New Study Validates Longevity Pathway:

Resveratrol-like compound binds to sirtuin protein. 

Credit: Image courtesy of Sinclair lab
 
A new study demonstrates what researchers consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models.

What's more, the researchers have uncovered the molecular mechanism for this interaction, and show that a class of more potent drugs currently in clinical trials act in a similar fashion.

Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the authors contend.

These findings are published in the March 8 issue of Science.

For the last decade, the science of aging has increasingly focused on sirtuins, a group of genes that are believed to protect many organisms, including mammals, against diseases of aging.

Mounting evidence has demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin, SIRT1, that protects the body from diseases by revving up the mitochondria, a kind of cellular battery that slowly runs down as we age.

By recharging the batteries, SIRT1 can have a profound effects on health.

Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies and mice, lifespan has been extended.

"In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1," said David Sinclair, Harvard Medical School professor of genetics and senior author on the paper. "Almost all drugs either slow or block them."

In 2006, Sinclair's group published a study showing that resveratrol could extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was started by HMS researchers, was founded to make drugs more potent than resveratrol.

But while numerous studies, from Sinclair's lab and elsewhere, underscored a direct causal link between resveratrol and SIRT1, some scientists claimed the studies were flawed.

The contention lay in the way SIRT1 was studied in vitro, using a specific chemical group attached to the targets of SIRT1 that fluoresces more brightly as SIRT1 activity increases.

This chemical group, however, is synthetic and does not exist in cells or in nature, and without it the experiments did not work.

As a response to this, a paper published in 2010 surmised that resveratrol's activation of SIRT1 was an experimental artifact, one that existed in the lab, but not in an actual animal. SIRT1 activity in mice was, the paper claimed, at best an indirect result of resveratrol, and perhaps even a sheer coincidence.

As a result, a debate erupted over the particular pathway that resveratrol and similar compounds affected. Does resveratrol directly activate SIRT1 or is the effect indirect?

"We had six years of work telling us that this was most definitely not an artifact," said Sinclair. "Still, we needed to figure out precisely how resveratrol works. The answer was extremely elegant."

Sinclair and Basil Hubbard, then a doctoral student in the lab, teamed up with a group of researchers from both the National Institutes of Health and Sirtris Pharmaceuticals to address this question.

First, the team addressed the problem of the fluorescent chemical group. Why was it required for resveratrol to rev up SIRT1 in the test tube?

Instead of dismissing the result as an artifact, the researchers surmised that the chemical might be mimicking molecules found naturally in the cell.

These turned out to be a specific class of amino acid, the building blocks of proteins. In nature, there are three amino acids that resemble the fluorescent chemical group, one of which is tryptophan, a molecule abundant in turkey and notable for inducing drowsiness.

When researchers repeated the experiment, swapping the fluorescing chemical group on the substrate with a tryptophan residue, resveratrol and similar molecules were once again able to activate SIRT1.

"We discovered a signature for activation that is in fact found in the cell and doesn't require these other synthetic groups," said Hubbard, first author of the study.

"This was a critical result, which allowed us to bridge the gap between our biochemical and physiological findings.

The above story is reprinted from materials provided by Harvard Medical School.

Bipolar Disorder, Depression and Circadian Clock

An off-kilter body clock can throw off our sleep-wake cycle, eating habits, body temperature and hormones—and mounting evidence suggests a malfunctioning clock may also underlie the mood cycles in bipolar disorder.

In a new study led by psychiatrist Alexander Niculescu of Indiana University, researchers found that children with bipolar disorder were likely to have a mutated RORB gene, which codes for a protein crucial to circadian clock function.

The team’s previous work identified alterations to this gene and other clock genes in animal models of the disorder. In the new study, the scientists compared the genomes of 152 bipolar kids with those of 140 typical kids. (Children were studied because their moods cycle more rapidly than the moods of bipolar adults, and a quicker cycle suggests a stronger connection to the circadian clock.)

The team found that the bipolar children were more likely to have one of four alterations to RORB, and the investigators suspect the mu­tations prevent the body from producing the correct amount of the pro­tein to support normal clock function.

Previous studies had shown that strictly regulating a bi­polar patient’s sleep schedule could improve extreme mood cycles, but experts weren’t sure why—until animal studies started showing a connection to circadian clock genes.

“Every time we investigate some [abnormality] of molec­ular machinery linked to the clock genes, we find an associ­ation with bipolar disorder,” says Francesco Benedetti, a neuroscientist at the San Raffaele Scientific Institute in Milan, Italy, who was not involved in the Indiana research.

The ultimate goal, he adds, is to pinpoint the precise mech­anism that links clock function with mood swings, in the hope of designing new drugs and treatments that will restore the clock to working order.

Glaucoma's unique protein expression could enhance diagnosis and treatment

An eye under pressure appears to express a unique set of proteins that physicians hope will one day help them better diagnose and treat glaucoma.

Glaucoma, the second leading cause of blindness worldwide, tends to progress silently until decreased vision indicates trouble, said Dr. Kathryn Bollinger, Medical College of Georgia clinician-scientist specializing in glaucoma.

