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Reducing p38MAPK levels delays aging of multiple tissues in lab mice

24.07.2009
Singapore and NC researchers report findings in Developmental Cell

In the new issue of the Developmental Cell journal, a team of scientists at Singapore's Agency for Science, Technology and Research (A*STAR) and the University of North Carolina School of Medicine at Chapel Hill, report research findings about the molecular mechanisms behind the aging process, which has up till now been poorly understood, that offer the possibility that a novel, pharmacological approach could be developed to combat age-related disorders.

In their research with lab rodents, the scientists found that the p38MAPK protein, already known for its role in inflammation, also promotes aging when it activates another protein p16, which has long been linked to aging.

In addition, they found that reducing the levels of p38MAPK delayed the aging of multiple tissues.

Through their experiments, the scientists found that partial inactivation of p38MAPK was sufficient to prevent age-induced cellular changes in multiple tissues, as well as improve the proliferation and regeneration of islet cells, without affecting the tumour suppressor function of p16 in mice.

Dmitry Bulavin, M.D., Ph.D., research team leader and principal investigator in A*STAR's Institute of Molecular and Cell Biology (IMCB), said, "We are excited by this new found role for p38MAPK in aging. Due to the previously established involvement of p38MAPK in inflammatory diseases, small molecule inhibitors of p38MAPK signalling have already entered clinical trials for the treatment of other medical conditions such as rheumatoid arthritis. Our latest discovery offers the possibility that a novel, pharmacological approach could be developed to combat age-related disorders."

In the paper, the scientists described how they studied the role of p38MAPK in aging by using genetically modified mice. They found that several organs, including the pancreas, in the mice that had a reduced amount of p38MAPK protein exhibited a delayed degeneration as the mice grew older.

These mice also displayed an improved growth and regeneration of pancreatic islet beta cells compared to the control group of mice with normal levels of p38MAPK. Beta cells make and release insulin.

In Type 2 diabetes, these cells are unable to produce enough insulin to meet the body's demand, partly due to a decrease in beta cell mass.

In addition, the scientists also found that the forced activation of p38MAPK stunted the growth of insulin-producing islet beta cells and caused insulin resistance in mice, which is the basis of Type 2 diabetes.

These results suggest that by controlling p38MAPK levels, scientists could potentially treat age-related degenerative conditions dependent on the p38MAPK signalling pathways.

Such findings may prove important to the development of novel treatment approaches for Type 2 diabetes in the elderly.

While investigating the effects of lowering p38MAPK levels to achieve a significant delay in aging in mice, the scientists had another consideration: insuring that the level of p16, a tumour suppressor, did not fall below the threshold that was required to protect the animals from developing tumours.

Through their experiments, the scientists found that partial inactivation of p38MAPK was sufficient to prevent age-induced cellular changes in multiple tissues, as well as improve the proliferation and regeneration of islet cells, without affecting the tumour suppressor function of p16 in mice.

The scientists went on to investigate the upstream mechanisms that regulated p38MAPK in old mice and that have not been widely studied to date.

They found that high levels of the protein Wip1, a protein that has been known to be implicated in cancer, suppressed the activity of p38MAPK, and this led to islet proliferation, which in turn improved the pancreatic function in aging mice.

Their results, therefore, identified Wip1 as an additional target to which anti-aging therapies could be directed.

Neal Copeland, Ph.D., Executive Director of IMCB, said, "Dr. Bulavin's team has achieved an important breakthrough in the study of ageing. These significant findings, together with other recent discoveries made by IMCB's scientists, illustrate how IMCB has worked with its international collaborators to fully harness the knowledge and tools of modern medical science, to increase understanding of the causes behind common human diseases. The resulting knowledge will hopefully contribute to the development of effective treatment for clinical conditions."

The research findings are described in the following article, "p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age," published in the 21 July 2009 print issue of Developmental Cell.

Authors: Esther Sook Miin Wong1,4, Xavier Le Guezennec1,4, Oleg N. Demidov1, Nicolette Theresa Marshall1, Siew Tein Wang2, Janakiraman Krishnamurthy3, Norman E. Sharpless3, N. Ray Dunn2 and Dmitry V. Bulavin1,*

1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
2 Institute of Medical Biology, Agency for Science, Technology and Research, Singapore
3 Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA

4 These authors contributed equally to this work.

* Corresponding author: Dr Dmitry Bulavin, dvbulavin@imcb.a-star.edu.sg

Institute of Molecular and Cell Biology (IMCB):

The Institute of Molecular and Cell Biology (IMCB) is a member of Singapore's Agency for Science, Technology and Research (A*STAR) and is funded through A*STAR's Biomedical Research Council (BMRC). It is a world-class research institute that focuses its activities on six major fields: Cell Biology, Developmental Biology, Structural Biology, Infectious Diseases, Cancer Biology and Translational Research, with core strengths in cell cycling, cell signalling, cell death, cell motility and protein trafficking. Its recent achievements include leading an international consortium that successfully sequenced the entire pufferfish (Fugu) genome. The IMCB was awarded the Nikkei Prize 2000 for Technological Innovation in recognition of its growth into a leading international research centre and its collaboration with industry and research institutes worldwide. Established in 1987, the Institute currently has 35 independent research groups with more than 400 staff members.

For more information about IMCB, please visit www.imcb.a-star.edu.sg.

Institute of Medical Biology (IMB):

The Institute of Medical Biology is a member of the Agency for Science, Technology and Research (A*STAR). With its roots in the Centre for Molecular Medicine since 2004, it became the Institute of Medical Biology in 2007, with a mission to study mechanisms of human disease in order to discover new and effective therapeutic strategies for improved quality of life. IMB is developing internationally excellent research programmes working closely with clinical collaborators, targeting the challenging interface between basic science and clinical medicine, and aiming to promote increased and effective throughput of research from bench to bedside. Its growing portfolio of strategic research topics aims to promote translational research on the mechanisms of human diseases with a cell to tissue emphasis that can help identify new therapeutic strategies for disease amelioration, cure and eradication.

For more information about IMB, please visit www.imb.a-star.edu.sg.

Agency for Science, Technology and Research (A*STAR):

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based Singapore. A*STAR actively nurtures public sector research and development in Biomedical Sciences, and Physical Sciences and Engineering, and supports Singapore's key economic clusters by providing intellectual, human and industrial capital to our partners in industry and the healthcare sector. It oversees 23 research institutes, consortia and centres located in Biopolis and Fusionopolis, and the area in their vicinity, and supports extramural research with the universities, hospital research centres, and other local and international partners.

Wang Yunshi | EurekAlert!
Further information:
http://www.a-star.edu.sg

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