The basic science of intermittent fasting.

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What is Intermittent Fasting

Intermittent fasting (IF) is a pattern of eating based on alternating periods of fasting and feeding. There are multiple forms. The milder variants practice 14 hour fasting periods over 8 hour feeding periods. More extreme versions such as the alternate day fasting (ADF) comprise 24 hours of fasting and 24 hours of non-fasting periods. This fasting protocol in its essence does not concern itself with caloric restriction. The fasting periods do not abstain from water and usually include low calorie drinks such as black coffee and tea. Intermittent fasting has been reported to have similar health benefits as caloric restriction. These include a lower risk for a host of diseases and a general increased lifespan. This paper will present the reported health benefits of caloric restriction and intermittent fasting, followed by an outline of the metabolic consequences of short term fasting and the long term epigenetic and metabolic effects.

 Caloric restriction and its relation to intermittent fasting

Caloric restriction (CR) is defined as undernourishment without malnourishment, that is to say a decrease in calories without loss of nutritional value. It has been studied extensively for its health effects in both animals and humans alike. Intensely studied are the benefits of caloric restriction on heart disease in humans. CR appears to have positive effects on atherosclerosis (Fontana, Meyer, Klein, & Holloszy, 2004). Quoted from the research paper: “The calorie-restricted group also fared much better than the control group in terms of average blood pressure (100/60 vs. 130/80 mm Hg), fasting glucose, fasting insulin (65% reduction), body mass index (19.6 ± 1.9 vs. 25.9 ± 3.2 kg/m2), body fat percentage (8.7% ± 7% vs. 24% ± 8%), C-reactive protein, carotid IMT (40% reduction), and platelet-derived growth factor AB” (Fontana et al., 2004). Although there are many health benefits associated with CR, some studies find no influence life span in certain primates (Naik, 2012). Other studies suggest many health benefits in different species (S.-J. Lin, Defossez, & Guarente, 2000; Wood et al., 2004). Indeed Rhesus monkeys have been shown to respond to CR with a prolonged lifespan and reducing disease onset with regards to diabetes, heart disease, cancer and brain atrophy (Colman et al., 2009; Mattison, Lane, Roth, & Ingram, 2003). Overall it can be said that there are strong indications but no conclusive evidence that CR increases lifespan. The disease preventing effects however are well documented. The effects of CR on disease resistance and longevity seem to be linked to the sirtuin gene family (Haigis & Guarente, 2006). In mammals these are the SIRT1-7 genes. IF relates to CR in the sense that similar effects have been observed. In fact it has been found that IF works through the same genes that CR does (Martin, Mattson, & Maudsley, 2006). The detailed benefits will be discussed on a deeper level in the paragraph dealing with epigenetic consequences of IF.

 Short term metabolic effects of fasting

When the body is deprived of food on the short term a cascade of metabolic changes occurs (Hall, 2010). This is primarily due to falling glucose levels. In the immediate time after glucose drops the body will start producing glycogen to stimulate the process of glucagon. Here the glycogen stored in the muscle cells and the liver are converted to glucose and secreted into the blood stream. The gastrointestinal tract also responds by producing ghrelin and motilin. These respectively stimulate appetite and activate gastrointestinal motility in an attempt to increase the substrate availability to the body.

Short Term Fasting

Towards glycogen depletion the body increases dependence on lipolysis. In this process triglycerides are broken down into fatty acids. This process is initiated by the hormones epinephrine, norepinephrine, ghrelin, growth hormone, testosterone, and cortisol. These act as a ligands to a receptor which activates adenylyl cyclase (cAMP), cAMP activates protein kinase A which activates triacylglycerol (TAG) lipase which removes the first fatty acid from the triglyceride. Di and monoacylglycerol (DAG/MAG) lipase respectively remove fatty acid 2 and 3. These fatty acids then enter beta oxidation which results in them being metabolized to acetyl CoA molecules. Most of these end up in the citric acid cycle, but some are processed to ketone bodies. These are important for brain energy supply. The risk of excessive beta oxidation is ketosis, in which an excessive amount of ketone bodies cause acidification of the blood. Short fasting Acetyl CoA           In addition to fatty acid metabolism the body initiates gluconeogenesis, to prevent total collapse of glucose levels in the blood. Gluconeogenesis is the process in which the body synthesizes new glucose from aminoacids, glycerol and piruvate. The process is limited to the liver, kidneys and intestine. The process begins in the mitochondria by carboxylating piruvate to oxaloacetate by piruvate carboxylase. This enzyme increases activity in response to high acetyl CoA concentrations as a result of beta-oxidation. This and the fact that the in lipolysis created glycerol is used in this reaction shows how these reactions are tightly coupled. It ends with the hydrolysis of glucose-phosphate (G6P) in the endoplasmic reticulum (ER) where transporters move glucose to the cytosol.

 The long term metabolic effects of IF

Intermittent fasting as mentioned have similar effects through similar pathways. The exact triggers for the systems that cause these effects are poorly understood.  A 2006 study found the benefits depicted in the figure below, where DR stands for dietary restriction and is analog with CR (Martin et al., 2006). In the following paragraphs certain benefits will be discussed on the molecular level.

