How does aging begin?
The key events of the onset of cellular aging have been identified
LifeSciencesToday by Fred Hutchinson Cancer Research Center:
Researchers define key events early in the process of cellular agingScientists at the Fred Hutchinson Cancer Research Center have identified key events that occur at the earliest stages of cell aging.
The discoveries made during the yeast experiments bring unprecedented clarity to the complex cascade of events that make up the aging process, and pave the way to understanding the impact on life expectancy, aging and age-related diseases, such as cancer and neurodegenerative diseases, has the interaction of genetics and environmental factors.
The results obtained, including unexpected data linking aging and life expectancy with the nutrient storage mechanism used by cells, are published in the journal Nature (Hughes et al., An early-age increase in vacuolar pH limits mitochondrial function and lifespan in yeast).
Scientists have found that the acidity of the structure of the yeast cell, known as a vacuole, plays a crucial role in aging and the functioning of the mitochondria that provide the cell with energy. In addition, they described a new mechanism, probably present in human cells, explaining the connection of calorie restriction with an increase in life expectancy.
The work began with the search for the source of age-related damage to mitochondria. "Mitochondria usually look like beautiful long tubes, but as cells age, they fragment, as well as shorten and thicken," explains study co–author Daniel Gottschling, PhD, researcher at the Department of Fundamental Sciences at the Hutchinson Center. "The changes in the shape of mitochondria observed in aging yeast cells are also inherent in some human cells, such as neurons and pancreatic cells, and these changes are associated with a number of age-related diseases."
What leads to a change in the shape and dysfunction of mitochondria in aging cells has long remained a mystery, but Dr. Gottschling and postdoctoral fellow in his laboratory Adam Hughes, PhD, co-author of the study, found that mitochondrial dysfunction is directly related to specific changes in the vacuole.
Yeast cell (Saccharomyces cerevisiae) (X-ray microscopy). The core and a large vacuole (red) are visible. (Photo: Carolyn Larabell, University of California, San Francisco and the Lawrence Berkeley National Laboratory)
The vacuole (and its analog in humans and other organisms – the lysosome) performs two main functions: it destroys proteins and accumulates the molecular building blocks necessary for the vital activity of the cell.
In order for the vacuole to be able to cope with this work, its internal environment must be very acidic.
Gottschling and Hughes found that the vacuole becomes less acidic already at a relatively early stage of the cell's life, and, importantly, a drop in acidity reduces its ability to store certain nutrients.
This, in turn, deprives the mitochondria of an energy source and causes their destruction. Conversely, preventing a decrease in the acidity of the vacuole allows you to preserve the function and shape of the mitochondria and prolong the life of the yeast cell.
Each of the yeast cells (blue) contains one vacuole (red). Green dye is an indicator of the acidity of the vacuole: lower acidity corresponds to a brighter green glow. (Photo: Gottschling Lab, Fred Hutchinson Cancer Research Center)
"Until now, the main role played by the vacuole was considered to be the destruction of proteins. We were surprised to learn that the function of storage, not protein degradation, is responsible for mitochondrial dysfunction in aging yeast cells," says Dr. Hughes.
This unexpected discovery prompted Hughes and Gottschling to investigate the effect of calorie restriction on vacuole acidity, which is known to increase the lifespan of yeast, worms, flies and mammals. Scientists have come to the conclusion that calorie restriction – that is, limiting the reserves of raw materials necessary for the cell – delays aging, at least partially, by increasing the acidity of the vacuole.
"Preliminary data on how calorie restriction prolongs the life of yeast can hopefully be transferred to higher organisms such as humans," Dr. Hughes continues.
Given the similarity of the fundamental biology of yeast and human cells, the newly established link between their nutrition and aging can shed light on the events preceding the development of age-related human diseases.
"Recently, a lot of information has appeared in the scientific literature and the media about how what we eat affects the aging process, but this information is incredibly confusing. Now we have a new paradigm for understanding how the interaction of genetics and the environment affects life expectancy, aging and the development of age-related diseases. I'm just thrilled about it!" exclaims Dr. Gottschling.
Gottschling and Hughes suggest that if the decrease in acidity in the vacuole limits its ability to store certain nutrients and metabolites, they can accumulate in the cell, filling the mitochondria. "Flooded" in this way, mitochondria spend all their energy – in fact, burning out their motors – to assimilate this excess. Deprived of the energy to import proteins needed to maintain their elegant shape and perform normal functions, the mitochondria are literally destroyed. Now Dr. Gottschling and his colleagues are engaged in a detailed test of this hypothesis. In addition, they are trying to figure out what is the trigger of the primary drop in the acidity of the vacuole.
The latter question is of particular scientific interest, since researchers have found that even if the vacuolar acidity decreases as the age of maternal yeast cells increases, the acidity in the vacuoles of newborn daughter cells turns out to be normal. This corresponds to the data previously obtained in this field that, regardless of the age of the mother cells, all daughter cells of yeast have the same life expectancy potential. The release of vacuolar acidity in daughter cells is the earliest event observed in cellular rejuvenation, a phenomenon in which age–related defects appear to be erased in the descendants of the organism. The study of this phenomenon can help to understand what is the contribution to the aging process of the very act of cell division.
Over the past ten years, Professor Gottschling and his colleagues have made several landmark discoveries, including establishing that aging yeast cells are characterized by genomic instability similar to that observed in human cancer cells, and proved that this instability is due to mitochondrial dysfunction. In addition, Gottschling's group has developed a number of innovative tools for using yeast as a model organism, including a method called the Mother Enrichment Program, which makes it possible to increase the efficiency of experiments by obtaining large populations of aging yeast cells.
Professor Gottschling is an elected member of the US National Academy of Sciences (National Academy of Sciences), the American Academy of Arts and Sciences (American Academy of Arts & Sciences), the Washington State Academy of Sciences (Washington State Academy of Sciences) and the American Academy of Microbiology (American Academy of Microbiology).
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