Molecular 'switch' contributes to cellular aging process: Discovery suggests new treatments for metabolic diseases

ScienceDaily (Nov. 30, 2010) ? A team of Harvard School of Public Health (HSPH) scientists reports finding a molecular "switch" that can "turn off" some cellular processes that are protective against aging and metabolic diseases. While more research is needed, the findings may open doors for new drug treatments to halt or slow development of metabolic diseases like type 2 diabetes or heart disease. The research findings appear in the December 1, 2010 issue of Cell Metabolism.

Scientists want to better understand why some people -- often those who are older, overweight, or obese -- develop metabolic syndrome, a condition characterized by a group of risk factors, including high blood glucose, high cholesterol, insulin resistance, fatty liver, and increased abdominal fat. This condition increases the risk of heart disease, type 2 diabetes, and other diseases, including cancer.

Using genetically altered mouse models, senior author Chih-Hao Lee, assistant professor of genetics and complex diseases at HSPH, first author Shannon Reilly, an HSPH graduate student, and their colleagues focused on the role of the protein SMRT (silencing mediator of retinoid and thyroid hormone receptors) in the aging process. They found aged cells accumulate more SMRT and wanted to see if SMRT increases the damaging effects of oxidative stress on mitochondria, the cell component that converts food and oxygen into energy and powers metabolic activities. Oxidative stress is a cellular process that damages DNA, protein, and other cell functions and can lead to age-related diseases such as type 2 diabetes, Alzheimer's, Parkinson's, and atherosclerosis.

In laboratory experiments, Reilly, Lee, and colleagues found that in older animals SMRT acts like a "switch," turning off the protective cellular activities of proteins known as peroxisome proliferator-activated receptors (PPARs). PPARs help regulate genes that promote fat burning to maintain lipid (blood fat) balance and reduce oxidative stress. The researchers were able to reduce the negative effects of oxidative stress by giving antioxidants or drugs known to turn the protective activities of PPARs back on.

The scientists knew that oxidative damage causes the body to age. What they did not know is why aged cells have more oxidative damage. "The significance of our study is that we show SMRT facilitates this process," Lee said. "In other words, the normal metabolic homeostasis is maintained, in part, by PPARs. SMRT acts as a metabolic switch to turn off PPAR activities when the cells age."

PPAR drugs have been used to increase insulin sensitivity and lower blood lipid levels. "Our study shows PPARs might also be used to boost the body's ability to handle oxidative stress," Lee said.

"With what we have learned, we believe SMRT is one of the key players that causes age-dependent decline in mitochondrial function by blocking PPAR activity, and we've found a way to boost the body's ability to better handle metabolic and oxidative stress," Lee said. "This finding is significant since increased oxidative stress, coupled with reduced metabolic function, contributes to the aging process and the development of age-related metabolic diseases."

In collaboration with epidemiologists at HSPH, the team found genetic variations in the human SMRT gene that are associated with risk of type 2 diabetes. "Through this study we were able to validate that our findings in the animal model apply to human diseases," Lee said.

Support for the study was from the National Institutes of Health as well as from the American Diabetes Association and American Heart Association. Lee received a Career Incubator Fund from HSPH that also supported the work.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Harvard School of Public Health, via EurekAlert!, a service of AAAS.

Journal Reference:

Shannon M. Reilly, Prerna Bhargava, Sihao Liu, Matthew R. Gangl, Cem Gorgun, Russell R. Nofsinger, Ronald M. Evans, Lu Qi, Frank Hu, Chih-Hao Lee. Nuclear Receptor Corepressor SMRT Regulates Mitochondrial Oxidative Metabolism and Mediates Aging-Related Metabolic Deterioration. Cell Metabolism, 2010; DOI: 10.1016/j.cmet.2010.11.007

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New Strategies For Treating Diseases And Illnesses Such As Cancer And Flu

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology;??Diabetes;??Flu / Cold / SARS
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Biochemist and protein crystallographer Dr. Oliver Daumke of the Max Delbruck Center for Molecular Medicine (MDC) Berlin-Buch, Germany, has won the "Bayer Early Excellence in Science Award 2010" in the biology category. He will receive the prize worth EUR 10,000 for his contributions to the understanding of the structure and function of GTP-binding (G) proteins next spring in Berlin. Together with him, two other scientists, Professor Nicolai Cramer (Lausanne, Switzerland) and Dr. Andreas Walther (Helsinki, Finland) will also be honored and receive EUR 10,000 each. G proteins play an important role in cellular signaling pathways and in the defense against infections. The Bayer Foundation presents this award to talented young scientists in the early stages of their academic careers.

