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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T cell discovery shows promise for Type 1 diabetes treatment

ScienceDaily (Oct. 7, 2010) ? A research team from the University of British Columbia and the Child & Family Research Institute (CFRI) at BC Children's Hospital has identified the role of a type of T cell in type 1 diabetes that may lead to new treatment options for young patients.

Also known as juvenile diabetes, type 1 diabetes is an autoimmune disease primarily affecting children and young adults. In patients with type 1 diabetes, the body attacks itself by destroying insulin-producing cells in the pancreas that regulate glucose, or blood sugar.

Led by Rusung Tan, a Pathology professor in the UBC Faculty of Medicine and co-head of the Immunity in Health and Disease research cluster at CFRI, the research team has identified the increased presence of Th17 cells, a type of T cell discovered in 2005, in children newly diagnosed with type 1 diabetes.

"T cells are white blood cells and key members of the immune system that control infections," says Tan, who is also a member of the Department of Pathology & Laboratory Medicine at BC Children's Hospital and a senior scholar of the Michael Smith Foundation for Health Research. "In healthy individuals, Th17 cells provide a strong defence against bacteria and viruses by guiding the immune system to strongly attack infected targets within our bodies."

However, Th17 has been associated with other autoimmune diseases such as Crohn's disease, which suggests they can play a harmful role. Treatments designed to block Th17 cells are in clinical trials for these diseases.

"The elevated levels of Th17 cells in type 1 diabetes patients suggest that these cells may also play a key role in the early development of this disease in young patients," says Tan. "This discovery opens the door to new treatments for childhood diabetes that target Th17 cells."

The findings are published in the current issue of the Journal of Immunology. The team consists of researchers from UBC, CFRI and the Vancouver Coastal Health Research Institute. At the time of the study, lead author Dr. Ashish Marwaha was a master's student at UBC and CFRI. The study was supported by grants from the Canadian Institutes of Health Research and the Juvenile Diabetes Research Foundation.

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 University of British Columbia.

Journal Reference:

A. K. Marwaha, S. Q. Crome, C. Panagiotopoulos, K. B. Berg, H. Qin, Q. Ouyang, L. Xu, J. J. Priatel, M. K. Levings, R. Tan. Cutting Edge: Increased IL-17-Secreting T Cells in Children with New-Onset Type 1 Diabetes. The Journal of Immunology, 2010; 185 (7): 3814 DOI: 10.4049/jimmunol.1001860

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Epigenomics discovery yields new information about fat cells

ScienceDaily (Sep. 30, 2010) ? By creating a "map" of histone modifications in fat cells, investigators have discovered two new factors that regulate fat formation, a key step on the road to better understanding obesity, diabetes and other metabolic disorders. Led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Broad Institute, the study appears in the October 1 issue of the journal Cell.

"These findings help to demonstrate the power of epigenomic mapping when it comes to gleaning key insights into fat cell formation," explains senior author Evan Rosen, MD, PhD, an investigator in the Department of Endocrinology, Diabetes and Metabolism at BIDMC and Associate Professor of Medicine at Harvard Medical School. Fat cells, also called adipocytes, play an integral role in regulating metabolism by controlling lipid and glucose balance.

To better understand how adipocytes control the genes that impart the specialized functions of these cells, the researchers turned to epigenomics, and specifically the arm of epigenomics known as histone modifications.

"Deoxyribonucleic acid [DNA] is tightly wound around proteins called histones, which, over time, can accumulate chemical modifications or 'marks,'" explains Rosen. "These marks instruct the cell which genes to turn on and off, and by mapping these modifications, we can gain important insights that would be unattainable through traditional means."

Unlike previous investigations, which examined fat cells at a single static time point, this new study mapped several histone modifications throughout the course of the fat cell development, using a technique called chromatin immunoprecipitation followed by massively parallel sequencing or ChIP-Seq. This method relies on the ability to sequence tens of millions of short stretches of DNA (in this case DNA bound to modified histones) and then to reassemble results into a coherent genome. In addition to following these histone markers across time, the scientists also mapped the markers across species.

"Our study looked at both mouse cells and human cells," explains Rosen. "This is key because each cell type can accumulate histone marks that actually have nothing to do with fat cell differentiation. Consequently, by comparing two different cell models, we were able to sift through and focus on the epigenetic marks that appeared in both cell types."

What emerged was a "core" set of histone modifications that formed the basis of a "road map" for the scientists to follow. And, by using this new map, the investigators discovered two transcription factors (proteins that control the copying of DNA into RNA) that regulate fat cell formation.

"We found two new transcription factors -- SRF and PLZF -- involved in fat cell development," explains Rosen. "We have essentially demonstrated how an epigenomic 'road map' can be used to identify biology that could not have been predicted through any other means." Subsequent experiments confirmed the proteins' roles in fat cell development: When either the SRF or the PLZF protein was decreased, fat cells generated at a faster rate and, conversely, when the amount of either protein was increased, fat cell development ceased.

"Although these particular studies were focused on the development of fat cells, we have reason to think that SRF and PLZF may be involved in the workings of mature fat cells as well," notes Rosen, adding that these new findings, therefore, have the potential to impact metabolic diseases such as obesity and Type 2 diabetes.

"The huge costs of obesity and metabolic disease, both in terms of health and from a financial standpoint, are making adipocyte biology increasingly important," he adds. "With these new findings we now have a better understanding of normal fat cell development, and going forward, we can compare normal fat cells to fat cells in disease states. If we can better understand why fat cells behave as they do, then we can work to develop therapies for obesity or diabetes."

This study was funded by grants from the National Institutes of Health and the American Diabetes Association.

Co-first authors of the study are Zhao Xu of BIDMC and Tarjei Mikkelsen of the Broad Institute. Coauthors include Broad Institute investigators Xiaolan Zhang, Li Wang and Eric Lander; and Jeffrey Gimble of the Pennington Biomedical Research Center, Louisiana University System.

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 Beth Israel Deaconess Medical Center.

Journal Reference:

Tarjei S. Mikkelsen, Zhao Xu, Xiaolan Zhang, Li Wang, Jeffrey M. Gimble, Eric S. Lander, Evan D. Rosen. Comparative Epigenomic Analysis of Murine and Human Adipogenesis. Cell, Volume 143, Issue 1, 156-169, 1 October 2010 DOI: 10.1016/j.cell.2010.09.006

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