Not all sirtuins are bad? (SIRT3)
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So i have noticed haidut sees sirtuins as unfavorable but sirt3 specifically seems favorable does it not?
SIRT3 (Sirtuin 3) is the primary mitochondrial deacetylase that increases Pyruvate Dehydrogenase (PDH) activity over Pyruvate Dehydrogenase Kinase (PDK).It does this through the following mechanisms:
Deacetylation of PDHA1: SIRT3 interacts with and deacetylates the E1 alpha subunit of PDH (PDHA1) at specific lysine residues (such as K321 in cancer cells, K336 in skeletal muscle, or K83 in other tissues), which directly increases PDH enzymatic activity.
Reversing the Warburg Effect: SIRT3 acts as a tumor suppressor in several cancers by promoting the shift from glycolysis to oxidative phosphorylation, which reduces lactate production.
Conversely, a lack of SIRT3 (SIRT3 deletion) leads to hyperacetylation of PDHA1, increased PDK activity, and decreased PDH activity, which promotes a metabolic shift towards glycolysis.
a lack of SIRT3 (SIRT3 deletion or knockdown) leads to the hyperacetylation of mitochondrial proteins, specifically the pyruvate dehydrogenase E1α subunit (PDHA1). This hyperacetylation, often occurring at residues such as K321 or K83, leads to reduced activity of the pyruvate dehydrogenase complex (PDH) and increased activity of pyruvate dehydrogenase kinase (PDK), which further inactivates PDH.
Consequently, this inhibition of PDH restricts the entry of pyruvate into the tricarboxylic acid (TCA) cycle, prompting a metabolic shift towards glycolysis and increased lactate production (often called the Warburg effect).Does SIRT3 Affect Warburg Metabolism?
Yes, SIRT3 acts as a critical tumor suppressor by opposing the Warburg effect (the increased reliance of cancer cells on glycolysis).HIF1α Destabilization: Mechanistically, SIRT3 suppresses the Warburg effect by destabilizing hypoxia-inducible factor-1α (HIF1α). HIF1α is a transcription factor that promotes glycolytic genes, and its stabilization is a hallmark of the Warburg effect.
SIRT3 is pro-NAD+, favoring an elevated NAD+/NADH ratio through its enzymatic activity.Now something like sirt4 is bad we certainly want to inhibit it. SIRT4 acts as a lipoamidase, hydrolyzing lipoamide cofactors from the PDH E2 subunit (DLAT), which diminishes PDH activity independent of phosphorylation by PDK. This shifts metabolism away from glucose oxidation toward glutamine or fat utilization, as seen in glutamine-stimulated cells and mouse liver.Contrasting SIRT3. SIRT3 does the opposite: it deacetylates PDHA1 and PDP1 to activate PDH, while indirectly reducing PDK via HIF-1α downregulation, enhancing pyruvate entry into the TCA cycle
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Finally someone is catching on to this.
I've written about this here extensively.
https://bioenergetic.forum/topic/6911/sirtuins-klotho-and-ray-peat/2?_=1771433092484I don't think Peat's and Haiduts logic is bulletproof.
Simply increasing NAD will increase Sirtuins they're NAD-dependant enzymes.
One previously posted study shows that the oh-so-peaty Vitamin B3 increases Sirt1, 2, 3, and 6 in vivo.Also: SIRT3 reduced the conversion of SFAs to MUFAs
https://pubmed.ncbi.nlm.nih.gov/31160717/ -
@Mauritio wow glad you saw my post you are one of my favourite peaters on twitter. Yeah as intelligent as they are when it comes to sirtuins i find it hard to completely agree. While you are here i would like to ask a question. Georgi and peat say Vitamin K can act in place of coq10 to affect the transport chain in humans but this study seems to say otherwise
Vitamin K2 cannot substitute Coenzyme Q10 as electron carrier in the mitochondrial respiratory chain of mammalian cells
https://pubmed.ncbi.nlm.nih.gov/31024065/The authors conclude that, although vitamin K2 can act as an electron carrier in certain bacteria and has been proposed to do so in Drosophila, this role is not generalizable to mammalian mitochondria
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@user73636 SIRT 1 binds to NAMPT and deactylates it, reactivating it
