The effects of ketone bodies and ketogenesis on the PI3K/AKT/mTOR signaling pathway: A systematic review

• Suppression of PI3K/AKT/mTOR pathway in ketogenesis results in positive outcomes. • Activation of the pathway may be anabolic to aid muscle recovery. • Expression patterns of mTOR and downstream proteins are tissue-specific. Ketogenesis and the PI3K/AKT/mTOR pathway are linked to metabolic imbalance and disease progression. While ketone metabolism and mTOR inhibition are mechanistically connected, their functional relationship across disease models remains unclear. Although ketogenesis can be induced by ketone ingestion, ketogenic diet, or fasting, their individual effects on this pathway require further clarification. This study systematically reviews the relationship between ketogenesis and PI3K/AKT/mTOR signaling, following PRISMA guidelines across 3 databases. Eligible studies that met the selection criteria were evaluated using the risk of bias tools. In most studies involving the ketogenic diet or ketone bodies, suppression of the signaling pathway may lead to positive outcomes in terms of survival rate, lifespan, improved metabolic homeostasis, enhanced neurovascular function and suppressed progression of tumors. By contrast, β-hydroxybutyrate supplementation is associated with the up-regulation of AKT and downstream markers. It may exert an anabolic activity by activating the mTOR signaling pathway in muscle atrophy models and is associated with muscle recovery. Although fasting increases p-AKT expression, this may not necessarily indicate activation of the downstream mTOR signaling cascade, as it could result from an insulin response or regulatory feedback mechanisms. Regulation of the mTOR signaling by ketogenesis may be tissue-specific. Inhibition of PI3K/AKT/mTOR in ketogenesis-induced circumstances may justify the importance of a ketogenic-based diet regimen in combating metabolic diseases. However, future studies should consider standardizing factors such as the duration of fasting, timing, composition of the ketogenic diet and target tissues as these factors may affect study outcomes. Graphical summary of the systematic literature review based on PRISMA guidelines on the relationship between ketogenesis and PI3K/Akt/mTOR signaling pathway. Ketogenesis or ketone bodies downregulate the expression of the PI3K/Akt/mTOR pathway. Inhibition of mTOR signaling facilitates ketogenesis during fasting. However, the PI3K/AKT/mTOR expression patterns depend on several factors such as tissue-specificity, disease models, duration and timing of ketogenesis induction.