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Citrus Chemical Prevents Obesity in Mice

Researchers have reported that a particular flavonoid (naringenin) derived from citrus fruit shows promise for preventing weight gain and other signs of metabolic syndrome, which can lead to type 2 diabetes and increased risk of cardiovascular disease. Metabolic syndrome is characterized by a group of metabolic risk factors present in one person. These risk factors include abdominal obesity, blood fat disorders, elevated blood pressure, and insulin resistance or glucose intolerance. In the current study, one group of mice was fed a high-fat (western) diet to induce the symptoms of metabolic syndrome. A second group was fed the exact same diet and treated with naringenin. Naringenin corrected the elevations in triglyceride and cholesterol, prevented the development of insulin resistance, and completely normalized glucose metabolism. The researchers found that naringenin worked by genetically reprogramming the liver to burn up excess fat, rather than store it. "Furthermore, the marked obesity that develops in these mice was completely prevented by naringenin," said Dr. Murray Huff, senior author of the study. "What was unique about the study was that the effects were independent of caloric intake, meaning the mice ate exactly the same amount of food and the same amount of fat. There was no suppression of appetite or decreased food intake, which are often the basis of strategies to reduce weight gain and its metabolic consequences,” Dr. Huff said.

Animal Evidence That Dietary Supplement May Help Prevent, Treat Cataracts

New evidence, obtained in a rat model, supports earlier suggestions that the dietary supplement carnosine might be effective in preventing and treating cataracts. Cataracts are a clouding of the lens of the eye and are a leading cause of vision loss worldwide. Cataracts develop when the main structural protein in the lens, alpha-crystallin, forms abnormal clumps. The clumps make the lens cloudy and impair vision. Previous studies had hinted that carnosine might help block the formation of these clumps. In the current work, scientists from the University of Catania in Italy, and colleagues, exposed tissue cultures of healthy rat lenses to either guanidine, a substance known to induce the formation of cataracts, or to a combination of guanidine and carnosine. The guanidine lenses became completely cloudy, while the guanidine/carnosine lenses developed 50 to 60 percent less cloudiness. Carnosine also restored most of the clarity to clouded lenses. The results demonstrate the potential of using carnosine for preventing and treating cataracts, the scientists said. The study is scheduled to be published in the July 28 edition of Biochemistry. [Press release]

Enzyme Deletion Preserves Thymus Function, Extends Lifespan

Researchers have shown, in a mouse model, that deletion of the gene for a particular enzyme [pregnancy-associated plasma protein A (PAPPA)] can preserve thymus function throughout life and extend lifespan by as much as 30 percent. The so-called PAPPA “knockout” mice also showed a significantly lower occurrence of spontaneous tumors than typical mice. It is suggested that preservation of thymus function permits the mice to maintain a robust immune system that contributes to healthy longevity. In all normal mammals, the thymus―the organ that produces T-cells to fight disease and infection―degenerates with age. PAPPA controls the availability in tissues of a hormone known as insulin-like growth factor (IGF) that is a promoter of cell division. Hence, IGF is required for normal embryonic and postnatal growth. But IGF also is associated with tumor growth, inflammation, and cardiovascular disease in adults. By deleting PAPPA, the researchers were able to control the availability of IGF in tissues and dampen its many ill effects. In the thymus, deletion of PAPPA maintained just enough IGF to sustain production of T cells without consuming precursor cells, thereby preventing the degeneration of the thymus. "Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune protection throughout life," study leader Dr. Abbe de Vallejo said. "This study has profound implications for the future study of healthy aging and longevity." The results were published in the July 7 issue of PNAS. [Press release] [PNAS article]

Progress on Life-Saving Antibody for Inhalation Anthrax

The New England Journal of Medicine has published the results of two pivotal animal efficacy studies showing the life-saving potential of a human monoclonal antibody drug raxibacumab (ABthrax) in inhalation anthrax disease. The publication also included the results of human safety studies that supported the use of raxibacumab in the event of life-threatening inhalation anthrax disease. Raxibacumab is manufactured by Human Genome Sciences, Inc., which conducted the studies together with collaborators. "The results published today showed that a single dose of raxibacumab was highly effective as a treatment for inhalation anthrax in both rabbits and monkeys," said Dr. Sally D. Bolmer, senior author of the NEJM report and Senior Vice President, Development and Regulatory Affairs, Human Genome Sciences. "Raxibacumab acted quickly to provide a significant survival benefit to animals showing clinical signs of disease caused by exposure to a dose of aerosolized anthrax spores that was approximately 200 times the median lethal dose. We also note that the safety profile shown in healthy human volunteers provides support for use of raxibacumab in the clinical setting of immediately life-threatening inhalation anthrax disease." Raxibacumab represents a new way to address the anthrax threat. While antibiotics can kill the anthrax bacteria, they are not effective against the deadly toxins that the bacteria produce. Raxibacumab targets anthrax toxins after they are released by the bacteria into the blood and tissues. In an inhalation anthrax attack, people may not know they are infected with anthrax until the toxins already are circulating in their blood, and it may be too late for antibiotics alone to be effective.

