The most comprehensive model of the brain’s metabolism, incorporating more than 16,800 biochemical interactions, has identified key targets to reverse the age-related decline in brain function. The new analysis of complex interactions between neuronal activity, metabolism, and blood flow found that restoring blood chemistry to youthful levels through diet, exercise, and supplements could improve the brain’s resilience to damage. Scientists can now use this model to find ways to prevent age-related diseases, such as dementia.

A new open-source model of brain metabolism – the most complex ever generated – has shown how altering key chemicals could restore aged cells to their youthful activity and resilience.

The researchers, writing in Frontiers in Science, found that reducing blood glucose, as well as increasing blood ketone and lactate levels, could help restore metabolic function in aging brains. Potentially, these could all be achieved through lifestyle changes, including exercise and the food we eat.

The findings come from the most comprehensive computer model of brain metabolism to date, which incorporates more than 16,800 biochemical interactions between proteins and chemicals across brain cells, supporting cells, and the blood.

Scientists can now use this open-source model to find ways to prevent age-related diseases, such as dementia.

“This study provides an x-ray view into the battery that powers the brain,” said Henry Markram, Professor of Neuroscience at École Polytechnique Fédérale de Lausanne (EPFL), Switzerland, the senior author of the study. “We can now track how the energy system of the brain ages at the molecular level.”

Youthful resilience

The detailed simulation - an analysis of complex interactions between neuronal activity, metabolism, and blood flow – provides a glimpse into how brain metabolism breaks down with age and impairs its function, as well as identifying actionable potential ways to restore youthful resilience.

We place heavy demands on our brain’s neurons to navigate our everyday lives. This requires a lot of energy and support, which comes from the blood supply and supporting ‘glial’ cells called astrocytes.

To understand the impact of aging on the brain’s metabolism, the team included these elements in their model, which they used to compare the metabolic states of young and aged brains. In all, they calculated the impact of age-related changes on 16,800 interactions between proteins and chemicals across neurons, glia, and the blood.

The model revealed that changes in the amounts of certain molecules can have complex knock-on effects, affecting many different metabolic reactions at once. This meant the cells were more vulnerable to damage as they were less able to adapt and recover.

It also highlighted potential drug targets, as well as the potential benefit of supplementing with nicotinamide adenine dinucleotide (NAD) - a molecule that plays a vital role in the brain’s energy supply. NAD-boosting supplements have been previously studied as a potential healthy aging therapy.

Dr Polina Shichkova, the lead author of the Frontiers in Science study, said: “We were surprised by the interdependencies of molecular reactions, tight regulation, and signaling within this system. We showed how the fragility of brain metabolism results from the collapse of many metabolic pathways, not just one, a finding that calls for multiple target therapies.”

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A discovery beyond lifestyle factors

The discovery allowed the team to understand the complex molecular mechanisms that determine the robustness, flexibility, and adaptability of the aging brain. By altering the amounts of key chemicals, the researchers found that the aged cells could be restored back to their youthful activity and resilience.

“Our findings go beyond what we already knew about these lifestyle factors,” said Shichkova. “Our model offers a detailed molecular mechanism of these practices, which will help guide researchers to develop more precise or effective interventions.”

The researchers also used the model to identify possible drug targets that could restore resilience to brain cells. They identified a protein called estrogen-related receptor alpha (ESRRA), which is connected to the predicted age-related decline. This finding could lead to further research into developing effective treatments to support aging neurons.

“While there are usually many steps between a computational model’s predictions and practical guidance for people, some of the suggestions of our model include already approved supplements, dietary changes, or lifestyle habits,” said Shichkova.

A tool for further research

The researchers built the model using publicly available data detailing the gene activity of brain cells in humans and mice. When they compared its results to experimental data not used for training, the model accurately predicted changes in biochemical activity in neurons with age. This verified its usefulness as a research tool and the value of its findings.

Shichkova said: “This modeling approach was needed due to the complexity of the system, which cannot be easily studied experimentally. While the model was built from experimental data, the simulation’s predictions of the behavior of the molecular network will in turn guide further biological research.”

The study was part of the Blue Brain Project, which aimed to develop simulations and reconstructions of the mouse brain. The model will be available on the Open Brain Platform hosted by the Open Brain Institute, allowing neuroscientists to run simulations based on the research.

The team hopes this will help accelerate research into age-related neurodegenerative diseases, such as dementia. Energy metabolism is a potential root cause of such conditions, so further research on this, as well as validating the findings in human subjects, might help find new ways to boost the brain’s defenses.

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 Eidgenössische Technische Hochschule (ETH) Board of the Swiss Federal Institutes of Technology.

This article is part of the Frontiers in Science multimedia article hub ’Modeling metabolism in the aging brain’, which also features an editorial, two viewpoints, and a policy outlook from other eminent experts: Prof Mark Mattson (Johns Hopkins University School of Medicine, USA), Prof Richard Buxton (University of California, San Diego, USA), Prof Luc Pellerin (Université de Poitiers and CHU de Poitiers, France), and Marian Breuer, Silvia Bolognin, Shuyi Yang, and Prof Renaud B. Jolivet (Maastricht Universit, The Netherlands) —as well as an explainer with infographics. 

About Frontiers in Science

Frontiers in Science is Frontiers’ multidisciplinary, open-access journal focused on transformational science to accelerate solutions for healthy lives on a healthy planet.

The journal publishes a select number of exceptional peer-reviewed lead articles invited from internationally renowned researchers, whose work addresses key global challenges in human and planetary health. Each lead article is enriched by a diverse hub of content that extends its reach and impact across society – from researchers and policymakers to lay audiences and kids.

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