Impaired energy production may explain why brain is susceptible to age-related diseases

Indigophoton · May 29, 2018

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Aged mitochondria (green) in old neurons (gray) appear mostly as small punctate dots rather than a large interconnected network. Credit: Salk Institute

Defective energy production in old neurons might explain why our brains are so prone to age-related diseases. Salk researchers used a new method to discover that cells from older individuals had impaired mitochondria—the power stations of cells—and reduced energy production. A better understanding of the effects of aging on mitochondria could reveal more about the link between mitochondrial dysfunction and age-related brain diseases, such as Alzheimer's and Parkinson's. The work appeared in Cell Reports on May 29, 2018.

"Most other methods use chemical stresses on cells to simulate aging," says senior author Rusty Gage, a professor in Salk's Laboratory of Genetics. "Our system has the advantage of showing what happens to mitochondria that age naturally, within the human body."

Mitochondria, small structures found within cells, are responsible for converting our food into chemical energy our cells can use. Defects in mitochondrial genes can cause disease, but researchers also know that mitochondria become less efficient with aging and can drive age-related disorders.
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The article, https://medicalxpress.com/news/2018-05-impaired-energy-production-brain-susceptible.amp

Highlights
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iNs from old human donor fibroblasts show reduced OXPHOS-related gene expression

Old iNs display a variety of mitochondrial aging phenotypes

Fibroblast-to-iN conversion is accompanied by a metabolic switch toward OXPHOS

Neuronal bioenergetic profile causes increased vulnerability to mitochondrial aging

Summary
Mitochondria are a major target for aging and are instrumental in the age-dependent deterioration of the human brain, but studying mitochondria in aging human neurons has been challenging. Direct fibroblast-to-induced neuron (iN) conversion yields functional neurons that retain important signs of aging, in contrast to iPSC differentiation. Here, we analyzed mitochondrial features in iNs from individuals of different ages. iNs from old donors display decreased oxidative phosphorylation (OXPHOS)-related gene expression, impaired axonal mitochondrial morphologies, lower mitochondrial membrane potentials, reduced energy production, and increased oxidized proteins levels. In contrast, the fibroblasts from which iNs were generated show only mild age-dependent changes, consistent with a metabolic shift from glycolysis-dependent fibroblasts to OXPHOS-dependent iNs. Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs. Our data indicate that iNs are a valuable tool for studying mitochondrial aging and support a bioenergetic explanation for the high susceptibility of the brain to aging.
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The paper, https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30703-4

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