Discovery May Aid Search for Anti-Aging Drugs: Gene's Action May Help Explain Why Restricting Diet Lengthens Life in Animals

Ao-Lin Hsu. (Credit: Image courtesy of University of Michigan Health System)

Aug. 18, 2010 — A team of University of Michigan scientists has found that suppressing a newly discovered gene lengthens the lifespan of roundworms. Scientists who study aging have long known that significantly restricting food intake makes animals live longer. But the goal is to find less drastic ways to achieve the same effect in humans someday.

The U-M results offer promising early evidence that scientists may succeed at finding targets for drugs that someday could allow people to live longer, healthier lives.

In a study in the August issue of Aging Cell, U-M scientists found that a gene, drr-2, is an important component in a key cellular pathway, the TOR nutrient-sensing pathway, where many scientists are looking for potential drug targets. The U-M scientists then found that when they caused the drr-2 gene to be under- or over-expressed, they could lengthen or shorten lifespan in C. elegans, a worm widely used in research. Manipulating the drr-2 gene's action produced the same effects as reducing or increasing caloric intake.

"We showed that in C. elegans, drr-2 is one of the essential genes for the TOR pathway to modulate lifespan," says Ao-Lin Allen Hsu, Ph.D., the study's senior author and a scientist at the U-M Geriatrics Center. He also is an assistant professor in internal medicine and molecular and integrative physiology at U-M. The study also found that drr-2 appears analogous to a human gene, eIF4H, that controls similar cell functions.

Context

To find possible avenues for future anti-aging drugs, many scientists around the world are focusing on signaling pathways in cells that sense nutrients. The one Hsu examined, the target of rapamycin pathway or TOR pathway, is so named because its activity can be influenced by the drug rapamycin. Recent results from a large federal study being conducted at U-M and elsewhere have shown that in mice, rapamycin is effective at mimicking the anti-aging effects of dietary restriction.

Research in the last 25 years has shown that animals, including mammals, live longer and have lower levels of certain measures of age-related decline when scientists have restricted their food intake. No one has been able to show yet that the same effect happens in humans, though some studies are under way.

When calories or certain nutrients are restricted, scientists detect less oxidative damage in animal cells and a slower decline in DNA repair, a decline that normally occurs with age. It's thought that limiting oxidative damage and slowing the decline in DNA repair could help postpone or avoid many age-related diseases.

But scientists know relatively little about why reducing food intake causes these effects. In the last 10 years, they have made progress in identifying genes and associated proteins that are suppressed when diet is restricted. By learning more about the cell processes involved, they may be able to discover targets for future drugs that could delay aging without the need to restrict food intake.

Drugs tailored to block specific genes or proteins involved in nutrient-sensing pathways would have much more appeal than reducing what one eats. To achieve anti-aging benefits, it's thought that people would have to restrict food intake by 30 to 40 percent, a grim prospect. In addition, drugs might be designed to avoid other disadvantages of this level of dietary restriction, which include reduced fertility.

C. elegans is a tiny roundworm, a nematode whose two-week lifespan is a great advantage for scientists studying aging. The 1-millimeter-long transparent worms have other advantages, too. C. elegans exhibits many age-associated changes observed in higher organisms.

"Many genes identified in C. elegans to control the speed of aging turned out to be evolutionarily conserved, meaning that you can find them in other animals, too. And many are very similar to those found in humans," Hsu says.

Research details

Hsu and his team created different mutant strains of roundworms, some with drr-2 genes silenced and others in which the gene was over-expressed. They wanted to learn whether inactivating drr-2 is essential for TOR to influence longevity, and found that it was. Other newly discovered genes may affect TOR signaling as well. But Hsu's team has found a promising lead for anti-aging drugs of the future: They were able to show that silencing drr-2's action alone was sufficient to make worms live longer than wild-type C. elegans used as controls.

"It is known that reduction of TOR signaling in response to a change in the environment or genetic manipulation triggers a cascade of cellular signals that alter cell growth, metabolism, and protein synthesis, and decrease the pace of aging," says Hsu. "Our recent studies have shown that drr-2 might play a pivotal role in the TOR signaling network to control protein synthesis as well as longevity."

