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3 December 2008

Scientists Find Clues to Aging in a Red Wine Ingredient’s Role in Activating a Protein

By NICHOLAS WADE
Published: November 26, 2008
A new insight into the reason for aging has been gained by scientists trying to understand how resveratrol, a minor ingredient of red wine, improves the health and lifespan of laboratory mice. They believe that the integrity of chromosomes is compromised as people age, and that resveratrol works by activating a protein known as sirtuin that restores the chromosomes to health.

The finding, published online Wednesday in the journal Cell, is from a group led by David Sinclair of the Harvard Medical School. It is part of a growing effort by biologists to understand the sirtuins and other powerful agents that control the settings on the living cell’s metabolism, like its handling of fats and response to insulin.

Researchers are just beginning to figure out how these agents work and how to manipulate them, hoping that they can develop drugs to enhance resistance to disease and to retard aging.

Sirtris, a company Dr. Sinclair helped found, has developed a number of chemicals that mimic resveratrol and are potentially more suitable as drugs since they activate sirtuin at much lower doses than resveratrol. This month, one of these chemicals was reported in the journal Cell Metabolism to protect mice on fatty diets from getting obese and to enhance their endurance in treadmills, just as resveratrol does.

Though the sirtuin field holds considerable promise, the dust has far from settled. Resveratrol is a powerful agent with many different effects, only some of which are exerted through sirtuin. So drugs that activate sirtuin may not be as splendid a tonic for people as resveratrol certainly seems to be for mice.

The new finding concerns maintenance of the chromosomes, the giant molecules of DNA that make up the genome.

Each cell has six feet of DNA packed into its nucleus, carrying the 20,000 or so genetic instructions needed to operate the human body. Each cell must provide instant access to the handful of these genes needed by its cell type, but also keep the rest firmly switched off to avoid chaos.

Sirtuin’s normal role is to help gag all the genes that a cell needs to keep suppressed. It does so by keeping the chromatin, the stuff that wraps around the DNA, packed so tightly that the cell cannot get access to the underlying genes.

But sirtuin has another critical role, one that is triggered by emergencies like a break in both DNA strands of a chromosome. After a double strand break, sirtuin rushes to the site to help knit the two parts of the chromosome back together. But in this salvage operation, it leaves its post, and the genes it was repressing are liable to come back into action, causing mayhem.

This, Dr. Sinclair and his colleagues suggest, may be a fundamental cause of aging in mice and probably people, too.

The gene-gagging role of sirtuin was discovered in the 1980s by biologists studying yeast, a standard laboratory organism. Dr. Sinclair and Leonard Guarente of the Massachusetts Institute of Technology found in 1997 that sirtuin could also repair a certain kind of genomic damage in yeast, and in doing so extended the yeast cell’s lifespan. But this particular kind of damage does not occur in mammalian cells, raising the puzzle of why extra sirtuin should be good for them.

Dr. Sinclair’s new report, if verified, resolves this problem by showing that sirtuin has retained its genomic repair role in higher organisms but that the repair is focused on a different kind of genomic damage — that of breaks in a chromosome.

These experiments “elegantly demonstrate” that sirtuin works in much the same way in mammals as in yeast, Dr. Jan Vijg of the Albert Einstein College of Medicine wrote in a commentary in Cell. The question now is whether sirtuin is a pro-longevity factor in mammals, he said in an e-mail message.

Ronald Evans, a biologist at the Salk Institute, said the new report was provocative but did not prove the case that the relocation of sirtuin was a cause of aging. Tests with mice genetically engineered to lack the sirtuin gene could show if the mice suffered from premature aging, as Dr. Sinclair’s idea would predict.

Dr. Sinclair said he agreed that the case for sirtuin’s role in aging had not been proved. “We are careful not to say this is the cause of aging, but based on everything we know it’s not a bad hypothesis,” he said.

It would be nice to test aging in mice that lack the sirtuin gene, as Dr. Evans proposed, but they die too young, Dr. Sinclair said.

Dr. Sinclair has been taking large daily doses of resveratrol since he and others discovered five years ago that it activated sirtuin. “I’m still taking it, and I feel great,” he said, “but it’s too early to say if I’m young for my age.”

New Solution for Colon Cancer

ScienceDaily (Nov. 26, 2008) — A colon cancer cell isn't a lost cause. Vitamin D can tame the rogue cell by adjusting everything from its gene expression to its cytoskeleton. In the Nov. 17 issue of the Journal of Cell Biology, Ordóñez-Morán et al. show that one pathway governs the vitamin's diverse effects. The results help clarify the actions of a molecule that is undergoing clinical trials as a cancer therapy.

Vitamin D stymies colon cancer cells in two ways. It switches on genes such as the one that encodes E-cadherin, a component of the adherens junctions that anchor cells in epithelial layers. The vitamin also induces effects on the cytoskeleton that are required for gene regulation and short-circuiting the Wnt/b-catenin pathway, which is overactive in most colon tumors. The net result is to curb division and prod colon cancer cells to differentiate into epithelial cells that settle down instead of spreading.
To delve into the mechanism, the team dosed colon cancer cells with calcitriol, the metabolically active version of vitamin D. Calcitriol triggered a surge of calcium into the cells and the subsequent switching on of RhoA–RhoGTPases, which have been implicated in the cytoskeletal changes induced by vitamin D. The activated RhoA in turn switched on one of its targets, the rho-associated coiled kinase (ROCK), which then roused two other kinases. Each step in this nongenomic pathway was necessary to spur the genomic responses, the researchers showed. The team also nailed down the contribution of the vitamin D receptor (VDR). The receptor was crucial at the beginning of the pathway, where it permitted the calcium influx, and at the end, where it activated and repressed genes.
The study is the first to show that vitamin D's genomic and nongenomic effects integrate to regulate cell physiology. One question the researchers now want to pursue is whether VDR from different locations—the nucleus, the cytosol, and possibly the cell membrane—has different functions in the pathway.
Reference: Ordóñez-Morán, P., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200803020.

Exercise Stops Stem Cell Drop in Middle Age

A new study confirms that exercise can reverse the age-related decline in the production of neural stem cells in the hippocampus of the mouse brain. This may happen because exercise restores a brain chemical which promotes the production and maturation of new stem cells.

Neural stem cells and progenitor cells differentiate into a variety of mature nerve cells which have different functions. There is evidence that when fewer new stem or progenitor cells are produced in the hippocampus, it can result in impairment of the learning and memory functions.

The researchers built on earlier studies that found that the production of stem cells in the area of the hippocampus known as the dentate gyrus drops off dramatically by the time mice are middle age, and that exercise can slow that trend.

They found that exercise significantly slows down the loss of new nerve cells in the middle-aged mice. In fact, they discovered that production of neural stem cells improved by approximately 200 percent in active mice. In addition, the survival of new nerve cells increased by 170 percent and growth by 190 percent, compared to sedentary middle-aged mice. Exercise also significantly enhanced stem cell production and maturation in the young mice.



Sources:
Science Daily November 27, 2008

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