What is SIRT1?

New Research: SiRT1 Regulation As A Potential Metabolic Disease Therapy

Hypothalamic Sirt1 Regulates Food Intake in a Rodent Model System

Sirt1 is an evolutionarily conserved NAD⁺ dependent deacetylase involved in a wide range of processes including cellular differentiation, apoptosis, as well as metabolism, and aging. In this study, we investigated the role of hypothalamic Sirt1 in energy balance. Pharmacological inhibition or siRNA mediated knock down of hypothalamic Sirt1 showed to decrease food intake and body weight gain. Central administration of a specific melanocortin antagonist, SHU9119, reversed the anorectic effect of hypothalamic Sirt1 inhibition, suggesting that Sirt1 regulates food intake through the central melanocortin signaling. We also showed that fasting increases hypothalamic Sirt1 expression and decreases FoxO1 (Forkhead transcription factor) acetylation suggesting that Sirt1 regulates the central melanocortin system in a FoxO1 dependent manner. In addition, hypothalamic Sirt1 showed to regulate S6K signaling such that inhibition of the fasting induced Sirt1 activity results in up-regulation of the S6K pathway. Thus, this is the first study providing a novel role for the hypothalamic Sirt1 in the regulation of food intake and body weight. Given the role of Sirt1 in several peripheral tissues and hypothalamus, potential therapies centered on Sirt1 regulation might provide promising therapies in the treatment of metabolic diseases including obesity.

Citation: Çakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, et al. (2009) Hypothalamic Sirt1 Regulates Food Intake in a Rodent Model System. PLoS ONE 4(12): e8322. doi:10.1371/journal.pone.0008322

Is Zinc (Zn(2+) Good or Bad For SIRT1 Activity?

J Inorg Biochem. 2009 Oct 29. [Epub ahead of print]

Dual role of Zn(2+) in maintaining structural integrity and suppressing deacetylase activity of SIRT1.

Chen L, Feng Y, Zhou Y, Zhu W, Shen X, Chen K, Jiang H, Liu D.

Department of Molecular Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.

Zn(2+) directly participates in catalysis of histone deacetylase (HDAC) Classes I, II, IV enzymes while its role in HDAC Class III activity is not well established. Herein we investigated the effects of Zn(2+) on the deacetylase activity of sirtuin 1 (silent mating type information regulation 2 homolog 1, SIRT1). We found that the inherent Zn(2+) at the zinc-finger motif of SIRT1 is essential for the structural integrity and the deacetylase activity of SIRT1, whereas the exogenous Zn(2+) strongly inhibits the deacetylase activity with an IC(50) of 0.82muM for Zn(Gly)(2). SIRT1 activity suppressed by the exogenous Zn(2+) can be fully recovered by the metal chelator EDTA but not by the activator resveratrol. We also identified Zn(2+) as a noncompetitive inhibitor for the substrates of NAD(+) and the acetyl peptide P53-AMC. The 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence titration experiments and site-directed mutagenesis study suggested that the exogenous Zn(2+) binds to SIRT1 but not at the zinc-finger motif. These results indicate that Zn(2+) plays a dual role in SIRT1 activity. Inherent Zn(2+) at the zinc-finger motif is structurally related and essential for SIRT1 activity. On the other hand, Zn(2+) may also bind to another site different from the zinc-finger motif or the binding sites for the substrates or resveratrol and act as a potent inhibitor of SIRT1.

PMID: 19923004 [PubMed - as supplied by publisher]

SiRT1 Increase Chemotherapy Drug Resistance

A new study completed by researchers at the National Cancer Institute (NCI) that was published in the September 15th, 2008 issue of Molecular Cancer Research has shown that the increased expression of SiRT1 causes resistance when used with Cisplatin, a chemotherapy drug.

Researchers found the resistance increase as the amount of Cisplatin dosage was increased.  This resistance makes the drug ineffective in its use.  By learning the cause of the resistance factor scientists can research ways to lessen these effects and increase the benefits of chemotherapy using Cisplatin.

