Genetic and Epigenetic Modifiers of Ketogenic Diet Responses: Roles of Sex and Age

Abstract

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.

1. Introduction

The ketogenic diet (KD) is a high-fat, very-low-carbohydrate dietary pattern that induces nutritional ketosis and has been used for decades as an effective therapy for drug-resistant epilepsy [1,2]. Beyond seizure control, a KD and related low-carbohydrate regimens are increasingly applied to metabolic disorders, where they can promote weight loss, improve glycemic control, and reduce insulin requirements in many individuals with obesity and type 2 diabetes [1,3]. However, these benefits are not universal: in some contexts a KD may aggravate dyslipidemia, trigger pro-inflammatory responses, or worsen insulin resistance, underscoring the need to clarify which patients are most likely to benefit [4]. Several KD variants are currently employed in both experimental and clinical settings, including the classic 4:1 diet, the medium-chain triglyceride KD, the modified Atkins diet, and the low-glycemic-index treatment. These protocols differ in fat sources, protein allowance, carbohydrate thresholds, energy restriction, and fiber content, leading to distinct metabolic, hormonal, and microbiome responses. In practice, the clinical effect of a KD depends not only on macronutrient composition but also on total caloric intake, quality of fats and proteins, micronutrient and trace-element sufficiency, concomitant medications, comorbid diseases, and broader environmental factors such as physical activity and stress [5]. Consequently, a KD can exert both therapeutic and pathogenetic effects on metabolic health, and a one-size-fits-all approach is unlikely to be adequate. Genetic diversity significantly influences an individual’s ability to adapt to and benefit from nutritional ketosis, emphasizing the need for a personalized approach to dietary interventions. Individual variability in KD response is further shaped by genetic and epigenetic factors that influence substrate utilization, mitochondrial function, inflammation, and neuronal excitability. Variants in genes involved in carbohydrate and lipid metabolism, insulin secretion, and neurotransmission can determine whether a KD improves or worsens glycemic control, lipid profile, and seizure burden. Recent studies highlight that the KD induces different epigenomic modifications, including changes in DNA methylation, histone acetylation, and microRNA expression, which regulate gene expression and metabolic adaptation [6]. Moreover, KD-induced alterations in the gut microbiota and its metabolites, including short-chain fatty acids (SCFA) and ketone bodies, provide additional layers of epigenetic and immunometabolic regulation. Sex-specific genetic and epigenetic frames modulate the metabolic and physiological outcomes of a KD. Studies have shown that during a KD, male and female individuals and model organisms display unique patterns of gene activation and hormonal interactions impacting therapeutic benefit [7,8,9]. Age is another critical factor that determines the epigenome’s plasticity and the metabolic response to a KD. The integration of genetic background, epigenomic mechanisms, sex, and age not only predicts the individual response to the ketogenic diet but also sets up future strategies for personalized nutrition and disease management.

In this review, the focus is on how genetic background, epigenomic mechanisms, sex, and age shape both the therapeutic and pathogenetic effects of a KD rather than on describing the diet itself in detail. By synthesizing current evidence across these domains, the article aims to identify molecular and physiological determinants of KD responsiveness and to outline how genetic and epigenetic profiling, together with sex- and age-specific considerations, could inform the development of more precise and safer KD-based interventions for metabolic and neurological diseases.

2. Genes and Genetic Diversity Associated with the Response to the Ketogenic Diet

Genetic diversity significantly shapes the metabolic and therapeutic outcomes of individuals on the ketogenic diet (KD). The interaction between specific genes and the KD could define an individual’s response, affecting everything from weight loss to the treatment of neurological and metabolic diseases. Studies have shown that some genetic markers predict greater benefits or better responses to a KD, highlighting the value of nutrigenomics in optimizing a KD for personalized nutrition. Genes involved in lipid metabolism, energy expenditure, appetite regulation, and inflammation—such as FTO, APOA2, and PPARα—are leading examples where polymorphisms modulate the efficacy of KD interventions [10,11,12]. There is a broad spectrum of genes whose molecular mechanisms are related to appetite, lipid metabolism, energy expenditure, inflammation, seizure sensitivity, intellectual disability, and generally cognitive outcomes, and all of them contribute to the efficacy of the ketogenic diet. Genetic variants in genes like SCN1A, KCNQ2, and STXBP1 are linked to favorable KD responses [13], while mutations in genes such as CDKL5 are associated with poorer long-term outcomes [14]. Genes and genetic diversity associated with the response to the KD can be grouped based on their biological functions and roles in metabolic and neurological processes. Based on that, we group them in five common functional groups: carbohydrate metabolism, lipid metabolism and energy expenditure, inflammation and immune response, mitochondrial function and oxidative stress, and neurotransmission-related genes. A metabolic shift toward fat- and ketone-based energy sources, away from glucose metabolism, combines the effects of all those gene groups in different pathological conditions and contributes to the KD’s therapeutic effect.

2.1. Glucose and Carbohydrate Metabolism

Glucose and carbohydrate metabolism genes play a significant role in individual responses to the KD, which restricts carbohydrate intake and shifts energy metabolism toward fat utilization and ketone body production. Studies have shown that a KD affects the expression of genes involved in gluconeogenesis and insulin secretion. Experimental data on hepatic gluconeogenesis and pancreatic insulin-secretion pathways during a KD are heterogeneous and appear to depend on species, diet composition, and study duration. In a recent mouse study, ketogenic diets shifted the gut microbiota, reduced SCFA levels, altered bile acid composition, and were associated with impaired glucose tolerance and disruption of glucose and lipid metabolism, rather than metabolic improvement [15,16]. In that model, the KD downregulated Ins1 and Pdx1 expression and modified gluconeogenic genes in a diet-specific manner, illustrating that the KD can induce dysbiosis and adverse glycemic effects in parallel with changes in hepatic and pancreatic gene expression. These findings highlight the gut microbiota as an important mediator of KD-induced metabolic changes but also emphasize that a KD may worsen, rather than relieve, insulin resistance and glucose homeostasis in some contexts, particularly in animal studies using very low-fiber, energy-dense formulations. Maturity-Onset Diabetes of the Young Overview (MODY) is a group of monogenic diabetes subtypes caused by negative variants in single genes that impair pancreatic beta-cell development or glucose-stimulated insulin secretion. In the case of those mutations, it is crucial to distinguish MODY from type 1 and type 2 diabetes, as the effectiveness of a KD may vary depending on the specific gene mutation and individual response. Individual treatment is essential because a KD can improve glycemic control, but the long-term safety, like potential side effects such as cardiovascular risk, is still not clear [10].

Table 1. Overview of the most relevant genes related to glucose and carbohydrate metabolism and the KD effect.

