Scientists identify key “middle-age window” to prevent age-related brain decline

A landmark study published in PNA shows that brain aging follows a unique but nonlinear trajectory with key transition points. This study, led by an international team of scientists led by Dr. Lilianne R. Mujica-Parodi of Stony Brook University, provides new insights to prevent cognitive decline in interventions most effectively.

The team analyzed functional communication between more than 19,300 brain regions (brain networks) in four large data sets. Their findings suggest that brain networks are reduced in a manner with an S-shaped statistical curve with clear transition points rather than previously assumed late clinical onset or gradual linear decline. The effect first appeared around 44 years old, and the degeneration reached a peak acceleration of around 67 years old, and to the plateau at 90 years old. Previous work by the team led by collaborator Nathan Smith shows that brain signaling is affected by energy loss in neurons (reduces energy). Therefore, demographic transition points indicate that there are specific windows when interventions are most influential.

Mujica-Parodi (Baszucki), director of the Laboratory of Computational Neuro, Baszucki, Chairman of Metabolic Neuroscience at Laufer and renatory for norritation and renaton and renatone and The and the and reen and reen and in reen, “Learn exactly when and how to accelerate brain aging provides us with strategic time points for intervention.

“We have identified a critical window for middle age, where the brain is accessing energy down, but before irreversible damage occurs, it is basically a “bending” before “rest”. In middle age, neurons are subject to metabolic stress due to insufficient fuel. They are struggling, but still doable,” she explains. “So, providing alternative fuel in this critical window can help restore function. However, by the end, prolonged starvation of neurons may trigger a range of other physiological effects, which reduces the efficiency of the intervention.”

The researchers not only mapped this aging trajectory, but also identified its main driver: neuronal insulin resistance.

By comparing metabolic, vascular and inflammatory biomarkers, they found that metabolic changes always precede vascular and inflammatory changes. Gene expression further analyzed the insulin-dependent glucose transporter glut4 and lipid transporter APOE (known risk factors for Alzheimer’s) in these aging patterns.

However, these same gene expression analyses also identified the neuronal ketone transporter MCT2 as a potential protective factor, suggesting that enhanced the brain’s ability to utilize ketones, an alternative brain fuel that neurons can metabolize in the absence of insulin, which may be beneficial.

The discovery of keto transporter then prompted an interventional study in which the researchers compared individual weight doses and calorie-matched glucose and ketones at different stages of the aging trajectory with the administration of 101 participants.

In this cohort, this effect is shocking. Unlike glucose, ketones effectively stabilize the worsening brain network, but the effects vary widely between key transition points. During the “metabolic stress” period in middle-aged age (40-59 years), ketones showed moderate benefits for young people (20-39 years), after which the network began to be unstable, but the impact of the elderly (60-79 years) was reduced, and once the network was not turbulent, accelerated stability was maximized and accelerated.

Mujica-Parodi and co-authors say these findings could revolutionize approaches to age-related cognitive decline and neurodegenerative diseases such as Alzheimer’s.

Current treatments are usually targeted after symptoms appear, usually too late to meaningful interventions. This study shows that metabolic interventions may be most effective when they begin in their 40s, whether through dietary methods such as diet or supplements, just before cognitive symptoms appear.

“This represents a paradigm shift in our perception of preventing brain aging,” said Botond Antal, Ph.D., a postdoctoral assistant and first author of biomedical engineering at Stony Brook. “ Rather than waiting for cognitive symptoms that may not occur until a significant damage occurs, we can identify people at risk through neurometabolic markers and intervene in this critical window.”

From a public health perspective, these findings could inform new screening guidelines and prevention methods, highlighting Mujica-Parodi. Early (middle-age) identification of increased insulin resistance in the brain (not only blood), coupled with targeted metabolic interventions, may significantly delay cognitive aging in millions of people.

With the global population rapidly aging, dementia cases are expected to triple by 2050, these insights into the timing and mechanisms of brain aging provide new hope for prevention strategies that can allow cognitive health to be well maintained in life later.

The research was funded by the WM Keck Foundation and the National Science Foundation (NSF) Brain Research through the Advance Neurotechnology (BRAIT) initiative.

The work was done by scientists at Stony Brook University in collaboration with Massachusetts General Hospital, the Mayo Clinic of Oxford University and Memorial Sloan Kettering.