Yeast Model May Aid Understanding of Friedrich’s Ataxia

Friedrich’s ataxia is one of the most common hereditary ataxias and its most common molecular cause is a massive expansion in the number of GAA triplet nucleotide repeats in intron 1 of the frataxin gene on chromosome 9. There is no cure for the condition which damages the nervous system and can cause heart disease. Until now, research has been hampered by the lack of an animal model in which the GAA triplet expansions could be replicated and studied. But in the July 10 issue of Molecular Cell, researchers report that they have created such a model in yeast. In doing so, the scientists were able to analyze GAA repeat expansions and then identify cellular proteins that thwarted normal replication and promoted the elongated sequence. "In essence, we believe that the replication machinery occasionally gets tangled within a repetitive run, adding extra repeats while trying to escape," said Dr. Sergei Mirkin, senior author of the study. “And the longer the repeat, the more likely the entanglement is. That is as if a car which entered a roundabout misses the right exit due the heavy traffic and has to make the whole extra circle before finally escaping.” Dr. Mirkin and his team carried out a genetic screen to identify yeast proteins affecting repeat expansions. They found that the proteins within the cell that are known to facilitate the smooth replication fork progression decreased repeat expansions. Meanwhile the proteins responsible for the fork deviations, such as template switching and reversal, increased repeat expansions. It is possible that study of the yeast model may illuminate molecular mechanisms underlying Friedrich’s ataxia and may point the way toward effective interventions.

Crohn’s Disease Defect Associated with Poor Response to Mycobacteria

Approximately 25 perecent of patients with Crohn’s disease have a mutation in the NOD2 gene, but until now it has not been clear how this mutation might influence the disease. Now, researchers have obtained evidence that the NOD2 protein influences the binding of mycobacteria and the subsequent launching of an immune response. Defects in NOD2 can prevent binding of the mycobacteria and allow the establishment of persistent infections. The researches showed that the NOD2 protein preferentially recognizes a peptide called N-glycolyl-MDP, which is only found in mycobacteria. When mycobacteria invade the human body, they cause an immediate and very strong immune response via the NOD2 receptor. "Now that we have a better understanding of the normal role of NOD2, we think that a mutation in this gene prevents mycobacteria from being properly recognized by the immune system," explained Dr. Marcel Behr, senior author of the report. "If mycobacteria are not recognized, the body cannot effectively fight them off and then becomes persistently infected." This new discovery associates the predisposition for Crohn's disease with both the NOD2 mutation and the presence of mycobacteria, but researchers must still determine the precise combination of these factors to understand how the disease develops. The research was published online on July 6 in the Journal of Experimental Medicine. [Press release] [JEM abstract]

Caloric Restriction Extends Lifespan in Primates

A 20-year study in adult rhesus monkeys has shown that caloric restriction (CR) in these primates can extend healthy lifespan. At the end of the study, 37 percent of the control group had died of age-related causes, while only 13 percent of the CR group had. This finding means that the control monkeys experienced a death rate from age-related conditions such as diabetes, cancer, cardiovascular disease, and brain atrophy almost three times that of the CR group. Previous studies with yeast, worms, flies, and rodents have suggested that this kind of caloric restriction–a reduction of about 30 percent, and very different from malnutrition–can lead to such health benefits in some mammals, but given the many parallels between rhesus monkeys and humans, this study suggests that these benefits might occur in humans as well. "We have been able to show that caloric restriction can slow the aging process in a primate species," said Dr. Richard Weindruch, senior author of the study. "We observed that caloric restriction reduced the risk of developing an age-related disease by a factor of three and increased survival." The incidence of cancerous tumors and cardiovascular disease in animals on a restricted diet was less than half that seen in animals permitted to eat freely. Remarkably, while diabetes or impaired glucose regulation is common in monkeys that can eat all they want, it has yet to be observed in any animal on a restricted diet. "So far, we've seen the complete prevention of diabetes," said Dr. Weindruch. Furthermore, he noted, "The atrophy or loss of brain mass known to occur with aging is significantly attenuated in several regions of the brain. That's a completely new observation." The results of this study were published in the July 10 issue of Science.

