Neurometabolism "Bends" Before It "Breaks," Providing a Critical Window for Early Intervention.
Presented During:
Friday, June 27, 2025: 11:30 AM - 12:45 PM
Brisbane Convention & Exhibition Centre
Room:
M1 & M2 (Mezzanine Level)
Poster No:
922
Submission Type:
Abstract Submission
Authors:
Lilianne Mujica-Parodi1, Botond Antal1
Institutions:
1State University of New York at Stony Brook, Stony Brook, NY
First Author:
Co-Author:
Introduction:
Brain aging involves multiple degenerative processes, including glucose hypometabolism, atrophy, and cerebrovascular disease. While these manifestations often become detectable only in later stages, neuroimaging-based biomarkers can identify changes decades earlier. Previous research indicates that brain networks undergo substantial reorganization starting in the late 40s, with patterns similar to those observed in Type 2 diabetes mellitus, suggesting neuronal insulin resistance as a potential mechanism. While glucose is the brain's primary fuel, ketones provide an alternative that can be metabolized by neurons without insulin and thus bypass insulin resistance. This study integrates lifespan brain-aging trajectory, mechanistic, and interventional findings to distinguish earlier catalyzing processes from later downstream effects.
Methods:
Four large-scale neuroimaging datasets (totaling 19,300 participants) were analyzed for brain network stability using functional magnetic resonance imaging (fMRI). Brain network instability was quantified by measuring the persistence of functional networks over time, with larger values indicating more unstable networks. Gene expression data from the Allen Human Brain Atlas was used to investigate mechanistic correlations, focusing on genes encoding for glucose transporters (GLUT1, GLUT3, GLUT4), ketone/lactate transporters (MCT1, MCT2), and APOE. An interventional study of 101 participants examined the effects of ketones versus glucose on brain network stability across different age groups (20-39, 40-59, and 60-79 years). Participants received individually weight-dosed ketone monoester or calorically matched glucose in a within-subjects design. Additional biomarkers measured included HbA1c (metabolic), blood pressure (vascular), and C-reactive protein (inflammatory).
Results:
Analysis revealed a nonlinear (sigmoid) trajectory in brain network destabilization with key transition points: onset at age 43.7 years (α) and most rapid destabilization at age 66.7 years (I). The onset coincided with increased HbA1c levels (t=4.8, p=4E-6), while the inflection point corresponded with profound vascular changes, particularly systolic blood pressure (t=5.7, p=3E-8). Gene expression analyses implicated neuronal mechanisms through GLUT4 (insulin-dependent glucose transporter) and APOE (impairing insulin signaling), with MCT2 (neuronal ketone transporter) emerging as a potential counteracting factor. Notably, no significant associations were found with glial ketone transporter (MCT1) or insulin-independent glucose transporters (GLUT1, GLUT3), suggesting neuron and insulin-specific effects. The ketone intervention showed maximum effectiveness in stabilizing brain networks during ages 40-59 (84.62% larger effect than in young adults, t=-4.8, p=0.00003), with diminished effects after age 60. These effects were specific to ketones, as matched-calorie glucose administration showed no significant stabilizing effects in any age group.
·Metabolic changes predominate during the acceleration phase of brain aging, as depicted by nonlinear lifespan trends in brain network instability
·D-β-hydroxybutyrate circumvents insulin resistance to reverse brain network destabilization during the accelerated phase of brain aging
Conclusions:
Brain aging follows a specific progression, with metabolic changes predominating in early stages, followed by vascular alterations. The findings suggest a critical window for intervention during middle age (40-59 years), when neurons are metabolically stressed but still viable. This period represents a time when regulatory mechanisms that maintain the brain's optimal energy supply "bend" before they "break." Ketones, which bypass insulin resistance, show promise as a therapeutic strategy, particularly when administered during this critical period. The diminished effectiveness of ketone intervention in later years (60+) suggests that sustained metabolic stress may lead to irreversible neuronal damage, emphasizing the importance of early intervention. These results contribute to understanding brain aging mechanisms and suggest neurometabolic strategies for targeted early intervention in preventing age-related cognitive decline.
Genetics:
Transcriptomics
Lifespan Development:
Aging 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
Neuroinformatics and Data Sharing:
Brain Atlases
Physiology, Metabolism and Neurotransmission:
Physiology, Metabolism and Neurotransmission Other 2
Keywords:
Aging
Cerebrovascular Disease
FUNCTIONAL MRI
Pharmacotherapy
1|2Indicates the priority used for review
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Provide references using APA citation style.
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