Role of Mitochondrial Function in Aging Process Discovered

In a discovery that could lead to new ways to extend healthy aging, scientists at the Miller School of Medicine have uncovered a critical mechanism of mitochondrial oxidative phosphorylation and its effects on the aging process. The researchers, led by senior author Antoni Barrientos, Ph.D., associate professor of neurology and biochemistry and molecular biology, discovered that cellular respiration controls chronological life span and its extension by caloric restriction in yeast models of aging of non-dividing cells.

The study, “Mitochondrial Respiratory Thresholds Regulate Yeast Chronological Lifespan and its Extension by Caloric Restriction,” is published in the July issue of Cell Metabolism.

Despite some controversies, it is widely accepted that mitochondria play fundamental roles in the mechanisms of aging and life span. In this study, the team genetically and pharmacologically modified the cellular respiration of yeast cells during two key phases: exponential and stationary growth phases. The goal was to determine the minimum respiratory capacity needed to sustain a normal chronological life span (CLS), the amount of time a yeast cell naturally survives.

“Our results are relevant to the physiology of aging of higher organisms,” said Barrientos, who led a team that included Alejandro Ocampo, Ph.D., post-doctoral associate, and Jingjing Liu, Ph.D. student, both of the Department of Biochemistry and Molecular Biology, in collaboration with Gerald S. Shadel, Ph.D., professor of pathology and genetics, and graduate student Elizabeth A. Schroeder, both of Yale University.

The team discovered that yeast cells have a large reserve respiratory capacity to sustain CLS. In fact, respiration only limited the life span when depleted below 40 percent. During the exponential growth phase, cells that respired at a higher rate in response to stress increased the amount of stored nutrients for later use, and were then able to extend their life span. In contrast, cells that respired below the threshold during the growth phase had poor respiratory capacity in the stationary phase and very short life span.

Finally, the team discovered that cells unable to respire consume their nutrient stores very fast and develop an energetic crisis that leads to poor stress resistance and cell death. To prove this discovery, the researchers showed it was possible to restore standard life span to cells unable to respire by providing them with trehalose, a carbohydrate used by yeast as a nutrient reserve. They concluded that mitochondrial respiratory thresholds regulate yeast CLS and its extension by caloric restriction by increasing stress resistance, along with the efficient use of nutrient stores which in turn extends chronological life span.

Some effects of caloric restriction on mammalian metabolism remain controversial, but it is accepted that caloric restriction increases mitochondrial efficiency. Additionally, several studies have shown that long term caloric restriction decreases metabolic rate in rodents as it does in yeast.

While yeast accumulate carbohydrates, mammals can increase fat mass as a stress response to the uncertainty of food availability, such as occurs in hibernating animals in anticipation of the winter. “It’s possible that a conserved response to starvation stress is to accumulate carbon sources that would maximize long-term survival and to utilize them efficiently later in life,” said Barrientos. He adds that respiratory deficiencies underlie the pathogenic mechanisms of classical mitochondrial disorders and are also frequently associated with age-related pathology such as neurodegeneration.

“It is tempting to speculate that interventions mimicking caloric restrictions might lower the energetic thresholds of critical affected tissues,” said Barrientos. Coupled with an enhancement of cellular protection systems, “it could extend health span in normal and diseased individuals.”

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