Gene	Function	Effect of Gene Mutation	KD
AMPK	Encode the AMP-activated protein kinase (AMPK) enzyme complex	Cause genetic disorders like cardiomyopathy, characterized by left ventricular hypertrophy and glycogen storage	No evidence for human treatment with a KD in these cases to date. Experimental evidence suggests AMPK deficiency would undermine normal ketogenic adaptation [17].
G6PC	Encodes glucose-6-phosphatase	Glycogen storage disease type Ia;	Recommended—Improve glycemic control [18].
GYS2	Encodes hepatic glycogen synthase (GS) that regulates glycogen synthesis in the liver.	Glycogen storage disease type 0 (GSD-0) [19]	Not recommended—significant risk of hypoglycemia, neurological injury, poor growth, acidosis, and metabolic crises [10,20].
INS1	Encoding insulin	Diabetes mellitus and beta-cell dysfunction.	Not recommended— [21]
“MODY genes” * [22]	Insulin production and blood sugar control	Maturity-Onset Diabetes of the Young Overview (MODY)	Individualized approach based on the specific MODY type. Potentially useful for in patients with mutations in HNF1A and HNF4A
PCK1	Encodes phosphoenolpyruvate carboxykinase 1 (PEPCK-C)	PEPCK deficiency—a rare metabolic disorder characterized by hypoglycemia, growth failure, liver dysfunction, and neurological issues [23].	Not recommended—increased risk for severe hypoglycemia [24].
“PDH genes” **	Encodes components of the pyruvate dehydrogenase complex (PDH complex)	PDH Complex Deficiency—Impaired glucose oxidation [25].	Recommended—bypasses glucose metabolism defect [26]
OXCT1	Encodes the enzyme succinyl-CoA:3-ketoacid CoA transferase (SCOT)	SCOT deficiency	Not recommended—risk of recurrent and severe ketoacidosis crises
SLC1A2	Encodes excitatory amino acid transporter 2 (EAAT2)	Neurological disorders, including epilepsy and amyotrophic lateral sclerosis (ALS) [27,28].	Recommended—modulates neuronal excitability and neurotransmitter balance [29].
SLC2A1	Encodes the GLUT1 protein	Glucose Transporter Type 1 Deficiency Syndrome (GLUT1DS)	Recommended—significantly improves seizure control and improves neurological symptoms [30,31]

* MODY genes: HNF1A, HNF4A, GCK, HNF1B, PDX1/IPF1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, APPL1; ** PDH genes: PDHA1, PDHB, DLAT, DLD, PDHX, PDP1, LIAS.

presents the most common genes related to glucose and carbohydrate metabolism whose modifications cause different pathological conditions that are related to the ketogenic diet (Table 1).

2.2. Lipid Metabolism and Energy Expenditure

Lipid metabolism and energy expenditure are tightly regulated processes influenced by multiple genetic pathways. Gene mutations affecting key enzymes, transporters, or regulators in these pathways can significantly alter body responses to diets, including the KD (

Table 2. Overview of the most relevant genes related to lipid metabolism and energy expenditure and the KD effect.

Gene	Function	Effect of Gene Mutation	KD
ABCG5/8	Encode proteins (sterolins)	Sitosterolemia [39].	Not recommended—high risks of worsened hypercholesterolemia and atherosclerosis [40].
ADIPOQ	encodes the protein adiponectin	Obesity and T2DM, cardiovascular and renal disease	No evidence for treatment with a KD in these cases to date. The KD is likely to amplify these risks, including greater susceptibility to dyslipidemia, NAFLD, inflammation, and insulin resistance [41].
APOE	Encodes apolipoprotein E	Increases the risk for late-onset Alzheimer’s (APOE e4) Reduces the risk of developing Alzheimer’s disease (APOE e2)	Can be used under strict monitoring and consideration of lipid/cardiovascular risk [42,43].
BDH1	Encodes the enzyme 3-hydroxybutyrate dehydrogenase 1	Increased fat accumulation in the liver (hepatic steatosis) and poor energy balance during fasting. It has been linked to diabetes and certain cancers.	Not recommended—disrupts cellular capacity to efficiently utilize ketone bodies, increases susceptibility to oxidative stress, and can worsen energy metabolism in critical organs, especially under ketogenic conditions [44].
CETP	Encodes the cholesteryl ester transfer protein (CETP).	Cholesteryl ester transfer protein (CETP) deficiency	Recommended—compatible with CETP gene mutations and may even show enhanced metabolic benefits [45].
CPT1A	Encodes enzyme carnitine palmitoyltransferase 1A (CPT1A)	CPT1A deficiency	Recommended for Arctic populations Not recommended for non-Arctic populations due to risk of hypoketotic hypoglycemia [10].
FASN	Encodes fatty acid synthase enzyme	Multisystem metabolic disorders, including hypoglycemia, hepatic dysfunction, and impaired energy homeostasis	No evidence for treatment with a KD in these cases to date
FGF21	Encodes the Fibroblast Growth Factor 21 (FGF21)	Increased preference for sugar and alcohol, metabolic syndrome risk.	Can be used, but the metabolic benefits may be diminished or altered depending on the nature of the mutation [46,47].
HMGCR	Encodes the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase	Autosomal recessive limb girdle muscular dystrophy (LGMD)	Effects would depend on the specific functional impact, but there are no clinical series or case reports on this intersection [48].
LDLR	Encodes the low-density lipoprotein (LDL) receptor protein	Familial hypercholesterolemia (FH)	Not recommended—risk of a severe and dangerous increase in LDL cholesterol and cardiovascular complications [10,49].
LEP	Encodes the leptin hormone	Congenital leptin deficiency (CLD)	There is no clinical precedent or published case for using a ketogenic diet in individuals with LEP gene mutations.
LIPA	Encodes lysosomal acid lipase (LAL)	Lysosomal Acid Lipase (LAL) Deficiency	Recommended—increase lysosomal acid lipase (LAL) activity and reduce liver steatosis and cardiovascular risk factors, especially in morbid obesity [50].
LIPC	Encodes the hepatic lipase (HL) enzyme	Lysosomal Acid Lipase Deficiency (LAL-D)	Recommended under close lipid monitoring [51].
LIPF	Encodes gastric lipase	Lysosomal Acid Lipase (LAL) Deficiency	Recommended—compatible but may be especially effective for weight loss [10,52].
LPL	Encodes lipoprotein lipase (LPL) enzyme	Familial chylomicronemia syndrome	Not recommended—it may trigger or worsen hypertriglyceridemia, pancreatitis, and systemic lipid overload [53].
UCP1	Encodes uncoupling protein 1 (UCP1)	Risk of metabolic disorders like obesity	Can be used, but the metabolic benefits may be diminished or altered depending on the nature of the mutation
PPAR	Encodes nuclear receptors that regulate genes involved in metabolism, inflammation, and cell development	Familial partial lipodystrophy (FPLD3). severe insulin resistance, partial lipodystrophy, type 2 diabetes and hypertension.	Not recommended—Inefficient due to ectopic lipid accumulation [54]. Personal approach is recommended.
PCSK9	Encodes protein that regulates blood cholesterol levels by promoting the breakdown of low-density lipoprotein (LDL) receptors	Causing high cholesterol and increased cardiovascular risk (GOF)	Can be used, but for GOF there is a risk of excessive LDL cholesterol [55,56].
SCD1	Encodes the stearoyl-CoA desaturase 1 enzyme	Alters fatty acid profiles and influences metabolic diseases like obesity and insulin resistance, as well as plays a role in cell stress, cancer, and liver function.	There are no clinical reports or studies. Potentially, a KD could cause excessive lipid depletion or hepatic stress.
SREBF1	Encodes the sterol regulatory element-binding protein 1	Downregulation of FASN, SCD1, ACLY, ACACA, and LDLR genes resulting in reduced lipogenesis and altered lipid homeostasis	There are no clinical reports or studies. Experimental and genetic data only suggest that both SREBF1 loss and ketogenic metabolism suppress lipogenesis via similar pathways [57].

). Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that serves as a master regulator of lipid metabolism, mitochondrial fatty acid oxidation, and hepatic ketogenesis—making it highly relevant to the effects of the KD [32]. All three isoforms, PPARα, PPARγ, and PPARβ/δ, contribute to the metabolic adaptations induced by the KD, including regulation of fatty-acid oxidation, adipogenesis, and insulin sensitivity. Experimental and clinical data indicate that a KD can modulate the expression and activity of each isoform and that coordinated PPAR signaling is important for preventing or attenuating metabolic disorders such as obesity, insulin resistance, and non-alcoholic fatty liver disease. Activation of PPARα enhances fatty acid oxidation, promoting the use of fatty acids as an energy source rather than glucose [33]. A study had shown that the ketogenic diet significantly alters the expression profiles of metabolic genes in the liver, particularly those regulated by PPARα [34]. PPARα directly induces transcription of enzymes such as carnitine palmitoyltransferase 1A (CPT1A), acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase (MCAD), and HMG-CoA synthase 2—the rate-limiting enzyme in ketone body synthesis [32]. Mice lacking functional PPARα cannot fully upregulate fatty acid oxidation or ketogenesis during fasting or a ketogenic diet, resulting in hypoketotic hypoglycemia, fatty liver, and defective adaptation to nutrient deprivation. In humans, PPARα activity supports the safe entry into and maintenance of nutritional ketosis and potentiates the lipid-lowering, anti-inflammatory, and possible neuroprotective effects of the ketogenic diet. Activation of PPARγ promotes adipocyte differentiation and lipid storage, thereby influencing systemic insulin sensitivity and inflammatory status. Ketogenic and other low-carbohydrate diets can modulate PPARγ-dependent genes involved in fatty-acid uptake and adipokine secretion, which may improve insulin sensitivity in some contexts but favor ectopic lipid accumulation in others. In individuals with PPARγ dysfunction, such as familial partial lipodystrophy, this axis is disturbed, so a KD may exacerbate insulin resistance and cardiometabolic risk rather than confer metabolic benefit [35,36]. PPARβ/δ is broadly expressed and regulates fatty-acid oxidation and mitochondrial biogenesis, particularly in skeletal muscle and other oxidative tissues. Nutritional ketosis can activate PPARβ/δ-controlled programs that increase muscle fatty-acid utilization and energy expenditure, supporting exercise capacity and metabolic flexibility. When PPARβ/δ signaling is impaired, the ability to upregulate fatty-acid oxidation during a KD is reduced, which may limit therapeutic effects and promote lipid accumulation and insulin resistance in susceptible individuals [37,38]. (Table 2).

2.3. Inflammation and Immune Response

The functional subgroup of genes related to immune regulation, including those governing cytokine signaling, inflammasome activation, and immune cell differentiation, plays a crucial role in the clinical benefits and risks associated with the KD. Among the most studied genes, NLRP3 stands out as a pivotal regulator of the inflammasome pathway. The KD and its key metabolite, beta-hydroxybutyrate, directly inhibit NLRP3 activation, suppressing downstream pro-inflammatory cytokines such as IL-1β and IL-18. Genetic variants that enhance NLRP3 signaling are associated with intense inflammatory responses but may also confer a greater anti-inflammatory benefit from KD-mediated blockade of this pathway. Similarly, functional polymorphisms in pro-inflammatory cytokine genes such as microglial phenotype genes modulate susceptibility to inflammation-driven complications; individuals carrying high-expression variants could experience pronounced benefit from the KD’s suppressive effect on these pathways [1,58,59,60]. Clinical studies assessing the effects of the KD on immune biomarkers consistently show an anti-inflammatory profile, with the KD producing reductions in several key inflammatory markers. Meta-analyses and randomized controlled trials in overweight, obese, and neurologically affected populations have shown decreases in C-reactive protein (CRP) and pro-inflammatory cytokines, predominantly TNF-α and IL-6 [12,58,61]. These findings indicate that a KD can reliably modulate chronic low-grade inflammation and may have adjunctive therapeutic benefit in metabolic, autoimmune, and neurologic diseases through its impact on immune biomarkers (

Table 3. Overview of the most relevant genes related to inflammation and immune response and the KD effect.

