Clinical and animal studies suggested that a medium-chain triglyceride (MCT)-based ketogenic diet provides an alternative energy substrate to the brain and has neuroprotective effects, but the clinical evidence is still scarce. Here we examined the effect of an MCT-based ketogenic formula on cognitive function in patients with Alzheimer's disease (AD). The subjects were 20 Japanese patients with mild-to-moderate AD (11 males, nine females, mean age 73.4 ± 6.0 years) who, on separate days, underwent neurocognitive tests 120 min after consuming 50 g of a ketogenic formula (Ketonformula®) containing 20 g of MCTs or an isocaloric placebo formula without MCTs. The patients then took 50 g of the ketogenic formula daily for up to 12 weeks, and underwent neurocognitive tests monthly. In the first trial, although the patients' plasma levels of ketone bodies were successfully increased 120 min after the single intake of the ketogenic formula, there was no significant difference in any cognitive test results between the administrations of the ketogenic and placebo formulae. In the subsequent chronic intake trial of the ketogenic formula, 16 of the 20 patients completed the 12-week regimen. At 8 weeks after the trial's start, the patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline scores, and at 12 weeks they showed significant improvements in the digit-symbol coding test and immediate logical memory test compared to the baseline. The chronic consumption of the ketogenic formula was therefore suggested to have positive effects on verbal memory and processing speed in patients with AD.

Low-carbohydrate, high-fat diets (ketogenic diets) might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF) is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR), tumor-bearing (TB), and ketogenic formula (KF) groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KF ad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia.

Evidence suggests that oral intake of medium-chain triglycerides (MCTs), which promote the production of ketone bodies, may improve cognitive functions in elderly people; however, the underlying brain mechanisms remain elusive. We tested the hypothesis that cognitive improvement accompanies physiological changes in the brain and reflects the use of ketone bodies as an extra energy source. To this end, by using functional magnetic resonance imaging, cerebral blood oxygenation level-dependent (BOLD) signals were measured while 20 healthy elderly subjects (14 females and 6 males; mean age: 65.7 ± 3.9 years) were engaged in executive function tasks (N-back and Go-Nogo) after ingesting a single MCT meal (Ketonformula^®) or placebo meal in a randomized, double-blind placebo-controlled design (UMIN000031539). Morphological characteristics of the brain were also examined in relation to the effects of an MCT meal. The MCT meal improved N-back task performance, and this was prominent in subjects who had reduced grey matter volume in the dorsolateral prefrontal cortex (DLPFC), a region known to promote executive functions. When the participants were dichotomized into high/low level groups of global cognitive function at baseline, the high group showed improved N-back task performance, while the low group showed improved Go-Nogo task performance. This was accompanied by decreased BOLD signals in the DLPFC, indicative of the consumption of ketone bodies as an extra energy source.

There is ongoing debate as to whether or not α-hydroxyisocaproic acid (HICA) positively regulates skeletal muscle protein synthesis resulting in the gain or maintenance of skeletal muscle. We investigated the effects of HICA on mouse C2C12 myotubes under normal conditions and during cachexia induced by co-exposure to TNFα and IFNγ. The phosphorylation of AMPK or ERK1/2 was significantly altered 30 min after HICA treatment under normal conditions. The basal protein synthesis rates measured by a deuterium-labeling method were significantly lowered by the HICA treatment under normal and cachexic conditions. Conversely, myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by the HICA pretreatment, and this improvement was accompanied by the inhibition of iNOS expression and IL-6 production. Moreover, HICA also suppressed the TNFα/IFNγ co-exposure-induced secretion of 3-methylhistidine. These results demonstrated that HICA decreases basal protein synthesis under normal or cachexic conditions; however, HICA might attenuate skeletal muscle atrophy via maintaining a low level of protein degradation under cachexic conditions.

Ketogenic diets, which are carbohydrate-restricted high-fat diets, may have therapeutic effects on various diseases, including cancer. However, ketogenic diets are often not standardized and, therefore, results are difficult to interpret. We previously investigated the usefulness of ketogenic diets in cancer therapy, where ketogenic formulas (KF) were used as supplements to enhance blood ketone bodies; however, the amount of KF was determined empirically with reference to blood ketone bodies levels. Here, to determine a standardized optimal amount of KF, we investigated temporal changes in blood ketone bodies (acetoacetic acid (AcAc), β-hydroxybutyrate (BHB)) and safety in 20 healthy individuals when KF was taken repeatedly under the conditions of a ketogenic diet (UMIN000034216). The diurnal variation in total ketone bodies, and AcAc and BHB levels significantly increased after lunch and after dinner, on the 4th day of KF administration. There were no significant safety issues related to KF in the context of anthropometric, metabolic, nutritional, urological and gastrointestinal parameters. In addition, ketogenic diets lead to changes in gut microbiota. KF showed a decrease in phylum Firmicutes. Our study provides baseline data of the usefulness of KF in a ketogenic diet.

Cancer chemotherapy is frequently accompanied by adverse effects, such as diarrhoea and leukopenia, which lead to malnutrition and a decrease in the patients’ quality of life. We previously demonstrated that an immune-modulating formula (IMF)—an enteral formula enriched with immunonutrients, whey-hydrolysed peptides, and fermented milk—had anti-inflammatory effects and protective effects on intestinal disorders in some experimental models. Here, we investigated whether nutritional treatment with the IMF could prevent 5-fluorouracil (5-FU)-induced adverse effects in rats. Rats were randomised into CTR and IMF groups, which received a control formula or the IMD supplemented formula ad libitum. Two weeks after starting the formula, rats were intraperitoneally injected with 5-FU (300 mg/kg) on day 0. The treatment with 5-FU decreased their body weights, food intake, and leukocyte counts, and worsened the diarrhoea score. However, the body weights, food intake, and leukocyte counts were significantly higher in the IMF rats than in the CTR rats on day 1. The IMF also delayed the incidence of diarrhoea and significantly preserved the villus heights in the jejunum on day 2. In conclusion, nutritional treatment with the IMF alleviated the adverse effects induced by 5-FU injection in rats.