Matawali Azlinah, Yeap Jia Wen, Sulaiman Shaida Fariza, Tan Mei Lan
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia; Preparatory Centre for Science and Technology, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia.
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
Nutr Res. 2025 Jul;139:16-49. doi: 10.1016/j.nutres.2025.04.010. Epub 2025 Apr 22.
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.
生酮作用与PI3K/AKT/mTOR信号通路与代谢失衡和疾病进展相关。虽然酮体代谢与mTOR抑制在机制上相互关联，但它们在不同疾病模型中的功能关系仍不清楚。尽管生酮作用可通过摄入酮体、采用生酮饮食或禁食诱导，但它们对该信号通路的具体影响仍需进一步阐明。本研究按照PRISMA指南，系统回顾了3个数据库中生酮作用与PI3K/AKT/mTOR信号传导之间的关系。使用偏倚风险工具对符合入选标准的合格研究进行评估。在大多数涉及生酮饮食或酮体的研究中，该信号通路的抑制可能在生存率、寿命、改善代谢稳态、增强神经血管功能以及抑制肿瘤进展方面带来积极结果。相比之下，补充β-羟基丁酸与AKT及下游标志物的上调有关。在肌肉萎缩模型中，它可能通过激活mTOR信号通路发挥合成代谢活性，并与肌肉恢复相关。虽然禁食会增加p-AKT表达，但这不一定表明下游mTOR信号级联被激活，因为这可能是胰岛素反应或调节反馈机制导致的。生酮作用对mTOR信号的调节可能具有组织特异性。在生酮诱导情况下抑制PI3K/AKT/mTOR可能证明了生酮饮食方案在对抗代谢性疾病中的重要性。然而，未来的研究应考虑使诸如禁食持续时间、时间点、生酮饮食组成和靶组织等因素标准化，因为这些因素可能影响研究结果。
