The Mysteries of the Aging Brain
Image by © David C Preston
Why do we age? What happens to our brain as we get older? Why do risks of brain related illnesses like Alzheimer’s disease increase with age? Many of us have to go through the devastating experience of having a loved one, like a grandparent, get diagnosed with Alzheimer’s disease. This experience can take an emotional, financial, and physical toll on us as individual caregivers but also as a society. The prevalence of dementia in Canadians over the age of 65 is approximately 7.1%, and according to the World Health Organization, over 55 million people worldwide are living with dementia (including Alzheimer’s disease). In our aging population, the number is expected to rise significantly over the next few decades. There is no easy, all-encompassing answer for what goes on in our bodies and brains as we get older, or why our brains become vulnerable to neurological diseases. However, understanding the cause of the disease and finding targets for potential treatments are crucial for the wellbeing of our growing society.
There are numerous research projects across the world dedicated to better understanding the aging brain and the related diseases. One such project was undertaken by a team of researchers from multiple universities, including Western University, that collaborated to understand how the brain uses energy and how this changes with age. Specifically, they studied the production of lactate and found that too much of it can be detrimental to brain function and life span. Lactate is a molecule that can be used to produce energy molecules that are consumed by the body, namely ATP.
In order to appreciate the importance of studying lactate production in the aging brain, it is important to first understand how ATP is normally made. In healthy cells where plenty of oxygen is present, our mitochondria will generally use glucose and oxygen to make several molecules of ATP. However, when oxygen is scarce, such as after physical exercise, our cells can make fewer molecules of ATP by converting the glucose into lactate byproduct. The amount of lactate in the body and brain is normally low, but the levels are known to be increased in brains of people with Alzheimer’s disease. However it is unknown exactly what effect lactate has in the brain, and whether it contributes to the disease or not.
In the current study, the researchers used fruit flies (Drosophila melanogaster) to study how changes in the levels of lactate dehydrogenase (Ldh), a molecule that is needed to make lactate, affects their lifespans and brain health. Although fruit fly brains are a lot less complex than human brains, they can be useful for studying consequences of basic molecular changes as they are relatively easy to modify. Since all the processes involved in ATP production are fundamental for life, they are conserved across all animals and can therefore be studied in model organisms like the fruit fly.
In this study they conducted several experiments that ultimately indicate that increased lactate is detrimental to health. The researchers first investigated Ldh under 2 different conditions 1) young vs old and 2) increased Ldh vs normal Ldh. The first experiment found that brains of old flies had much higher levels of Ldh and lactate than young flies. In the second modified the flies so they had increased levels of Ldh and compared them with unmodified flies, and found that the flies with increased Ldh and lactate had much shorter lifespans. This finding established that increased Ldh, and as a result increased lactate, is deleterious to the health of flies.
While the researchers had established the negative effects of increased lactate on the brain, its impact on different cell types was unknown. Particularly, it was still not known if the deleterious effect of increased Ldh stemmed from all cells in the brain or if certain cell types contributed more to the health and lifespans of the flies. The brain is made of different cell types including neurons, which are the main cells in the brain involved in transmitting information, and glial cells, which provide support to neurons. In order to parse out the effect of increased Ldh in different cell types on the health of the flies, the researchers made flies that had increased Ldh in 3 major cell types: neurons, glia, or clock cells. Clock cells are a subset of neurons involved in maintaining the circadian rhythm, and were an important group of cells to study since lactate is known to fluctuate in human and fly brains with the sleep-wake cycle.
The researchers found that increased Ldh levels in clock cells resulted in the most reduction of lifespans, which was followed by neurons, and finally glia. Increased degeneration of brains was seen when Ldh was increased in neurons, but not when increased in glia. Furthermore, increased Ldh in neurons also resulted in decreased circadian rhythmic activity in the flies, which further adds to the idea that increased lactate disrupts normal brain processes. These experiments showed that the negative effects of Ldh do indeed stem from specific cell types instead of the whole brain, and particularly neurons seem to be the main cells involved.
Altogether, the researchers show that increased lactate is detrimental, therefore they sought to determine if reduced lactate would be beneficial. To test this, the researchers created flies that had reduced levels of Ldh in neurons. In support of their theory, they found that the modified flies had longer lifespans and less brain degeneration compared to control flies. This means that decreased lactate levels could actually be protecting the brains of the flies!
But what does this mean for humans? Lactate is known to be increased in brains of Alzheimer’s patients, but it is unknown whether it contributes to the disease symptoms or not. This study provides evidence that increased Ldh levels, and as a result increased lactate levels, can be detrimental to health and could be one of the explanations for some of the cognitive and health impairments seen in Alzheimer’s disease. Since reducing Ldh levels in neurons improved brain health in this study, this could mean we should consider lactate metabolism as a potential target for treatment in human patients.
https://www.who.int/en/news-room/fact-sheets/detail/dementia
Long, D. M., Frame, A. K., Reardon, P. N., Cumming, R. C., Hendrix, D. A., Kretzschmar, D., & Giebultowicz, J. M. (2020). Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster. Aging (Albany, NY.), 12(11), 10041–10058. https://doi.org/10.18632/aging.103373
Mullins, R., Reiter, D. and Kapogiannis, D. (2018), Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain. Ann Clin Transl Neurol, 5: 262-272. https://doi.org/10.1002/acn3.530
Original article:
Mullins, R., Reiter, D. and Kapogiannis, D. (2018), Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain. Ann Clin Transl Neurol, 5: 262-272. https://doi.org/10.1002/acn3.530