Gene	Function	Effect of Gene Mutation	KD
Cytokine Genes: IL1B, IL6, TNF, IL18	Pro-inflammatory cytokine	Chronic inflammatory conditions (rheumatoid arthritis), infections and age-related diseases.	The KD is not contraindicated and may offer clinical benefit by suppressing downstream inflammatory signaling [1].
Immune Cell Metabolism Genes *	Encoding the carnitine palmitoyltransferase 1A enzyme, HMG-CoA lyase, 3-hydroxybutyrate dehydrogenase 1, transport proteins (MCTs).	Carnitine palmitoyltransferase 1A (CPT1A) deficiency, HMGCLD, ketone body metabolism, lactate transport defects and exercise-induced hypoglycemia, Allan-Herndon-Dudley syndrome.	Not recommended—All those genes are essential for successful and safe use of the KD. Mutations in these genes can render a KD unsafe or ineffective, so functional assessment or genetic screening may be indicated in high-risk patients or populations [44,62,63].
Microglial Phenotype Genes (M1 -Pro-inflammatory) **	Encodes proteins widely used as functional and phenotypic markers of the pro-inflammatory (M1) microglial state	Dysregulated immune responses in the central nervous system	Recommended—the KD is not contraindicated. KDs suppress NF-κB and NLRP3 pathways, reducing production of TNF-α, IL-1β, IL-6, and reactive oxygen species [60]. A KD may help reduce the inflammatory consequences of such mutations within the central nervous system [64].
Microglial Phenotype Genes (M2 -Anti-inflammatory) ***	Encodes proteins widely used as functional and phenotypic markers of anti-inflammatory (M2) microglial state	These genes are upregulated under a KD, reflecting a shift from pro-inflammatory (M1) to reparative, neuroprotective microglial polarization.	Recommended—KDs enhance Arg1 and CD206 expression, increase IL-10 and TGF-β release, and activate HCA2 and PPARγ signaling [65].
NF-κB Pathway Genes ****	Regulating immune and inflammatory responses, cell survival, and development	Cancer, immunodeficiency, and chronic inflammation	The KD is not contraindicated and may offer clinical benefit by suppressing downstream inflammatory signaling [1].
NLRP3	Encodes NLRP3 protein, which is a component of the NLRP3 inflammasome	Cryopyrin-associated periodic syndromes (CAPS): familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID)	Recommended—inhibit NLRP3 inflammasome activation, reduce IL-1β/IL-18 secretion, and ameliorate systemic inflammation [66].
Regulatory T Cell (Treg) Genes: FOXP3, CTLA4	Encodes FOX4 and CTLA4 proteins	Autoimmune diseases (FOXP3), cancer (CTLA4)	The KD increases the expansion and activation of FOXP3+ regulatory T cells, enhancing immunosuppressive and tolerance functions [67].

* CPT1A, HMGCL, BDH1, SLC16A family; ** iNOS (NOS2), CD86, IL1B, IL6, TNF, COX2, TLR4; *** Arg1, CD206 (MRC1), IL10, YM1 (CHI3L3), TGFβ1, FIZZ1; **** NF-κB1, NF-κB2, RelA, RelB, c-Rel.

).

2.4. Mitochondrial Function and Oxidative Stress

Genetic diversity in mitochondrial function and oxidative stress response critically shapes the physiological and therapeutic outcomes of the KD. Mitochondria are responsible for cellular energy production and play a pivotal role in managing reactive oxygen species (ROS), both of which are deeply influenced by cellular genetics. A key functional group of responsive genes includes those encoding central mitochondrial enzymes, antioxidants, and regulators of mitochondrial biogenesis and quality control (

Table 4. Overview of the most relevant genes related to mitochondrial function and oxidative stress and the KD effect.

Gene	Function	Effect of Gene Mutation	KD
ACOX1	Encodes peroxisomal straight-chain acyl-CoA oxidase enzyme	Peroxisomal acyl-CoA oxidase deficiency (a loss-of-function mutation) or Mitchell syndrome (a gain-of-function mutation).	Not recommended as a first-line antioxidant therapy. Clinical consideration depends on the specific mutation and patient context.
BNIP3	Encodes a mitochondrial protein called BNIP3	Altered apoptosis, cancer progression	Recommended—a KD increases BNIP3 expression, facilitating selective removal of damaged mitochondria and maintaining mitochondrial quality [70].
CAT, PRDXs	Encodes a key antioxidant enzyme.	Impair their antioxidant functions, leading to a buildup of oxidative stress and increased risk for various diseases	Recommended—Additional antioxidant defense [71].
Complexes I–V, mitochondrial respiratory chain *	Encodes mitochondrial respiratory chain proteins	Rare autosomal recessive disorders that affect the mitochondrial respiratory chain	Recommended—increased efficiency and reduced production of reactive oxygen species in aging [72].
GPX, GSR	Encode enzymes GPX (Glutathione Peroxidase) and GSR (Glutathione Reductase)	Mutations in the GSR gene can lead to hereditary glutathione reductase deficiency, while GPX gene variants have been associated with an increased risk of cancer and cardiovascular conditions.	Recommended—upregulated during KD, strengthening the cellular redox defense [71].
Nrf2	Encodes a transcription factor that is a master regulator of the cellular response to oxidative stress	Promoting tumor growth, chemoresistance, and survival	Recommended—Activating NRF2 through the KD can lead to beneficial effects like increased antioxidant production, improved mitochondrial function, and neuroprotection. Clinical consideration depends on the specific mutation and patient context [73].
NQO1	Encodes the NAD(P)H quinone dehydrogenase 1 (NQO1) enzyme	Can lead to a non-functional or less stable enzyme that may increase susceptibility to certain diseases, including various cancers, neurodegenerative disorders, and cardiovascular issues	Recommended—The effectiveness of a KD may vary based on individual genetic makeup, and the presence of an NQO1 mutation could affect the diet’s therapeutic potential and its impact on outcomes like oxidative stress [74].
SOD1, SOD2	Encode superoxide dismutase (SOD) enzymes	Mutations in the SOD1 gene are linked to neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), while SOD2 mutations can lead to oxidative stress and tissue damage	Recommended—A ketogenic diet shows promise in models of SOD1 gene mutations, particularly in slowing disease progression, improving motor function, and protecting motor neurons [75].
UCPs	Encodes mitochondrial uncoupling proteins	Increased risk of obesity and related metabolic disorders	Recommended—neuroprotective effects [76].
PGC-1α	Encodes a protein that is a master regulator of mitochondrial biogenesis and a key player in energy metabolism	Type 2 diabetes and insulin resistance.	Recommended—a KD may stimulate PGC-1α and promote mitochondrial number and function, especially in neural tissue [77,78].

* Complexes I-V, mitochondrial respiratory chain: COX4I1, NDUFS1, SDHA, MT-ATP6, ND genes.

). Transcription factor Nrf2 (NFE2L2) controls the expression of many antioxidant defense genes. Variants impairing Nrf2 activity may weaken the KD-induced upregulation of essential enzymes such as SOD2, GPX, and CAT, limiting the diet’s protective effect against oxidative stress [68]. Polymorphisms in mitochondrial biogenesis regulators, such as PGC-1α (PPARGC1A) and TFAM, also influence how robustly tissues adapt to ketosis by increasing mitochondrial number and function [69]. Genes like UCP2 and UCP3 modulate mitochondrial membrane potential and ROS leakage, with their variants shaping the extent of ROS reduction under a KD. Overall, interindividual variability in these gene groups underlies diverse metabolic and therapeutic responses to the KD, from strong enhancement of antioxidant capacity and mitochondrial biogenesis to suboptimal effects in carriers of pathogenic or inactivating gene variants.

2.5. Neurotransmission

Genes involved in neurotransmission play a major role in modulating how individuals respond to the KD, with significant implications for neurological and neuropsychiatric outcomes (

Table 5. Overview of the most relevant genes related to neurotransmission and the KD effect.

