction of sirtuins in NAFLD.

SIRT1/3/5/6 are reported to be reduced in patients with NAFLD. This reduction is accompanied by an increase in lipogenic genes such as fatty acid synthase and SREBP-1. SIRT1 and SIRT3 have particularly been investigated in regard to NAFLD. SIRT1 expression is reduced by HFD.

Overexpression of SIRT1 upregulates fatty acid oxidation pathways and downregulates lipogenic pathways, protecting the liver from steatosis. SIRT3 function is impaired in HFD, leading to hyperacetylation of target proteins in the mitochondria and impairing their activities. SIRT3-deficient mice exacerbate these phenotypes, while overexpression can ameliorate NAFLD.

Re: How the 7 gatekeepers of health works

Posted: Sat Nov 16, 2019 3:31 am
by Fred
SIRT1 has been shown to improve vascular function. SIRT1 is positioned to affect many pathways important for endothelial function.

SIRT1 suppresses the expression of inflammatory factors, including interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase 14 (MMP14), and vascular cell adhesion molecule 1 (VCAM-1) 64.

Additionally, SIRT1 improves free fatty acid, triglyceride, total cholesterol, and blood glucose levels. These protective effects of SIRT1 indicate that it acts as an anti-atherosclerosis agent.

Consistent with these findings, NMN administration dramatically improves vascular function in aged mice, partly through the activation of SIRT1.

Re: How the 7 gatekeepers of health works

Posted: Sat Nov 16, 2019 3:32 am
by Fred
Alzheimer’s disease
Alzheimer’s disease (AD) is marked by multiple pathologies, including neuroinflammation, amyloid-beta plaques, mitochondrial damage, and increased oxidative stress.

Patients with AD have lowered expression of SIRT1, which is recapitulated in the hippocampus of AD model mice. SIRT1 activation is capable of reducing the amount of oligomerized amyloid beta through upregulating the production of alpha-secretase. This is corroborated by mouse models overexpressing SIRT1 and amyloid precursor protein.

Additionally, SIRT1 promotes neuronal function and survival in AD model mice. CA1-localized SIRT1 overexpression not only preserves learning and memory in AD mice but enhances cognitive function in non-AD model mice.

Re: How the 7 gatekeepers of health works

Posted: Sat Nov 16, 2019 3:33 am
by Fred
Retinal degeneration
Retinal degeneration is prominent in diseases such as macular degeneration and diabetic retinopathy. A recent study reported the importance of SIRT3 and SIRT5 in the survival of retinal photoreceptors.

In particular, mitochondrial SIRT3 activity is sensitive to the reduction in NAD +. Decreases in retinal NAD + were detected in multiple retinal degenerative disorders, including age-associated dysfunction, diabetic retinopathy, and light-induced degeneration.

Supplementation with the NAD + intermediate NMN was able to restore retinal function. These findings suggest a possible therapeutic treatment for a wide variety of diseases with photoreceptor degeneration.

Re: How the 7 gatekeepers of health works

Posted: Sat Nov 16, 2019 3:33 am
by Fred
Depression is a complex psychiatric disorder associated with a number of pathologies, including inflammation, synaptic dysfunction, metabolic syndrome, and cognitive deficit. Sirtuins have been shown to have a role in the development of depression.

In the dentate gyrus region of the hippocampus, it has been shown that SIRT1 is decreased under conditions of chronic stress, which has been associated with depressive-like behaviors.

Additionally, inhibition of SIRT1 by genetic or pharmacological methods has reproduced depressive behaviors. Activation of SIRT1 is able to lead to anti-depressive behaviors.

However, it has been observed that SIRT1 regulates expression of monoamine oxidase A (MAO-A), which lowers serotonin and drives anxiety-like behaviors, indicating that a balance in SIRT1 expression/activity is important for mood disorders.

SIRT2 has also been reported in mood disorders. Hippocampal SIRT2 expression is decreased in chronic stress conditions. Pharmacological inhibition of SIRT2 recapitulates depressive behaviors. Adenovirus-mediated overexpression of SIRT2 produces anti-depressive behaviors, which were abolished when hippocampal neurogenesis was disrupted by X-irradiation.

Re: The 7 gatekeepers of health

Posted: Sat Nov 16, 2019 8:48 am
by Taytaytay195
All great information for sure Fred!