Naturally Aged Mitochondria May Improve Study of Brain Aging

Defective energy production in old neurons might explain why our brains are so prone to age-related diseases. The 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.

When the mitochondria within neurons age, they lose vigor, leaving the brain more vulnerable to age-related diseases and the ravages of aging generally. Yet well-aged mitochondria are usually hard to come by, at least in laboratory models, which tend to lose genetic markers of aging – at both the nuclear and mitochondrial levels. Unfortunately, mitochondria that have their markers of aging restored by artificial means, by chemical stresses, may lack all the subtleties of naturally aged mitochondria. Consequently, naturally aged mitochondria would be a welcome addition to laboratory models of aging.

Such mitochondria have, in fact, been introduced to a new in vitro neuronal model of aging. This model relies on a process called direct fibroblast-to-induced neuron (iN) conversion. Unlike an alternative process, the differentiation of induced pluripotent stem cells, iN conversion yields functional neurons that retain important signs of aging.

The new model, which was developed by researchers based at the Salk Institute, was described in the journal Cell Reports, in an article entitled “Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile.” The article suggests that the new model could replicate the effects of progressive aging.

“Here, we analyzed mitochondrial features in iNs from individuals of different ages,” the article’s authors wrote. “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.”

“Pretty much every area we looked at had defects,” said Jerome Mertens, Ph.D., a co-corresponding author of the new paper and a staff scientist in the laboratory of Rusty Gage, Ph.D., a professor in Salk’s Laboratory of Genetics.

The researchers hypothesized that the reason the mitochondria of iNs were more impacted by aging than the mitochondria of skin cells was that neurons rely more heavily on mitochondria for their energy needs. “If you have an old car with a bad engine that sits in your garage every day, it doesn’t matter,” Mertens explained. “But if you’re commuting with that car, the engine becomes a big problem.”

“…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,” the article continued. “Indeed, OXPHOS-induced old fibroblasts show increased mitochondrial aging features similar to iNs.”

Previously, the Gage lab developed a method to directly convert skin cells into neurons (called induced neurons, or iNs). Most methods to create neurons from patient cells rely on an intermediary stem cell step (creating what are called induced pluripotent stem cells), which resets cellular markers of aging. But the Gage lab’s iNs retained signs of aging, including changes to gene activity and the cells’ nuclei, the team reported in 2015.

In the new work, the researchers asked whether mitochondria in the cells also retained hallmarks of aging during the iN conversion process. Using skin cells collected from humans ranging in age from 0 to 89 years old, the team created iNs from each donor and then used a variety of methods to study the mitochondria of each set of cells.

Mitochondria in the skin cells isolated from each person showed few age-related changes. However, once the cells were directly converted to neurons, mitochondria from older donors were significantly different. Mitochondrial genes related to energy generation were turned off and the mitochondria were less dense and more fragmented and generated less energy.

“Most other methods use chemical stresses on cells to simulate aging,” said Gage, the new paper’s senior author. “Our system has the advantage of showing what happens to mitochondria that age naturally, within the human body.”

The researchers next want to begin to apply their method to study age-related diseases, including Alzheimer’s and Parkinson’s. In the past, mitochondrial defects have been implicated in these diseases. By collecting skin cells from patients and creating iNs, the team can look at how neuronal mitochondria from patients with those diseases are different from neuronal mitochondria from unaffected older individuals.