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SIRT3 enzyme protects brain cells from stress, helped by exercise

As animals, including humans, age or develop brain diseases such as Alzheimer’s, their brain cells may not produce enough energy to remain fully functional. A new study shows that an enzyme, SIRT3, may protect brain cells against stresses believed to contribute to energy loss. Researchers also found that physical exercise increases the expression of SIRT3, helping to protect the brain against degeneration. The results were published online Nov. 19, 2015, in Cell Metabolism.

Scientists at NIH’s National Institute on Aging Intramural Research Program, Baltimore, used a new mouse model to investigate whether they could aid brain cells called neurons in resisting the energy-depleting stress caused by neurotoxins and other factors. They found a biochemical hero in SIRT3, located in mitochondria, the cell’s powerhouses. SIRT3 is part of the sirtuin family of proteins, which are thought to play an important role in aging, stress resistance, and metabolic regulation.

The researchers, led by Mark Mattson, Ph.D., of NIA’s Laboratory of Neurosciences, found that mice that did not produce SIRT3 became highly sensitive to cellular stress when exposed to neurotoxins that cause neurodegeneration and cell death. In mouse models of Huntington’s disease and epilepsy, mice with SIRT3 deficiency had greater brain neuron degeneration and associated behavioral symptoms than those with sufficient SIRT3 after exposure to certain toxins.

In addition, normal mice that exercised on running wheels for 30 days had significantly higher SIRT3 levels in neurons of the hippocampus, a brain region important for learning and memory, than mice that did not exercise. Researchers concluded that running helped protect neurons against cell death in mice by increasing SIRT3 levels.

The researchers also found that they could protect neurons against stress using a gene-therapy technology to increase levels of SIRT3 in neurons. Neurons without SIRT3 were significantly more vulnerable to toxic stress than those with SIRT3.

The findings suggest that bolstering mitochondrial function and stress resistance by increasing SIRT3 levels may offer a promising therapeutic target for protecting against age-related cognitive decline and brain diseases.

Reference: Cheng A., et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise, and metabolic and excitatory challenges. Cell Metabolism. Published online Nov. 19, 2015.