G proteins can act as molecular switches that control growth signals in biological cells. Other G proteins function as molecular motors that deform cellular membranes. The group headed by Dr. Daumke investigates the differences and similarities between these two classes of G proteins. The researchers hope that their findings will help develop new strategies to treat diseases such as cancer, diabetes or flu.

Only recently, Dr. Daumke - together with virologists in Freiburg, Germany - elucidated how the human immune system is activated to fight against new, unknown flu viruses. They showed how a G protein called MxA stops flu viruses from replicating.

Dr. Daumke came to the MDC in 2007 as Helmholtz Young Investigator. Prior to his position in Berlin he was a researcher at the Laboratory for Molecular Biology in Cambridge (England). In September this year he was named Junior Professor at the Charite - Universitatsmedizin Berlin. His previous awards include a grant within the Human Frontier Science Program, the Otto Hahn Medal of the Max Planck Society and the Klaus Liebrecht Prize for the best PhD thesis at the University of Cologne.

Source:
Barbara Bachtler
Helmholtz Association of German Research Centres

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Scientists Describe New Approach For Identifying Genetic Markers For Common Diseases

Main Category: Genetics
Also Included In: Diabetes;??Cancer / Oncology
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A group of researchers at The Scripps Research Institute and the Scripps Translational Science Institute has published a paper that reviews new strategies for identifying collections of rare genetic variations that reveal whether people are predisposed to developing common conditions like diabetes and cancer.

In our modern genetic age, the entire DNA sequences, or "genomes," of humans and thousands of other animals, plants, and microbial life forms have been completely decoded and are publicly available to scientists worldwide. One of the hopes now that this data is available is that scientists will be able to find genetic markers of diseases - particular bits of DNA that would identify someone as being at risk for developing a particular disease.

Knowing that a person has such a genetic predisposition could be a powerful tool for preventative medicine because, depending on the disease in question, there may be specific drugs or behavioral modifications like diet or exercise that doctors could prescribe to their patients early on to prevent or significantly lessen the impact of those diseases later in life.

Finding these genetic markers has proven to be difficult, however, and despite the fact that the human genome has been available to researchers for years, scientists have only discovered the underlying genetic determinants for about five to ten percent of the heritable component of most common human diseases.

"There's a long way to go," says Nicholas J. Schork, Ph.D., who is a professor at Scripps Research and director of biostatistics and bioinformatics at the Scripps Translational Science Institute. In the November 2010 issue of Nature Reviews Genetics, Schork and his colleagues outline new statistical strategies that may help to close the gap in the coming years.

Part of the problem, Schork says, is that most studies up to now have focused on identifying common genetic markers of diseases - those definitive DNA signatures that are unmistakably linked to diseases because they are shared by large groups of people who have those diseases.

Such investigations, typically referred to as "genome-wide association studies," use statistical algorithms to sift through DNA samples and pull out whatever common variations exist that exhibit signs of association with a condition. While powerful, these statistical methods may not shed light on many diseases, says Schork, because not all diseases have such definitive DNA signatures. Many of the most common diseases are more complex. They are associated with multiple genes and multiple environmental factors.

According to Schork, the key to identifying the genetic components of these complex diseases is not to focus on finding single common genetic signatures that people share - but rather to identify whole collections of rare genetic signatures, any one of which may indicate a predisposition toward a disease.

The situation is analogous to asking how someone from outside New York City could get to Times Square in Manhattan. There is no single answer to that question because there are any number of approaches and modes of transportation - from New Jersey, from Brooklyn, from Wall Street, or from the Bronx, and via plane, bus, train, taxi, ferry, bridge, tunnel, subway, or sidewalk.

Regardless of where they start or how they get there, it is possible for many people to wind up at exactly the same spot, though, and Schork says the same is true for many human diseases. There may not be one single genetic marker for many diseases, but multiple markers involving any number of genes, even among people who share the same disease.

Finding these rare signatures requires a great deal more scientific sleuthing, says Schork, and in their Nature Review Genetics article Schork and his colleagues suggest a new approach to discover all the possible combinations.