A Molecular Link Between Obesity and Type 2 Diabetes Discovered

Although obesity is a major risk factor for type 2 diabetes, the factors linking these disorders are not well defined. Now, scientists at Monash University in Australia, and collaborating institutions, have obtained evidence for a molecular link between the two conditions. In a mouse model, the researchers have shown that a novel protein (pigment epithelium-derived factor or PEDF) released by fat cells triggers a chain of events and interactions that lead to the development of type 2 diabetes. "When PEDF is released into the bloodstream, it causes the muscle and liver to become desensitized to insulin. The pancreas then produces more insulin to counteract these negative effects," said Dr. Matthew Watt, senior author of the study. “This insulin release causes the pancreas to become overworked, eventually slowing or stopping insulin release from the pancreas, leading to type 2 diabetes. Our research was able to show that increasing PEDF not only causes type 2 diabetes-like complications but that blocking PEDF reverses these effects. The body again returned to being insulin-sensitive and therefore did not need excess insulin to remain regulated," Dr. Watt continued. "Until now scientists knew there was a very clear pattern and had strong suspicions that a link existed between the two conditions, but our understanding of the chain of events that are caused by the release of PEDF shows a causal link," Dr. Watt said. The results of this work were published in the July 8 issue of Cell Metabolism. [Press release] [Cell Metabolism abstract]

Easter Island Compound Extends Lifespan of Older Mice

In a multi-center study, scientists have shown that a compound first discovered in the soil of Easter Island can extend the lifespan of older mice. The compound is rapamycin, named from the Polynesian for the island, Rapa Nui. Discovered in the 1970s, rapamycin was first noted for its anti-fungal properties and later was used to prevent organ rejection in transplant patients. It is also used in stents, which are implanted in patients during angioplasty to keep coronary arteries open. It is in clinical trials for the treatment of cancer. In the current work, when rapamycin was added to the diets of older, genetically diverse mice (at an age equivalent to 60 years in humans), it extended lifespan by 28 to 38 percent. In human terms, this would be greater than the predicted increase in extra years of life if cancer and heart disease were both cured and prevented. "I've been in aging research for 35 years and there have been many so-called 'anti-aging' interventions over those years that were never successful," said Dr. Arlan G. Richardson, director of the Barshop Institute for Longevity and Aging Studies, and not involved in the study. "I never thought we would find an anti-aging pill for people in my lifetime; however, rapamycin shows a great deal of promise to do just that." "We believe this is the first convincing evidence that the aging process can be slowed and lifespan can be extended by a drug therapy starting at an advanced age," said Dr. Randy Strong, a lead author of the study. Aging researchers currently acknowledge only two life-extending interventions in mammals: calorie restriction and genetic manipulation. Rapamycin appears to partially shut down the same molecular pathway as restricting food intake or reducing growth factors.

Two Genes Associated with Mole Number and Melanoma Risk

Researchers from the Queensland Institute of Medical Research in Australia, and collaborators, have shown that variants in two genes (MTAP and PLA2G6) are associated with an increased number of moles and with an increased risk of melanoma, the deadliest form of skin cancer. "These are the first genes found to increase melanoma risk by influencing the number of moles a person has," explained Dr. Nick Hayward, a lead author of the study. "This finding improves our understanding of the genetics of melanoma and therefore the molecular pathways that lead to its development.” He noted that “it has long been known that having a large number of moles is the biggest risk factor. Therefore we predicted we would find genes linking moles and melanoma. We now have conclusive genetic evidence that having a large number of moles increases an individual's risk of developing melanoma." The study found that having an associated variant in one of the two genes increased the risk of melanoma by 25 percent, while having associated variants in both genes doubled the risk. Australia has the highest incidence of melanoma in the world with more than 10,000 new cases and 1,000 people dying from the disease every year. Queensland has the highest incidence of any state in Australia with seven Queenslanders diagnosed with melanoma every day. More than one in 20 Queenslanders is expected to develop melanoma during his or her lifetime. The new research was reported online in Nature Genetics on July 5. [Press release] [Nature Genetics abstract]

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