Hypothesis\n\nAging does not selectively eliminate whole neurons for inefficiency; instead, it triggers a progressive failure of axonal quality control that preferentially degenerates long‑range, high‑metabolic‑cost projections while sparing local cortical neurons. This axonal pruning is driven by lysosomal overload from accumulated myelin debris and impaired autophagic flux, which compromises the ability of axons to clear damaged mitochondria and protein aggregates. Partial reprogramming with cyclic Yamanaka factors restores axonal lysosomal function by reactivating TFEB‑mediated lysosomal biogenesis and enhancing mitochondrial‑axon coupling, thereby rescuing long‑range connectivity without altering neuronal numbers.\n\n## Mechanistic Basis\n\n* Axonal vulnerability – Long‑range axons have high mitochondrial turnover and rely on efficient mitophagy; age‑related rise in mitochondrial ROS and declining PINK1/Parkin activity leads to accumulation of damaged mitochondria that obstruct axonal transport (3).\n* Lysosomal burden – Microglial phagocytosis of myelin debris creates lipofuscin‑like inclusions that also accumulate in axons, overwhelming the axonal lysosomal system and reducing autophagosome‑lysosome fusion (2).\n* Synaptic vs axonal pruning – Complement‑mediated synaptic tagging (C1q/C3) remains intact, but extracellular matrix buildup shields synapses, decreasing synaptic pruning efficiency (1). Consequently, the brain shifts its quality‑control effort from synapses to axons when synaptic removal falters.\n* Reprogramming rescue – Cyclic expression of Yamanaka factors re‑activates PGC‑1α and TFEB, boosting mitochondrial biogenesis and lysosomal gene expression in neurons; secreted factors from young microglia can similarly rejuvenate axonal lysosomal capacity (4).\n\n## Testable Predictions\n\n1. In aged mice, the proportion of degenerated axons (measured by phosphorylated neurofilament accumulation) in corticospinal and callosal tracts will increase by >30% relative to young, while cortical neuronal density remains unchanged.\n2. Lysosomal markers (LAMP1, cathepsin D) will show reduced colocalization with axonal mitochondria in aged axons, indicating impaired mitophagy.\n3. Acute elevation of extracellular brevican/aggrecan will further diminish synaptic C3 tagging without affecting axonal degeneration rates.\n4. Cyclic Yamanaka factor expression (e.g., 48 h on/48 h off) will restore axonal mitophagy flux (measured by mt‑Keima) and improve conduction velocity in aged tracts to levels indistinguishable from young, without altering total cortical neuron numbers.\n5. Microglia‑conditioned medium from young mice will rescue axonal lysosomal function in aged neurons in vitro, an effect blocked by TFEB siRNA.\n\n## Potential Experiments\n\n- Perform anterograde axonal tracing combined with immuno‑EM for phosphorylated neurofilament in young (3 mo) vs aged (24 mo) mice; quantify axon loss in specific tracts.\n- Use live‑imaging of mt‑Keima in cultured cortical neurons treated with age‑mimetic serum (high lipid peroxidation) +/- young microglial conditioned medium; assess mitophagy flux.\n- Apply chondroitinase ABC to degrade aggrecan in aged brain slices and measure synaptic C3 deposition vs axonal degeneration.\n- Induce cyclic OSKM expression via inducible AAV in aged mice; assess behavior (rotarod, grid walk) and electrophysiological callosal conduction.\n\nIf axonal degeneration, not neuronal loss, tracks functional decline and is reversible by lysosomal rejuvenation, the hypothesis that aging optimizes the brain by evicting inefficient neurons is falsified; instead, aging impairs axonal quality control, and rejuvenation targets this specific pathway.