Changes in metabolism impair neurons in aging brains

Globally, the number of people living with dementia is projected to increase from approximately 57 million cases in 2019 to 153 million in 2050. This increase will be mostly driven by the growth of older populations. So, understanding age-related changes in the brain could help to identify new ways of preventing, delaying, diagnosing, and treating neurodegenerative disorders.

In their Frontiers in Science lead article, Shichkova et al. present the first comprehensive, data-driven molecular model to explore how aging affects the interlinked processes of metabolism, neuronal activity, and blood flow in the brain. This important new computational tool could help scientists identify and test ways to protect and repair brain function during aging, for example via diet, exercise, and new drug targets.

This explainer summarizes the article’s main points.

How does aging metabolism affect the brain?

The brain requires large amounts of oxygen and glucose to supply the energy needed to support neuronal activity. Weaker metabolism as we age is thought to impair the electrical activity generated in the brain and may be one of the root causes of neurodegenerative diseases. Recent research found that restoring the activity of mitochondria, which power cells, can help maintain connections between neurons.

The new model by Shichkova et al. provides a way to examine the highly complex system of biochemical reactions that support metabolism in the brain. The model predicts that, as we age, the metabolic system becomes less adaptable, and less able to recover from damage or respond to change.

The model’s simulations show metabolic differences between young and old brains, both at rest and during electrical stimulation.

The results reveal how age-related changes to metabolism affect the ability of neurons to generate electrical impulses that are key to signaling in the brain. In addition, the model predicts lower supply and demand for energy in older brain cells.

What is needed to create a model simulating the brain’s aging?

Shichkova et al. based their model on existing data on the so-called ‘neuro-glia-vascular' system, linking brain metabolism, neuronal activity, and blood flow. Comprising 16,800 interaction pathways within this network, the model is the most complex yet—integrating all key cells, proteins, chemicals, and processes involved in brain metabolism.

As well as brain nerve cells (neurons), the model includes glial cells called astrocytes, which perform many important roles to support and maintain the neurons. It allows simulation of the movement of chemicals within and between these cells, and between these cells and their environment. Importantly, it also allows modelling of the supply of nutrients to brain cells via the bloodstream.

Next, the authors simulated the effects of aging within this model. To do this, they used publicly available genetic information (RNA sequencing data) to replicate age-related changes in protein production, and also altered the levels of various chemicals and nutrients. They tested the effects of these age-related changes on brain metabolism and neuronal activity in the model.

Can exercise and diet repair the aging metabolic system?

Shichkova et al. analyzed the model’s results to find key points in the system where interventions could restore the brain’s metabolic adaptability. This identified three chemicals whose levels could be altered through lifestyle changes:

• Reducing blood glucose—achievable through diet

• Increasing β-hydroxybutyrate, a type of ketone, in the blood—achievable through diet

• Increasing blood lactate—achievable through physical exercise.

These findings correspond with other proposed anti-aging interventions.

The ketogenic diet and caloric restriction, for example, raise the levels of β-hydroxybutyrate and lower glucose in the blood. Exercise, meanwhile, helps to improve brain health and slow aging by increasing blood lactate levels.

Can supplements and medication repair the aging metabolic system?

The model shows that, in addition to the changes supported by diet and exercise, the impact of age could be reversed by nicotinamide adenine dinucleotide (NAD) supplementation. NAD is a vital molecule for generating and transporting energy-carrying molecules from mitochondria.

Shichkova et al. also analyzed proteins known as transcription factors, which play a key role in regulating the production of other proteins. This revealed that a protein called estrogen-related receptor alpha (ESRRA) is connected to the predicted age-related changes. This means that ESRRA and the proteins it regulates could be important targets for drug development.

How do the different types of brain cells change with age?

The model found that the adaptability of most metabolic pathways in neurons decreases with age. By contrast, the adaptability of the glia mostly increases.

Glia are important cells that support the neurons in many ways. So, Shichkova et al. suggest that the increased adaptability of glia could be a “self-sacrifice” to support the declining neurons. This could potentially be a way of stabilizing the fragile metabolic system in older neurons.

Can the aging brain metabolism model be used in further research?

Shichkova et al. validated the model by comparing its results with reported experimental data. This showed that the model accurately predicted changes in biochemical activity and molecular concentrations in response to neuronal electrical impulses. These predictions matched many age-specific differences seen in previous research, highlighting the model’s reliability and value as a research tool. The model could also be used to understand the impact of genetic mutations, enzyme deficiencies, and the effects of different treatments or interventions. Such findings could help guide laboratory or clinical experiments to test potential new treatments.

However, the model is limited by not accounting for changes in oxygen availability with age. Although oxygen affects multiple processes in cells, there was insufficient data for it to be included. In addition, the model does not factor in metabolic waste management nor how neuronal activation regulates blood flow.

The model is available as an open-source resource on at the Open Brain Platform hosted by the Open Brain Institute for other researchers to study brain metabolism. This could accelerate research into age-related neurodegenerative diseases, potentially finding ways of delaying or preventing their onset.