Almanac A1C

Fat Fasting: Metabolic Shifting Through Ketone Production and Cellular Renewal

Posted

by

dr. Karunia Valeriani Japar

Table of Contents
Keywords: , , , ,

Introduction

Fat fasting is targeted metabolic approach designed to shift the body into a fat burning state while avoiding the extreme deprivation of water only fasting. In this short-term dietary method, typically lasting two to five days, about 80-90% of calories come from fat, with minimal protein and carbohydrate intake. This macronutrient profile encourages the liver to produce ketones, lowers insulin levels, and promotes satiety while preserving lean tissue. By mimicking the metabolic effects of fasting, fat fasting helps the body transition efficiently to using fat as its primary fuel source [1,2].

At its core, fat fasting capitalizes on the body’s ability to adapt to limited carbohydrate availability. With reduced glucose, the liver increases fat oxidation and ketone production, providing energy for both the brain and muscles. The result is a controlled state of nutritional ketosis that supports mitochondrial performance, triggers autophagy, and reduces oxidative stress. These processes linked to enhanced cellular repair and metabolic rejuvenation, mirror many of the benefits observed in prolonged fasting but with reduced physical and psychological strain [1,3].

Through modern nutrition science only recently began exploring fat fasting, fasting itself is rooted in ancient tradition. Across cultures, fasting was practiced not only for spiritual discipline but also for healing and purification. The medicalization of fasting emerged in the early 20th century through Dr. Otto Buchinger, who developed supervised therapeutic protocols combining broths and herbal teas. Later decades saw fasting evolve from total abstinence toward structured models aimed at metabolic regulation. Approaches such as intermittent fasting, time restricted eating, and the fasting mimicking diet represent modern iterations that balance metabolic benefit with nutritional adequacy [4,5].

In the context of modern research, fat fasting aligns with a growing body of work on metabolic health, flexibility, and longevity. Lipid based fasting protocols and fasting mimicking diets have shown promise in lowering biological age markers, improving insulin sensitivity, and reducing inflammation. These effects are through to stem from activation of cellular stress response pathways such as AMPK, FOXO and autophagy that maintain energy balance and promote repair. Importantly, such fasting models offer a practical alternative to full caloric restriction by sustaining energy levels while fostering similar molecular benefits [4,5].

In essence, fat fasting bridges the wisdom of historical fasting with the precision of modern metabolic science. It represents an adaptive tool to modulate energy metabolism, enhance cellular resilience, and support long-term health and longevity.

Mechanism of Action

Fat fasting leverages a sophisticated biochemical cascade that reorients cellular metabolism from carbohydrate utilization to fat derived energy production. This process involves multilevel regulation at metabolic, hormonal and cellular signaling levels that together enable metabolic flexibility and cellular rejuvenation.

Metabolic Switch: From Glycolysis to Ketogenesis

The transition from glycolysis to ketogenesis represents a fundamental metabolic reprogramming event triggered by reduced carbohydrate availability and increased fat intake. Under normal post prandial conditions, glucose I the preferred cellular fuel, oxidized through glycolysis and the tricarboxylic acid cycle to generate ATP. When carbohydrate stores become depleted, as occurs during fat fasting, glycogen mobilization is followed by a dramatic upregulation of fatty acid oxidation and ketone body production [6].

Ketogenesis occurs primarily in hepatic mitochondria. Fatty acids are transported into mitochondria via carnitine palmitoyltransferase 1 (CPT-1) and undergo beta-oxidation to produce acetyl-CoA. Under low carbohydrate conditions, oxaloacetate, a critical intermediate in the citric acid cycle is diverted to gluconeogenesis, limiting the cycle’s capacity to process acetyl-CoA. Consequently, acetyl-CoA accumulates and enters the ketogenic pathway. Two molecules of acetyl-CoA condensed by thiolase to form acetoacetyl-CoA, which is then converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by HMG-CoA synthase. HMG-CoA lyase cleaves HMG-CoA into acetoacetate, which is subsequently reduced to beta-hydroxybutyrate or spontaneously decarboxylated to acetone. Beta-hydroxybutyrate and acetoacetate serve as transportable energy substrates that are taken up by peripheral tissues, reconverted to acetyl-CoA, and oxidized to yield 22 ATP molecules per ketone body [6,7].

This metabolic switch is highly coordinated process. Studies demonstrate that fasting activates the expression of uncoupling protein 3 (UCP3) in skeletal muscle by fivefold within 15 hours and tenfold by 40 hours, facilitating enhanced fatty acid handling and oxidative capacity without requiring changes in other lipid metabolism genes. Furthermore, prolonged fasting increases whole-body fat oxidation while paradoxically reducing intrinsic mitochondrial oxidative capacity in skeletal muscle, suggesting complex tissue specific adaptations [8,9,10].

Effects On Insulin and Glucose Regulation

The hormonal milieu during fat fasting is characterized by low insulin and elevated counter-regulatory hormones, which together drive the metabolic shift toward ketogenesis. Insulin is the primary hormonal regulator of ketogenesis and it suppression is essential for initiating this pathway. In a low insulin state, hormone-sensitive lipase is disinhibited, leading to increased lipolysis in adipose tissue and elevated circulating free fatty acids. Simultaneously, reduced insulin signaling decreases the activity of acetyl-CoA carboxylase, which lowers malonyl-CoA levels. Since malonyl-CoA normally inhibits CPT-1, its reduction allows increased fatty acid entry into mitochondria for beta-oxidation [6].

Counter regulatory hormones such as glucagon, cortisol, catecholamines, and thyroid hormones further amplify ketogenesis by stimulating lipolysis and increasing substrate availability for ketogenic pathway. Glucagon, in particular, activates hormone-sensitive lipase and inhibits acetyl-CoA carboxylase, thereby promoting both fatty acid mobilization and mitochondrial uptake [6].

Fat fasting also modulates glucose homeostasis, high-fat overfeeding for as little as five days has been shown to increase fasting hepatic glucose production by 26% and raise fasting glucose levels by 0.46mmol/L in young healthy men, despite borderline elevated insulin levels. This phenomenon reflects hepatic insulin resistance, likely mediated by elevated plasma gastric inhibitory peptide (GIP) and compensatory hyperinsulinemia. Interestingly, while short-term fat exposure reduces fasting free fatty acid levels due to suppression of adipose tissue lipolysis, it does not necessarily increase whole body lipid oxidation rates in the fasting state. These findings underscore the complexity of metabolic adaptation to fat based nutritional intervention and highlight the differential responses of hepatic versus peripheral tissues [11].

Fat Oxidation and Mitochondrial Adaptation

Fat oxidation is central to the energy provision during fat fasting, and mitochondrial adaptation is crucial for sustaining this elevated oxidative flux. Fasting induces a complex array of metabolic and hormonal responses that enhance mitochondrial fatty acid oxidation in skeletal muscle and other tissues. This adaptation is mediated by transcriptional coactivators, notably PGC-1a, which is deacetylated by SIRT1 during nutrient deprivation. Deacetylation of PGC-1a is required for the activation of genes encoding mitochondrial fatty acid oxidation enzymes, effectively shifting cellular fuel preference from glucose to lipids [8,12].

Time-controlled fasting has been shown to prevent mitochondrial dysfunction induced by high-fat diets. In mice subjected to weekly fasting cycles, mitochondrial respiration efficiency in skeletal muscle was maintained, and systemic markers of metabolic health, including blood glucose and lipid profiles were improved. This protective effect was mediated by sustained expression of adipose tryglyceride lipase (ATGL), which is critical for intracellular lipolysis and mitochondrial substrate supply.  Conversely, prolonged fasting (60hours) paradoxically reduces intrinsic skeletal muscle mitochondrial oxidative capacity despite elevated plasma free fatty acids and whole-body fat oxidation, suggesting that mitochondrial function may be compromised secondary to lipid overload in the insulin resistant state. This underscores the importance of cyclic rather than prolonged fasting protocols to optimize mitochondrial health [9,13].

Ketone bodies themselves exert signaling functions that modulate mitochondrial metabolism. Beta-hydroxybutyrate act as a feedback inhibitor of hepatic fatty acid oxidation and ketogenesis, preventing excessive ketone accumulation. Additionally, ketone bodies serve as histone deacetylase inhibitors, altering the acetylation status histones and non-histones proteins to modulate gene expression programs involved in oxidative stress response and metabolic adaptation [14,15].