Additional U-M authors: Tsui-Ting Ching, Alisha B. Paal, Avni Mehta, and Linda Zhong, all of the Division of Geriatric Medicine, U-M Department of Internal Medicine Funding: Ellison Medical Foundation and the National Institutes of Health

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Journal Reference:

1. # Tsui-Ting Ching, Alisha B. Paal, Avni Mehta, Linda Zhong and Ao-Lin Hsu. drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell, 2010;
   

Study Finds Evidence of Genetic Response to Diet

By NICHOLAS WADE
Could people one day evolve to eat rich food while remaining perfectly slim and svelte?
This may not be so wild a fantasy. It is becoming clear that the human genome does respond to changes in diet, even though it takes many generations to do so.
Researchers studying the enzyme that converts starch to simple sugars like glucose have found that people living in countries with a high-starch diet produce considerably more of the enzyme than people who eat a low-starch diet.
The reason is an evolutionary one. People in high-starch countries have many extra copies of the amylase gene which makes the starch-converting enzyme, a group led by George H. Perry of Arizona State University and Nathaniel J. Dominy of the University of California, Santa Cruz, reported yesterday in the journal Nature Genetics.
The production of the extra copies seems to have been favored by natural selection, according to a genetic test, the authors say. If so, the selective pressure could have occurred when people first started to grow cereals like wheat and barley at the beginning of the Neolithic revolution some 10,000 years ago, or even much earlier.
Paleoanthropologists have long wondered what change in the usual primate diet of fruit and nuts enabled the emerging human lineage to support a brain that eventually swelled to three times the size of chimpanzees’.
Neural tissue requires large amounts of energy, and the usual assumption is that humans began to eat meat some 2.5 million years ago when brain volume started to expand. But another possibility is that the extra nutrients came from starch.
As soon as the human lineage split from the chimp’s about five million years ago and started to live in open woodland, its diet may have expanded to include tubers, corms and the other underground structures in which plants store starch. In support of this idea, Dr. Dominy, a paleoanthropologist, said that the teeth of early humans “are not well suited for eating meat.”
Chimpanzees, whose fruit-based diet does not include much starch, have a single amylase gene. Dr. Dominy, Dr. Perry and their colleagues believe that the number of amylase genes in the human genome had started to expand by at least 200,000 years ago and perhaps much earlier, but the exact date cannot yet be determined.
Richard Wrangham, a primatologist at Harvard and an advocate of the tuber-eating thesis, said the amylase finding was a convincing insight into the different digestive physiology of people and chimps, but that the date of 200,000 years ago, derived from limited genetic information, was not old enough to give direct support to his ideas.
The amylase enzyme studied by Dr. Perry’s team exists in the saliva, where it predigests starch and lets glucose get absorbed from the mouth into bloodstream. The evolutionary advantage of this strange arrangement is not clear, but it could provide the body with energy during episodes of diarrhea, or might protect against diarrhea. Or it could just make the digestion of starch more efficient.
Whatever the exact mechanism, the extra copies of the amylase gene seem to have arisen through positive selection, the researchers said. Their conclusion is based on comparing the genomes of the Japanese and the Yakut, a Siberian people who eat mostly reindeer. Dr. Perry, a geneticist, said he could not tell whether the Japanese, who have a high-starch diet, including rice, had gained the extra copies of the gene or whether the Yakut had lost theirs.
Geneticists realized only in 2004 that having extra copies of genes was a widespread form of variation in the human genome. Many of the extra copies seem to have arisen through mistakes in the duplication process that doubles the number of chromosomes in dividing cells. The effect of these extra copies is largely unknown and the story of the amylase gene is one of the first to be understood, at least to some degree.
Dr. Perry and his team started their research by having undergraduates at Arizona State University give samples of saliva, which were analyzed for amylase. The researchers found the amount of amylase a person produced was correlated with the number of copies they possessed of the amyloid gene, which ranged from 2 to 15. The copies are arranged in the genome like a string of beads, with each gene being about 120,000 units of DNA in length.
Wondering whether the copy number varied with diet, the researchers then collected saliva and blood samples from the Yakut and other low-starch eating populations, showing that this was indeed the case.