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. 2017 Mar 2;7:43679.
doi: 10.1038/srep43679.

Alkylresorcinols Activate SIRT1 and Delay Ageing in Drosophila Melanogaster

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Free PMC article

Alkylresorcinols Activate SIRT1 and Delay Ageing in Drosophila Melanogaster

Yasunari Kayashima et al. Sci Rep. .
Free PMC article

Abstract

Sirtuins are enzymes that catalyze NAD+ dependent protein deacetylation. The natural polyphenolic compound resveratrol received renewed interest when recent findings implicated resveratrol as a potent SIRT1 activator capable of mimicking the effects of calorie restriction. However, resveratrol directly interacts with fluorophore-containing peptide substrates. It was demonstrated that the SIRT1 activation of resveratrol is affected by the amino acid composition of the substrate. Resveratrol did increase the enzyme activity in cases in which hydrophobic amino acids are at the +1 position to the acetylated lysine in the substrate. Alkylresorcinols (ARs) are compounds that belong to the family of phenolic lipids, and they are found in numerous biological species. Here we show that the natural activators ARs increased the Vmax of recombinant SIRT1 for NAD+ and peptide substrate, and that ARs decreased acetylated histone in human monocyte cells by stimulating SIRT1-dependent deacetylation of substrates. ARs also extended the lifespan of Drosophila melanogaster, which was shown to be dependent on functional Sir2. Our results demonstrated that ARs are natural catalytic activators for sirtuin.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. The effects of the ARs on recombinant SIRT1.
(a) The time course of SIRT1 deacetylation activity of ARs. ARs and SRT1720 were assessed at 10 μM, and sirtinol was assessed at 100 μM by recombinant SIRT1 with 25 μM of NAD+. All values are the mean of three determinations. (b) The dose-dependency of olivetol for SIRT1 activity with 100 μM of NAD+ (±standard error [s.e.]) at 1000 sec. All values are the mean of at least four determinations. (c) The rate of the increase of SIRT1 activation with native p53 peptide monitored by the HPLC assay and CycLex assay at 1000 sec. All values are the mean of three determinations. Errors = s.e. *p < 0.05, **p < 0.01, compared with the control.
Figure 2
Figure 2
Michaelis-Menten plot of C17:0-AR for SIRT1 activity with various concentrations (12.5–200 μM) of NAD+ at 1000 sec (a) and with various concentrations (0.5–20 μM) of peptide substrate at 1000 sec (b). Lineweaver-Burk plot of C17:0-AR for SIRT1 activity with various concentrations (12.5–200 μM) of NAD+ at 1000 sec (c) and with various concentrations (0.5–20 μM) of peptide substrate at 1000 sec (d). Black lines: control. Red lines: C17:0-AR. All values are the mean of at least three determinations.
Figure 3
Figure 3. Effects of ARs on human monocyte cells.
(a) Effect of ARs (10 μM) on TSA-insensitive deacetylase activity for histone in THP-1 cells. (b) Effect of ARs (10 μM) and GR condition on the mRNA expression levels of SIRT1 in THP-1 cells. (c) Effect of ARs (10 μM) and GR condition on the mRNA expression levels of SIRT1 in HepG2 cells. Errors = s.e. *p < 0.05, **p < 0.01 compared with the control. All values are the mean of at least three determinations.
Figure 4
Figure 4. Survival of wild-type and Sir2-deficient genotype D. melanogaster adults fed an ARs or resveratrol.
Males (a) and females (b) of the wild-type w1118 line. Males (c) and females (d) with the strong hypomorphic genotype Sir217/Sir2KG00871.

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