Hormonal And Cellular Responses: mTOR, AMPK, And Autophagy

The cellular response to fat fasting is orchestrated by nutrient-sensing pathways, particularly the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and autophagy machinery. These pathways integrate signals of energy sufficiency and scarcity to coordinate anabolic and catabolic processes.

mTOR Inhibition and Autophagy Activation

During fat fasting, reduced amino acid and glucose availability inhibits mTOR complex 1 (mTORC1), a master regulator of cell growth and metabolism. mTORC1 inhibition occurs through suppression of the Rag GTPase-dependent recruitment of mTORC1 to the lysosomal surface, where it would otherwise be activated by the small GTPase Rheb. Inhibition of mTORC1 has two major consequences: first, it removes the inhibitory phosphorylation of ULK1 (unc-51-like autophagy-activating kinase1), thereby initiating autophagosome formation. Second, it dephosphorylates and activates transcription factor EB (TFEB), allowing its nuclear translocation and transcriptional activation of genes encoding lysosomal biogenesis and autophagy machinery. This dual mechanism ensures both rapid initiation of autophagy and sustained enhancement of degradative capacity [16,17,18].

Figure 1. Autophagy Molecular Machinery [16]

Autophagy provides amino acids for gluconeogenesis and maintains energy homeostasis during fasting. Mice with constitutively active mTORC1 due to mutations in RagA or deletion of TSC1 are unable to induce autophagy upon fasting, leading to severe hypoglycemia and neonatal lethality. This genetic evidence underscores the essentiality of mTORC1 inhibition for survival during nutrient deprivation [17,18].

Figure 2. The mTOR-Autophagy Axis [17]

AMPK Activation

AMPK is an intracellular energy sensor activated by rising AMP: ATP ratios during fasting. AMPK activation promotes fatty acid oxidation, ketogenesis, and autophagy. AMPK directly phosphorylates and activates ULK1 at sites distinct from mTORC1 phosphorylation, providing a complementary mechanism for autophagy induction. AMPK also inhibits mTORC1 by phosphorylating TSC2 and Raptor, further reinforcing the shift from anabolism to catabolism. In the context of fat fasting, AMPK-driven pathways support the efficient utilization of fatty acids and the maintenance of cellular ATP levels [3,16,18,19].

Figure 3. Hypothesized Mechanism by Which Fasting Affects Lipid and Glucose Metabolism [3]

Ketone Bodies and mTOR-Autophagy Crosstalk

Emerging evidence suggests that ketone bodies themselves modulate mTOR signaling and autophagy. Ketogenesis is tightly regulated by mTORC1: hepatic mTORC1 activation suppresses fasting-induced ketogenesis, while mTORC1 inhibition is permissive for ketone production. Conversely, beta-hydroxybutyrate and fibroblast growth factor 21 (FGF21) act as signaling molecules that activate AMPK and induce oxidative stress response genes via PPARa and PGC-1a pathways. This bidirectional regulation creates a feedback loop whereby ketone production both results from and contributes to sustained mTOR inhibition and autophagy activation [14,15,17,19].

Autophagy and Metabolic Homeostasis

Autophagy-derived amino acid can partially reactivate mTORC1, creating a regulatory loop that prevents excessive catabolism. This homeostatic mechanism is essential for metabolic flexibility. Mice with defective autophagy (Atg5 or Atg7 knockout) exhibit impaired glucose homeostasis, muscle wasting, and neonatal lethality following fasting, highlighting the indispensability of autophagy for survival during nutrient scarcity. In the liver, autophagy contributes to the maintenance of blood glucose and amino acid levels, and hepatic autophagy deficiency results in fasting hypoglycemia that can be rescued by exogenous serine supplementation [17].

In summary, fat fasting induces a coordinated metabolic and cellular response characterized by enhanced ketogenesis, insulin suppression, mitochondrial fat oxidation, mTOR inhibition, AMPK activation, and autophagy induction. These interconnected pathways enable the body to sustain energy production, preserve lean tissue, and promote cellular renewal during periods of carbohydrate restriction and elevated fat intake. The molecular orchestration of these processes underscores the metabolic sophistication of the fat fasting strategy and its potential applications in. metabolic health and longevity interventions.

Nutritional Composition and Protocols

Fat fasting is a precision-targeted dietary intervention distinguished by its unique macronutrient distribution, strategic food selection, defined temporal parameters, and distinct physiological effects when compared to other fasting modalities. Understanding these compositional and procedural elements is essential for safe and effective implementation.

Defining The Macronutrient Ratios in Fat Fasting

The hallmark of fat fasting is its extreme skewing of macronutrient proportions toward dietary lipids. Specifically, fat fasting protocols stipulate that 80-90% of total daily caloric intake derives from fat, with correspondingly minimal contributions from protein and carbohydrate. Total caloric intake is typically restricted to 1,000-1,200 calories per day, distributed across four to five small meals of approximately 200-250 calories each. This caloric restriction is significantly below typical maintenance requirements for most adults, rendering fat fasting a hypocaloric as well as ketogenic intervention [20].

Within this macronutrient framework, protein intake is deliberately suppressed to approximately 6-11% of total calories (roughly 15-30grams per day), and carbohydrate consumption is limited to 3-10% of calories (approximately 7-17 grams per day). This stringent restriction of gluconeogenic precursors and direct glucose sources accelerates glycogen depletion and expedites the transition into nutritional ketosis. The lack of significant carbohydrate and protein ingestion forces the body to rely almost exclusively on exogenous and endogenous fat for energy, thereby inducing lipolysis and hepatic ketogenesis within 18 to 24 hours [20,21].

These ratios contrast sharply with standard ketogenic diets, which typically maintain fat intake at 70-75% of calories with more liberal protein allowances (15-20%). The more extreme macronutrient composition of fat fasting is designed to mimic the metabolic state of water fasting while maintaining some caloric and micronutrient intake, theoretically reducing hunger and preserving lean mass [20,21,22].

Common Food Sources and Formulations (MCT, Omega-3s, Monounsaturated Fats)

Food selection during fat fasting prioritizes nutrient-dense, high-fat sources that provide satiety while minimizing carbohydrate and protein content. The emphasis is placed on three primary categories of dietary fats: medium-chain triglycerides (MCTs), omega-3 polyunsaturated fatty acids, and monounsaturated fatty acids (MUFAs).

Medium-Chain Triglycerides (MCTs)

MCTs are fatty acids containing 6 to 12 carbon atoms, including caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12). Commercial MCT oil is predominantly composed of caprylic and capric acids. Due to their shorter chain length, MCTs bypass the typical lymphatic absorption pathway and are transported directly to the liver via the portal circulation, where they undergo rapid oxidation and conversion to ketones. This unique metabolic property makes MCTs particularly effective for inducing and sustaining ketosis during fat fasting [23,24,25].

MCT oil supplementation has been shown to increase circulating beta-hydroxybutyrate levels more efficiently than long-chain triglycerides (LCTs), facilitating deeper and more rapid ketosis even in the presence of small amounts of dietary carbohydrate. In fat fasting protocols. MCTs are commonly consumed as pure oil (1-2 tablespoons per day), incorporated into “bulletproof” coffee (coffee blended with MCT oil and butter or ghee), or included in fat bombs, small, high fat snacks designed to deliver concentrated energy. However, MCT oil should be introduced gradually, as doses exceeding 60-100mL per day may cause gastrointestinal distress, including abdominal cramping, diarrhea, and bloating [23,24,25].

Figure 4. Medium-Chain Fatty Acids, Acetyl-CoA and Intersecting Liver Metabolic Pathways [25]

Omega-3 Polyunsaturated Fatty Acids

Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fatty fish such as salmon, mackerel, sardines, and trout, are emphasized in fat fasting for their anti-inflammatory properties and cardiovascular benefits. These long-chain polyunsaturated fats support cellular membrane integrity, modulate inflammatory pathways, and may enhance mitochondrial function. Fatty fish can be consumed fresh or canned, often combined with full fat mayonnaise to increase the fat-to-protein ratio and meet the 80-90% fat target [20].