Gene	Function	Effect of Gene Mutation	KD
GABA-T (ABAT)	Provides instructions for making the GABA-transaminase enzyme, which breaks down the neurotransmitter GABA in the brain	Causes GABA-T (GABA transaminase) deficiency, a rare, autosomal recessive genetic disorder	The KD’s ability to increase GABA levels by reducing its breakdown may be beneficial for individuals with a GABA-T deficiency.
GAD1, GAD2	Encodes the enzyme glutamate decarboxylase (GAD), which synthesizes the neurotransmitter gamma-aminobutyric acid (GABA)	GAD1 mutations are linked to early-infantile-onset developmental and epileptic encephalopathy, while GAD1 and GAD2 gene variations are associated with an increased risk of anxiety disorders, schizophrenia, and major depression. Specific GAD1 variants may also impact sleep regulation	Recommended—a KD increases expression/activity of GAD, shifting neurotransmitter balance toward GABA and enhancing seizure control [80].
GRIN1, GRIN2A/B	Encodes subunits of the NMDA receptor (NMDAR), a crucial ion channel for excitatory neurotransmission in the brain	Neurodevelopmental disorders, collectively known as GRIN disorders, which can include intellectual disability, epilepsy, and autism spectrum disorder.	Recommended—may be a beneficial treatment, as it can restore NMDAR function in animal models by increasing Grin2a and Grin2b expression through histone acetylation.
Monoamine Genes *	Involved in the synthesis, transport, and degradation of neurotransmitters like dopamine and serotonin	range of neurological and psychiatric conditions, such as the behavioral issues seen in Brunner syndrome (MAOA mutation) and potential links to disorders like ADHD, autism spectrum disorder, and Parkinson’s disease (MAOB mutation).	Recommended—alter expression, improving dopaminergic and serotonergic signaling, mood, and neuroprotection [79].
SLC32A1	Encodes the vesicular inhibitory amino acid transporter (VIAAT), a protein critical for nervous system function	Generalized epilepsy with febrile seizures plus (GEFS+) and developmental and epileptic encephalopathy. Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS).	Recommended—highly effective treatment because it provides the brain with an alternative fuel source (ketone bodies) when glucose transport is compromised [31,81].
SLC6A1, SLC6A3	Encodes the dopamine transporter protein (DAT), which regulates dopamine signaling.	ADHD, Tourette syndrome, and substance abuse, as well as dopamine transporter deficiency syndrome.	Recommended—The diet, which is high in fat and low in carbohydrates, is suggested to help stabilize neurons and may work by affecting GABA reuptake [82].
VGLUT1/SLC17A7	Encodes the Vesicular Glutamate Transporter 1 protein, which is essential for loading glutamate into synaptic vesicles for neurotransmission in the brain	Various neurological and psychiatric conditions affecting glutamate transport and synaptic function	The preliminary findings suggest that a KD is safe, feasible, and potentially neuroprotective and disease-modifying for patients with MS [83].

* Monoamine Genes: TH, DDC, TPH1, MAOA/B.

). The KD exerts many of its beneficial effects by shifting the excitatory/inhibitory balance within the brain, in part through gene-regulated changes in key neurotransmitter pathways. GAD1 and GAD2 catalyze the conversion of glutamate to GABA, the primary inhibitory neurotransmitter. The KD increases the expression and activity of GADs and suppresses GABA transaminase (ABAT/GABA-T), elevating GABA levels and synaptic inhibition, effects associated with seizure control and improved neuronal stability [79,80]. Variants in these genes can thus modify the extent to which a KD enhances inhibitory tone and seizure resistance. An individual’s genetic background across transporters, receptors, and enzymatic machinery for neurotransmitter synthesis and turnover directly influences the clinical benefit of the KD. Functional polymorphisms or pathogenic mutations in these genes underlie much of the observed variability in neuroprotective and anticonvulsant outcomes, validating the need for personalized KD strategies in neurological disease.

These five functional gene groups are interconnected (Figure 1), forming a dynamic metabolic–immunological–neuronal network that shapes physiological responses to the KD.

3. Epigenomic Mechanisms Induced by Ketogenic Diet

The KD induces several epigenomic mechanisms that, by the action of keton bodies such as β-hydroxybutyrate (BHB), mainly affect DNA methylation, histone modifications, and microRNA expression [6]. Modulation of such epigenomic mechanisms underlies the anti-inflammatory, neuroprotective, anti-aging, and metabolic benefits promoted by ketogenic therapy [84].

3.1. DNA Methylation

DNA methylation is a primary epigenetic mechanism by which the ketogenic diet exerts its biological effects, affecting both global and gene-specific methylation patterns. The main modification involves the adding of a methyl group to a DNA molecule, often to the C5 position of a cytosine base, mainly mediated by DNA methyltransferases (DNMTs) [6], resulting in changed gene activity without altering the underlying DNA sequence. Generally, it is a key mechanism in cell differentiation, gene regulation, and maintaining cellular memory [85]. In animal models and epilepsy patients, the KD consistently reduces global and gene-specific DNA methylation, especially in the brain [86]. This hypomethylation results in a decreased proportion of methylated versus unmethylated cytosines, leading to the activation of normally silenced genes, chromosomal instability, and a general loss of gene expression that is related to the development of various diseases [87]. A reason why hypomethylation occurs, in part, is to increase adenosine in the brain, which inhibits DNMT activity via elevation of S-adenosylhomocysteine (SAH), an inhibitor of methyltransferases [6,86,88]. Reduced methylation caused by the KD aligns the epigenome of obese patients closer to that of normal-weight subjects after significant weight loss, modifying hundreds of genes associated with metabolic processes [89]. Several genes show significant DNA methylation changes after KD treatment, with modifications most often observed in genes related to epilepsy (SLC12A5, BDNF), metabolism and transcriptional regulation (KLF14, ELOVL2, FHL2 (metabolic), ZNF331, FGFRL1, CBFA2T3, C3orf38, JSRP1), neuroplasticity, and cell function. Importantly, changes in methylation at epilepsy-related genes (for example, SLC12A5 and BDNF) and metabolic regulators (such as KLF14 and ELOVL2) have been associated with seizure reduction and improved metabolic profiles in patients and animal models on KDs, indicating that gene-specific methylation signatures may predict or mediate clinical response to the diet. This hypomethylation activates otherwise silenced genes, which has been clinically linked to improved epilepsy outcomes and metabolic regulation [86,88]. These findings illustrate the complex and multi-pathway nature of KD-induced methylation effects, which are increasingly recognized as contributors to both therapeutic and long-term health benefits. Future studies should systematically correlate locus-specific methylation patterns with seizure control, cognitive performance, and weight loss or metabolic endpoints to refine KD personalization and identify individuals most likely to benefit [89].

