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The spinal cord is vital for the processing of sensorimotor information and for its propagation to and from both the brain and the periphery. Spinal cord function is affected by aging, however, the mechanisms involved are not well-understood. To characterize molecular mechanisms of spinal cord aging, microarray analyses of gene expression were performed on cervical spinal cords of aging rats. Of the metabolic and signaling pathways affected, cholesterol-associated pathways were the most comprehensively altered, including significant downregulation of cholesterol synthesis-related genes and upregulation of cholesterol transport and metabolism genes. Paradoxically, a significant increase in total cholesterol content was observed-likely associated with cholesterol ester accumulation. To investigate potential mechanisms for the perturbed cholesterol homeostasis, we quantified the expression of myelin and neuroinflammation-associated genes and proteins. Although there was minimal change in myelin-related expression, there was an increase in phagocytic microglial and astrogliosis markers, particularly in the white matter. Together, these results suggest that perturbed cholesterol homeostasis, possibly as a result of increased inflammatory activation in spinal cord white matter, may contribute to impaired spinal cord function with aging.

The causes of ageing remain poorly understood, although a role for mitochondria is widely accepted. These unique organelles that are responsible for a cell's energy, rely on their own small genome and translational machinery to produce proteins that, together with nuclear genome encoded proteins, form the electron transport chain complexes necessary for ATP production. Various forms of mitochondrial genome mutation and rearrangements are thought to be involved in the ageing process, particularly in post-mitotic cells, such as those of the nervous system. In the present study, we have characterised mitochondrial DNA (mtDNA) deletion mutations in five central nervous system (CNS) regions of the young, middle-aged, and old Fischer 344 (F344) rats. DNA was extracted from the cerebral cortex, striatum, midbrain, cerebellum and spinal cord, and long-PCR was used to detect mtDNA with deletions in the minor and major arcs. This approach has the advantage that all deletions can be detected without a priori knowledge of breakpoints. In the minor arc, we found evidence for deletions in the striatum of five out of six old animals and in the spinal cords from two of six old animals. In contrast, mtDNA deletions in the major arc appeared markedly more abundant, both in terms of affected CNS regions and number of deleted mtDNA molecules. Furthermore, major arc deletions were apparent earlier with a number of CNS regions showing deletions in the middle-aged group. The cerebral cortex, striatum and spinal cord were the most affected regions, while the midbrain and cerebellum were relatively spared. These findings are remarkably consistent with previous human brain data and further underscore the value of the rat model for investigation of ageing-related changes in the mitochondrial genome.