Monounsaturated Fatty Acids (MUFAs)

MUFAs, abundant in avocados, olive oil, macadamia nuts, and olives, constitute another foundational component of fat fasting. Avocados are particularly valued for their high fat content (approximately 77% of calories from fat), fiber, potassium, and phytonutrients. Olive oil, a staple of Mediterranean diets, is rich in oleic acid and polyphenolic compounds with antioxidant and anti-inflammatory effects. Macadamia nuts, with one of the highest fat to protein ratios among nuts, are frequently recommended as snacks or processed into nut butter [20].

Additionally, food sources commonly incorporated into fat fasting include full-fat dairy products such as cream cheese, heavy cream, sour cream, butter, and ghee; coconut products including coconut oil, coconut butter, and unsweetened coconut flakes; and small amounts of animal proteins such as eggs (especially yolks), bacon, and cured meats, selected for their high fat content. Vegetables are typically limited to low-carbohydrate, non-starchy options such as leafy greens, cucumber, often consumed with high fat dressings or dips [20].

Typical Duration and Cyclic Patterns

Fat fasting is explicitly designed as a short-term metabolic intervention, not a sustainable long-term dietary pattern. Recommended durations range from 2 to 5 days, with 3 days being the mot commonly prescribed protocol. Extending fat fasting beyond 5 days is strongly discouraged due to the risk of nutrient deficiencies, excessive lean mass catabolism, metabolic adaptation, and psychological stress [20].

The rationale for limiting duration is multifaceted. First, the severe caloric restriction (1,000-1,200 kcal/day) and macronutrient imbalance create nutritional inadequacy, particularly with respect to protein, fiber, vitamins and minerals. Prolonged adherence increases the risk of deficiencies in B vitamins, and minerals. Prolonged adherence increases the risk of deficiencies in B vitamins, vitamin C, calcium, magnesium, and other micronutrients. Second, insufficient protein intake over extended periods promotes muscle protein degradation to support gluconeogenesis, potentially leading to clinically significant losses in lean body mass. Third, sustained severe caloric restriction may trigger metabolic adaptations characterized by reduced resting metabolic rate, diminished thyroid hormone production, and downregulation of energy expenditure, collectively referred to as “starvation mode”, which undermines long-term weight management goals [20,26].

Fat fasting is typically employed in two specific contexts: first, to accelerate entry into ketosis at the initiation of a ketogenic diet or following a dietary deviation, and second, to break through weight loss plateaus lasting two weeks or longer in individuals already following a low-carbohydrate diet. In the latter scenario, the acute metabolic perturbation induced by fat fasting may overcome adaptive thermogenesis and restore weight loss momentum [20].

Cyclic Implementation

While fat fasting itself is transient, it is often embedded within broader cyclic or intermittent dietary frameworks. For instance, individuals may perform a 3-day fat fast once per month or quarter as part of a metabolic reset strategy. Alternatively, fat fasting may be integrated with intermittent fasting protocols, such as time restricted eating, wherein the eating window is further constrained and the consumed calories are predominantly fat-derived. Such cyclical approaches aim to leverage the metabolic benefits of periodic ketosis and autophagy induction while minimizing the risks associated with continuous restriction [27,28].

Comparison With Water Fasting and Intermittent Fasting

Fat fasting occupies a unique position within the spectrum of fasting modalities, sharing metabolic features with both water fasting and intermittent fasting while diverging in key physiological and practical dimensions.

Fat Fasting versus Water Fasting

Water fasting, also known as complete or absolute fasting, involves the total abstinence from all caloric intake, with only water consumption permitted. This represents the most extreme form of dietary restriction and induces the most profound metabolic alterations. Water fasting durations typically range from 24 hours to 7 days in supervised settings, though medically monitored extended fasts of 10-20 days have been documented [26].

Figure 5. Typical of Prolonged Fasting [26]

Water fasting leads to rapid depletion of hepatic and muscular glycogen stores within 12-24 hours, followed by a transition to ketogenesis and gluconeogenesis. Circulating ketone levels rise dramatically, often exceeding 3-5mM after 5-7 days of water fasting, providing an alternative cerebral fuel source and exerting appetite suppressant effects. Weight loss during water fasting is substantial, averaging 2-10% of initial body weight over 5-20 days, though approximately two-thirds of this loss comprises lean mass, primarily water and muscle glycogen with only one-third representing true fat mass reduction. This unfavorable body composition change is a major limitation of prolonged water fasting [21,26].

Metabolic benefits of water fasting include reduction in systolic an diastolic blood pressure (averaging 20 mmHg and 7 mmHg, respectively), decreases in fasting insulin and glucose in normoglycemic individuals, and increased markers of autophagy. However, water fasting is associated with significant adverse effects, including electrolyte depletion (particularly sodium, potassium, magnesium, and calcium), metabolic acidosis, headaches, insomnia, fatigue, dizziness, and hunger. Furthermore, most metabolic improvements achieved during water fasting are not sustained after refeeding, with benefits dissipating within 3-4 months even when weight loss is maintained [26].

Fat fasting diverges from water fasting in several critical respects. First, by providing 1,000-1,200 calories per day, fat fasting supplies exogenous energy that reduces the metabolic stress of complete deprivation, potentially sparing lean tissue and mitigating hypoglycemia. Second, the consumption of fat particularly MCTs accelerates ketone production and may achieve ketosis more rapidly than water fasting alone. Third, fat fasting allows for the intake of electrolytes, vitamins, and minerals from food sources, reducing the risk of deficiencies and adverse events. Fourth, fat intake promotes satiety via stimulation of cholecystokinin (CCK) and modulation of ghrelin, theoretically reducing hunger and improving adherence relative to water fasting. Finally, fat fasting avoids the extreme psychological and physiological stress of total food abstinence, making it more accessible for unsupervised use [23,25].

However, fat fasting does not fully replicate the autophagy inducing effects of water fasting. While ketosis, and caloric restriction activate AMPK and inhibit mTOR, the provision of exogenous calories especially fat, partially sustain mTOR activity and may attenuate autophagic flux compared to complete fasting. Thus, fat fasting represents a compromise: it captures many of the metabolic benefits of water fasting while reducing risks and improving tolerability, but may not achieve the same depth of cellular rejuvenation [17,26].

Fat Fasting versus Intermittent Fasting

Intermittent fasting (IF) encompasses a diverse array of dietary patterns characterized by recurring cycles of fasting and feeding. Common IF modalities include time-restricted eating (TRE), which confines daily food intake to a window of 4-10 hours (e.g., 16:8, 18:6, or 20:4 protocols); alternate-day fasting (ADF), which involves 24-hour fasting periods alternated with ad libitum feeding days; and whole day fasting (e.g., the 5:2 diet), which prescribes two non-consecutive days per week of severe caloric restriction (500-600 kcal) or complete fasting [28,29,30].

Intermittent fasting induces metabolic switching from glucose to fat-derived fuel sources during fasting periods, typically occurring after 12-18 hours of fasting as hepatic glycogen is depleted. TRE protocols with 16-hour fasting windows (16:8) have been shown to reduce body weight by 2-4%, decrease body fat mass, and improve insulin sensitivity without mandating caloric restriction, though adherence to longer fasting windows (>16 hours) enhances fat oxidation and ketone production. ADF and 5:2 diets produce moderate weight loss of 4-7% and improvements in metabolic markers including triglycerides, LDL cholesterol, blood pressure, and inflammatory markers [21,27,29,30,31,32].

Fat fasting differs fundamentally from IF in its macronutrient composition rather that its temporal structure. While IF does not prescribe specific macronutrient ratios and allows for balanced or ad libitum eating during feeding windows, fat fasting enforces extreme macronutrient restriction (80-90% fat) regardless of timing. However, fat fasting can be combined with IF by restricting the eating window to 4-8 hours and consuming only high-fat foods within that window, thereby synergizing the metabolic effects of temporal restriction and macronutrient manipulation [20,27,29].

In terms of metabolic outcomes, both IF and fat fasting promote ketosis, enhance fat oxidation, improve insulin sensitivity, and activate autophagy, though through partially distinct mechanisms. IF achieves these effects primarily via extended fasting duration and energy deficit, whereas fat fasting relies on macronutrient composition to suppress insulin and drive ketogenesis even in the presence of caloric intake. IF is generally more sustainable as a long-term lifestyle intervention, with studies documenting adherence for 12-24 weeks or longer, whereas fat fasting is inherently transient and unsuitable for prolonged use [29,30].

