Age-dependent modifications of axons, mitochondrial dynamics, and Ca2+ homeostasis underlie the vulnerability of aging white matter to ischemia

Aging white matter (WM) is increasingly susceptible to neurodegenerative diseases and stroke. Among others, changes in ATP production, mitochondrial dynamics, and Ca2+ homeostasis contribute to increased susceptibility of aging WM to stroke. We utilized a pure white matter tract, mouse optic nerve (MON), obtained from 2- and 12-month old mice to quantify axon structure and function using electrophysiology, 3D-EM, immunoblots, and ATP assays. Functionally, aging axons did not recover as well after ischemia compared to young axons. Structurally, aging axons became thicker with lower G ratios, indicating increased myelin thickness, as well as increased internodal distances and nodal lengths. Aging axonal mitochondria were larger and thicker with lower incidence of smooth endoplasmic reticulum (SER) association. An increase of mitochondrial fusion proteins with aging resulted in aggregation of mitochondria and together with lower ATP levels suggested mitochondrial dysfunction. Our results suggest that aging alters axonal and mitochondrial structure and function resulting from reduced ATP production that may disrupt Ca2+ homeostasis to underlie the vulnerability of aging WM to ischemia and neurodegenerative diseases.