ArticleProceedings of the National Academy of Sciences of the United States of America2025
Brain aging shows nonlinear transitions, suggesting a midlife "critical window" for metabolic intervention.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A systematic review of neuroimaging studies of adults aged 35 and older with clinical, symptomatic and genetic risk for attention-deficit/hyperactivity disorder.Dialogues in clinical neuroscience · 2026Pooled it
- Effects of a three-month exercise programme on cognition, mood and neurogenesis: the NeuroFit randomised controlled trial.npj aging · 2026Article
- A peripheral perspective on brain health: vascular and skeletal muscle contributions.American journal of physiology. Heart and circulatory physiology · 2026Review
- Embracing non-linearity in human ageing.Nature reviews. Genetics · 2026Review
- Higher fasting brain glucose is associated with lower gray matter volume in healthy adults.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Article
- Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease.Research square · 2026Article
- Nourish the mind: protocol for an umbrella review on nutrients and bioactive food components supporting brain health across the lifespan.Systematic reviews · 2026Article
- Metabolic crosstalk in the ageing brain: astrocyte-neuron coupling as a target for homeostatic restoration and therapy.Translational neurodegeneration · 2026Review
- Profiling the molecular and physiological effects of senolytic treatment on aged mice identifies immune, fibrotic and metabolic remodeling.Nature aging · 2026Article
- Fifteen years on: a review of the Cam-CAN study of the cognitive neuroscience of ageing.GeroScience · 2026Review
- Advancing Precision Nutrition Through Multimodal Data and Artificial Intelligence.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- The Lactate Nexus: A Molecular Bridge Linking Physical Activity, Sleep, and Cognitive Enhancement.Biomedicines · 2026Review
- One-month early time-restricted eating enhances cognition via white matter-cortical pathways in males with metabolic syndrome: evidence from TBSS and SBM analyses.Frontiers in nutrition · 2026Article
- Bias-reduced Regression Analysis in Nutrition (BRAiN) index: self-reported diet and predicted cognitive function.Frontiers in nutrition · 2026Article
- Nonlinear association between age and verbal fluency and moderation by adiposity: cross-sectional evidence from the Look Up 8+ study.Frontiers in aging neuroscience · 2026Article
- Toward personalized medicine in AD/ADRD through genetic-exposome dementia risk assessments.NPJ dementia · 2026Review
- Neuroanatomical patterns of dementia risk in autism spectrum disorder.Frontiers in aging neuroscience · 2026Article
- Article
- Spatially convergent functional MRI signatures of diabetes and male sex identify genetic vulnerabilities to accelerated brain ageing.Brain communications · 2026Article
- Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.Frontiers in neuroscience · 2026Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.