From a practical standpoint, IF offers greater dietary flexibility and lower risk of nutrient deficiencies, as individual can consume balanced meals during feeding periods. Fat fasting, by contrast, is highly restrictive, monotonous, and nutrient limited, making it appropriate only as a short-term metabolic tool. Both approaches are more effective than ad libitum diets for weight management, and both are comparable to continuous energy restriction (CER) in magnitude of weight loss, though IF and fat fasting may offer superior fat loss and metabolic flexibility outcomes in some studies [29,30].

In summary, fat fasting is characterized by a precise macronutrient distribution (80-90% fat, 1,000-1,200 kcal/day), strategic selection of MCTs, omega-3s, and MUFAs, a short duration of 2-5 days, and distinct metabolic effects relative to water fasting and intermittent fasting. It represents a specialized dietary intervention for rapid ketosis induction and plateau breaking, offering a middle ground between the extreme deprivation of water fasting and the sustained flexibility of intermittent fasting, but is unsuitable for long-term use due to nutritional inadequacy and metabolic risk.

Physiological and Clinical Benefits

Fat fasting exerts multifaceted effects on metabolic, neurological, inflammatory, and cellular health pathways, positioning it as a compelling therapeutic strategy in the prevention and management of chronic metabolic diseases and potentially in the promotion of longevity. Understanding these benefits requires careful examination of the underlying physiological mechanisms and emerging clinical evidence.

Improved Insulin Sensitivity and Glycemic Variability

One of the most clinically significant benefits of fat fasting relates to its effects on insulin dynamics and glucose homeostasis. Intermittent fasting protocols, which share metabolic features with fat fasting, have been shown to significantly improve short-term glycemic control in individuals with type 2 diabetes mellitus. A meta-analysis of 16 randomized controlled trials involving 5,369 patients demonstrated that intermittent fasting significantly reduced glycated hemoglobin (HbA1c) by 0.36% and fasting plasma glucose by 12.38mg/dL compared to standard dietary interventions. These improvements were accompanied by enhanced insulin sensitivity, reduced insulin resistance, and favorable changes in body composition, including reductions in body weight, body mass index, and waist circumference [33,34].

The mechanisms underlying these glycemic benefits are multifactorial. Fat fasting suppresses insulin secretion due to minimal carbohydrate intake, thereby relieving pancreatic beta cells from chronic overstimulation and allowing for recovery of insulin secretory capacity. Simultaneously, the low insulin state disinhibits hormone-sensitive lipase, promoting lipolysis and increased circulating free fatty acids, which are preferentially oxidized rather than stored. This metabolic shift enhances hepatic and peripheral insulin sensitivity, as evidenced by increased phosphorylation of AS-160, a key mediator of insulin-stimulated glucose uptake. Furthermore, fat fasting reduces hepatic glucose production and circulating glucose levels, thereby decreasing glycemic variability, a critical risk factor for microvascular and macrovascular complications in diabetes [6,11,34,35].

It is important to note, however, that the relationship between high-fat intake and insulin sensitivity is complex and context dependent. Short-term consumption of diets very high in total and saturated fats (55% fat, 25% saturated fat) without metabolic adaptation has been shown to decrease insulin sensitivity and impair glucose disposal rates in overweight individuals. This suggests that the benefits of fat fasting on insulin sensitivity are contingent on the induction of ketosis, caloric restriction, and temporal dynamics rather than simply high fat intake per se. When properly implemented as a transient, controlled intervention, fat fasting appears to improve insulin sensitivity and glycemic control, particularly in insulin-resistant populations [33,35,36,37].

Enhanced Ketone Production and Cognitive Clarity

Ketone bodies, particularly beta-hydroxybutyrate (BHB), serve not only as alternative fuels but also as signaling molecules that profoundly influence brain metabolism and cognitive function. Under normal physiological conditions, the brain derives approximately 95% of its energy from glucose oxidation. However, during fat fasting, elevated circulating ketone levels (typically 0.5-5mM) enable ketones to contribute substantially to cerebral energy provision, with studies showing that ketones can supply up to 60% of the brain’s energy requirements during prolonged fasting or ketogenic intervention [38].

The cognitive benefits of ketone availability are supported by both acute and chronic intervention studies. In healthy middle-aged individuals, intravenous infusion of BHB to levels of approximately 2.4mM resulted in a 14% reduction in cerebral glucose consumption while maintaining oxygen utilization, indicating efficient substitution of ketones for glucose as a brain fuel. Acute ketogenic interventions, including single doses of medium-chain triglycerides or ketone esters, have been shown to improve working memory performance, attention, and executive function within hours of administration. These immediate cognitive effects suggest that ketones rapidly enhance neuronal energy availability and synaptic function [38,39].

Longer-term ketogenic interventions yield more pronounced and sustained cognitive benefits. A six-month supplementation trial with medium chain triglycerides in patients with mild cognitive impairment demonstrated significant improvements in memory (free and cued recall), executive function (verbal fluency and Trail-Making Test), and language (Boston Naming Test). These cognitive gains were associated with increased cerebral ketone metabolism and enhanced total brain energy supply, as measured by positron emission tomography. Similarly, ketogenic diets for 6-12 weeks improved verbal memory and cognitive performance in elderly individuals and those with early Alzheimer’s disease, with improvements correlating directly with circulating ketone levels [40,41].

The mechanisms underlying ketone-mediated cognitive enhancement are multifaceted. Ketones bypass deficits in neuronal glucose transporter expression and insulin signaling, which are characteristic of aging and neurodegenerative diseases. Beta-hydroxybutyrate enhances mitochondrial efficiency by improving the NAD+/NADH ratio, stimulating mitochondrial biogenesis, and increasing the phosphocreatine-to-creatine ratio in the hippocampus, a region critical for memory formation. Additionally, BHB acts as a histone deacetylase inhibitor, promoting the expression of brain-derived neutrophic factor (BDNF) and neuroprotective genes. Ketones also reduce neuronal hyperexcitability by inhibiting glutamatergic AMP receptors, potentially mitigating excitotoxicity. Collectively, these effects translate improved neuronal resilience, synaptic plasticity, and cognitive performance [38,39,40,42].

Anti-Inflammatory And Antioxidant Effects

Chronic low-grade inflammation and oxidative stress are central pathophysiological features of metabolic diseases, accelerated aging, and neurodegenerative disorders. fat fasting and ketogenic interventions exert potent anti-inflammatory and antioxidant effects through multiple interconnected pathways.

Anti-Inflammatory Mechanisms

Oxidative stress, characterized by exercise production of reactive oxygen species (ROS) relative to antioxidant defenses, is a critical driver of cellular damage in metabolic and neurodegenerative diseases. Beta-hydroxybutyrate functions as a direct free radical scavenger, particularly against hydroxyl radicals, due to its hydroxyl functional group. In vitro studies demonstrate that BHB and acetoacetate reduce ROS production induced by calcium-mediated glutamate excitoxicity in neocortical neurons [38,43,44].

Indirectly, ketones enhance endogenous antioxidant capacity by activating the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), which upregulates the expression of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase, and catalase. In mice consuming ketogenic diets, hepatic and cerebral levels of FoxO3a and manganese superoxide dismutase (MnSOD) were significantly elevated, reflecting enhanced oxidative stress defense. Furthermore, ketones improve the NAD+/NADH ratio, which supports NADPH regeneration, an essential cofactor for glutathione reductase and other antioxidant systems [35,38,43,44].

Ketogenic diets also reduce oxidative damage to lipids, proteins, and DNA. Animal studies show that ketogenic interventions decrease lipid peroxidation markers (such as malondialdehyde and 4-hydroxynonenal), protein carbonylation, and oxidative DNA lesion in the brain, liver, and muscles. These effects are mediated in part by enhanced mitochondrial efficiency and reduced electron leak from the respiratory chain, achieved through the expression of mitochondrial uncoupling proteins (UCP4 and UCP5). By reducing mitochondrial membrane potential, uncoupling proteins decrease ROS generation while stimulating mitochondrial biogenesis to maintain ATP production [38,43,44,45].

