Aging Affects Our Bodies…and Brains!

As people get older, their bodies go through a number of obvious changes—they get more wrinkles, their hair turns gray (or falls out!), and sometimes they move more slowly. People’s brains also change as they age, but these changes are not as easy to see. For some people, aging-related brain changes are normal and do not cause any major issues. But for others, the brain can age in an unhealthy way, leading to conditions like dementia. Dementia is a disorder that makes it hard for people to remember things, understand new information, and do everyday tasks. Globally, the number of people living with dementia is expected to increase from ~57 million in 2019 to 153 million in 2050 [1].

Scientists still do not know exactly what happens in the brain as it ages, nor do they understand what causes the difference between healthy vs. unhealthy brain aging. The brain is a difficult organ to study—it contains many types of cells and molecules working together in complex ways. One idea is that the brain’s energy metabolism plays a big part in how well it ages [2, 3]. Just like a car needs fuel to keep going, our brains need energy to work well. Brain energy metabolism is how the brain makes and uses energy to keep all its functions running smoothly. Metabolism involves thousands of tiny chemicals called metabolites that work together in a complicated network to keep brain cells active and healthy. Could changes in metabolite levels explain the changes that are seen in the brain as it ages?

A Computer Model to Study the Aging Brain

Since studying the human brain directly can be tricky, our research group decided to build a computer model of brain energy metabolism. A computer model is like a virtual experiment that uses math equations to represent real-life processes—whether it is how a car engine works, how weather systems move, or, in our case, how the brain’s cells and molecules interact. Our computer model allows us to simulate what happens inside the brain as it ages, giving us a way to explore complex processes that would be hard to study directly.

We built three main brain elements into our computer model: neurons, astrocytes, and blood vessels. Neurons are brain cells that communicate with other cells using electrical signals, to help a person think, move, and feel. Astrocytes are helper cells that support neurons and keep them healthy. Blood vessels bring nutrients, like oxygen and glucose (a type of sugar), to the brain so it has the fuel it needs to keep going.

To understand how changing levels of metabolites and other important molecules affect the brain during aging, we collected and combined a lot of data about brain proteins, nutrients, and brain functions from scientific papers published by other researchers. By plugging these data into our computer model, we could ask questions and test ideas that would be impossible to test on living people—like how aging might affect metabolite levels, neuron electrical activity, or the metabolic network that keeps the brain strong and adaptable. We can also study which treatments could help the brain stay strong as we age.

We wanted other researchers to be able to use our model as an example, to help them build their own computer models of other conditions and diseases. So, we made the computer program (written in the Julia programming language) publicly available. For more information, you can check out the Blue Brain Project.

Brain Energy Supply and Energy Use Decrease With Aging

As the brain ages, its energy metabolism begins to change [3]. Our model showed that aging affects the levels of several molecules in brain cells. Some molecules appear to increase in aging, while others seem to decrease or stay basically the same (Figure 1).

One of the most important metabolites in the brain is adenosine triphosphate (ATP)—a molecule that serves as the main energy source for all cells in the body. Our computer model showed that more ATP is available in young brains than in aging brains. As ATP production starts to slow down, it may be more difficult for brain cells to keep up with the demands of thinking, moving, and learning.

Next, we used our model to ask whether aging-related changes in metabolism can change the way neurons work. We found that neurons send weaker signals in the aging brain. Neurons need energy to send their electrical signals, so the model tells us that the aging brain has both a lower supply of energy (in the form of ATP) and a lower need for energy (because of weaker signaling). Reduced signaling ability means that neurons may struggle to keep up with daily tasks.

The Aging Brain “Breaks” More Easily

In addition to producing and using less energy, our computer model showed that the aging brain also becomes more fragile and less able to repair itself. Think of the brain’s metabolic network as the system of streets in your town, and imagine that you need to bring some medicine to a sick friend. In a young brain, there are lots of open routes and well-maintained roads, making it easy for essential molecules, like energy-carrying ATP, to reach all parts of the brain. This is like having many ways to get to your friend’s house—you could take Main Street, cut through the park, or take the highway. Even if one route is closed, there are still plenty of other ways to get there quickly (Figure 2A).

But as the brain ages, it is like more and more roads are blocked off, and some bridges are out. Now, there might only be one or two paths left, or maybe you cannot make it to your friend’s house at all. The same thing happens in an aging brain—when it experiences stress (like a minor injury or everyday wear-and-tear) there are fewer ways to get important metabolites where they are needed to help the brain recover (Figure 2B). This makes the brain more fragile and less adaptable, meaning it is less able to handle challenges or repair itself over time.