3.2. Histone Modifications

The KD induces pronounced histone modifications—chemical changes to histone proteins that regulate DNA packaging and gene expression, mainly through the actions of ketone bodies (BHB), which serve as both metabolic signaling molecules and direct substrates for histone posttranslational modifications [90]. Among the major histone modifications—acetylation, methylation, phosphorylation, and ubiquitylation—the ketogenic diet is primarily associated with histone acetylation and histone β-hydroxybutyrylation, which directly influence chromatin structure and gene expression, while phosphorylation and ubiquitylation have not been shown to be directly influenced by the ketogenic diet or BHB in a significant or consistent manner based on current literature. The ketone body BHB, elevated during a KD, acts as an endogenous inhibitor of histone deacetylases (HDACs). This inhibition increases histone acetylation levels, leading to chromatin relaxation and activation of genes involved in neuroprotection, metabolism, and inflammation regulation [91,92]. For instance, enhanced acetylation of histone H3 and H4 at BDNF promoters has been linked to higher BDNF expression and improved hippocampal memory and neuroprotection under KD or ketone exposure, directly tying specific acetylation events to functional brain outcomes [93,94,95]. Unique to states of ketosis, histone lysine β-hydroxybutyrylation (Kbhb) is a novel modification where BHB serves as a substrate, adding a hydroxybutyryl group to histone lysines. This modification is distinct from acetylation but similarly promotes active chromatin and transcription, especially in fasting and ketogenic conditions [96].

The direct relationship of histone methylation with the KD is more complex and less prominent compared to histone acetylation. Recent research indicates that ketone bodies, especially BHB, affect histone methylation at specific sites such as H3K4me3 (trimethylation at lysine 4 on histone H3) and H3K27me2/36me1 (dimethylation and monomethylation on histone H3), which impact gene expression relevant to mitochondrial function and stress resistance [97]. The KD’s effects on histone methylation contribute to compensating neurogenesis defects and hippocampal memory impairment in models of genetic disorders (e.g., Kabuki syndrome) through increased H3K4me3 [6]. Beyond host genetics, diet-induced shifts in gut microbiota likely contribute to the epigenomic remodeling observed under a KD [98]. The KD and other low-carbohydrate diets consistently reshape gut microbial communities and their metabolites, including SCFAs and ketone bodies, which can act as endogenous histone deacetylase inhibitors and modulators of DNA methylation and histone acylation in metabolic and inflammatory genes [99,100]. SCFA and ketone-driven epigenetic changes in turn influence pathways linked to inflammation, mitochondrial function, and neuronal excitability, providing a plausible mechanism by which microbiome composition modulates seizure control, weight loss, and other KD outcomes. Recent work in KD-treated epilepsy and obesity cohorts further suggests that baseline microbial signatures and their metabolite profiles correlate with seizure reduction and metabolic improvement, indicating that microbiome–epigenome crosstalk may underlie individual differences in KD efficacy [101]. Future studies integrating gut microbiome profiling with locus-specific epigenetic marks and clinical readouts are therefore needed to identify microbiota-dependent epigenetic biomarkers of KD responsiveness and to design adjunct strategies (e.g., prebiotics or probiotics) that enhance therapeutic success.

3.3. MicroRNA Expression

The KD regulates microRNA (miRNA) expression, which impacts gene regulation at the posttranscriptional level, especially in metabolism and neuroprotection [102]. BHB, as the main ketone body elevated in a KD, acts as a signaling molecule that regulates miRNA synthesis and expression, contributing to epigenetic modulation [103].

The KD modulates miRNAs involved in antioxidant and anti-inflammatory pathways. Normalization of specific miRNAs has been observed after a KD in obese individuals, which helps reduce oxidative stress and inflammation [104]. Studies in obese subjects report miRNAs like hsa-let-7b-5p, hsa-miR-143-3p, and hsa-miR-504-5p vary after a KD, correlating with metabolic changes [105]. In neurological contexts, the KD alters miRNAs linked to neurodevelopment and cognitive functions. Key miRNAs affected by the KD are miR-34a, miR-132, miR-134, and miR-330, which are associated with synaptic activity, neuroprotection, and brain-derived neurotrophic factor (BDNF) regulation [103]. In studies of epilepsy, autism, and migraine, specific miRNAs, including miR-211-5p and miR-590-5p, change in response to a KD, suggesting roles in both neurological symptoms and metabolic adaptation [105]. Some miRNAs are used as biomarkers for KD response, helping monitor effectiveness and guide interventions in obesity, epilepsy, and neurologic disorders [106]. miR-34a is upregulated by a KD and could be used as a potential biomarker in obesity and neurodegeneration monitoring, while miR-132-3p and miR-134-5p serve as markers for neuroprotection and cognitive improvement [103]. These KD-responsive miRNAs correlate with seizure reduction, cognitive improvement, and metabolic changes, and emerging data indicate that pre-treatment miRNA panels can predict response to modified Atkins or ketogenic regimens, highlighting their value as minimally invasive biomarkers to guide dietary interventions [103,106].

Overall, integrating gene-specific DNA methylation, histone acetylation/β-hydroxybutyrylation patterns, and miRNA signatures with clinical and metabolic outcomes will be crucial to translate KD-induced epigenomic changes into targeted preventive and therapeutic strategies for obesity, epilepsy, and neurodegenerative disorders.

4. Sex Differences: Distinct Epigenetic and Metabolic Effects

Sex differences shape both the epigenetic and metabolic responses to the ketogenic diet in rodents, with clear implications for humans as well. Females and males show distinct profiles in terms of ketosis, glucose homeostasis, insulin sensitivity, tissue-specific gene expression, and histone modifications [7,8,107] (Figure 2). Sex-specific differences in the metabolic response to a KD are complex and have not yet been fully investigated, but they can be partially explained by the role of sex hormones. Women may face more pronounced difficulties in fat mobilization and muscle metabolism when following a KD compared to men [8]. During ovulation, estrogen receptor α (ER-α) actively regulates lipid metabolism, including the synthesis and remodeling of HDL, enhancing its production and improving its ability to remove cholesterol from tissues [108]. However, ER-α can also contribute to fibrosis development in the liver and kidneys upon a KD by increasing expression of the PNPLA3 p.I148M gene variant (Patatin-like phospholipase domain-containing protein 3) [109]. The KD interferes with hormonal status in females, but the effects are nuanced and depend on factors like age, reproductive status, and overall metabolic health [110]. Vandel et al. demonstrated that during the early stages of metabolic dysfunction-associated steatotic liver disease (MASLD) in women, the liver retains resistance to inflammation and fibrosis. But, under certain conditions—such as increased fat intake without caloric restriction, as well as perimenopause or menopause—this protection may be compromised [111]. During the menstrual cycle, hormonal fluctuations can make it more challenging to enter ketosis and effectively lose weight [8,112]. Higher estrogen levels suppress sensitivity of α-adrenergic receptors, possibly disturbing lipolysis and leading to insulin resistance [113,114]. These mechanisms suggest that estrogen is not always a protective hormone; rather, its effects depend on the specific metabolic environment, the stage of the reproductive cycle, and genetic factors.