Potential Longevity and Cellular Health Implications

Emerging evidence suggests that fat fasting and ketogenic interventions may extend health span and lifespan by modulating fundamental aging pathways, enhancing cellular maintenance mechanisms, and promoting metabolic resilience.

Longevity Extension in Animal Models

The most compelling evidence for longevity effects comes from controlled animal studies. Roberts et al. demonstrated that a ketogenic diet initiated at 12 months of age (middle-aged mice) significantly increased median lifespan by 13.6% and maximum lifespan by 10% compared to control diets in male C57BL/6 mice. Importantly, the ketogenic diet not only extended lifespan but also preserved health span: age mice consuming the ketogenic diet exhibited superior motor function (grip strength and hanging wire performance), cognitive function (novel object recognition), and muscle mass compared to age-matched controls. Similar lifespan extension has been reported in other mammalian models with cyclic ketogenic diets (alternating weekly with control diets) reducing midlife mortality without affecting maximum lifespan [35,46].

Cellular and Molecular Mechanisms of Longevity

The longevity promoting effects of ketogenic interventions are mediated by several interconnected mechanisms. First ketones modulate nutrient-sensing pathways critical for aging regulation. As discussed previously, fat fasting inhibits mTORC1 signaling in a tissue specific manner, particularly in the liver, where decreased phosphorylation of downstream targets (4E-BP1 and S6 ribosomal protein) indicates reduced anabolic drive. This inhibition is mediated by hyperacetylation and stabilization of p53, which increases expression of DDIT4 (REDD1), a negative regulator of mTORC1. Concurrently, ketogenic diets activate AMPK, promoting catabolic processes such as autophagy, fatty acid oxidation, and mitochondrial biogenesis [3,16,35,47].

Second, beta-hydroxybutyrate acts as an endogenous histone deacetylase (HDAC) inhibitor, inducing widespread protein hyperacetylation. In mice consuming ketogenic diets, total acetylated lysine levels increased fivefold in the liver and 2.5-fold in skeletal muscle after one month. HDAC inhibition is a well-established mechanism of lifespan extension across species from yeast to mammals, associated with enhanced stress resistance, DNA repair, and metabolic flexibility. Ketone-induced hyperacetylation specifically increases acetylation of histone H3 at lysine 9 (H3K9), a mark associated with active transcription of genes involved in oxidative stress defense, including FoxO3a and MnSOD [35,48].

Third, ketogenic interventions enhance mitochondrial quality and function. Studies in aged mice show that ketogenic diets increase mitochondrial mass, upregulate expression of mitochondrial proteins involved in oxidative phosphorylation, and improve skeletal muscle mitochondrial respiratory capacity. These adaptations are mediated by activation of peroxisome proliferator-activated receptors (PPARs) and PGC-1a, master regulators of mitochondrial biogenesis and fatty acid oxidation. Enhanced mitochondrial function is associated with reduced cellular senescence and improved health span [47,49].

Autophagy and Cellular Rejuvenation

Autophagy, the cellular process of degrading and recycling damaged organelles and misfolded proteins is a critical determinant of longevity and cellular health. Fat fasting potently induces autophagy through dual mechanisms: AMPK activation directly phosphorylates and activates ULK1 (the autophagy-initiating kinase), while mTORC1 inhibition removes inhibitory phosphorylation of ULK1 and activates transcription factor EB (TFEB), which drives expression of lysosomal and autophagy genes. The induction of autophagy during fasting provides amino acids for gluconeogenesis, removes damaged mitochondria and protein aggregates, and enhances cellular resilience to stress [16,17,18,50].

Importantly, the timing and duration of fasting induced autophagy are critical. Short term intermittent fasting (12-48 hours) activates adaptive autophagy, promoting cellular repair and stress resistance. In contrast, excessive or prolonged fasting may induce autophagic cell death, underscoring the importance of cyclic rather than continuous fasting protocols. In mouse models, intermittent fasting increased autophagy markers (LC3-II, Beclin-1) and improved cardiac and hepatic function by reducing proinflammatory high-mobility group box 1 (HMGB1) and enhancing cellular clearance mechanisms [16].

Cellular Senescence: A Complex Relationship

Recent studies have raised important caveats regarding long-term ketogenic diet effects on cellular aging. Wei et al.reported that prolonged continuous ketogenic diets (7-21 days) induced cellular senescence in multiple organs, including the heart, kidney, liver, and brain in mice of various ages. This effect was mediated by AMPK activation of p53-dependent pathways, resulting in increased expression of senescence markers including senescence-associated beta-galactosidase, p21, and p16. Importantly, this senescence induction was reversible upon cessation of the ketogenic diet, and occurred independently of age, lipid composition or obesity status. Conversely, mice with impaired endogenous ketone synthesis (Hmgcs2 knockout) exhibited shortened maximum lifespan, which was rescued by administration of ketone precursors. These findings suggest that endogenous ketone production is beneficial for longevity, but continuous exogenous ketogenic diets may accelerate senescence, highlighting the importance of cyclic ketogenic interventions [49,51].

Clinical implications for Metabolic Health and Aging

Translating these preclinical findings to humans remains an active area of investigation. Clinical trials of fasting0mimicking diets (which induce ketosis through caloric and macronutrient restriction) have demonstrated reductions in biological age markers, visceral fat, inflammatory cytokines, and improvements in cardiovascular risk profiles in middle aged adults. A five-day fasting-mimicking diet repeated monthly for three months reduced biological age by 2.5 years as measured by epigenetic clocks. However, long-term safety and efficacy data for continuous ketogenic diets in humans are limited, and concerns about nutrient deficiencies, lipid abnormalities, and adherence remain [5,20].

In summary, fat fasting confers substantial physiological and clinical benefits across multiple domains: it enhances insulin sensitivity and glycemic control, supports cognitive function through alternative fuel provision and neuroprotection, exerts potent anti-inflammatory and antioxidant effects and activates longevity, associated pathways including mTOR inhibition, AMPK activation, autophagy induction, and mitochondrial optimization. However, these benefits are contingent on appropriate implementation, specifically, short term, cyclic protocols that balance metabolic benefits with potential risk of prolonged restriction, future research should focus on optimizing the duration, frequency, and composition of fat fasting protocols to maximize health span and longevity benefits while minimizing adverse effects.

Risk and Considerations

Fat fasting can offer benefits for metabolism and weight management, but it also carries risks if used incorrectly or for too long. It should be done carefully, preferably under professional supervision, especially in people with medical conditions.

Potential Side Effects and Contraindications

Common short-term side effects include fatigue, headache, dizziness, nausea, and muscle cramps often called the “keto flu” as body adapt to burning fat instead of sugar to fuel. Digestive problems are frequent, such as constipation (due to low fiber), or diarrhea if large amounts of MCT oil are used to quickly. Because the diet is low in certain vitamins and minerals, long-term use can cause deficiencies in B vitamins, calcium, magnesium, and vitamin D, as well as dehydration or kidney stones in some individuals [22,23,52].

Fat fasting is not recommended for people with liver or pancreatic disease, inherited disorders of fat metabolism (e,g,, carnitine deficiency, MCAD deficiency), porphyria, or uncontrolled diabetes due to the risk of hypoglycemia. Pregnant or breastfeeding woman should also avoid it because of increased nutrient needs [22,53].

Effects on Lipid Profile and Hormonal Balance

Responses vary between individuals. Some experience reduced triglycerides and increased HDL cholesterol, but others develop marked increases in LDL and total cholesterol, sometimes reaching levels that reverse after stopping the diet. Elevations are more likely if saturated fat intake is very high or if the diet is maintained longer than four to six weeks [54].

Hormonal changes can also occur. Short fasting periods tend to slightly raise cortisol due to stress adaptation, while prolonged fasting may lower thyroid hormones (T3) and slow metabolism. In men, ketogenic diets can increase testosterone and improve insulin sensitivity, but in women, especially premenopausal, long fasting or very low carbohydrate intake may disrupt menstrual cycles and increase fatigue [55,56].

