Natural polyphenols as sirtuin 6 modulators

Abstract

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.

Mechanism of activation for the sirtuin 6 protein deacylase

“…The importance of a terminal negative charge is a novel feature identified in the current study. A few activators described by others lack this feature and are structurally unrelated (25)(26)(27), suggesting that there may be multiple activator binding modes or alternative mechanisms of activation. Unfortunately, the mechanism of activation for these previously described compounds is unknown.…”

Does traditional asian vegetables (ulam) consumption correlate with brain activity using fMRI? A study among aging adults from low‐income households

“…10 The high level of antioxidants and polyphenols in ulam 26 was also found to be a major contributor to the cognitive pathway, where the latter is known for attenuating apoptosis, removing reactive oxygen species, preventing oxidative stress that causes cognitive decline, 8 as well as initiating the activation of sirtuins in the regulation of the human body cells that alleviates the occurrence of neurodegenerative illnesses. 27 Also, the flavonoid from the plants would scavenge for free radicals and decrease the neuron apoptosis that impedes neuroinflammation. 28 The association of the ulam metabolites with the improvement of working memory, however, is yet to be elucidated by future research.…”

The failure of “engineered rejuvenation”: laboratory genomics do not translate into precision anti-aging therapies

“…Examples include not only rejuvenation biotechnologies in general, but also anti-senescence drugs (senolytics) [27,28] such as quercetin, dasatinib, navitoclax [29] , drugs or compounds such as sirtuin modulators [30] , rapamycin [31] , lifespan-extending herbs [32] , metformin [33] , telomere and telomerase modulators [34] . A common characteristic of these is that there is a clear separation between an outside agent (a physician, surgeon, healer, nutritionist) and the patient (healthy or unhealthy young or older people).…”