Studies bring unprecedented clarity to aging process and provide paradigm for studying how genes and environment -- including calorie restriction -- may influence lifespan
For the first time, scientists at Fred Hutchinson Cancer Research Center have defined key events that take place early in the process of cellular aging.
Together the discoveries, made through a series of experiments in yeast, bring unprecedented clarity to the complex cascade of events that comprise the aging process and pave the way to understanding how genetics and environmental factors like diet interact to influence lifespan, aging and age-related diseases such as cancer and neurodegenerative disorders.
The findings, including unexpected results that link aspects of aging and lifespan to a mechanism cells use to store nutrients, are described in the Nov. 21 issue of Nature by co-authors Daniel Gottschling, Ph.D., a member of the Hutchinson Center's Basic Sciences Division, and Adam Hughes, Ph.D., a postdoctoral fellow in the Gottschling Lab.
The researchers found the acidity of a structure in yeast cells known as the vacuole is critical to aging and the functioning of mitochondria - the power plants of the cell. They also describe a novel mechanism, which may have parallels in human cells, by which calorie restriction extends lifespan.
The work began with Hughes and Gottschling searching for the source of age-related damage in mitochondria.
"Normally, mitochondria are beautiful, long tubes, but as cells get older, the mitochondria become fragmented and chunky," said Gottschling, also an affiliate professor in the Department of Genome Sciences at the University of Washington. "The changes in shape seen in aging yeast cells are also observed in certain human cells, such as neurons and pancreatic cells, and those changes have been associated with a number of age-related diseases in humans."
What causes mitochondria to become distorted and dysfunctional as cells age had long been a mystery, but Gottschling and Hughes have discovered that specific changes in the vacuole lead directly to its malfunctioning.
The vacuole - and its counterpart in humans and other organisms, the lysosome - has two main jobs: degrading proteins and storing molecular building blocks for the cell. To perform those jobs, the interior of the vacuole must be highly acidic.
Hughes and Gottschling found that the vacuole becomes less acidic relatively early in the yeast cell's lifespan and, critically, that the drop in acidity hinders the vacuole's ability to store certain nutrients. This, in turn, disrupts the mitochondria's energy source, causing them to break down. Conversely, when Hughes prevented the drop in vacuolar acidity, the mitochondria's function and shape were preserved and the yeast cells lived longer.
"Until now, the vacuole's role in breaking down proteins was thought to be of primary importance. We were surprised to learn it was the storage function, not protein degradation, that appears to cause mitochondrial dysfunction in aging yeast cells," Hughes said.
The unexpected discovery prompted Hughes and Gottschling to investigate the effects of calorie restriction, which is known to extend the lifespan of yeast, worms, flies and mammals, on vacuolar acidity. They found that calorie restriction - that is, limiting the raw material cells need - delays aging at least in part by boosting the acidity of the vacuole.
"Now that we have preliminary evidence in yeast of how calorie restriction extends lifespan, our hope is that it can be translated to higher organisms like humans," Hughes said. Given the similarities in the fundamental biology of yeast and human cells, the researchers' newly defined link between what cells "eat" and how they age could shed valuable light on the events that lead to age-related disorders in humans.
"There has been a lot in the scientific literature and the general media lately about how what you eat affects the aging process, but it has been incredibly confusing. Now we have a new paradigm for understanding how genetics and environment interact to influence lifespan, aging and age-related diseases. That's what I'm really excited about," Gottschling said.
Gottschling and Hughes speculate that if the vacuole's declining acidity limits its ability to store certain nutrients and metabolites, they may build up in the cell, flooding the mitochondria. Overwhelmed, the mitochondria use up all their energy - essentially burning out their motors - taking in the surplus. With no power left to import the proteins they need to maintain their elegant shape and execute their regular duties, the mitochondria literally break down. Gottschling and his colleagues are now investigating this hypothesis in detail. They are also exploring what triggers the initial drop in the vacuole's acidity.