- Research Article
- 10.3390/obesities5040092
Genetic and Epigenetic Modifiers of Ketogenic Diet Responses: Roles of Sex and Age
- Dec 10, 2025
- Obesities
- Marko Sablić + 6 more +6
The ketogenic diet (KD) is a metabolic intervention characterized by high fat and very low carbohydrate intake, showing significant metabolic, neuroprotective, and therapeutic effects. However, its efficacy varies widely due to individual genetic and epigenetic factors. This review synthesizes current knowledge of genes most strongly associated with KD response, including polymorphisms in FTO, APOA2, PPAR, SCN1A, KCNQ2, STXBP1, CDKL5, the MODY gene group, and SLC2A1, which shape outcomes across lipid metabolism, energy expenditure, inflammation, and neurotransmission. Epigenomic modifications induced by a KD, such as changes in DNA methylation and histone acetylation involving BDNF, SLC12A5, KLF14, and others, modulate functional metabolic and neurological effects. Sex and age further modulate KD effects through distinct patterns of gene activation and hormonal interactions. These variables together impact metabolic and neurological outcomes and are critical for developing personalized nutrition and disease management strategies. Based on the reviewed evidence, genetic and epigenetic profiling can help identify patients who are likely to benefit from a KD (e.g., GLUT1DS, PDH deficiency) and those in whom a KD may be ineffective or harmful (e.g., SCOT or SLC2A1-independent defects). The review concludes that genetic and epigenetic profiling is recommended for personalized dietary interventions.
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