Exercise may protect against neurodegenerative diseases

November 19, 2015

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Exercise may protect aging brains against the neurodegenerative diseases resulting from energy-depleting stress caused by neurotoxins and other factors, according to researchers at the National Institute on Aging Intramural Research Program and Johns Hopkins University School of Medicine.

They found that running-wheel exercise increased the amount of SIRT3 in neurons of normal mice and protected them against degeneration.

However, mice models genetically modified to not produce SIRT3 became highly sensitive to stress when exposed to neurotoxins that cause neurodegeneration and epileptic seizures, and running failed to protect the neurons. In that case, neurons could be protected against stress by a gene-therapy technology to increase levels of SIRT3 in neurons, they found.

These findings suggest that bolstering mitochondrial function and stress resistance by increasing SIRT3 levels — either by exercise or gene therapy — may protect against age-related cognitive decline and brain diseases, the researchers say.

The research team report their findings online today (Nov. 19) in the journal Cell Metabolism. This work was supported by the Intramural Research Program of the National Institute on Aging and the Glenn Foundation for Biomedical Research.

Abstract of Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise, and metabolic and excitatory challenges

The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington’s disease and epilepsy, Sirt3-/- mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration.