Bengaluru: A “happy chemical” released by our body when we exercise and eat healthy may also prove key to preventing as well as treating neurodegenerative diseases like Alzheimer’s, a breakthrough study involving Indian researchers has suggested.
The study, published in the journal Proceedings of the National Academy of Sciences (PNAS) Wednesday, was conducted by an international team of scientists from Tata Institute of Fundamental Research (TIFR)-Mumbai, Kasturba Health Society (KHS)-Mumbai, University of Buenos Aires, Argentina, and Columbia University, US.
Serotonin is a chemical produced by our nerve cells. Its production increases with response to stimuli, like exercise, and the chemical is a key component in regulating our mood on an everyday basis. Low levels of serotonin are also linked with depression.
According to the researchers, it also helps boost mitochondria growth in the brain cells.
Mitochondria are known as the powerhouse of our cells, and are responsible for energy production and good health of nerve cells.
The researchers additionally found that serotonin helps nerve cells survive longer and better under stress by increasing the energy output from mitochondria.
This has potential implications for the treatment of neurodegenerative disorders and age-related diseases like Alzheimer’s and Parkinson’s that affect about 3 crore people in India and are incurable so far.
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Serotonin, SIRT1, and neural health
Serotonin is an important neurotransmitter in the human body. It transmits messages between nerve cells, also known as neurons.
It helps regulate many aspects of mental and physiological health such as mood, depression, sleep cycles, and bowel movement. It is produced in both the brain and the intestine.
The most well-known association serotonin has with health is its role in depression. It is found to be in low levels in patients of depression and mood-related disorders.
Anti-depressants and other drugs that treat such disorders (Prozac, Celexa, Zoloft) all target serotonin production.
While the pattern of low serotonin levels leading to depression is recognised, the mechanism by which this occurs is as yet unknown.
Unlike other cells in our body, neurons have a very long lifespan.
But just like all other cells, what keeps the neurons functioning, and ultimately maintains their health throughout their lifespan, is mitochondria. These cell organelles need to be at optimum performance for human nerves to continue functioning.
“Studies have shown that most neurological diseases are associated with mitochondria, either consequentially or causally,” said Ullas Kolthur-Seetharam of TIFR, one of the team leads for the study. “Some of them involve mitochondria dysfunction, while some are caused because of mitochondrial dysfunction.”
A core component of neuronal health in mitochondria is a gene called SIRT1, which synthesises an important regulatory protein that plays a role in age-related disorders.
Because of this, SIRT1 is also called the ‘longevity gene’, which has also been shown to play a role in mood-related disorders and depression.
SIRT1 responds to metabolic shifts, such as exercise and changes in diet, and can control the expression of several hundreds of genes as a master regulator.
“There is this neurotransmitter that regulates neuronal health, as well as mood and depression on the one side,” said Kolthur-Seetharam.
“There is a gene and a protein that responds to calories on the other. And the link between the two is mitochondria, which is important for neutrons to function,” he added.
The study
The study was done by research groups led by Kolthur-Seetharam and Vidita Vaidya, who also works at TIFR.
Vaidya’s lab works extensively with serotonin, and understanding its role in regulating emotion. Kolthur-Seetharam’s lab works on age-related disorders. In collaboration with Sashaina Fanibunda, another TIFR scholar, and Ashok Vaidya of KHS, the team started out to look for substances that could potentially serve as neuroprotective agents, safeguarding the health of nerve cells by affecting mitochondria.
Since Vaidya’s lab works extensively with serotonin, it was added as one of the chemicals to be studied.
“The finding was serendipitous and unexpected,” said Vaidya. “We have so much serotonin in our lab, we thought. So why don’t we try to see what it does?”
The collaborators knew that all three cornerstones of neuronal health — serotonin, SIRT1, and mitochondria — decrease with age.
Increasing age also boosts the risk of neurodegenerative diseases, and mitochondria is at the forefront of this confrontation. So, the researchers hit the mitochondria with serotonin directly to see what would come of it.
The response they received with modulating serotonin levels was so drastic that they abandoned other potential neuroprotective agents to focus solely on this.
“In older mice, neurons exposed to serotonin produced more fuel (called ‘ATP’) in the mitochondria,” Vaidya said, “Furthermore, the number of mitochondria produced also shot up.”
It doesn’t stop there. The team noticed that with the increased levels of serotonin, each individual mitochondrion’s energy output also increased tremendously. They observed that serotonin had antioxidant-like properties, enabling the nerve cells to thrive far better than usual under stress.
The findings suggest that serotonin could be an effective treatment to prevent dysfunction and decline of mitochondria, and thus maintain neuronal health.
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The road ahead
The team now has its sights set on several other questions that arise from their research.
“It is fundamental to find out how the three centrepieces of neuronal health function together,” said Kolthur-Seetharam, “And how the others are affected if one of them is changed.”
“What would be interesting to find out is why a neurotransmitter, whose job is to basically signal between nerve cells, is also affecting mitochondria,” added Vaidya.
“We’d also like to know if serotonin affects other cells, and if this works on not just mice, but across all mammals,” she said.
The researchers hope to find out if serotonin also helps boost levels of SIRT1 in older mice with neurological disorders, whether behaviours can be changed by changing SIRT1 and serotonin levels through calorie deficiency, and the extent to which increased amounts of serotonin help cope with anxiety and avoiding depression.
Ultimately, they want to understand how well ageing-related neurological decline can be reversed or slowed down through the use of serotonin.
The authors propose the adoption of combined therapy in treating psychological disorders like schizophrenia and depression as well as neurological disorders. There are multiple ways to increase serotonin, both through pharmacological means as drugs, as well as changing one’s environment to stimulate natural production within the body through diet and exercise.
Because SIRT1 responds to reduced calories, the researchers hope to find out if dietary changes would affect serotonin levels in the body. When studying humans, the authors hope to find out if there’s increased efficiency when treating a patient with antidepressants in combination with dietary and exercise regimes.
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