Two Publications Identify “Longevity” Enzyme Interactions

For the last couple decades, a particular enzyme has been the focus of intense study. Sirtuin1 was found to be a key protein affecting the longevity of some organisms such as yeast. Decrease in caloric intake, which could lengthen cell life, became ineffective in the absence of sirtuin1. At the time of its discovery it was hailed as a potential “fountain of youth.”

Although its promise as the fountain of youth remains unfulfilled, the discovery of sirtuin1 has still opened plenty of other interesting avenues for research. Years of research into this enzyme and its reach have resulted in two recent, high-profile publications from the University of Iowa. The first, appearing in the January issue of PNAS, identifies a connection between sirtuin 1 and p66Shc, a protein that promotes oxidative stress and has been shown to degrade or limit the life span of some mammals. For example, by deleting p66Shc in mice, their lifespan could be extended as much as 30 to 35 percent. In addition, higher levels of p66Shc have been linked to diabetes and heart disease.

Dr. Kumar

Dr. Santosh Kumar is an Associate of Cardiovascular Medicine, working in the lab of Dr. Kaikobad Irani, Professor of Cardiovascular Medicine. Dr. Kumar is first author on the PNAS article, which finds that p66Shc’s negative effects can be moderated by sirtuin1, that the two proteins counteract one another. Specifically, Dr. Kumar’s work showed that the negative effects of p66Shc in blood vessels debilitated by diabetes could be moderated by sirtuin1. Thus, in some patients with diabetes, presence of sirtuin1 could help mitigate some of the cardiovascular complications of their disease.

Immunofluorescence for phospho-p66ShcS36 in aortas of mice with conditional deletion of e-SIRT1KO and wild-type mice. Arrow indicates endothelial layer.

The second publication appeared this week in Nature Medicine. This article reveals a connection between sirtuin1 and the channel that conducts sodium in heart cells and is responsible for triggering the electrical impulse of the heart. While presence of the longevity enzyme is known to protect the heart muscle from insults, this discovery showed that sirtuin 1 is also essential for the electrical activity that makes the heart muscle contract with every heartbeat.

vikramyoonThe article also represents the culmination of a lengthy collaboration between members of Dr. Irani’s lab as well as those in the lab of Dr. Barry London, Division Director of Cardiovascular Medicine. The teamwork began when both of them were still at the University of Pittsburgh and continued through relocation to the University of Iowa. The bulk of the work in the last couple years was performed by primary authors Dr. Ajit Vikram in the Irani Lab, Dr. Jin-Young Yoon in the London Lab, and Dr. Chris Lewarchik, who remained at Pittsburgh after Dr. London came to Iowa.

Photomicrographs showing the localization of Sirt1 and Nav1.5 in cardiomyocytes. White, pixel colocalization analyzed using the RG2B plugin in ImageJ. Insets show higher-magnification views of the boxed areas. Scale bar, 20 μm.

Dr. Yoon explains the discovery: “Mice lacking Sirt1 in hearts had increased acetylation of the cardiac sodium channel, decreased sodium current, and died of cardiac arrhythmias.” Dr. Vikram notes the implications: “These findings could pave the way for the use of sirtuin1 activators as a novel anti-arrhythmic therapy.”

“A lot of science is based on hunches,” Dr. Irani says of his and Dr. London’s guess at the connection between the presence of sirtuin1 and its ability to regulate electrical processes in the heart. He started this collaboration with Dr. London based on an an educated guess more than six years ago, when he saw the potential to synergize strengths of both labs to answer a question neither could independently. Dr. Irani encourages more scientists to reach out to colleagues outside their areas of expertise in search of these possibilities. “Talking to people who don’t know what you’re talking about and vice versa. That’s where the best science comes from, some of the most exciting discoveries.”

2 Responses

  1. […] Collaboration, especially when it allows us to push the envelope in terms of innovation, will often reap impressive dividends. This is true across all of our missions. In research, a collaboration that began between the labs of Dr. Kaikobad Irani and Dr. Barry London more than six years ago has now resulted in a groundbreaking publication in the journal Nature Medicine. Both labs brought their unique expertise and perspectives to their collaborations which identified an interaction between a long-studied enzyme implicated in longevity (Sirtuin1) and the cardiac sodium channel, providing novel and fundamental insight into certain cardiac arrhythmias. I encourage you to read this publication and another recent publication from the Irani laboratory also concerning the so-called longevity protein Sirtuin1 in this post. […]

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