Brain aging shows nonlinear transitions, suggesting a midlife critical window for metabolic intervention

• 成果类型: Article
• 署名作者: Antal, Botond B.; van Nieuwenhuizen, Helena; Chesebro, Anthony G.; Strey, Helmut H.; Jones, David T.; Clarke, Kieran; Weistuch, Corey; Ratai, Eva-Maria; Dill, Ken A.; Mujica-Parodi, Lilianne R.
• 署名单位: State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; State University of New York (SUNY) System; Stony Brook University; Mayo Clinic; University of Oxford; Memorial Sloan Kettering Cancer Center; The Santa Fe Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9912
• DOI: 10.1073/pnas.2416433122
• 发表日期: 2025-03-11
• 关键词: dynamic functional connectivity; mitochondrial dysfunction; alzheimers-disease; cognitive decline; fuel metabolism; messenger-rna; ketone-bodies; insulin; glut4; expression

摘要

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.