Potential Found in a New Approach to Alzheimer's

A potentially promising approach to treating Alzheimer’s disease has been developed by researchers studying sirtuin, a protein thought capable of extending lifespan in laboratory animals.

Using mice prone to developing Alzheimer’s, the researchers showed that activating sirtuin suppressed the disease and that destroying sirtuin made it much worse.

The finding was made by Gizem Donmez, Leonard Guarente and colleagues at the Massachusetts Institute of Technology, who say it raises the hope of treating Alzheimer’s, and possibly other neurodegenerative diseases like Parkinson’s and Huntington’s, with drugs that activate sirtuin.

Researchers not involved in the study agreed. “We think it is a scientifically compelling story that ties the sirtuins to the biology of Alzheimer’s disease,” said Dr. Dennis J. Selkoe, an Alzheimer’s expert at Harvard Medical School. But the therapeutic implications, Dr. Selkoe added, “remain quite up in the air.”

Another expert, Dr. Juan C. Troncoso of Johns Hopkins University School of Medicine, said the finding “opens a very good avenue, but it’s not without a lot of technical challenges.”

Drugs that activate sirtuin already exist, including resveratrol, a minor ingredient of red wine and other foods, and small-molecule chemicals designed to mimic resveratrol. Sirtris, the company that developed the drugs, is testing them against diabetes and other diseases. This generation of drugs does not cross the blood-brain barrier so would not work against Alzheimer’s.

But George P. Vlasuk, Sirtris’s chief executive, said the company had developed other sirtuin-activating chemicals that do reach the brain and are in preclinical trials. “We think it has very significant potential in neurodegenerative diseases,” Dr. Vlasuk said.

Sirtuin has been the subject of intense research in the last few years because it seems to protect the body’s various organs against disease by stepping up maintenance programs. The substance came to light through studies of longevity, particularly the discovery that reduced-calorie diets could lengthen the lifespan of mice by 30 percent. Sirtuin appears to convey much of the beneficial effect of such diets, even though drugs that activate sirtuin have not yet been shown to prolong mice’s lifespan in experiments.

Dr. Guarente, a leading sirtuin researcher, said the protein’s protective power against other diseases made him wonder if it might also help against Alzheimer’s. He obtained mice that tend to develop Alzheimer’s-like symptoms because they are genetically engineered to carry two mutated human genes that cause a buildup of plaque in the brain. The mice were crossed with a strain of mice in which the sirtuin-making gene is particularly active. They were also crossed with a strain in which the sirtuin gene was deleted entirely. Dr. Guarente’s team could thus test the effect of having either more or less sirtuin in the brains of Alzheimer’s-prone mice.

The decline in memory typical of Alzheimer’s “was clearly suppressed” in the Alzheimer’s-prone mice with abundant sirtuin, the M.I.T. group reports in Friday’s issue of Cell, while the mice with Alzheimer’s genes and no sirtuin started to lose memory at a much younger age.

The team found the sirtuin protected the mice’s brains two ways. First, it activated a system called the notch pathway, which protects brain cells against stress. Second, it enhanced an enzyme whose activity avoids the buildup of the plaque characteristic of Alzheimer’s and particularly of a toxic component called A-beta peptide.

Reducing the amount of A-beta peptide is helpful only in Alzheimer’s but turning on the notch pathway could provide general protection for the brain. Activating sirtuin, the M.I.T. researchers conclude, “is a viable strategy to combat Alzheimer’s disease and perhaps other neurodegenerative diseases.”

Dr. Guarente said he was looking into whether extra sirtuin had an effect in mice made vulnerable to Parkinson’s and Huntington’s disease.

Activating the notch pathway with sirtuins “opens a lot of options,” Dr. Troncoso said. “If we can activate the same gene we may provide a tonic for nerve cells under stress, and that may be of use in other diseases such as Huntington’s and Parkinson’s in which the nerve cells degenerate,” he said.

Sirtuin research is a highly active field but one whose ultimate benefit remains to be seen. The sirtuins seem to be powerful players in maintaining the body’s health, but many aspects of their behavior are still unclear.

Also unclear is whether sirtuin’s protective effects can be elicited by drugs instead of by the usual natural stresses, like lack of nourishment. There are continuing disputes as to whether resveratrol activates sirtuin directly or indirectly. Much may depend on a Phase 2 clinical trial of resveratrol with Type 2 diabetes. The results of the trial should be known later in the year, Dr. Vlasuk said in an interview last month.

Should resveratrol prove ineffective, Sirtris has two small-molecule chemical drugs, known as 2104 and 2379, which are also in clinical trials. The chemicals can be given in much smaller doses than resveratrol. There have been no safety issues with any of the drugs, Dr. Vlasuk said, with the possible exception of a multiple myeloma trial, using very high doses of resveratrol, in which several patients developed a symptom common with the disease. The trial ceased new enrollment of patients in May.

