Hein Zaw Myo, Arbain Muhammad Faqhrul Fahmy, Kumar Suresh, Mehat Muhammad Zulfadli, Hamid Hafizah Abdul, Che Ramli Muhammad Danial, Che Mohd Nassir Che Mohd Nasril
Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates.
Department of Anatomy and Physiology, School of Basic Medical Sciences, Faculty of Medicine, University Sultan Zainal Abidin, Kuala Terengganu 20400, TGG, Malaysia.
Nutrients. 2025 Jul 9;17(14):2266. doi: 10.3390/nu17142266.
Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut-brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF's capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience.
间歇性禁食（IF）正在成为一种具有异质性的神经代谢干预方式，有可能改变神经退行性疾病的病程。通过调节肠-脑轴（GBA）、细胞生物能量学（或代谢）重编程以及参与保留应激适应途径，IF影响一系列生理机制，包括线粒体生物发生、自噬、昼夜节律调节和神经炎症。本综述批判性地综合了当前临床前和早期临床证据，这些证据表明IF有能力在阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症模型中补充突触可塑性和完整性、减轻有毒蛋白质（蛋白毒性）负担以及恢复神经胶质和免疫稳态。这些作用背后的关键因素是生物活性代谢物，如短链脂肪酸（SCFA）和β-羟基丁酸酯（BHB），以及分子介质，如脑源性神经营养因子（BDNF）。我们重点介绍了IF诱导的肠道微生物群组成、免疫反应和线粒体动力学变化的治疗相关性，并讨论了将IF纳入精准医学框架的新方法。关键挑战包括个体差异、方案优化、认知脆弱人群的安全性，以及开展生物标志物引导、符合伦理的临床试验的必要性。最后，我们提出IF是一种可扩展且灵活的干预措施，当进行个性化并与其他方式相结合时，可能会将神经退行性变从一种不可逆转衰退的模式转变为一种可改变恢复力的模式。
