Ketone body β-hydroxybutyrate helps clear misfolded, toxic proteins from the ageing and Alzheimer’s brain. By selectively targeting unstable proteins for removal, it supports cellular detox and brain resilience. This natural fasting-related molecule could be key to enhancing proteostasis, cognitive function, and long-term neurological health.
January 2025 – Cell Chemical Biology
Key takeaways
- Ketones clear toxic brain proteins: β-hydroxybutyrate (bHB), a ketone body produced during fasting or ketogenic diets, selectively binds to misfolded proteins like amyloid-β, promoting their clearance from the brain. This process reduces neurotoxic protein build-up, a hallmark of ageing and neurodegeneration, potentially supporting better cognitive function and long-term brain health
- Proteostasis without energy trade-offs: Unlike many cellular processes, bHB’s action does not depend on altering pH, covalent modification, or cellular energy status. It binds directly to unstable proteins and alters their solubility, triggering their degradation. This highlights a unique, energy-efficient route to manage protein quality control in ageing tissues
- Functional benefits in living systems: In aged mice and C. elegans models of Alzheimer’s, bHB reduced protein aggregation and related neurotoxicity. These effects led to preserved neuron integrity, improved mobility, and better cell viability—demonstrating real-world benefits for longevity and neuroprotection across diverse biological systems
- A new pathway for metabolic therapy: bHB reshapes how the brain handles misfolded proteins by engaging both proteasome and autophagy pathways. Short-term ketone supplementation achieved measurable protein clearance, pointing to therapeutic potential through diet, fasting, or ketone esters—offering a compelling, non-invasive strategy for healthy brain ageing
Read the article at: Madhavan, Sidharth S., et al. “β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.” Cell Chemical Biology, vol. 32, no. 1, 2025, pp. 174–191. https://doi.org/10.1016/j.chembiol.2024.11.001.