Department of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London, WC1E 6BT, United Kingdom.
Sci Rep. 2020 Mar 24;10(1):5338. doi: 10.1038/s41598-020-62162-0.
SIRT1 protects against several complex metabolic and ageing-related diseases (MARDs), and is therefore considered a polypill target to improve healthy ageing. Although dietary sirtuin-activating compounds (dSTACs) including resveratrol are promising drug candidates, their clinical application has been frustrated by an imprecise understanding of how their signals are transduced into increased healthspan. Recent work indicates that SIRT1 and orthologous sirtuins coactivate the oestrogen receptor/ER and the worm steroid receptor DAF-12. Here they are further shown to ligand-independently transduce dSTACs signals through these receptors. While some dSTACs elicit ER subtype-selectivity in the presence of hormone, most synergize with 17β-oestradiol and dafachronic acid respectively to increase ER and DAF-12 coactivation by the sirtuins. These data suggest that dSTACs functionally mimic gonadal steroid hormones, enabling sirtuins to transduce the cognate signals through a conserved endocrine pathway. Interestingly, resveratrol non-monotonically modulates sirtuin signalling, suggesting that it may induce hormesis, i.e. "less is more". Together, the findings suggest that dSTACs may be informational molecules that use exploitative mimicry to modulate sirtuin signalling through steroid receptors. Hence dSTACs' intrinsic oestrogenicity may underlie their proven ability to impart the health benefits of oestradiol, and also provides a mechanistic insight into how they extend healthspan or protect against MARDs.
SIRT1 可预防多种复杂的代谢和衰老相关疾病（MARDs），因此被认为是改善健康衰老的多效药物靶点。虽然包括白藜芦醇在内的饮食 Sirtuin 激活化合物（dSTACs）是很有前途的候选药物，但由于对其信号如何转导为增加健康寿命的机制了解不精确，其临床应用受到了阻碍。最近的研究表明，SIRT1 和同源 Sirtuins 共同激活雌激素受体/ER 和线虫类固醇受体 DAF-12。在这里，它们进一步被证明可以通过这些受体独立配体地转导 dSTACs 信号。虽然一些 dSTACs 在存在激素的情况下表现出 ER 亚型选择性，但大多数与 17β-雌二醇和 dafachronic 酸分别协同作用，以增加 Sirtuins 对 ER 和 DAF-12 的共激活。这些数据表明，dSTACs 在功能上模拟了性腺类固醇激素，使 Sirtuins 能够通过保守的内分泌途径转导同源信号。有趣的是，白藜芦醇非单调地调节 Sirtuins 信号，表明它可能诱导应激反应，即“少即是多”。总之，这些发现表明，dSTACs 可能是信息分子，它们利用剥削性模拟通过类固醇受体来调节 Sirtuins 信号。因此，dSTACs 的固有雌激素活性可能是其能够赋予雌二醇健康益处的基础，并且还为它们如何延长健康寿命或预防 MARDs 提供了机制上的见解。
