Lifelong calorie restriction alleviates age-related oxidative damage in peripheral nerves

Aging is associated with protein damage and imbalance in redox status in a variety of cells and tissues, yet little is known about the extent of age-related oxidative stress in the peripheral nervous system. Previously, we showed a drastic decline in the expression of glial and neuronal proteins in myelinated peripheral nerves with age, which is significantly ameliorated by lifelong calorie restriction. The age-related decline in functional molecules is associated with alterations in cellular protein homeostatic mechanisms, which could lead to a buildup of damaged, aggregated proteins. To determine the extent of oxidative damage within myelinated peripheral nerves, we studied sciatic nerves from rats of four different ages (8, 18, 29, and 38 months) maintained on an ad libitum or a 40% calorie-restricted diet. We found a prominent accumulation of polyubiquitinated substrates with age, which are associated with the conglomeration of distended lysosomes and lipofuscin adducts. The occurrence of these structures is notably less frequent within nerves of age-matched rodents kept on a lifelong reduced calorie diet. Markers for lipid peroxidation, inflammation, and immune cell infiltration are all elevated in nerves of ad libitum-fed rats, whereas food restriction is able to attenuate such deleterious processes with age. Together these results show that dietary restriction is an efficient means of defying age-related oxidative damage and maintaining a younger state in peripheral nerves.