But inside fluid-filled eyeballs, a changing protein profile -- 30 with significant increases and 17 with significant decreases identified among hundreds of proteins present -- appears to also give a heads-up, Bollinger reported during the Association for Research in Vision and Ophthalmology Annual Meeting April 30-May 6. The MCG ophthalmologist received the 2010 ARVO/Alcon Early Career Clinician-Scientist Research Award for the study.

With glaucoma, elevated pressures inside the eyeball stress the optic nerve and nerve arms -- called axons ? that reach out to communicate with the brain. Over time, increased pressure can kill nerve cells and axons and decrease vision. "At this point, we don't have a regenerative strategy," Bollinger said.

The pressure results from an imbalance in fluid production and loss. In a healthy eye, the fluid, called the aqueous humor, moves continually from the back to the front of the eye where it exits ? mostly via a natural tract between the iris and cornea ? first into spongy tissue near the cornea's base called the trabecular meshwork then into the venous system and back into the body.

In open-angle glaucoma, the most common type in this country, the tract remains open but fluid still backs up and scientists suspect changes in the permeability of the trabecular meshwork may be to blame. Topical glaucoma treatments work by reducing fluid production or increasing outflow through a secondary drainage system, also near the front of the eye. Ophthalmologists such as Bollinger can also create a new pathway surgically if needed.

To get a better picture of what happens to the trabecular meshwork, Bollinger examined tissues from the outflow tracts and trabecular meshwork of patients with and without glaucoma. She added TGF-?, a protein and inflammatory element known as a cytokine that is consistently found at high levels in patients with open-angle glaucoma. After comparing treated and untreated tissue, she found that TGF-? resulted in a similarly unique protein pattern. Current therapies don't target TGF-? or its effects in the trabecular meshwork.

Next steps include identifying additional proteins expressed in glaucoma, determining the impact of the unique protein profile on the trabecular meshwork and clarifyingTGF-?'s normal role inside the eye, Bollinger said.

Risk factors for glaucoma include age, a family history and black and Asian ethnicity.


Link: http://www.mcg.edu

Don't go Hungry, Eat Your Cotton Socks!

It's as true in today's world as it was in the antebellum South: cotton is king.

The plant has been cultivated for its fiber for over 7,000 years, and today it's grown by more than 20 million farmers in some 80 countries.

But while cotton accounts for nearly 40% of the fiber used worldwide to make clothing, there's one thing the plant has never been able to do well: feed people.

Cottonseeds are a rich source of protein--the current cotton crop produces enough seeds to meet the daily requirements of half a billion people a year. But the seeds can be consumed only after an extensive refining process removes the gossypol, a toxic chemical that helps protect the plant from insect and microbe infestation.

"People, pigs, chickens--none of us can stomach gossypol," says Kater Hake, vice president of agricultural research for the industry group Cotton Inc. Only cows and other ruminants can handle it.

Remove the gossypol, however, and you'd have a cheap and abundant form of protein for everyone. But get rid of all the gossypol, as plant breeders did in the 1950s, and insects will devour the defenseless cotton. Enter Keerti Rathore, a professor at Texas A&M University, who found a way around the problem through genetic engineering.

In new field-trial data, Rathore's team demonstrated that it can turn off the genes that stimulate the production of gossypol in the cottonseeds while the rest of the plant keeps its natural defenses. "This research potentially opens the door to utilizing safely the more than 40 million tons of cottonseed produced annually as a large, valuable protein source," says Norman Borlaug, an American agronomist who won the Nobel Peace Prize in 1970 for developing high-yield wheat varieties that have helped increase the world's food supply.

Rathore used a new technique, called RNA interference, to construct a genetic sequence that blocked the gossypol-producing enzyme in the seeds only. After succeeding in the lab, he began a test in a greenhouse to see if the genetically modified cotton plant would survive and pass on its new trait.

Rathore's just-compiled data show that the modified cotton appears to be normal in every way other than the fact that it has instantly edible seeds. "What works in the greenhouse should hold true in the fields," he says. By the way he also says "It takes like chick peas!"

Unhapiness of Blue Birds: Losing their Sparkle

Brightly coloured birds can become infected with bacteria that eat the coating on their feathers. That in turn can affect the health of the birds and dull their plumage.

The discovery comes from a study that found that 99% of all Eastern US bluebirds srveyed, were infected with feather-degrading bacteria. Such bacteria were first discovered a decade ago, but the latest research is the best evidence yet that the bugs affect the colour and general health of the birds.

New to Bird studies

"Feather-degrading bacteria are relatively new to ornithologists," says Alex Gunderson of Duke University in Durham, North Carolina, US. "The first report of their occurrence on wild birds was published only ten years ago."

Since then, scientists have found that most species of wild bird probably harbour some feather-degrading bacteria in their plumage, sometimes of more than one species.

Impacts on their hosts

Feather-degrading bacteria work by hydrolysing the protein beta-keratin, which constitutes over 90% of a feather's mass but these bugs are usually found in a minority of birds sampled, and it has not been clear what impact they have on their hosts.

So Gunderson and colleagues Mark Forsyth and John Swaddle of the College of William and Mary in Williamsburg, Virginia, US surveyed a population of Eastern bluebirds (Sialia sialis) living in Virginia.

They found that 99% of all the birds surveyed carried feather-eating bugs. The full report can be found in the Journal of Avian Biology.