The New York Times, July 23, 2010

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More Than Half the World's Population Gets Insufficient Vitamin D, Says Biochemist

Vitamin D surfaces as a news topic every few months. How much daily vitamin D should a person get? Is it possible to have too much of it? Is exposure to the sun, which is the body’s natural way of producing vitamin D, the best option? Or do supplements suffice?

In the July 2010 issue of Endocrine Today, a monthly newspaper published by SLACK, Inc., to disseminate information about diabetes and endocrine disorders, Anthony Norman, a distinguished professor emeritus of biochemistry and biomedical sciences and an international expert on vitamin D, notes that half the people in North America and Western Europe get insufficient amounts of vitamin D.

“Elsewhere, it is worse,” he says, “given that two-thirds of the people are vitamin D-insufficient or deficient. It is clear that merely eating vitamin D-rich foods is not adequate to solve the problem for most adults.”

Currently, the recommended daily intake of vitamin D is 200 international units (IU) for people up to 50 years old; 400 IU for people 51 to 70 years old; and 600 IU for people over 70 years old.

“There is a wide consensus among scientists that the relative daily intake of vitamin D should be increased to 2,000 to 4,000 IU for most adults,” Norman says. “A 2000 IU daily intake can be achieved by a combination of sunshine, food, supplements, and possibly even limited tanning exposure.”

While there is now abundant data on vitamin D and its benefits, Norman believes there is room for more study.

“The benefits of more research on the topic justifies why this field of research deserves additional governmental funding,” he says. “Already, several studies have reported substantial reductions in incidence of breast cancer, colon cancer and type 1 diabetes in association with adequate intake of vitamin D, the positive effect generally occurring within five years of initiation of adequate vitamin D intake.”

Because vitamin D is found in very few foods naturally (e.g. fish, eggs and cod liver oil) other foods such as milk, orange juice, some yogurts and some breakfast foods are fortified with it. The fortification levels aim at about 400 IU per day.

Norman, who holds the title of Presidential Chair in Biochemistry-Emeritus, has been researching vitamin D for nearly 50 years. In 1967, his laboratory discovered that the vitamin is converted into a steroid hormone by the body. Two years later, his laboratory discovered the vitamin D receptor (or VDR), an essential receptor for the steroid hormone form of vitamin D that is present in more than 37 target organs of the body that respond biologically to the vitamin.

“There is now irrevocable evidence that receptors in the immune, pancreas, heart-cardiovascular, muscle and brain systems in the body generate biological responses to the steroid hormone form of vitamin D,” he says.

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Luteolin Stars in Study of Healthful Plant Compounds

Natural compounds in plants may protect us against unwanted inflammation. However, human nutrition researchers agree that many questions remain about exactly how these compounds, known as phytochemicals, do that.

Studies led by Agricultural Research Service (ARS) molecular biologist Daniel H. Hwang are providing some of the missing details.

Certain kinds of inflammation can increase risk of cancer and of some other disorders, including heart disease and insulin resistance, according to Hwang. He’s with the ARS Western Human Nutrition Research Center at the University of California-Davis.

Some of Hwang’s on-going studies build upon earlier research in which he and colleagues teased out precise details of how six natural compounds in plants — luteolin, quercetin, chrysin, eriodicytol, hesperetin, and naringenin — apparently act as anti-inflammatory agents.

Luteolin is found in celery, thyme, green peppers, and chamomile tea. Foods rich in quercetin include capers, apples, and onions. Chrysin is from the fruit of blue passionflower, a tropical vine. Oranges, grapefruit, lemons, and other citrus fruits are good sources of eriodicytol, hesperetin, and naringenin.

Hwang’s team showed, for the first time, that all six plant compounds target an enzyme known as “TBK1.” Each compound inhibits, to a greater or lesser extent, TBK1’s ability to activate a specific biochemical signal. If unimpeded, the signal would lead to formation of gene products known to trigger inflammation.

Of the six compounds, luteolin was the most effective inhibitor of TBK1. Luteolin is already known to have anti-inflammatory properties. However, Hwang and his colleagues were the first to provide this new, mechanistic explanation of how luteolin exerts its anti-inflammatory effects.

The approaches that the researchers developed to uncover these compounds’ effects can be used by scientists elsewhere to identify additional anti-inflammatory compounds present in fruits and vegetables.

Their findings on phytochemicals that act as TBK1 inhibitors appear in Biochemical Pharmacology and in the Journal of Immunology.

Read more about the research in the July 2010 issue of Agricultural Research magazine at: http://www.ars.usda.gov/is/pr/2010/www.ars.usda.gov/is/AR/archive/jul10/plant0710.htm

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