Individual Variability: Sex, Age, And Metabolic Context

Men often lose fat faster on high-fat or ketogenic diets because testosterone supports fat burning and preserves muscle mass, whereas estrogen can make fat mobilization more difficult in women. Women may also find it harder to maintain ketosis during hormonal changes across the menstrual cycle. Older adults can benefit from improved insulin sensitivity but need careful monitoring to prevent muscle loss and nutrient deficiencies. People who are lean or metabolically healthy often see sharper rises in LDL cholesterol compared to those with metabolic syndrome or obesity [56,57,58].

Monitoring Biomarkers During Fat Fasting

To ensure safety and track progress, several biomarkers should be watched during fat fasting:

  • KETONES (bhydroxybutyrate): ideal rage 0.5-3.0 mmol/L to confirm nutritional ketosis [59].
  • Glucose: fasting levels should stay stable (70-90 mg/dL) to avoid hypoglycemia
  • Lipid panel: monitor LDL, HDL, triglycerides, and apolipoprotein B every few weeks during the diet.
  • Electrolytes and kidney function: especially in those with preexisting conditions or on diuretics [54].
  • Thyroid and cortisol levels: for those fasting recurrently or with symptoms of fatigue and mood changes [55,57].

In summary, fat fasting can enhance metabolism and ketone production but should be practiced short-term (2-5 days) with close monitoring of lipid markers, hydration, and hormones. It is safest when individualized by metabolic status, age and sex.

Integration into Longevity and Metabolic Health Strategies

Fat fasting, characterized by high fat intake with limited protein and carbohydrates. For a short period, is increasingly viewed as a valuable tool within broader metabolic health and longevity approaches. Its effectiveness is enhanced when combined thoughtfully with exercise, circadian rhythm optimization, nutritional ketosis and personalized guidance.

Combining Fat Fasting with Exercise and Circadian Optimization

Physical activity synergizes with fat fasting by promoting metabolic flexibility and enhancing fat oxidation. During fasting periods, exercise shifts fuel utilization further away from carbohydrates to fatty acids and ketones, amplifying metabolic benefits. Recent evidence shows that exercising during fasting hours improves lipid utilization and can reduce insulin resistance, potentially lowering type 2 diabetes risk. However, timing matters: integrating exercise with circadian rhythms, such as performing workouts earlier in the day aligned with natural hormone peaks, optimizes energy metabolism and mitochondrial function. Disrupted circadian patterns can increase inflammation and oxidative stress, blunting these benefits. Therefore, aligning fat fasting, physical activity, and feeding schedules with the body’s internal clock supports better metabolic outcomes and cellular repair processes [60,61,62].

Synergy With Nutritional Ketosis and Time-Restricted Feeding

Fat fasting naturally induces nutritional ketosis by sharply reducing carbohydrate and protein intake, elevating circulating ketones that serve as efficient energy substrates and signaling molecules. This state improves insulin sensitivity, supports cognitive function, and promotes autophagy, and mitochondrial health. When combined with time restricted feeding (TRF), restricting eating windows to daytime hours, fat fasting enhances circadian alignment of metabolism. Early TRF, which confines meals to earlier hours in the day, improves metabolic hormones like insulin and adiponectin and reduces appetite and overall caloric intake. Together, these approaches potentiate weight loss, reduce visceral fat, and decrease inflammation, while promoting longevity-associated pathways. Clinical studies of fasting-mimicking diets (a related low calorie, low-protein, plant-based regimen) show reduction in biological age markers and improved immune profiles, indicating the longevity potential of ketosis and fasting paradigms when properly cycled [5,63,64,65].

Role Of AI-Guided Personalization in Fasting Protocols

The integration of artificial intelligence (AI) into nutritional planning enables precise personalization of fat fasting protocols according to individual metabolic status, lifestyle, genetic background, and goals. AI-driven apps can analyze dietary intake, fasting patterns, activity levels, and biometrics to tailor macronutrient ratios, caloric targets, and feeding windows to optimize fat fasting benefits while minimizing risks. These systems support adherence through reminders, real-time feedback, and adaptive plan adjustments, and may incorporate continuous glucose monitoring and ketone data to refine fasting duration and refeeding phases. As personalized approaches are crucial given the variability in lipid responses, hormonal effects, and metabolic flexibility across sexes, ages, and health conditions, AI tools significantly enhance safety and efficacy of fasting-based strategies for metabolic health and longevity promotion [66,67,68].

Practical Guidelines

Preparing For a Fat Fast

Successful fat fasting requires structured planning to minimize side effects and maximize metabolic benefits. Preparation begins with gradually lowering carbohydrate intake two to three day prior, replacing it with healthy fats from sources like avocado, olive oil, and coconut MCT oil. This eases the metabolic transition to ketosis and reduces symptoms such as headache or fatigue that often accompany abrupt dietary shifts. It’s important to hydrate well and monitor electrolyte intake, especially sodium, potassium, and magnesium, as shifts in body fluids and minerals occur during carbohydrate restriction [20].

Recommended fat fast protocols usually involve consuming between 1,000 and 1,200 calories daily, with 80-90% of calories from fat and minimal protein and carb sources, over a short window of 205 days. Organizing meals from simple, high-fat, low-carb foods like avocado, eggs, fatty fish, butter, MCT oil ensures that macronutrient targets are met efficiently [20,69].

Refeeding Strategies and Transition Back to Regular Diet

After completing a fat fast, transitioning or ‘refeeding’ must be handled thoughtfully to prevent adverse effects like rebound hypoglycemia or digestive discomfort. Leading guidelines advise slowly increasing calorie and carbohydrate intake, starting with 50% of energy requirements on the first day back, and progressively restoring balanced nutrition over several days. This helps prevent refeeding syndrome, after longer fasting periods. Reintroducing high-quality proteins, vegetables, and moderate carbohydrates (e.g., whole grains, fruit) in small, frequent meals supports stable blood sugar and gut comfort. Enhancing vitamin and mineral levels, including B vitamins, magnesium, and potassium during refeeding provides further safety. Avoiding processed sugars and heavy meals reduces stress on digestion and metabolism [70].

Tracking Outcomes: Glucose, Ketones, And Biometrics

Outcome tracking informs whether metabolic and health goals are achieved and ensures safety throughout the fat fast and refeeding phase. Regular measurement of blood glucose (aiming for fasting values between 70-90mg/dL) and beta-hydroxybutyrate (BHB) ketones (target range 0.5-3.0 mmol/L for ketosis confirmation) offers direct insight into metabolic status. Commercial fingerstick meters, such as the Abbott Precision Xtra, provide accurate readings. Tracking weight, body composition (fat/muscle ratio), waist circumference, and subjective wellness, including energy, mood and sleep, offers broader feedback. Lab test for lipid profiles and electrolytes are advisable before, during, and after the intervention, especially for those with pre-existing conditions [71].

Conclusion

In conclusion, fat fasting is a scientifically grounded, short-term nutritional strategy designed to induce rapid ketosis, enhance fat oxidation, and activate multiple cellular and hormonal pathways linked to metabolic health and longevity. By restricting caloric intake predominantly to fats while minimizing proteins and carbohydrates, fat fasting mimics several benefits of complete fasting, including improved insulin sensitivity, glycemic control, cognitive function, and reductions in inflammation and oxidative stress, all while reducing physical and psychological strain compared to water-only fasting. When appropriately implemented in cyclic or intermittent patterns, and synergized with exercise, circadian rhythm alignment, and personalized biomarker monitoring, fat fasting serves as a practical and adaptable tool for metabolic reprogramming, cellular renewal, and sustainable health span improvement, provided by with attention to individual risk, proper preparation, and mindful refeeding to ensure safety and nutritional adequacy.

