SIRT6: Difference between revisions

Revision as of 03:03, 25 December 2023

SIRT6 is a member of the sirtuin family of proteins, known to be involved in longevity and metabolism regulation. It is primarily known for its role in DNA repair, chromatin remodeling, and maintaining genomic stability, which are critical in aging and age-related diseases.

Role in Longevity

Genetic Mechanisms

SIRT6 influences longevity through its deacetylase activity, which impacts various cellular processes like DNA repair, telomere maintenance, and inflammation. Studies have shown that overexpression of SIRT6 can extend lifespan in certain organisms.

Metabolic Regulation

SIRT6 also plays a critical role in regulating metabolism, including glucose and lipid metabolism, which are vital for healthy aging. It affects the expression of genes involved in metabolic pathways, influencing longevity and age-associated diseases.

Research Findings

Numerous studies have highlighted the potential of SIRT6 in extending healthspan and lifespan. For example, mice with overexpressed SIRT6 show signs of extended lifespan and improved health markers. Similarly, research in human cells indicates that SIRT6 may protect against age-related decline.

Potential Implications

The study of SIRT6 opens up possibilities for therapeutic interventions in aging and metabolic diseases. Understanding its mechanisms can lead to the development of drugs or therapies aimed at mimicking its longevity effects.

Modulating Compounds

Activating Compounds

Activating compounds, also known as agonists, are molecules that can enhance the activity of SIRT6, thereby influencing its role in longevity, metabolism, and DNA repair. These compounds typically bind to SIRT6 and induce a conformational change that increases its enzymatic activity or stability, leading to amplified beneficial effects in cellular processes related to aging and disease prevention. The table below lists several compounds identified through scientific research as activators of SIRT6. Their effectiveness is usually measured in terms of EC₅₀ values, which indicate the concentration needed to achieve half the maximal activation, and the fold increase in activity they produce. This section provides an overview of some key compounds that have been studied for their potential to enhance the function of SIRT6 and thereby contribute to longevity and healthspan.

Compound	EC₅₀ value (µM)	Maximal activation (fold)
Luteolin	270 ± 25	6.1
Kaempferol	n.d	3.0
Quercetin	990 ± 250	10
Myricetin	404 ± 20	7.7
Cyanidin	460 ± 20	55
Delphinidin	760 ± 200	6.3

Inhibiting Compounds

Compound	IC₅₀ value (µM)
(−)-Catechin gallate	2.5 ± 0.03
(−)-Gallocatechin gallate	5.4 ± 0.04

Todo

2018, Natural polyphenols as sirtuin 6 modulators ^[1]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841289/table/Tab1/?report=objectonly

References

↑ Rahnasto-Rilla M et al.: Natural polyphenols as sirtuin 6 modulators. Sci Rep 2018. (PMID 29515203) [PubMed] [DOI] [Full text] Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3-10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.

[pmid29515203-1] Rahnasto-Rilla M et al.: Natural polyphenols as sirtuin 6 modulators. Sci Rep 2018. (PMID 29515203) [PubMed] [DOI] [Full text] Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3-10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.

[1]

@@ Line 15: / Line 15: @@
 == Modulating Compounds ==
 === Activating Compounds ===
-Activating compounds, also known as agonists, are molecules that can enhance the activity of SIRT6, thereby influencing its role in longevity, metabolism, and DNA repair. These compounds typically bind to SIRT6 and induce a conformational change that increases its enzymatic activity or stability, leading to amplified beneficial effects in cellular processes related to aging and disease prevention. The table below lists several compounds identified through scientific research as activators of SIRT6. Their effectiveness is usually measured in terms of EC<sub>50</sub> values, which indicate the concentration needed to achieve half the maximal activation, and the fold increase in activity they produce. This section provides an overview of some key compounds that have been studied for their potential to enhance the function of SIRT6 and thereby contribute to longevity and healthspan.
+Activating compounds, also known as agonists, are molecules that can enhance the activity of SIRT6, thereby influencing its role in longevity, metabolism, and DNA repair. These compounds typically bind to SIRT6 and induce a conformational change that increases its enzymatic activity or stability, leading to amplified beneficial effects in cellular processes related to aging and disease prevention. The table below lists several compounds identified through scientific research as activators of SIRT6. Their effectiveness is usually measured in terms of [[EC50|EC<sub>50</sub>]] values, which indicate the concentration needed to achieve half the maximal activation, and the fold increase in activity they produce. This section provides an overview of some key compounds that have been studied for their potential to enhance the function of SIRT6 and thereby contribute to longevity and healthspan.
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