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Combating the Cellular Damage of Aging

  Combating the Cellular Damage of Aging

Illustration: Maja Moden

Researchers from UCLA and the California Institute of Technology have made discoveries that might help slow, and potentially reverse, the process of aging in cells. The scientists generated new methods that allow the identification of factors that selectively remove damaged mitochondrial DNA, which will affect the process of aging at the cellular level. Aging is, in part, due to changes in mitochondria, the energy-providing powerhouses of the cell.

Mitochondria contain their own DNA, and the accumulation of mutations of mitochondrial DNA throughout a lifetime contributes to aging. There are two strategies for combating age-related diseases. One way is to fight the individual disease, and the other aims to delay the aging process to prevent or delay the onset of age-related diseases.

Mitochondria provide most of the energy for cellular operations. Cumulative damage to mitochondrial DNA contributes to age-related disorders such as Parkinson’s disease, Alzheimer’s disease, heart disease and muscle wasting and frailty. One key goal to delay or reverse aging is to reduce the ratio of damaged-to-normal mitochondrial DNA. Inherited defects in mitochondrial DNA also cause a number of devastating childhood diseases, including strokes and muscle diseases.

“We showed that we could selectively cleanse the damaged mitochondrial DNA, effectively rejuvenating them and improving mitochondrial quality,” says Ming Guo, MD (RES ’01, FEL ’02), PhD, P. Gene & Elaine Smith Chair in Alzheimer’s Disease Research and professor of neurology and pharmacology. “This strategy might someday prove useful in treating or preventing age-related diseases, as well as the general declines in cognitive function and mobility that occur with aging.”

The researchers found that by activating cellular processes known as “autophagy,” it was possible to remove 95 percent of the damaged mitochondrial DNA. In addition, Dr. Guo’s team found the activation of pathways that are crucial in preventing Parkinson’s disease also dramatically cleansed damaged mitochondrial DNA.

Studying the role that these DNA mutations have in disease hasn’t been easy, in part because of the lack of good laboratory models. For the study, Dr. Guo and her laboratory teamed up with the lab of Bruce Hay, PhD, professor of biology and biological engineering at Caltech, to create a model of mitochondrial DNA using the fruit fly Drosophila. Fruit flies are an effective system in which to study fundamental biological processes and how the breakdown of these processes leads to human diseases. Eighty percent of human-disease genes have counterparts in fruit flies. This new fly model mimics aging in young animals.

The findings demonstrate that the level of damaged mitochondrial DNA can be reduced in cells simply by boosting the body’s natural quality-control processes. Drs. Guo and Hay now plan to use the model to screen for potential drugs that have a similar impact — drugs that might rejuvenate mitochondria to improve overall cellular health.

“Selective Removal of Deletion-bearing Mitochondrial DNA in Heteroplasmic Drosophila,” Nature Communications, November 14, 2016


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