The brain’s age‑related cognitive slowing stems less from irreversible neuron loss and more from a breakdown in synaptic remodeling pathways. While structural shrinkage of frontal cortex and hippocampus proceeds with age, the plasticity‑regulating protein drebrin declines, and autophagic degradation slows, causing protein buildup at synapses and spine density loss【https://www.publichealth.columbia.edu/news/changes-occur-aging-brain-what-happens-when-we-get-older】. We hypothesize that imposing a mild, repeated metabolic challenge—such as intermittent fasting that sustains mild ketosis—reactivates lysosomal function through TFEB‑driven gene expression, thereby restoring autophagic flux and clearing synaptic debris. This rescue would increase drebrin levels, stabilize dendritic spines, and improve learning performance without reversing cortical thinning or white‑matter loss. In other words, the intervention targets the modifiable functional arm of aging while leaving the underlying structural decay intact.

To test this, aged mice (20‑24 months) would be assigned to either an intermittent fasting regimen (16‑hour daily fast, maintaining β‑hydroxybutyrate ≈ 0.5‑1.0 mM) or ad libitum feeding for 12 weeks. Primary outcomes would include lysosomal acidification (LysoTracker), autophagosome‑lysosome fusion (LC3‑II/p62 turnover via western blot), drebrin protein density (immunohistochemistry), spine density on Golgi‑stained pyramidal neurons, and performance on a surprise‑based reversal learning task. Secondary outcomes would measure cortical thickness (MRI) and hippocampal volume to confirm that structural atrophy persists. A positive result—significant increases in lysosomal activity, drebrin, spine density, and behavioral flexibility alongside unchanged gross morphology—would support the hypothesis. Conversely, if fasting elevates autophagy markers but fails to raise drebrin, spine density, or cognition, the claim that enhanced lysosomal flux alone rescues plasticity would be falsified.

Mechanistically, ketone bodies act as histone deacetylase inhibitors, promoting transcription of lysosomal genes via TFEB nuclear translocation【https://www.portlandpress.com/neuronalsignal/article/6/2/NS20210063/231397/Keeping-synapses-in-shape-degradation-pathways-in】. Increased lysosomal capacity accelerates clearance of ubiquitinated synaptic proteins (e.g., PSD‑95, Arc) whose accumulation interferes with AMPA receptor turnover. Reduced synaptic crowding lowers the threshold for long‑term potentiation, allowing drebrin‑dependent actin remodeling to proceed. Importantly, this pathway does not require neurogenesis or axonal sprouting; it merely restores the efficiency of existing plasticity machinery. Super‑agers, who exhibit slower atrophy and preserved drebrin levels, may naturally engage similar metabolic cycling, offering a human correlate for future PET‑MRI studies tracking ketone flux and lysosomal biomarkers.

Thus, the hypothesis reframes cognitive aging as a tractable imbalance between persistent structural decline and dynamically regulatable synaptic housekeeping. By delivering calibrated metabolic uncertainty, we can shift the cost‑benefit calculation back toward model updating, rescuing function without demanding impossible tissue regeneration.