However, the model showed some interesting differences between neurons and astrocytes when it comes to adaptability. As the brain ages, metabolism in neurons becomes less adaptable. This means neurons struggle more to respond to changes or handle stress because the processes that produce energy are not as flexible as they used to be. On the other hand, astrocytes seem to have more adaptable metabolites as they age. What does this mean for the brain? One possibility is that astrocytes are doing more to keep themselves strong, becoming a bit “selfish” to stay healthy as they age [4]. Another way to think about it is that astrocytes are making a “self-sacrifice”—stepping up to help support the neurons, which are struggling with aging. Either way, these changes can make it harder for the brain to stay strong and bounce back from stress, increasing the risk of issues like dementia over time.

Can we help the aging brain become stronger and more adaptable? Are there ways to support neurons and astrocytes so they can keep working well as we grow older?

Lifestyle Habits May Help Repair the Aging Brain

Our computer model offers clues about strategies to keep the brain’s metabolism strong, even as people grow older. The model supports previous research showing that certain well-known healthy lifestyle habits—like a balanced diet, regular exercise, and specific vitamins or supplements—could help brain cells bounce back from stress and continue functioning well (Figure 3).

In terms of diet, the model suggests that eating in a way that lowers blood glucose and raises blood ketones (which are substances made when you burn fat for energy) may help the brain. These changes can make it easier for cells to get the energy they need, especially under stress. Exercise has a similar effect: it increases blood flow to the brain, which delivers nutrients that support energy production and help repair cells. Physical activity also raises the level of lactate in the blood, a substance the brain can use along with ATP for extra fuel during demanding tasks [5].

Many people already take vitamins and other dietary supplements to keep their brains and bodies healthy. NAD supplements are one type of supplement that may play an important role. NAD is a molecule that helps the brain’s mitochondria—the cell’s powerhouses—produce ATP. In the presence of higher NAD levels, our model shows that cells produce more ATP and respond better to challenges, which could help older brains stay alert and flexible.

Supporting Neuron Function and Future Directions

In our computer model, a combination of a healthy diet, regular exercise, and NAD supplements raised ATP levels in neurons and astrocytes, bringing them closer to the levels seen in a younger brain. However, the model showed that these lifestyle changes alone were not enough to make aged neurons signal like young neurons. In other words, the neurons could produce more energy, but they still were not signaling as strongly or precisely as those in a younger brain. To address this, we tweaked the model conditions to increase the activity of a molecule that neurons need to send electrical signals, called the sodium-potassium pump. Increasing the activity of this molecule to youthful levels made neurons’ signals stronger and more like those in a young brain. Interestingly, insulin, a substance well-known for controlling blood glucose, can also boost the sodium-potassium pump’s activity, supporting the model’s findings on the benefits of diet and exercise. So, our model suggests that the sodium-potassium pump could be a potential target for therapies aimed at restoring youthful brain function.

While these results are promising, they come from a computer model—so scientists need to conduct further experiments to confirm whether these strategies work in real life. Still, our findings provide exciting insights into how diet, exercise, and targeted supplements could help protect the brain as it ages. By better understanding the aging brain’s unique challenges, scientists can develop new ways to support brain health, potentially helping people stay sharp, active, and independent as they grow older—and hopefully reducing the risk of age-related conditions like dementia.

Glossary

Energy Metabolism: ↑ The process by which the brain converts nutrients like glucose and oxygen into energy, allowing brain cells to perform their functions effectively and stay healthy.

Metabolites: ↑ Small molecules produced or used during metabolism, which help keep the brain’s cells functioning properly by participating in energy production and other essential chemical processes.

Glucose: ↑ A type of sugar that acts as the main source of energy for the brain and body. It is essential for brain cells to perform tasks like thinking, learning, and moving.

Adenosine Triphosphate (ATP): ↑ A molecule that stores and provides energy for cells to perform their functions. It acts as the main energy source for all cells in the body, including brain cells.

Ketones: ↑ Molecules produced by the liver when the body burns fat for energy, often during low carbohydrate intake or fasting. The brain can use ketones as an alternative energy source.

Lactate: ↑ A molecule produced when the body breaks down glucose for energy, especially during exercise. The brain can use lactate as an additional energy source to support its functions.

NAD Supplements: ↑ Supplements that increase the levels of NAD, a molecule that helps cells, including brain cells, produce energy and respond better to stress and damage.

Sodium-potassium Pump: ↑ A protein in cell membranes that moves sodium out and potassium into cells, using energy. It helps maintain electrical signals in brain cells for proper communication and function.

Conflict of Interest

HM is a co-founder and board member of Frontiers Media SA. PS is employed as a proteomics application data scientist at Biognosys AG.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Edited by Susan Debad Ph.D., graduate of the UMass Chan Medical School Morningside Graduate School of Biomedical Sciences (USA) and scientific writer/editor at SJD Consulting, LLC. We would like to thank the coauthors of the original manuscript: Lida Kanari, Elvis Boci, Cyrille Favreau, and Stefano M. Antonel. This study was supported by funding to the Blue Brain Project, a research center of the École Polytechnique Fédérale de Lausanne, from the Swiss government’s ETH Board of the Swiss Federal Institutes of Technology. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.