References

  1. Fazeli PK, Steinhauser ML. A critical assessment of fasting to promote metabolic health and longevity. Endocrine Reviews [Internet]. 2025 Jul 23; Available from: https://academic.oup.com/edrv/advance-article/doi/10.1210/endrev/bnaf021/8211151
  2. Meyers K. What Is a Fat Fast and Is It Healthy? – Zero Longevity [Internet]. Zero Longevity. 2023 [cited 2025 Oct 23]. Available from: https://zerolongevity.com/blog/what-is-a-fat-fast/
  3. FINK J, TANAKA M, HORIE S. Effects of Fasting on Metabolic Hormones and Functions: A Narrative Review. Juntendo Medical Journal [Internet]. 2024 Jan 1;70(5):348–59. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11560338/
  4. Visioli F, Mucignat-Caretta C, Anile F, Panaite SA. Traditional and Medical Applications of Fasting. Nutrients [Internet]. 2022 Jan 19;14(3):433. Available from: https://pdfs.semanticscholar.org/a3d5/9bbde891f9746b02a4a29696ed64a24f2be4.pdf
  5. Longo VD, Di Tano M, Mattson MP, Guidi N. Intermittent and periodic fasting, longevity and disease. Nature Aging [Internet]. 2021 Jan;1(1):47–59. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932957/
  6. Dhillon KK, Gupta S. Biochemistry, Ketogenesis [Internet]. National Library of Medicine. StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493179/
  7. Li Y, Liu Q, Jia Z, Guo B. Ketone bodies in exercise, health and disease: Metabolic mechanisms, pathophysiology, and therapeutic implications. Advanced Exercise and Health Science [Internet]. 2025 Jun 3; Available from: https://www.sciencedirect.com/science/article/pii/S2950273X25000293
  8. Tunstall RJ, Mehan KA, Hargreaves M, Spriet LL, Cameron-Smith D. Fasting activates the gene expression of UCP3 independent of genes necessary for lipid transport and oxidation in skeletal muscle. Biochemical and Biophysical Research Communications [Internet]. 2002 Jun 7;294(2):301–8. Available from: https://pubmed.ncbi.nlm.nih.gov/12051710/
  9. Hoeks J, van Herpen NA, Mensink M, Moonen-Kornips E, van Beurden D, Hesselink MKC, et al. Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance. Diabetes. 2010 Jun 23;59(9):2117–25.
  10. Andriessen C, Doligkeit D, Moonen-Kornips E, Mensink M, Hesselink MKC, Hoeks J, et al. The impact of prolonged fasting on 24h energy metabolism and its 24h rhythmicity in healthy, lean males: A randomized cross-over trial. Clinical Nutrition [Internet]. 2023 Dec 1;42(12):2353–62. Available from: https://www.sciencedirect.com/science/article/pii/S026156142300328X
  11. Brøns C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, et al. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. The Journal of Physiology. 2009 May 14;587(10):2387–97.
  12. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. The EMBO Journal. 2007 Mar 8;26(7):1913–23.
  13. Lettieri-Barbato D, Cannata SM, Casagrande V, Ciriolo MR, Aquilano K. Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle. Aguila MB, editor. PLOS ONE [Internet]. 2018 May 9;13(5):e0195912. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942780/
  14. Geisler CE, Ghimire S, Bogan RL, Renquist BJ. Role of ketone signaling in the hepatic response to fasting. American Journal of Physiology Gastrointestinal and Liver Physiology [Internet]. 2019 May 1;316(5):G623–31. Available from: https://pubmed.ncbi.nlm.nih.gov/30767679/
  15. Kawakami R, Sunaga H, Iso T, Kaneko R, Koitabashi N, Obokata M, et al. Ketone body and FGF21 coordinately regulate fasting-induced oxidative stress response in the heart. Scientific Reports. 2022 May 5;12(1).
  16. Shabkhizan R, Haiaty S, Moslehian MS, Bazmani A, Sadeghsoltani F, Saghaei Bagheri H, et al. The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting. Advances in Nutrition [Internet]. 2023 Jul 30;14(5):1211–25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509423/
  17. Deleyto-Seldas N, Efeyan A. The mTOR–Autophagy Axis and the Control of Metabolism. Frontiers in Cell and Developmental Biology. 2021 Jul 1;9.
  18. Vendelbo MH, Møller AB, Christensen B, Nellemann B, Clasen BFF, Nair KS, et al. Fasting Increases Human Skeletal Muscle Net Phenylalanine Release and This Is Associated with Decreased mTOR Signaling. Trajkovic V, editor. PLoS ONE. 2014 Jul 14;9(7):e102031.
  19. Matawali A, Yeap JW, Sulaiman SF, Tan ML. The effects of ketone bodies and ketogenesis on the PI3K/AKT/mTOR signaling pathway: A systematic review. Nutrition Research [Internet]. 2025 Apr 22;139:16–49. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0271531725000624
  20. Clarke C. Keto Fat Fasting Techniques: Top Benefits, Side Effects, and FAQs [Internet]. Ruled Me. 2013 [cited 2025 Oct 23]. Available from: https://www.ruled.me/using-fat-fasting-technique/
  21. Ajmera R. What Are the Different Stages of Intermittent Fasting? [Internet]. Healthline. 2021. Available from: https://www.healthline.com/nutrition/stages-of-fasting
  22. Masood W, Uppaluri KR, Annamaraju P, Khan Suheb MZ. Ketogenic diet [Internet]. National Library of Medicine. StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499830/
  23. O’Brien S. 7 Science-Based Benefits of MCT Oil [Internet]. Healthline. 2020. Available from: https://www.healthline.com/nutrition/mct-oil-benefits
  24. McKenzie KM, Lee CM, Mijatovic J, Haghighi MM, Skilton MR. Medium-Chain Triglyceride Oil and Blood Lipids: A Systematic Review and Meta-Analysis of Randomized Trials. The Journal of Nutrition. 2021 Jul 13;151(10):2949–56.
  25. Shcherbakova K, Schwarz A, Apryatin S, Karpenko M, Trofimov A. Supplementation of Regular Diet With Medium-Chain Triglycerides for Procognitive Effects: A Narrative Review. Frontiers in Nutrition. 2022 Jul 15;9.
  26. Ezpeleta M, Cienfuegos S, Lin S, Pavlou V, Gabel K, Varady KA. Efficacy and safety of prolonged water fasting: a narrative review of human trials. Nutrition Reviews. 2023 Jun 27;82(5).
  27. Sampieri A, Paoli A, Spinello G, Santinello E, Moro T. Impact of daily fasting duration on body composition and cardiometabolic risk factors during a time-restricted eating protocol: a randomized controlled trial. Journal of Translational Medicine. 2024 Nov 29;22(1).
  28. Borer K. Effects of duration of uninterrupted fast in weekly intermittent fasting: Comparison of an 82-week 5:2 case report to an isocaloric modified 4:3 protocol. Research Square (Research Square) [Internet]. 2023 Dec 7 [cited 2025 Oct 23]; Available from: https://consensus.app/questions/duration-of-intermittent-fasting-protocols/
  29. Chen YE, Tsai HL, Tu YK, Chen LW. Effects of different types of intermittent fasting on metabolic outcomes: an umbrella review and network meta-analysis. BMC Medicine. 2024 Nov 13;22(1).
  30. Lange M, Coffey AA, Coleman P, Barber TM, Thijs van Rens, Oyinlola Oyebode, et al. Metabolic Changes following Intermittent fasting: a Rapid Review of Systematic Reviews. Journal of Human Nutrition and Dietetics. 2023 Oct 2;37(1).
  31. Templeman I, Gonzalez JT, Thompson D, Betts JA. The role of intermittent fasting and meal timing in weight management and metabolic health. Proceedings of the Nutrition Society. 2019 Apr 26;79(1):1–12.
  32. Derron N, Güntner AT, Weber IC, Braun J, Koska İÖ, Othman A, et al. Alternate-day fasting elicits larger changes in fat mass than time-restricted eating in adults without obesity – A randomized clinical trial. Clinical nutrition (Edinburgh, Scotland) [Internet]. 2025 Oct;53:212–21. Available from: https://pubmed.ncbi.nlm.nih.gov/40945487/
  33. Lakhani HA, Biswas D, Kuruvila M, Chava MS, Raj K, Varghese JT, et al. Intermittent fasting versus continuous caloric restriction for glycemic control and weight loss in type 2 diabetes: A traditional review. Primary Care Diabetes. 2025 Feb;
  34. Huang X, Huang G, Wei G. Intermittent fasting for glycemic control in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Nutricion hospitalaria [Internet]. 2025;10.20960/nh.05521. Available from: https://pubmed.ncbi.nlm.nih.gov/40008664/
