The ketogenic diet (KD) is a dietary approach characterized by high fat, low carbohydrate, and adequate protein intake. Its ultimate goal is to achieve a state of nutritional ketosis in the patient by producing compounds such as acetoacetate, beta-hydroxybutyric acid, and acetone, similar to those found in the fasting state. This affects the metabolism of blood lipids, promoting the utilization of fatty acids as an energy source in the absence of glucose. Since the 1920s, it has been used as a treatment for controlling seizures in epilepsy patients, especially those who do not respond well to antiepileptic drugs. Several variants of the KD have been developed to date, showing similar efficacy to the original form and offering flexibility to enhance compliance with the regimens. There are four main types of KD with proven efficacy: the classic long-chain triglyceride (LCT) KD, the medium-chain triglyceride (MCT) KD, the modified Atkins diet (MAD), and the low glycemic index treatment.The 21st century has witnessed the emergence of various diet programs with the increasing prevalence of obesity, and the KD has been at the forefront for promoting weight loss and improving physical performance. Additionally, it has been used in the treatment of type 2 diabetes, non-alcoholic fatty liver disease, polycystic ovary syndrome, heart disease, inflammatory bowel disease, and irritable bowel syndrome, where it has been found to have effects on the gut microbiota, with changes in bacterial composition that may have anticonvulsant effects. Therefore, it has been studied in several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, where mitochondrial dysfunction and oxidative stress play an important role, both of which generate high levels of reactive oxygen species (ROS) that are detrimental to all cellular macromolecules. Its impact on depression, bipolar disorder, and anxiety has also been investigated. It is worth noting that the KD could improve mitochondrial number and function by inhibiting glycolysis and increasing the formation of ketone bodies (KB), providing neuroprotective benefits in neuronal cell lines.
Cancer is one of the major global public health challenges and a leading cause of mortality worldwide. Complementary approaches to significantly enhance the efficacy of standard cancer therapies are scarce. The KD appears to sensitize most cancers to standard treatment by exploiting the reprogrammed metabolism of cancer cells, making it a promising candidate in adjuvant cancer therapy.The KD is a biochemical model of fasting or starvation that promotes the utilization of KB as the dominant fuel source to replace glucose in the central nervous system. This can modulate the neuropathological and biochemical changes observed in neurological diseases.