Abstract Background Caloric restriction (CR) can increase longevity in rodents and improve memory function in humans. α-Lipoic acid (LA) has been shown to improve memory function in rats, but not longevity. While studies have looked at survival in rodents after switching from one diet to another, the underlying mechanisms of the beneficial effects of CR and LA supplementation are unknown. Here, we use RNA-seq in cerebral cortex from rats subjected to CR and LA-supplemented rats to understand how changes in diet can affect aging, neurodegeneration and longevity. Results Gene expression changes during aging in ad libitum-fed rats are largely prevented by CR, and neuroprotective genes are overexpressed in response to both CR and LA diets with a strong overlap of differentially expressed genes between the two diets. Moreover, a number of genes are differentially expressed specifically in rat cohorts exhibiting diet-induced life extension. Finally, we observe that LA supplementation inhibits histone deacetylase (HDAC) protein activity in vitro in rat astrocytes. We find a single microRNA, miR-98-3p, that is overexpressed during CR feeding and LA dietary supplementation; this microRNA alters HDAC and histone acetyltransferase (HAT) activity, which suggests a role for HAT/HDAC homeostasis in neuroprotection. Conclusions This study presents extensive data on the effects of diet and aging on the cerebral cortex transcriptome, and also emphasises the importance of epigenetics and post-translational modifications in longevity and neuroprotection.