Research Article: Identification of a small molecule activator of SIRT1 gene expression

Date Published: March 6, 2013

Publisher: Impact Journals LLC

Author(s): Si-Young Cho, Miook Cho, Dae Bang Seo, Sang Jun Lee, Yousin Suh.

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Abstract

Increased SIRT1 expression exerts beneficial effects in transgenic animal models, ameliorating the onset and progression of aging-related disease phenotypes in various organs including the heart. The potential beneficial effects of SIRT1 have made SIRT1 a prime therapeutic target for age-related diseases and considerable efforts led to the identification of small molecule activator of SIRT1 protein. Thus far, however, a small molecule activator of SIRT1 gene expression has not been reported. Here, we report that syringaresinol, isolated from Panax ginseng berry pulp, is an activator of SIRT1 gene expression. Using human umbilical endothelial cells (HUVECs), we show that syringaresinol treatment induced binding of FOXO3 to the SIRT1 promoter in a sequence-specific manner, leading to induction of SIRT1 expression. Increased SIRT1 expression in HUVECs by syringaresinol treatment delayed cellular senescence and improved various markers of endothelial functions in a FOXO3 dependent manner. Collectively, these findings bring to light a new transcription activator of SIRT1 that may have therapeutic potential.

Partial Text

SIRT1 is a NAD+-dependent protein deacetylase that regulates stress response, metabolic homeostasis, and aging in animal models [1]. Tissue-specific overexpression of SIRT1 was shown to protect mice against age-related disorders such as cardiovascular, neurodegenerative, and metabolic diseases [2, 3], making SIRT1 a prime therapeutic target for such diseases[4-6]. Several small molecule activators of SIRT1 activity have been described and are currently being tested for clinical use against age-related diseases [7-9]. To date, a small molecule activator of SIRT1 gene expression has not been reported.

 

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