Small Molecule SIRT1 Activators are Promising Anti-aging Drugs

Novel drug candidates have been discovered that mimic the action of calorie restriction by extending lifespan and producing a metabolic profile desirable for treating diseases of aging such as type 2 diabetes.

The compounds are small molecule activators of the SIRT1 gene. SIRT1 (which stands for sirtuin [silent mating type information regulation 2 homologue] 1; also known as Sir2a) is the mammalian homologue of the yeast Sir2 gene. It produces an enzyme that removes acetyl groups from proteins in the presence of NAD+ (NAD+-dependent deacetylase with EC number 3.5.1). The enzyme adds the acetyl group from a protein to the ADP-ribose part of NAD+ to form O-acetyl-ADP-ribose. In yeast, overexpression of the Sir2 gene results in a lifespan extension of about 30%, if the lifespan is measured as the number of cell divisions the cell can undergo before dying. This is due to Sir2 deacetylating histone molecules, which results in tighter packaging and lower level of transcription of the cell's DNA.

Mice that overexpress SIRT1 show eight properties of calorie restriction, including low cholesterol, low blood glucose, and low insulin levels. They also show increased numbers of mitochondria in their neurons.

Development of anti-aging drugs is a major focus of investigators at Sirtris Pharmaceuticals, Inc. (Cambridge, MA, USA). After many years of research into the anti-aging properties of reservation, the company's researchers are now concentrating on other compounds that modulate the activity of SIRT1.

The investigators findings appear in the November 28, 2007, issue of the journal Nature. In this article, they described the identification and characterization of small molecule activators of SIRT1 that were structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bound to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lowered the Michaelis constant for acetylated substrates. When administered to mice, SIRT1 activators improved whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle, and the liver.

"The new drug candidates represent a significant milestone because they are the first molecules that have been designed to act on genes that control the aging process. For this reason, we feel they have considerable potential to treat diseases of aging such as Type 2 Diabetes,” said senior author Dr.Christoph Westphal, CEO of Sirtris Pharmaceuticals. "The breakthrough in potency we have achieved with the novel chemical entities (NCEs) means that we can obtain the health benefits of resveratrol with a considerably lower dose.”


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