  35. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metabolism [Internet]. 2017 Sep;26(3):539-546.e5. Available from: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30490-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413117304904%3Fshowall%3Dtrue
  36. Merovci A, Finley B, Hansis-Diarte A, Sivaram Neppala, Abdul-Ghani MA, Cersosimo E, et al. Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects. BMJ Open Diabetes Research & Care [Internet]. 2024 Oct 1;12(5):e004199–9.
  37. von Frankenberg AD, Marina A, Song X, Callahan HS, Kratz M, Utzschneider KM. A high-fat, high-saturated fat diet decreases insulin sensitivity without changing intra-abdominal fat in weight-stable overweight and obese adults. European Journal of Nutrition [Internet]. 2017 Feb 1;56(1):431–43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26615402
  38. Jensen NJ, Wodschow HZ, Nilsson M, Rungby J. Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases. International Journal of Molecular Sciences [Internet]. 2020 Nov 20;21(22):8767. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7699472/
  39. Bonnechere B, Stephens EB, Boileau AC, Ducker M, Stubbs BJ. The Effect of Exogenous Ketone Bodies on Cognition in Patients with Mild Cognitive Impairment, Alzheimer’s Disease and in Healthy Adults: A Systematic Review and Meta-Analysis. medRxiv (Cold Spring Harbor Laboratory). 2025 Sep 18;
  40. Ramezani M, Fernando M, Eslick S, Asih PR, Shadfar S, E.M.S. Bandara, et al. Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease. Frontiers in Neuroscience [Internet]. 2023 Nov 16;17. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687427/
  41. Rong L, Peng Y, Shen Q, Chen K, Fang B, Li W. Effects of ketogenic diet on cognitive function of patients with Alzheimer’s disease: a systematic review and meta-analysis. The Journal of nutrition, health and aging [Internet]. 2024 Aug 1;28(8):100306. Available from: https://www.sciencedirect.com/science/article/pii/S1279770724003932?via%3Dihub#sec0115
  42. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metabolism [Internet]. 2017 Sep;26(3):539-546.e5. Available from: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30490-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413117304904%3Fshowall%3Dtrue
  43. Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R. Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease. Antioxidants. 2018 Apr 28;7(5):63.
  44. Alhamzah SA, Gatar OM, Alruwaili NW. Effects of ketogenic diet on oxidative stress and cancer: A literature review. Advances in Cancer Biology – Metastasis [Internet]. 2023 Jul 1;7:100093. Available from: https://www.sciencedirect.com/science/article/pii/S2667394023000072#bib1
  45. Ruskin DN, Sturdevant IC, Wyss LS, Masino SA. Ketogenic diet effects on inflammatory allodynia and ongoing pain in rodents. Scientific Reports. 2021 Jan 12;11(1).
  46. Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, et al. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metabolism. 2017 Sep;26(3):547-557.e8.
  47. Pathak SJ, Baar K. Ketogenic Diets and Mitochondrial Function: Benefits for Aging but not for Athletes. Exercise and Sport Sciences Reviews. 2022 Sep 16;Publish Ahead of Print.
  48. Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017 Apr 3;69(5):305–14.
  49. Arima Y. The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases. Journal of Atherosclerosis and Thrombosis. 2023 Dec 1;30(12):1751–8.
  50. Longo Valter D, Mattson Mark P. Fasting: Molecular Mechanisms and Clinical Applications. Cell Metabolism. 2014 Feb;19(2):181–92.
  51. Wei SJ, Schell JR, E. Sandra Chocron, Mahboubeh Varmazyad, Xu G, Wan Hsi Chen, et al. Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Science advances. 2024 May 17;10(20).
  52. Streit L. 7 Potential Dangers of the Keto Diet [Internet]. Healthline. 2020. Available from: https://www.healthline.com/nutrition/dangers-of-keto-diet
  53. Watanabe M, Tuccinardi D, Ernesti I, Basciani S, Mariani S, Genco A, et al. Scientific evidence underlying contraindications to the ketogenic diet: An update. Obesity Reviews. 2020 Jul 10;21(10).
  54. Salas Noain J, Minupuri A, Kulkarni A, Zheng S. Significant Impact of the Ketogenic Diet on Low-Density Lipoprotein Cholesterol Levels. Cureus [Internet]. 2020 Jul;12(7). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449640/
  55. Wijdan Shkorfu, Fadel A, Hamsho M, Yazan Ranneh, Shahbaz HM. Intermittent Fasting and Hormonal Regulation: Pathways to Improved Metabolic Health. PubMed. 2025 Aug 1;13(8):e70586–6.
  56. Jiao Y, Chen X, Liu L, Lu Y, Gao M, Wang Q, et al. Sex differences in ketogenic diet: are men more likely than women to lose weight? Frontiers in Nutrition [Internet]. 2025 Jun 4;12. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12173872/
  57. Ana Inês Silva, Direito M, Filipa Pinto-Ribeiro, Ludovico P, Belém Sampaio-Marques. Effects of Intermittent Fasting on Regulation of Metabolic Homeostasis: A Systematic Review and Meta-Analysis in Health and Metabolic-Related Disorders. Journal of Clinical Medicine. 2023 May 26;12(11):3699–9.
  58. Joo M, Moon S, Lee YS, Kim MG. Effects of very low-carbohydrate ketogenic diets on lipid profiles in normal-weight (body mass index < 25 kg/m2) adults: a meta-analysis. Nutrition Reviews. 2023 Mar 17;81(11).
  59. Fante C, Spritzler F, Calabrese L, Laurent N, Roberts C, Deloudi S. The role of β-hydroxybutyrate testing in ketogenic metabolic therapies. Frontiers in Nutrition. 2025 Sep 1;12.
  60. Rynders CA, Broussard JL. Running the clock: new insights into exercise and circadian rhythms for optimal metabolic health. The Journal of Physiology. 2024 Nov 23;602(23):6367–71.
  61. Haupt S, Eckstein ML, Wolf A, Zimmer RT, Wachsmuth NB, Moser O. Eat, Train, Sleep-Retreat? Hormonal Interactions of Intermittent Fasting, Exercise and Circadian Rhythm. Biomolecules [Internet]. 2021 Mar 30;11(4). Available from: https://pubmed.ncbi.nlm.nih.gov/33808424/
  62. Najeha Rizwana Anwardeen, Naja K, Shamma Almuraikhy, Maha Sellami, Hadaia Saleh Al-Amri, Philip N, et al. The influence of circadian rhythm disruption during Ramadan on metabolic responses to physical activity: a pilot study. Frontiers in Neuroscience. 2025 Feb 24;19.
  63. Vasim I, Majeed CN, DeBoer MD. Intermittent fasting and metabolic health. Nutrients [Internet]. 2022 Jan 31;14(3):631. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8839325/
  64. Herrero L, Romero M del M, Cubeles-Juberias E. Effects of intermittent fasting on metabolism, cognitive function, and aging: a review of human and animal studies. Revista de la Sociedad Española de Cirugía de Obesidad y Metabólica y de la Sociedad Española para el Estudio de la Obesidad. 2024;
  65. Longo VD, Panda S. Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell metabolism. 2016;23(6):1048–59.
  66. Precision Ketogenic Therapy Path to Precise, Personalization and Proven – Borum PKT – UF/IFAS [Internet]. Ufl.edu. 2021. Available from: https://borum.ifas.ufl.edu/borum-lab/precision-ketogenic-therapy-path/
  67. AI Personalized Keto Diet – Nutriwork [Internet]. Nutriwork -. 2025 [cited 2025 Oct 23]. Available from: https://nutriwork.app/2025/07/03/ai-personalized-keto-diet/
  68. Tzenios N, Wong C. Personalized Ketogenic Diet Using AI for Optimal Brain Health. European Journal of Nutrition & Food Safety. 2024 Nov 8;16(11):12–35.
  69. West H. What Is Fat Fasting, and Is It Good for You? [Internet]. Healthline. Healthline Media; 2019. Available from: https://www.healthline.com/nutrition/keto-fat-fast
  70. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to prevent and treat it. British Medical Journal [Internet]. 2008 Jun 26;336(7659):1495–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440847/
  71. Tamas Szili-Torok, Martin, Garcia E, Gansevoort RT, Dullaart R, Connelly MA, et al. Fasting ketone bodies and incident type 2 diabetes in the general population. Diabetes [Internet]. 2023 Jun 23; Available from: https://diabetesjournals.org/diabetes/article/72/9/1187/151601/Fasting-Ketone-Bodies-and-Incident-Type-2-Diabetes