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Correcting glutathione deficiency improves impaired mitochondrial fat burning, insulin resistance in aging

As we get older, we get fatter. The same is true of mice.

One reason for that may be chronic deficiency in the body’s most abundant antioxidant - glutathione, said researchers at Baylor College of Medicine in a report online in the journal Aging Cell. They combined studies in mice and humans to show that glutathione controls oxidation of fatty-acids (‘fat’) by mitochondria, the "battery" of the cell where energy is generated. When the body is deficient in glutathione, less fat is burned and more fat may be stored.

"Aging is associated with a diminished capacity to make glutathione," said Dr. Rajagopal V. Sekhar, associate professor of medicine - endocrinology at Baylor College of Medicine and corresponding author of the study.

Lack of amino acids

In previous studies, Sekhar found that older people were not able to make glutathione as well as younger people because they lacked two main building block amino acids which make up glutathione - cysteine and glycine.

"Every cell has to make its own glutathione from its precursors," said Sekhar. "When these precursors are deficient, older people are not able to make enough glutathione and become deficient in it. When we provided additional amounts of these precursors in their diet, the concentration of precursors and the ability to make glutathione also normalized."

When glutathione levels were low, there was increased oxidative stress - which means that toxic effects left over from the oxidation lingered. Antioxidants and particularly glutathione hold this toxic effect in check.

Correcting deficiency

Sekhar and his colleagues found that lowering glutathione levels in young healthy mice decreased their ability to burn fat. Next, they tested old mice (which are deficient in glutathione and also have impaired fat-burning) and found that correcting glutathione deficiency improved their ability to burn fat to levels as high as those seen in young mice. These old mice also lost a lot of fat weight and lowered their risk for diabetes (called insulin resistance) to levels seen in young mice.

Then, Sekhar examined whether these same changes could occur in older humans by comparing the ability of glutathione-deficient elderly humans and glutathione-preserved young humans to burn fat.

"We wanted to know what happens to mitochondrial ability to burn fat with long-term glutathione deficiency in older people," said Sekhar. "In fasted younger people, their body was able to burn fat well for energy needs. However, glutathione-deficient older people were not able to burn fat very well under the same conditions."

"When we give these older people cysteine and glycine in their diets and corrected glutathione deficiency, amazingly their fat oxidation also normalized," he said. "The older people go back to burning fat as well as younger people within 14 days."

Improve metabolic health

Sekhar’s research is particularly interesting because it identifies a new reason for poor mitochondrial fat burning in aging, and as well as a new way to fix it. He said no toxic effects were noticed in either mice or humans with this approach.

"This could open up exciting possibilities to improve metabolic health in older people, and more studies are needed in this area," said Sekhar. PharmaPlan LLC, a BCM licensee, is working to develop a product based on Sekhar’s research programs.

Other members of the research team include Dan Nguyen, Susan Samson, Vasumathi Reddy and Erica Gonzalez, all from BCM.

Sekhar is currently recruiting older subjects for a 4-month study to determine if giving these older people the precursors to correct glutathione deficiency will be beneficial by restoring impaired mitochondrial fat oxidation and whether it could decrease excess stored fat.

This work was supported by the Baylor College of Medicine Faculty Seed Award and the Baylor College of Medicine Alkek Bridge Fund. The work was also supported by the Baylor's General Clinical Research Center and the NIH-funded Diabetes Research Center.