Hormonal Control Of Androgen Receptor Function Through Sirt1

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Abstract
The NAD-dependent histone deacetylase Sir2 plays a key role in connecting cellular metabolism with gene silencing and aging. The androgen receptor (AR) is a ligand-regulated modular nuclear receptor governing prostate cancer cellular proliferation, differentiation, and apoptosis in response to androgens, including dihydrotestosterone (DHT). Here, SIRT1 antagonists induce endogenous AR expression and enhance DHT-mediated AR expression. SIRT1 binds and deacetylates the AR at a conserved lysine motif. Human SIRT1 (hSIRT1) repression of DHT-induced AR signaling requires the NAD-dependent catalytic function of hSIRT1 and the AR lysine residues deacetylated by SIRT1. SIRT1 inhibited coactivator-induced interactions between the AR amino and carboxyl termini. DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins.

https://pubmed.ncbi.nlm.nih.gov/16923962/



Clock genes, hair growth and aging

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871241/



Interesting studies!

David Sinclair link the Sirtuins to longevity.

 

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SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress

Conclusions
In summary, we have shown that regulation of autophagy by SIRT1 plays a role in ESC survival against oxidative stress induced by high concentrations of H2O2. Notably, SIRT1-mediated oxidative stress-induced autophagy results in decreased mitochondrial damage that in turn leads to less apoptosis and increased cell protection.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991763/

 

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Autophagy Is Essential for Maintaining the Growth of a Human (Mini-)Organ: Evidence From Scalp Hair Follicle Organ Culture

https://pubmed.ncbi.nlm.nih.gov/29590104/

 

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Hydroxytyrosol Prevents Dermal Papilla Cells Inflammation Under Oxidative Stress by Inducing Autophagy

https://pubmed.ncbi.nlm.nih.gov/31332898/

 

[John Difool]

Hydroxytyrosol is the most powerful natural antioxidant currently known.

That alone is something that attests it could be a good addition to basic regimen.

 

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Metformin is given to female with PCOS. PCOS is pretty much females with irregular periods, Polycystic ovaries and Excess androgen.

See how things start to make sense!

Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation.

https://pubmed.ncbi.nlm.nih.gov/30459716/

 

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SIRT1: regulation of longevity via autophagy.
https://europepmc.org/article/med/19249351

 

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SIRT1 IS REQUIRED FOR ANTAGONIST-INDUCED TRANSCRIPTIONAL REPRESSION OF ANDROGEN-RESPONSIVE GENES BY THE ANDROGEN RECEPTOR
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839341/
Androgen antagonists or androgen deprivation is a primary therapeutic modality for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which the androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this report, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide-dependent histone deacetylase linked to the regulation of longevity, is required for androgen antagonist-mediated transcriptional repression and growth suppression. Androgen antagonist-bound androgen receptor (AR) recruits SIRT1 and NCoR to AR-responsive promoters and deacetylates histone H3 locally at the PSA promoter. Furthermore, SIRT1 down-regulation by siRNA or by pharmacological means increased the sensitivity of androgen-responsive genes to androgen stimulation, enhanced the sensitivity of prostate cancer cell proliferative responses to androgens, and decreased the sensitivity of prostate cancer cells to androgen antagonists. In this study, we demonstrate the ligand-dependent recruitment of a class III HDAC into a co-repressor transcriptional complex, and a necessary functional role for a class III HDAC as a transcriptional co-repressor in AR antagonist-induced transcriptional repression. Collectively, these findings identify SIRT1 as a co-repressor of AR and elucidate a new molecular pathway relevant to prostate cancer growth and approaches to therapy.

 

[alscarmuzza]

Found more info re: SIRT1
https://selfhacked.com/blog/nad-and-sirt1-their-role-in-chronic-health-issues/

 

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Sirt Activators:
http://www.isoquercetin.net/sirt1/


Sinclair: oleic acid is 10 to 100 times more potent than resveratrol

Olive Oil Diet Increases Oxidative Metabolism in a
SIRT1-Dependent Manner

"To investigate the effects of SIRT1 activating MUFAs in vivo, mice were fed diets enriched in lard and soybean oil (CTRL) or olive oil (OO), which contains 75% 18:1, and were fasted overnight prior to sacrifice to stimulate lipolytic signaling.

Olive oil (OO) feeding decreased body weight over the course of 12 weeks due to a decrease in fat mass. Without affecting energy intake or locomotion, OO feeding increased oxygen consumption and heat production, leading to increased energy expenditure.

To determine if the OO in the diet was exerting its physiological effects in a SIRT1-dependent manner, EX527, a potent and specific SIRT1 inhibitor, was administered over the course of three days prior to sacrifice. SIRT1 inhibition negated the decrease in body weight and the increase in serum b-hydroxybutyrate and free fatty acids observed with OO feeding.

The OO diet reduced white adipose tissue weights, an effect that was normalized in mice treated with EX527. OO feeding decreased hepatic LD size and liver TAG content while SIRT1 inhibition ablated these effects. Acetylation of SIRT1 targets PGC-1a and FOXO3a were decreased in OO-fed mice, an effect that was attenuated by EX527.

To further test the importance of SIRT1 in MUFA-mediated signaling, we determined gene expression of key PGC-1a/PPARa oxidative genes. Consumption of the OO diet universally increased the expression of PGC-1a/PPAR-a target genes, but these effects were ablated
with EX527.

The increased gene expression in OO-fed mice corresponded to increased protein abundance of UCP1, PGC-1a, CPT1a, and various respiratory chain complex proteins in the liver, and S5B). In addition to hepatic changes, histological examination of interscapular brown adipose tissue exhibited smaller LDs and decreased TAG, indicative of enhanced thermogenesis."

https://www.cell.com/molecular-cell/pdf ... 0894-9.pdf

 

[John Difool]

So how much olive oil per kg for its intake to take effects?

 

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Androgen Receptor Drives Cellular Senescence
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293868/

SIRT1 Suppresses the Senescence-Associated Secretory Phenotype through Epigenetic Gene Regulation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312089/

 

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[TheHawk]

There was a a 1952 study showing old eunuchs went bald in merely 3 months when supplemented DHT whereas younger ones went bald at the rate you’d expect for their age.


Cellular senescence and DNA damage will logically increase your androgen sensitivity.

I’m on TMG, fisetin and NAD+ precursors.

 

[likelycorrect]

There was a a 1952 study showing old eunuchs went bald in merely 3 months when supplemented DHT whereas younger ones went bald at the rate you’d expect for their age.


Cellular senescence and DNA damage will logically increase your androgen sensitivity.

I’m on TMG, fisetin and NAD+ precursors.

Can't seem to find the study, mind linking it?