| Title: | Brain aging shows nonlinear transitions, suggesting a midlife "critical window" for metabolic intervention |
| Journal: | Proceedings of the National Academy of Sciences of the United States of America |
| Published: | 3 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40030017/ |
| DOI: | https://doi.org/10.1073/pnas.2416433122 |
| URL: | https://escholarship.org/uc/item/82t377mn |
Publication 15657
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Abstract
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.</p>
13 Keywords
- Adult
- Aged
- Aging
- Apolipoproteins E
- Brain
- Female
- Glucose
- Glucose Transporter Type 4
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Symporters
10 Authors
- Botond B. Antal
- Helena van Nieuwenhuizen
- Anthony G. Chesebro
- Helmut H. Strey
- David T. Jones
- Kieran Clarke
- Corey Weistuch
- Eva-Maria Ratai
- Ken A. Dill
- Lilianne R. Mujica-Parodi
1 Application
| Application ID | Title |
|---|---|
| 37462 | Protecting the Aging Brain: Self-Organizing Networks and Multi-Scale Dynamics Under Energy Constraints |
Enabling scientific discoveries that improve human health