Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Single molecular switch may contribute to major aging-related diseases


Blocking effects of nitric oxide on SIRT1 protein could disrupt inflammation associated with diabetes, atherosclerosis, Parkinson's disease

A study led by Massachusetts General Hospital (MGH) investigators has identified what appears to be a molecular switch controlling inflammatory processes involved in conditions ranging from muscle atrophy to Alzheimer's disease.

In their report published in Science Signaling, the research team found that the action of the signaling molecule nitric oxide on the regulatory protein SIRT1 is required for the induction of inflammation and cell death in cellular and animal models of several aging-related disorders.

"Since different pathological mechanisms have been identified for diseases like type 2 diabetes, atherosclerosis and Parkinson's disease, it has been assumed that therapeutic strategies for those conditions should also differ," says Masao Kaneki, MD, PhD, MGH Department of Anesthesia, Critical Care and Pain Medicine, senior author of the paper. "In contrast, our findings identified nitric oxide-mediated inactivation of SIRT1 - believed to be a longevity gene - as a hub of the inflammatory spiral common to many aging-related diseases, clarifying a new preventive molecular target."

Studies have implicated a role for nitric oxide in diabetes, neurodegeneration, atherosclerosis and other aging-related disorders known to involve chronic inflammation. But exactly how nitric oxide exerts those effects - including activation of the inflammatory factor NF-kappaB and the regulatory protein p53, which can induce the death of damaged cells - was not known. SIRT1 is known to suppress the activity of both NF-kappaB and p53, and since its dysregulation has been associated with models of several aging-related conditions, the research team focused on nitric oxide's suppression of SIRT1 through a process called S-nitrosylation.

Cellular experiments revealed that S-nitrosylation inactivates SIRT1 by interfering with the protein's ability to bind zinc, which in turn increases the activation of p53 and of a protein subunit of NF-kappaB. Experiments in mouse models of systemic inflammation, age-related muscle atrophy and Parkinson's disease found that blocking or knocking out NO synthase - the enzyme that induces nitric oxide generation - prevented the cellular and in the Parkinson's model behavioral effects of the diseases. Additional experiments pinpointed the S-nitrosylation of SIRT1 as a critical point in the chain of events leading from nitric oxide expression to cellular damage and death.

"Regardless of the original event that set off this process, once turned on by SIRT1 inactivation, the same cascade of enhanced inflammation and cell death leads to many different disorders," says Kaneki, an associate professor of Anaesthesia at Harvard Medical School. "While we need to confirm that what we found in rodent models operates in human diseases, I believe this process plays an important role in the pathogenesis of conditions including obesity-related diabetes, atherosclerosis, Alzheimer's disease and the body's response to major trauma. We're now trying to identify small molecules that will specifically inhibit S-nitrosylation of SIRT1 and related proteins and suppress this proinflammatory switch."

The co-lead authors of the Science Signaling paper are Shohei Shinozaki, PhD, Tokyo Medical and Dental University, and Kyungho Chang, MD, PhD, University of Tokyo School of Medicine, both of whom previously were research fellows at MGH. Additional co-authors include Michihiro Sakai, Nobuyuki Shimizu, Marina Yamada, Tomokazu Tanaka, MD, PhD, Harumasa Nakazawa, MD and Fumito Ichinose, MD, PhD, all of the MGH Department of Anesthesia, Critical Care and Pain Medicine; and Jonathan S. Stamler, MD, Case Western Reserve University and University Hospital, Cleveland.

Support for the study includes National Institutes of Health grants R01-DK-058127, R01-GM-099921, 5P01-HL-075443-08 and R01-AG-039732; Defense Advanced Research Project Agency grant N66001-13-C-4054; American Diabetes Association grant 7-08-RA-77, and grants from Shriners Hospitals for Children.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $785 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Sue McGreevey | EurekAlert!

More articles from Life Sciences:

nachricht Biologists unravel another mystery of what makes DNA go 'loopy'
16.03.2018 | Emory Health Sciences

nachricht Scientists map the portal to the cell's nucleus
16.03.2018 | Rockefeller University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

Im Focus: Unique Insights into the Antarctic Ice Shelf System

Data collected on ocean-ice interactions in the little-researched regions of the far south

The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...

Im Focus: ILA 2018: Laser alternative to hexavalent chromium coating

At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.

When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...

Im Focus: Radar for navigation support from autonomous flying drones

At the ILA Berlin, hall 4, booth 202, Fraunhofer FHR will present two radar sensors for navigation support of drones. The sensors are valuable components in the implementation of autonomous flying drones: they function as obstacle detectors to prevent collisions. Radar sensors also operate reliably in restricted visibility, e.g. in foggy or dusty conditions. Due to their ability to measure distances with high precision, the radar sensors can also be used as altimeters when other sources of information such as barometers or GPS are not available or cannot operate optimally.

Drones play an increasingly important role in the area of logistics and services. Well-known logistic companies place great hope in these compact, aerial...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

International Virtual Reality Conference “IEEE VR 2018” comes to Reutlingen, Germany

08.03.2018 | Event News

Latest News

Wandering greenhouse gas

16.03.2018 | Earth Sciences

'Frequency combs' ID chemicals within the mid-infrared spectral region

16.03.2018 | Physics and Astronomy

Biologists unravel another mystery of what makes DNA go 'loopy'

16.03.2018 | Life Sciences

Science & Research
Overview of more VideoLinks >>>