SIRT6

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.

List of Activating SIRT6 Polyphenols^[1]
Compound	EC₅₀ value (µM)	Maximal activation (fold)
Cyanidin	460 ± 20	55
Quercetin	990 ± 250	10
Myricetin	404 ± 20	7.7
Delphinidin	760 ± 200	6.3
Luteolin	270 ± 25	6.1
Kaempferol	n.d	3.0

Inhibiting Compounds

Inhibiting compounds, or antagonists, are molecules that decrease the activity of SIRT6, offering a means to understand the functional importance of this enzyme in various cellular processes. These compounds typically bind to SIRT6 and reduce its enzymatic activity, which can be crucial for studying disease mechanisms or for developing therapeutic strategies targeting conditions where reduced SIRT6 activity might be beneficial. The inhibition of SIRT6 has been studied in the context of cancer biology, metabolic disorders, and other age-related diseases. In this section, we list compounds known to inhibit SIRT6, measured by their IC₅₀ values—the concentration at which they inhibit 50% of SIRT6's activity. Understanding these compounds provides insights into the regulatory mechanisms of SIRT6 and potential therapeutic avenues for diseases associated with its overactivity.

List of Inhibiting SIRT6 Polyphenols^[1]
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]
2021, Emerging roles of SIRT6 in human diseases and its modulators ^[2]

References

↑ ^1.0 ^1.1 ^1.2 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.
↑ Liu G et al.: Emerging roles of SIRT6 in human diseases and its modulators. Med Res Rev 2021. (PMID 33325563) [PubMed] [DOI] [Full text] The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty-acylation, and mono-ADP-ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life-threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6-mediated diseases.

[pmid29515203-1] 1.0 ^1.1 ^1.2 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.

[pmid33325563-2] Liu G et al.: Emerging roles of SIRT6 in human diseases and its modulators. Med Res Rev 2021. (PMID 33325563) [PubMed] [DOI] [Full text] The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty-acylation, and mono-ADP-ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life-threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6-mediated diseases.

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