This approach will require collaborations between mathematicians and computer scientists, who have the skills needed to tease out these elusive genetic markers, and biologists who can shed light on what those genes do.

"Mathematics, statistics, and fancy computers alone won't do it," Schork says. "A much more integrative approach has to occur in order to make sense of DNA sequence data."

The article, "Statistical analysis strategies for association studies involving rare variants," is authored by Vikas Bansal, Ondrej Libiger, Ali Torkamani, and Nicholas J. Schork. It appears in the November issue of Nature Reviews Genetics. See http://www.nature.com/nrg/journal/v11/n11/abs/nrg2867.html

This work was funded by grants and support from the National Institutes of Health, the Price Foundation, Scripps Genomic Medicine, and Charles University.

Source:
Mika Ono
Scripps Research Institute

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The Impact Of Chronic Diseases On Patients Also Depends On Their Perception Of The Disease

Editor's Choice
Main Category: Psychology / Psychiatry
Also Included In: Diabetes
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Researchers at the University of Granada have developed a test to measure and assess chronic patients' cognitive representation of their disease. This advance will enable the development of clinical psychological treatments much more efficient than those currently employed.

What do we mean by "common sense" when we talk about a disease? What affects the ideas and beliefs that patients have of their disease? Researchers at the University of Granada have developed a test for measuring and assessing chronic patients' cognitive representation of their disease. This advance will enable the development of clinical psychological treatments much more efficient than those currently employed.

The cognitive representation of a disease is the ideas and beliefs that patients have in relation to their condition, at a given time. These ideas are based around five aspects: symptoms, causes, impact of the disease on patients' lives, way and measures for controlling the condition, time-line and progression of the disease.

Cognitive representation is said to be based on "common sense", since patients are not experts and their ideas and perception of their disease are based on their own experience, self-knowledge and other sources (social, family environment, health center, etc). The researchers state that "the idea that patients have of their disease affects their own coping and adaptation to it".

This study was conducted by Macarena De los Santos Roig, at the department of Social Psychology and Methodology of Behavioral Sciences of the University of Granada, and led by professor Cristino Perez Melendez.

155 Patients

To carry out this study, the researchers used a sample of 155 patients with diabetes Type 1, treated at the Department of Endocronology of the University Hospital San Cecilio, Granada. Patients were given different tests and, although the study centered on patients with diabetes, this test is intended to be applicable to any patient with a chronic disease.

The study revealed that the profile of diabetic patients reporting many symptoms, with the perception of their disease having heavy impact on their lives, low perceived controllability, and a chronic course present significantly worse physical, psychological and social functioning, as well as a poor mental health, lower vitality and worse overall (physical) health, than those who represent their disease differently.

Conversely, patients face their disease more actively, (they seek social support, apply behavioral coping and express their emotions), when they perceive that their disease has significant impact on their lives, but some control is observed. Such results confirm the reliability of the scores obtained on the scale developed in this study. Thus, its effectiveness is demonstrated.

Although other similar assessment tools already existed in other countries, they had been deficiently translated (not adapted, and presenting some deficiencies) into Spanish by national researchers. Consequently, the tool developed by the University of Granada is the most complete and reliable of all existing assessment tools.

Source: Department of Social Psychology and Methodology in Behavioral Sciences, University of Granada

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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Chronic diseases a global problem requiring global solutions, researchers say

ScienceDaily (Sep. 15, 2010) ? Policymakers should increase their sense of urgency to stop the global spread of chronic diseases such as heart disease, cancer and diabetes that threaten the health and economies of industrialized and developing nations alike, Emory University global health researchers say.

Writing in the current issue of The New England Journal of Medicine, authors K. M. Venkat Narayan, MD, Mohammed Ali, MBChB, MSc, and Jeffrey Koplan, MD, MPH, assert that the worldwide spread of chronic conditions, also known as noncommunicable diseases, offers a unique opportunity for low-, middle- and high-income countries around the globe to unite in their efforts to find tangible solutions for reducing the health and economic burdens of these diseases.

Chronic diseases account for 60 percent of all deaths worldwide. Trends also suggest that the major risk factors for these diseases -- hypertension, high glucose levels, obesity, and inactivity -- are all on the rise, especially in developing countries. Six out of the 10 risk factors for mortality worldwide are related to chronic noncommunicable diseases, and not infections or lack of nutrition, as was previously the case.