Higher levels of testosterone in men enhance muscle protein synthesis and upregulate β-adrenergic receptors, which together facilitate increased lipolysis during the ketogenic state [115,116]. Interestingly, males appear to require stricter carbohydrate restriction to achieve and maintain ketosis [8]. This may reflect a higher threshold for insulin suppression and a greater reliance on gluconeogenesis. Testosterone influences AMPK and mTOR signaling pathways [117,118,119], which may modulate the metabolic response to a KD and contribute to sex-specific differences in energy homeostasis. There is also interplay between ketosis and testosterone. In one meta-analysis, the KD increased testosterone levels in an age-dependent way [120]. Considering inflammation, men or male mice fed with a KD showed variable results, depending on the study duration or maybe even diet formulation (very often not specified)—both decreases and increases in pro-inflammatory markers such as TNF-α have been reported [9,121,122]. KD benefits in men are oriented towards the CNS, where it has been shown to upregulate neuroprotective genes such as BDNF, enhance synaptic plasticity, and modulate neurotransmitter balance in male rodents [123]. These effects are particularly relevant in the context of neurodegenerative diseases and cognitive aging.

There is scarce literature on sex-specificity in KD-induced epigenetic changes, and so far, the existing data is focused on circulating BHB concentrations as a driver of epigenetic remodeling dependent on sex as a biological variable. BHB inhibits class I and IIa histone deacetylases. This leads to increased histone acetylation, which opens up chromatin structure and promotes gene transcription [124,125,126]. Female C57BL/6J mice fed with a KD had significantly higher BHB concentrations compared to males [127]. Another study in the VM/Dk mice strain, famous for glioblastoma and immunotherapy research, also revealed elevated BHB concentrations in blood in KD-fed females compared to males and standard diet-fed animals of both sexes [128]. At the level of epigenetic modifications, this study also reported that sex led to chromatin changes in a tissue-specific manner. In the hippocampus, male mice showed higher levels of global histone lysine acetylation (pan-Kac) and the activating marker H3K4me3 (a marker of transcriptionally active chromatin) than female mice [84]. Such epigenetic differences might imply that male hippocampi are more prone to activating specific gene networks upon a KD, potentially metabolic or neuroprotective genes. This might be explained by differences in higher BHB uptake or higher metabolism rate in males as well as developmental epigenetic differences emerging from early brain development (such as higher concentrations of acetylated and trimethylated H3 in the cortex/hippocampus of males at birth [129]. It is still an open question if an increase in markers specific for active chromatin in males is beneficial or not.

Interestingly, skeletal muscle (bicep) showed sex-specific epigenetic responses in mice fed with a KD. Under SD, females exhibited higher levels of H3K4me3—a marker of active gene transcription—compared to males [84], likely reflecting sex differences in muscle physiology and gene expression. Females typically express more type I fibers (endurance-related), while males have greater muscle mass [130]. However, the KD abolishes this epigenetic advantage, significantly reducing H3K4me3 levels in females, with no comparable change in males [84]. This could have functional consequences—genes involved in muscle growth or oxidative metabolism might be marked by H3K4me3. A KD might suppress those pathways in females (due to energy shortage or hormonal changes), while in males a KD may activate genes (due to stress response or fuel utilization) that were previously less expressed. The reduction in H3K4me3 in female muscle by ketosis might indicate a dampening of some anabolic pathways. It is yet to be discovered how sex-specific promoters change as a response to a KD. Understanding sex-specific responses to the KD is critical for optimizing dietary strategies in clinical practice, and future research should aim to elucidate the molecular details of these differences and explore their relevance across diverse populations, both sexes, and age groups.

5. Age-Related Considerations: Epigenome and Metabolic Flexibility

Aging leads to significant changes in the epigenome that directly impact metabolic flexibility, with distinct mechanisms linking age-related epigenetic modifications to a decline in the ability to efficiently switch between energy substrates like fats and carbohydrates [84,102].

5.1. Metabolic Improvements with Aging

The KD affects age-related metabolic changes primarily through enhancing mitochondrial function, stimulating fatty acid oxidation, and affecting metabolic switching between glucose and ketone metabolism. Evidence suggests that adherence to a KD can improve body composition by promoting fat loss while preserving lean muscle mass, which is crucial as sarcopenia becomes a concern with advanced age [131]. In younger populations, research has indicated that the ketogenic diet can induce significant metabolic changes, leading to increased energy expenditure and improved body composition. For instance, a study focusing on Taekwondo athletes found that a ketogenic diet was associated with reduced systemic inflammation, evidenced by decreased levels of pro-inflammatory cytokines such as TNF-α [132]. These reductions are particularly important in younger athletes, as inflammation plays a critical role in recovery and performance. Another consideration regarding the ketogenic diet’s implications for individuals of different ages relates to its metabolic flexibility. Phosphorylation of key regulatory enzymes in glucose and lipid metabolism provides insights into how individuals adapt to changes in nutrient availability; older adults may exhibit altered metabolic responses that could affect their adherence to dietary regimens such as the KD [133,134]. Studies have shown that the ketogenic diet facilitates a transition in oxidative metabolism, leading to improved lipid utilization in skeletal muscle, which is critical for maintaining metabolic health as people age [135]. This adaptability is further enhanced in response to physical training, which can synergize with the diet to improve energy efficiency and endurance performance in older adults [134]. Molecular studies have revealed that younger subjects on ketogenic diets may experience upregulation of genes associated with fatty acid metabolism, thereby having an enhanced ability to utilize fats rather than carbohydrates as an energy source [136]. Moreover, younger individuals generally exhibit a higher degree of metabolic flexibility, allowing them to switch efficiently between fuel sources, a phenomenon that the ketogenic diet capitalizes on [137]. Studies have shown that middle-aged and older adults have a diminished ability to control blood glucose levels effectively, which is critical since the ketogenic diet significantly reduces glucose availability [138]. A metabolic shift toward fat utilization might not yield the same levels of energy efficiency seen in younger individuals, as older adults often face conditions like sarcopenic obesity, where loss of muscle mass complicates the overall metabolic profile, making the balance between fat and muscle even more crucial [139]. Improved antioxidant capacity and reduced oxidative stress markers in older mice subjected to a ketogenic diet [140]. This suggests a potentially protective role against age-related oxidative damage, although the extent of these benefits can vary based on individual health conditions and adherence levels to the diet. While the ketogenic diet aims to stimulate ketone production to utilize as an alternative energy source, older adults may not reach the same state of ketosis as effectively as younger individuals. This discrepancy raises questions about the diet’s long-term sustainability and practicality within an older demographic [141]. Young mice and humans typically exhibit a more pronounced adaptive response to a ketogenic diet, largely due to their metabolic flexibility and regenerative capacities. Under a ketogenic dietary paradigm, there is observed upregulation in the expression of genes associated with fatty acid oxidation and ketone body utilization. For instance, studies have reported increased levels of genes such as ATF4 and fibroblast growth factor 21 (FGF21), which play critical roles in metabolic adaptations to fasting and high-fat intake [142]. Young organisms exhibit a robust capacity for energy conversion, allowing for enhanced gains in metabolic efficiency when exposed to a KD [143]. Moreover, factors such as reduced mitochondrial function and altered hormonal responses contribute to less favorable outcomes in older populations adhering to a ketogenic diet. Age-related differences in liver function and the capacity to produce ketones can hinder the effectiveness of dietary interventions like the KD in older adults [144]. Nutritional strategies involving the ketogenic diet may also influence the expression of stress-related and inflammatory genes differently in young versus older organisms. Studies have shown that while young rodents display a pronounced increase in antioxidant genes with a KD, older rodents do not exhibit the same level of upregulation. This differential response could potentially worsen the inflammatory status of older individuals and complicate health outcomes related to oxidative stress and chronic inflammatory conditions, which often worsen with age [145,146].

