Aging astrocytes metabolically support aging axon function by proficiently regulating astrocyte-neuron lactate shuttle.

The astrocyte-neuron lactate shuttle (ANLS) is an essential metabolic support system that uptakes glucose, stores it as glycogen in astrocytes, and provides glycogen-derived lactate for axonal function. Aging intrinsically increases the vulnerability of white matter (WM) to injury. Therefore, we investigated the regulation of this shuttle to understand vascular-glial metabolic coupling to support axonal function during aging in two different WM tracts. Aging astrocytes displayed larger cell bodies and thicker horizontal processes in contrast to thinner vertically oriented processes of young astrocytes. Aging axons recovered less following aglycemia in mouse optic nerves (MONs) compared to young axons, although providing lactate during aglycemia equally supported young and aging axonal function. Incubating MONs in high glucose to upregulate glycogen stores in astrocytes delayed loss of function during aglycemia and improved recovery in both young and aging axons. Providing lactate during recovery from aglycemia unmasked a metabolic switch from glucose to lactate in aging axons. Young and aging corpus callosum consisting of a mixture of myelinated and unmyelinated axons sustained their function fully when lactate was available during aglycemia and surprisingly showed a greater resilience to aglycemia compared to fully myelinated axons of optic nerve. We conclude that lactate is a universal substrate for axons independent of their myelination content and age.