In addition to the health consequences, the long-term costs of treatment of chronic ailments and the negative effects on productivity take devastating tolls on the economic situations of individuals, families and countries. According to estimates, China, India and Britain will lose $558 billion, $237 billion, and $33 billion, respectively, in national income over the next decade as a result of largely preventable heart disease, strokes and diabetes. In the U.S., cardiovascular disease and diabetes together cost the country $750 billion annually.

"There is a unique opportunity now for global cooperation to tackle noncommunicable diseases," says Narayan, professor of global health and epidemiology at Emory's Rollins School of Public Health and professor of medicine in the Emory School of Medicine. "In fact, unless noncommunicable diseases are tackled, goals relating to child health and infectious diseases cannot be achieved nor can economic development be sustained."

Narayan and his co-authors also cite examples of how global cooperation and connections have benefited the movement to reduce chronic disease, including the development and testing of a new screening test for cervical cancer in India that could result in a lower cost screening test for millions of women worldwide.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Emory University, via EurekAlert!, a service of AAAS.

Journal Reference:

Narayan KV, Ali MK, Koplan JP. Global Noncommunicable Diseases ? Where Worlds Meet. New England Journal of Medicine, 2010; DOI: 10.1056/NEJMp1002024

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Experts advocate realigning type 2 diabetes treatments with disease's natural history

ScienceDaily (Oct. 6, 2010) ? A new consensus statement published in the September 2010 issue of The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM) finds that the increasing recognition that beta-cell failure occurs much earlier and severely than commonly believed suggests that regular glycemia screening, early identification of patients at metabolic risk and prompt and aggressive intervention deserves greater emphasis.

The consensus statement is based on the findings of a working group of basic researchers, clinical endocrinologists and primary care physicians convened by The Endocrine Society, to consider whether current knowledge regarding pancreatic beta-cell defects justifies retargeting and retiming treatment for diabetes in clinical practice.

"There is widespread evidence that conventional approaches to the management of type 2 diabetes have been inadequate," said Jack L. Leahy, MD, of the Vermont Regional Diabetes Center in South Burlington, and one of the authors of the consensus statement. "Studies have increasingly shown that beta-cells have an important role in the progression of diabetes and if we could gain a better understanding of that role, we may be able to develop new and effective means of treatment. To that end, working group members advocate for continued basic research to elucidate the nature and mechanisms of beta-cell failure in type 2 diabetes."

Evidence from both human and animal studies suggests that type 2 diabetes is characterized by dysfunctional beta-cells that cannot adapt insulin secretion to compensate for increasing insulin resistance. Beta-cell failure is believed to occur at an early stage in the progression of diabetes, and accumulating evidence suggests that the decline in beta-cell function may be slowed or even reversed, particularly if addressed early.

"Another recommendation of the working group is to explore new educational approaches to promote pathophysiology-based clinical practices, and that is why the Society has launched the new Web site, BetaCellsinDiabetes.org," said Leahy. "It is our hope that the new site will aid primary care physicians in the interpretation of concepts of disease pathogenesis, such as beta-cell dysfunction, and improve medical decision-making regarding treatment of type 2 diabetes. We have made the site practical by synthesizing research, creating case studies, providing a curated list of the published literature, and inviting viewers to comment throughout the site."

In the consensus statement, experts also recommend additional studies to establish the clinical value of pharmacological therapies targeting beta-cell function. In addition, further research should aim to determine whether specific genetic subtypes of type 2 diabetes lend themselves to individualized therapy to slow or reverse beta-cell decline.

"More research is needed to determine whether preserving beta-cell function improves morbidity and mortality rates," said Leahy. "Nonetheless, the increasing recognition that beta-cell failure occurs much earlier and severely than commonly believed suggests that regular glycemia screening, early identification of patients at metabolic risk and prompt and aggressive intervention deserves greater emphasis."

The 2009 working group meeting was funded by an unrestricted educational grant from Novo Nordisk.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by The Endocrine Society, via EurekAlert!, a service of AAAS.

Journal Reference:

J. L. Leahy, I. B. Hirsch, K. A. Peterson, D. Schneider. Targeting β-Cell Function Early in the Course of Therapy for Type 2 Diabetes Mellitus. Journal of Clinical Endocrinology & Metabolism, 2010; 95 (9): 4206 DOI: 10.1210/jc.2010-0668

Note: If no author is given, the source is cited instead.

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