Early Cellular Aging Reveals How Lifestyle and Diet Affect Lifespan

By experimenting on yeast, two scientists in the US have for the first time identified key events that occur early in the aging process of cells that may explain how genes and environmental factors like lifestyle and diet, interact to influence lifespan, aging, and age-related diseases like cancer.

27 Nov 2012 --- They were surprised to find A mechanism that cells use to store nutrients may be significant.

Daniel Gottschling and Adam Hughes of the Fred Hutchinson Cancer Research Center in Seattle, Washington, write about their findings in the 21 November online issue of Nature.

Gottschling, who is a member of Hutchinson Center's Basic Sciences Division, explains in a statement why the findings are important:

"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," he adds.

Mitochondria and Aging

Gottschling and Hughes, a postdoctoral fellow in his lab, set out to uncover how age-related damage occurs in mitochondria, the tiny power plants inside cells that supply them with units of energy.

As Gottschling, who is also an affiliate professor in the Department of Genome Sciences at the University of Washington, explains:

"Normally, mitochondria are beautiful, long tubes, but as cells get older, the mitochondria become fragmented and chunky."

"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," he adds.

Low Acidity of Vacuoles Impairs Mitochondria

The reason why mitochondria become misshapen and stop working so well has until now been somewhat of a mystery, but Gottschling and Hughes found that certain changes inside vacuoles may be responsible.

Vacuoles are tiny pockets inside the cells of yeast, plants and other organisms, that help break down proteins and store molecular building blocks or nutrients for the cell. The equivalent of the vacuole in human cells is the lysosome.

One specific feature of vacuoles that appears to be critical to aging and the working of mitochondria is acidity.

The researchers found vacuoles become less acidic quite early in the life of a yeast cell. And when acidity drops, it stops vacuoles being able to store certain nutrients. This disrupts the energy supply to mitochondria, which in turn begin to degrade.

Hughes tested this effect: when he stopped the vacuoles from becoming less acidic, the mitochondria did not become misshapen and the yeast cells lived longer.

"We were surprised to learn it was the storage function, not protein degradation, that appears to cause mitochondrial dysfunction in aging yeast cells," says Hughes.

Calorie Restriction Boosts Vacuole Acidity

This surprising discovery led the researchers to investigate the effect of calorie restriction, which is known to extend lifespan in yeast, worms, flies and mammals.

They found that calorie restriction, or limiting the raw materials that cells need, appears to delay aging, at least in part, by boosting the acidity of the vacuole.

Hughes says now they have some initial evidence based on yeast, of how calorie restriction seems to extend lifespan, they hope to translate it to humans and other higher organisms.

Although hugely different organisms, in terms of the fundamental biology of their cells, such as how they consume, store and use nutrients, yeast and humans are remarkably similar.

Implications and Next Step

Speculating on their findings, Gottschling and Hughes propose that the effect of lowering acidity in vacuoles lessens their ability to store nutrients and metabolites (byproducts of protein breakdown), so they build up inside the yeast cell and flood the mitochondria.

They suggest this causes the mitochondria to use more and more of their energy to take in the surplus: effectively "burning out" their engines. Eventually they have insufficient power left to bring in the proteins they need to maintan their shape and do their job.

The researchers are now looking to test this idea, and they also want to find out what triggers the drop in vacuole acidity in the first place. This last point is particularly interesting because although acidity drops in mother yeast cells as they age, it is normal again in newborn daughter cells, no matter how old the mother cells were.

Grants from the National Institutes of Health, the Helen Hay Whitney Foundation, the University of Washington, the Glenn Foundation for Medical Research, as well as preliminary support from the Hutchinson Center's Hartwell Innovation Fund, helped pay for the study.

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