A link to the study press release can be found here:

Study Provides Clues about How Cancer Cells Develop Resistance to Chemotherapy Drug

Reference: Liang X, Finkel T, Shen D, Yin J, Aszalos A., and Gottesman MM. SIRT1 Contributes in Part to Cisplatin Resistance in Cancer Cells by Altering Mitochondrial Metabolism. Molecular Cancer Research. September, 15, 2008.

Sirtuin Researcher Lenny Gaurente PBS interview

I came across a recent interview with Lenny Guarente, a biology professor at MIT and a well know Sirtuin researcher, and thought you all might want to check it out.  The interview was done on the Earth & Sky Radio Series part of www.earthsky.org.

The interview posted on the website was brief but it had some very interesting response from Guarente.  (You can also find the complete 13 min video at the bottom of this post)  One part I found particularly helpful was a very simple explanation as to why calorie restriction is beneficial:

Guarente said a low-calorie diet – below 1,500 calories daily – triggers anti-aging genes called sirtuins.

"That can extend their life span by something like one-third."

Guarente said there’s an evolutionary reason for this.

"When conditions become harsh, and food is less available, what these sirtuin genes do is they shift the strategy towards maintenance, and that’s the state that would promote longevity and disease resistance."

The last part of the excerpt is what I find to be a great simple explanation into the mechanics of SiRT1.  When we tell our cells that maintenance is what should occur we stop them from telling the cell to die.  Thus we create more longevity for our individual cells and hopefully in turn longer life. 

What if SiRT1 can...?

So what if SiRT1 is the key to longevity, cell health, increased metabolism, etc?  It seems that almost every day more and more studies are coming out linking SiRT1 to better health.  If in fact it is the key to all of these things then who will benefit from it?  I'd like to think it will be "us!"

Most people think of the research surrounding SiRT1 as "voodoo", or something that just seems to good to be true.  Those people seem to forget that at one time scientists who found anti-biotics were told they were crazy as well.  Now it is the most commonly prescribed drug of our time.  I like to keep an open mind about these things and want to believe the research being done makes sense and "could" work.  If you think about what SiRT1 does it makes sense.  If we can activate "something" that tells our cells to fight to stay alive instead of die then why wouldn't that be a benefit to us?

Circadian Rhythm, Metabolism, and SiRT1 linked

On July 24th a new study was published showing Circadian Rhythm and Metabolism are linked to SiRT1.  There was a great deal of press coverage with several different takes on the study results.  Below I linked several of the news stories so you can get a good understanding of how this information can effect future research.

Circadian rhythm-metabolism link discovered
University of California - Irvine
July 24th, 2008

Circadian Rhythm-Metabolism Link Discovered
Science Daily
July 25th, 2008

Studies Link Circadian Rhythm, Metabolism, Longevity to One Protein
Yahoo News via Healthday, Jeffrey Perkel
July 24th, 2008

Eating affects the body clock
swissinfo.ch - Swiss News, World Wide, Jessica Dacey
July 26th, 2008

SIRT1 Research Links

Listed below are 3 great links to information on SIRT1.  The first link provides a link to just about all the most recently published studies on SIRT1 and is great for searching once or twice a week for updates.

http://www.bioportfolio.com/gene/23411-SIRT1/research.html
This link takes you to a search aggregator from BioPortfolio which grabs links about a particular subject (SIRT1) and posts them all on one page.  It is a great way to keep up-to-date on any new research that gets published on SIRT1.  Give it a try!

http://www.jbc.org/cgi/content/abstract/M802187200v2
SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase (May 14, 2008)
Xiuyun Hou, Shanqin Xu, Karlene A. Maitland-Toolan, Kaori Sato, Bingbing Jiang, Yasuo Ido, Fan Lan, Kenneth Walsh, Michel Wierzbicki, Tony J. Verbeuren, Richard A. Cohen, and Mengwei Zang
Department of Medicine, Boston University School of Medicine, Boston, MA 02481

http://www.bodybuilding.com/fun/beast1.htm
An excellent, easy to follow, explanation of ATP and AMPK (adensine monophosphate-activated protein kinase.)  This article is great to use as a reference to the research study listed above.  It helps to explain some of the biological terms and processes you may not be familiar with.