Prolonging life: slow down mitochondria?
Mitochondrial signals increase life expectancy
LifeSciencesToday based on the materials of the Salk Institute for Biological Studies:
When less is more: how mitochondrial signals extend lifespan
The understandable desire to live as long as possible leads you to decide to drink more red wine and remain socially active, but there is something you probably forgot about: the connection with your mitochondria. It turns out that slowing down the motors of these tiny cell factories can increase life expectancy – an observation relevant not only to the study of aging processes, but also to our understanding of how cells communicate with each other.
This is the opinion of scientists at the Salk Institute for Biological Research, who recently published an article in the journal Cell (The Cell-Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity). Andrew Dillin, Ph.D., from Howard Hughes Medical Institute, and his colleagues used Ceanorhabditis elegans roundworms to show that interference with the mitochondrial functions of certain types of worm cells causes the transmission of signals regulating the lifespan of the entire organism.
"In this work, we have shown how signals sent by stressed mitochondria are transmitted to distant tissues, contributing to survival and an increase in life expectancy," Dillin, associate professor at the Laboratory of Molecular and Cellular Biology, comments on his research.
The nature of the signal sent by cells with stressed mitochondria – a hypothetical factor called "mitokine" by Dillin– remains unknown. However, he suggests that mitokines may someday be used as messengers from healthy to unhealthy tissues to treat degenerative diseases.
"Imagine if we could disturb the mitochondria in the liver and make them send mitokine to degenerating neurons," he says. "Instead of trying to get a drug into the brain, we would be able to use the ability of the body itself to send natural rescue signals."
An increase in life expectancy due to a decrease in mitochondrial activity may seem paradoxical. How can maintaining power plants in an active state turn into anything but a plus?
But it turns out that many scientists, including Dillin, have observed a mysterious correlation between mitochondria, energy generation in the cell and life expectancy – a relationship that suggests that in order to live long, it is not necessary to thrive at the subcellular level.
"As a postdoctoral fellow, I conducted a screening of worm genes that increase life expectancy," says Dillin, recalling a study published in 2002 in the journal Science, which inspired his real work. "Many genes have been linked to mitochondrial functions. When they were turned off, the worms lived longer, although their respiration and metabolism decreased. We wondered if this was the reason for the increase in life expectancy of animals."
The latest article in Cell shows that everything is not so simple. Dillin and his graduate students Jenni Durieux and Suzanne Wolff have created "transgenic" worms with an inactivated cso-1 gene. The cco-1 gene encodes a protein important for biochemical reactions known as the electron transport chain (ETS), or the respiratory electron transport chain, which are necessary for mitochondria, and the entire cell, to generate energy. Worms with selectively impaired loss of the cso-1 gene by mitochondrial function in intestinal cells (shown in green in the picture) or neurons (shown in red) lived longer than normal worms, while this pattern did not extend to animals with ETC disorders in muscle cells, skin or germ cells.
Based on the results of experiments, scientists have suggested that life expectancy increases a unique signal emanating from stressed mitochondria in neurons or intestinal cells transmitted to distant tissues.
The main discovery was that worms with ETCS selectively impaired by the loss of sso-1 either in intestinal cells or in neurons lived longer than normal worms, while this pattern did not extend to animals with ETCS disorders in muscle cells, skin or germ cells. Based on the results of the experiments, the scientists suggested that a unique signal emanating from damaged mitochondria in neurons or intestinal cells and transmitted to distant tissues increased life expectancy.
"It is curious that in order to get the maximum effect, manipulations with ETCS had to be performed during a critical time window in the worm's life," Dillin emphasizes. "If we transfer this data to a person, then manipulating the mitochondria of a 30-year-old would add 15 years to his life, but an 80-year-old would win only 2-3 years."
In order to determine how cells respond to signals about an increase in life expectancy, scientists monitored an emergency cell rescue plan, called the Unfolded Protein Response (UPR) in Russian literature, although it would probably be more correct to call it a response to unstructured proteins, since in the first case it turns out that the unstructured proteins themselves squirrels organize defense against themselves. Cells activate this plan with an excessive accumulation of proteins, accompanied by a violation of their folding. Violation of the structure of proteins has a toxic effect on the cell and, in order to avoid its death, UPR mobilizes a team of assistants who restore the structure of the destructured proteins accumulating in the endoplasmic reticulum. If the mechanism does not work for some reason, a program of self-destruction of the cell is launched – apoptosis.
When Dillin and his colleagues began feeding the worms chemicals that block UPR, they found that the disruption of the function of cso-1 in neurons or intestinal cells no longer had a positive effect on life expectancy. This important discovery illustrates that the initiation of protein refolding, in this case in response to distant mitochondrial stress, is the factor that increases life expectancy.
Until 2000, biology textbooks described mitochondria only in terms of energy production. "We were captured by the metabolic function of mitochondria," says Dillin, noting that the life–extending signals described in their article are not metabolic in the strict sense of the word. "But now we have learned about many other important functions performed by mitochondria."
For example, the "metabolic" explanation of the increase in life expectancy, known as the "speed of life theory", looks like this: intensively working mitochondria burn a candle of cellular energy from two ends, leading to premature death. Conversely, cells that waste energy sparingly live longer.
Dillin's research refutes such a scenario. "We've shown that it all comes down to protein folding," he says. "This topic unites all the research of my laboratory."
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13.01.2011