Aging gets with the program

Study in yeasts suggests long life is more than protection from random accumulation of cell damage

SAN FRANCISCO — A study of aging yeast organisms reveals that aging follows a program and is not just a random accumulation of damage that kills cells. The study, by Vladimir Titorenko of Concordia University in Montreal and colleagues, shows that yeasts have at least two vulnerable checkpoints that determine longevity: the accumulation of lipids and fatty acids and the health of cellular power plants called mitochondria. Titorenko presented the research December 16 at the annual meeting of the American Society for Cell Biology.

Titorenko’s team put some yeasts on a restricted calorie diet by limiting the amount of sugar in the growth medium. Other yeasts in the experiment were allowed a normal yeast diet. Calorie restriction has been shown to lengthen the life of yeasts, mice, rats, dogs, worms, fruit flies and many other animals. It is not yet clear whether humans or other primates also live longer on calorie-restricted diets, although studies indicate that such diets can improve human health. Many researchers say that calorie restriction increases lifespan by preventing damage to cells.

Yeasts have some significant differences from humans, but scientists have found that many of the basic processes of yeast cells work the same in humans. For instance, a major regulatory protein linked to aging, a sirtuin, was first discovered in yeasts. Since yeasts are easy to use in the laboratory and are genetically tractable, scientists work out the details of cellular and genetic processes first in these organisms and then move on to rodents and humans.

Titorenko wanted to see whether calorie restriction would work at any stage of yeast life or if there are critical windows of maximum opportunity for the technique. Mice must be switched to lo-cal diets before they are 13 weeks old in order for calorie restriction to work, previous research has shown.

No one knew whether yeasts also have critical developmental stages during which calorie restriction would work best, so Titorenko’s group switched yeasts to the calorie restriction diet at various stages in the yeast life cycle. The researchers gave the yeasts periodic checkups, testing protein, lipid, fatty acid and carbohydrate levels; determining the health of the organelles inside the cells; and investigating patterns of protein production and gene activity.

Young yeasts on a full-calorie diet aren’t able to break down fatty acids as well as young yeasts on restricted-calorie diets can, the team found. The fatty acids build up in storage structures, leading to increased production of a lipid called diacylglycerol. Yeasts must avoid lipid buildup to safely pass the first checkpoint, Titorenko reported.

If the yeasts do pack on fat, they are soon on a dangerous path to necrotic cell death (a technical term for literally busting a gut). Yeasts with high levels of diacylglycerol are not able to defend themselves against stress as well as lean yeasts can, the researchers say.

Mitochondria in older, calorie-restricted yeasts are healthier than the power plants in old but well-fed yeasts, the researchers found. Mitochondria normally operate like one U.S. Senator’s definition of the Internet: as a series of tubes. When yeasts get old, the organelle network begins to break down into individual mitochondria, triggering cellular suicide known as apoptosis. Calorie-restriction helps keep the mitochondria functioning as an organelle network much longer, Titorenko found.

“We came to the conclusion that aging is a developmental program rather than a random accumulation of damage,” Titorenko says. Rather than preventing random damage to the cell, diet and genetics work together to influence the aging program, he says.

His group is developing a new set of antiaging compounds that target the lipid and mitochondria checkpoints to make yeasts live even longer than they do on calorie- restricted diets.

Aging does seem to follow a program, but that doesn’t take away the fact that damage to cells can influence the process, says Valter Longo, a molecular geneticist at the University of Southern California Ethel Percy Andrus Gerontology Center in Los Angeles. Even though the basic mechanisms of aging seem to be conserved between yeasts and humans, the two are not identical, he says.

Longo also studies aging in yeasts and has found a few differences in the way proteins linked to longevity behave in yeasts and human cells. But uncovering “the fundamentals is extremely important,” he says. Titorenko’s compounds, even if they don’t work in people, “might tell us what direction to go.”

Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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