5.2. Longevity and Neuroprotection

The exploration of the ketogenic diet (KD) as a method to potentially slow biological aging has garnered significant academic interest. Research indicates that the KD may impact metabolic processes, promote neuroprotection, and influence gene expression related to aging, thereby contributing to better health outcomes in both younger and older populations. Individuals following a ketogenic diet during aging might experience not only metabolic shifts but also modifications in cellular aging pathways, potentially leading to a lower incidence of age-associated pathologies [147]. In younger (pediatric) populations, the KD is frequently used in treating refractory epilepsy, where it has shown promising results in reducing seizure frequency and duration [148]. The KD has been found to improve biomarkers associated with cognitive health, potentially delaying the onset of neurodegenerative diseases [149]. Similarly, in older adults, there is a growing body of literature indicating that KDs might offer neuroprotective benefits, potentially mitigating cognitive decline associated with Alzheimer’s disease and other neurodegenerative disorders [149]. These benefits are hypothesized to occur via enhanced energy metabolism in brain cells, which significantly depends on efficient utilization of ketone bodies and regulation of neuroinflammatory processes [150,151]. Increased levels of β-hydroxybutyrate (BHB), a key ketone body produced during ketosis, have been linked to enhanced cognitive performance, suggesting that the KD may foster a more favorable neural environment in younger individuals [152]. As the brain ages, its ability to effectively use glucose declines; thus, a diet promoting ketone utilization could help sustain cognitive functions longer. On a genetic level, specific genes involved in neuronal resilience may be upregulated in young adults as a result of diet-induced ketosis, promoting enhanced learning and memory capabilities [153]. In contrast, older populations might not benefit long-term from some neuroprotective effects unless supported by additional comprehensive dietary strategies that include antioxidants and micronutrients vital for brain health [154]. Besides the physiological impacts, psychological factors must also be considered. Younger individuals may adopt the ketogenic diet with specific aesthetic or athletic goals in mind, which can enhance motivation and adherence to the diet. Older adults, on the other hand, may struggle with adherence due to predefined beliefs about dietary restrictions or the socio-economic implications of adhering to a high-fat diet influenced by cultural norms [155].

5.3. Potential Risks and Reversibility

While the KD exhibits numerous benefits for managing metabolic disorders and enhancing physical performance, it is essential to address potential drawbacks. The effects of the KD can be sex-specific and organ-specific, with aging impairments in endogenous ketone production that can be partly reversed by ketogenic diet stimulation [156]. Some studies indicate the ketogenic diet might accelerate cellular aging in some organs via increased senescent cells, although this might be reversible with appropriate interventions [157]. For older populations, adverse effects may include nutrient deficiencies, dysbiosis due to altered gut microbiota, and metabolic disturbances such as ketoacidosis [158]. These risks underscore the importance of conducting thorough assessments before initiating the KD, particularly in vulnerable groups where metabolic homeostasis is already challenged [159]. The adaptability of the diet is crucial; older adults generally have a reduced metabolic rate and different nutrient absorption capabilities, which can affect how well they respond to a stringent ketogenic regimen. Evidence suggests that while young individuals may thrive under such dietary controls, older adults could face complications like nutrient deficiencies or impaired kidney function if diet changes are not properly managed [155]. Integrating gene panels (e.g., MODY genes, SLC2A1, PDH-complex genes, lipid-metabolism loci such as PPARA, APOA2, FTO) with epigenetic and microbiome-linked markers may guide KD indication, intensity, and monitoring.

6. Knowledge Gaps and Future Directions

Despite rapid progress, several critical gaps limit the translation of KD-related genetic and epigenetic findings into routine clinical practice. First, mechanistic data linking specific KD-induced epigenetic modifications (DNA methylation, histone marks, non-coding RNAs) with defined metabolic and neuroprotective outcomes remain sparse, particularly when sex, age, and tissue specificity are considered. Future experimental studies should therefore combine controlled KD interventions with multi-omic profiling (genome, epigenome, transcriptome, microbiome) in relevant organs to establish causal pathways and to identify robust, KD-responsive molecular signatures. Second, clinical evidence for personalized KD prescriptions based on host genetics and epigenetics is still limited to selected monogenic disorders and small, often non-stratified cohorts. Prospective, adequately powered trials that stratify participants by genotype (e.g., glucose transport, mitochondrial, and lipid-metabolism genes) and epigenetic markers, and that include both sexes across the lifespan, are needed to define who benefits most, who is at risk of adverse effects, and how KD protocols should be adapted. Third, there is no consensus on standardized panels, analytical pipelines, or clinically actionable thresholds for KD-relevant genetic, epigenetic, or microbiome profiling. Future work should develop and validate harmonized biomarker sets, evaluate their reproducibility and predictive value across populations, and integrate cost-effectiveness and implementation research to determine when such profiling is justified outside highly specialized centers.

7. Conclusions

The ketogenic diet offers a broad range of benefits for metabolic and neurological health, but its effectiveness strongly depends on an individual’s genetic and epigenetic context, as well as sex and age. A personalized nutritional approach considering these factors is essential to optimize therapeutic outcomes of a KD. It should be explicitly cautioned that broad epigenetic profiling is not yet ready for routine clinical decision-making and should currently be applied within research or highly specialized centers, ideally in conjunction with standardized KD phenotyping and long-term follow-up. Further research is needed to clarify molecular mechanisms and establish guidelines for safe and effective KD application in diverse populations with different genetic profiles. This approach could enable targeted use of the KD for prevention and treatment of metabolic and neurodegenerative diseases in the future.