Longevity Briefs: Mitochondrial Health Influences Learning In Mice

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The energy demands of the brain are high – when not exercising, the calories consumed by the brain represent roughly 20% of the body’s total demand, despite the brain weighing only around 2% of the body’s total mass. For this reason, anything that affects the way the body processes energy is likely to have a significant impact on cognitive function, and nothing is more important for energy metabolism than the mitochondria – the power plants of the cell.

Mitochondria are the ‘cellular organs’ that use nutrients like glucose (sugar) and fats to generate adenosine triphosphate (ATP), the cell’s universal ‘fuel’. The efficiency of ATP production depends on a set of mitochondrial proteins that become damaged and dysfunctional in older age, leading to a state of mitochondrial dysfunction in which ATP production is significantly reduced. As if this wasn’t already bad enough, mitochondria produce reactive oxygen species or ROS (reactive molecules that can damage proteins and DNA) as a byproduct of ATP production. Mitochondrial dysfunction significantly increases ROS production, contributing to inflammation and age-related disease.

For these reasons, scientists suspect that mitochondrial dysfunction plays an important role in cognitive ageing and neurodegenerative disease. In this study, researchers find that the health of the mitochondria present in synapses can be directly linked to learning ability in ageing mice, and that cognitive function can be improved by targeting those mitochondria.

The discovery:

Researchers first studied learning decline in ageing mice by training young (8-12 weeks old), ‘middle-aged’ (50 weeks old), and old (75-85 weeks old) mice on a touchscreen task. Mice first learnt to identify visual patterns in the form of vertical vs horizontal lines and press the correct button in order to earn food rewards. After the mice had learnt these patterns, researchers changed the rules so that the mice had to respond based on the location of the button instead. Researchers found that both the young and ‘middle-aged’ mice adapted easily, but interestingly, the performance of the aged mice varied – some mice performed well while others struggled to adapt to the new pattern. This suggested that much like in humans, some mice suffered from a greater loss of cognitive flexibility with age than others, and so researchers set out to investigate what the difference could be.

To do this, they used electron microscopy to study the prefrontal cortex (the brain region involved in adaptive thinking) of four young and six aged mice that had completed the behavioural testing. They found that aged mice had fewer synapses (connections between two neurons) overall, but somewhat surprisingly, synapse density didn’t correlate with cognitive performance in either young or aged mice. However, one difference emerged: among the aged mice, those with a higher number of synapses containing presynaptic mitochondria (mitochondria on the side of the synapse that receives the electrical impulse first and transmits this signal to the second neuron) had performed significantly worse in the cognitive testing. While having more mitochondria might sound like it should be a positive thing, the presence of additional mitochondria can be a sign of mitochondrial dysfunction and reactive oxygen species, which can promote mitochondrial replication.

Researchers also analysed the levels of proteins present in brain tissue from mice in each age group to identify which ones correlated with ageing and cognitive performance. Interestingly, these turned out to be largely distinct protein signatures – that is to say, the set of proteins that correlated with differences in cognitive performance were largely different from those correlated with age, and many involved mitochondrial function, further pointing to the mitochondria as a potential explanation for why some mice performed better than others.

Finally, to test whether mitochondrial dysfunction actually caused cognitive inflexibility, researchers treated seven mice with MitoQ starting at 55 weeks of age (so closer to ‘middle aged’ mice). MitoQ is a mitochondria-targeted antioxidant supplement based on a mitochondrial coenzyme called coenzyme Q10. It helps to neutralise reactive oxygen species in order to protect the mitochondria against oxidative damage. After 20 weeks of treatment, these mice performed the same touch screen task and were able to learn the new pattern significantly faster than 5 mice that received a control treatment, suggesting that learning was improved.

The implications:

Two findings from this study seem particularly interesting. The first is that mitochondrial dysfunction seems to be directly linked to reduced cognitive flexibility in old age, and that targeting oxidative damage can reduce this aspect of cognitive decline, at least in mice. The other interesting finding is that the changes in mitochondrial presence and function that were linked to cognitive flexibility were not the same as those linked to age. In other words, this study seems to suggest that while mitochondrial function declines with age, there are other aspects of mitochondrial function and distribution that don’t change with age but influence individual variability in age-related cognitive decline. For example, the presence of presynaptic mitochondria varied in young mice, but only once these mice became old was this variability linked to cognitive performance.

It must be pointed out that the number of mice used in this study was fairly small, and so results should be taken with a pinch of salt until replicated in larger studies. Coenzyme Q10 has been trialled in various human diseases, but while it appears to be quite safe, there is currently not enough evidence to demonstrate a benefit for cognitive ageing. Lifestyle practices like physical exercise, consuming a plant-rich diet for antioxidants, and exposure to cold temperatures may help improve mitochondrial health.