Intermittent Fasting and Caloric Restriction effects

 Stress responses

CR and IF trigger mild stress responses throughout the body. These trigger compensatory mechanisms like the later discusses glucose-related protein. Another example is the expression of corticosterone (Wan, Camandola, & Mattson, 2003), which is associated positively with a human stress response. In contrast to more detrimental and uncontrolled forms of stress, IF downregulates glucocorticoid receptors with maintenance of mineralocorticoid receptors in neurons which can act to prevent neuronal damage and death (C.-K. Lee, Weindruch, & Prolla, 2000; J. Lee, Herman, & Mattson, 2000).


IF and CR induce a stress response in the central nervous system (CNS) neurons triggering compensatory mechanisms like the upregulation of neurotropic factors like Glial cell-derived neurotropic factor (GDNF) and brain-derived neurotropic factor (BDNF). These both promote survival of neurons as well as the making of new connections. Chaperone proteins like shock protein-70 (HSP-70) and glucose-regulated protein 78 (GRP-78) are also upregulated, these can protect the cells from damage and death from environmental conditions.

 Cytoprotective activity with regard to seizures and epilepsy

IF has been shown to be more efficient that CR in the previously mentioned ketogenic metabolic pathway. IF fed mice can develop a twofold concentration of the β-hydroxybutyrate ketone body compared to mice fed ad libidum (Anson et al., 2003). This ketone body exhibits neuroprotectivity in models of Alzheimer’s and Parkinson’s disease (Kashiwaya et al., 2000).

As described above, fasting periods limit the available free glucose and force the body to turn to alternative energy sources like a fatty acid based metabolism. Models suggest that blood glucose levels over time lead to non-enzymatic glycation, a process that causes protein damage. CR has been shown to prevent in specific oxyradical damage and production in addition to non-enzymatic glycation (Cefalu et al., 1995). Both CR and IF have reducing effects on glucose and insulin levels, but different effects on effects on serum IGF-1 levels and serum β-hydroxybutyrate levels. In the case of IF both of the latter are elevated (Anson et al., 2003; Dunn et al., 1997). The elevated IGF-I levels are due to the fact that fasting induces growth hormone (GH) secretion. In addition CR and IF show increased insulin sensitivity in Rhesus monkeys (Cefalu et al., 1997; Lane et al., 1995).

Mediation of cytokines

            Interferon-gamma (IFN-g) has been shown to enhance synaptogenesis, regulate synaptic plasticity and control neurogenesis (Brask, Kristensson, & Hill, 2004; Wong, Goldshmit, & Turnley, 2004). IF elevated IFN-g in the hippocampus (J. Lee, Kim, Son, Chan, & Mattson, 2006) protecting it against excitotoxicity and CR did the same in circulating leukocytes (Mascarucci et al., 2002), linking it to the aforementioned beneficial effects. Tumor necrosis factor alpha (TNF-a) has been shown to trigger insulin resistance in animals (Feinstein, Kanety, Papa, Lunenfeld, & Karasik, 1993). This can lead to complications due to elevated blood glucose, especially at a later age. CR and IF have shown to decrease adipose tissue, leading to reduced TNF-a secretion by those cells since adipose tissue secretes these tropic factors (Bordone & Guarente, 2005). Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) reduces the expression of TNF-a as well (Bordone & Guarente, 2005). Interestingly NF-kB is upregulated by CR and IF (Kim, Kim, Yu, & Chung, 2000).

 Leptin and adiponectin

Both Leptin and adiponectin are secreted by adipose tissue and mediate the hunger response (Hall, 2010). Both are involved in suppressing appetite. It is hypothesized that the downregulation of thyroid hormones in CR functions through leptin (Barzilai & Gupta, 1999). Adiponectin, which is elevated during CR (Combs et al., 2003), through the upregulation of AMP-activated protein kinase (Wu et al., 2003) triggers insulin sensitivity (Meier & Gressner, 2004; Pajvani & Scherer, 2003). This kinase also protects neurons against stress of metabolic origin (Culmsee, Monnig, Kemp, & Mattson, 2001)


Sirtiuns play a big role in life span in yeast and worms. The silent information regulator gene 2 (SIR2) can increase life span when upregulated and decrease lifespan when downregulated (Kaeberlein, McVey, & Guarente, 1999). The mammalian analog SIRT1 has many health and longevity related effects, as shown in the diagram below (Metoyer & Pruitt, 2008)

Sirtuin gene group influence

Both IF and CR have been shown to increase the expression of SIRT1 proteins (Cohen et al., 2004; Nemoto, Fergusson, & Finkel, 2004). Cell stressors such as osmolarity have been shown to upregulate SIR expression (S. J. Lin et al., 2002), thus leading to the hypothesis that CR and IF through their mild stress inducing capacity could activate SIR genes through that pathway as well (Martin et al., 2006).

 Peroxisome proliferator-activated receptor (PPAR)

PPAR are hetrodimers that regulate gene expression (Martin et al., 2006). PPAR gamma coactivator 1 (PGC-1) is closely regulated by dietary restriction in lower and higher mammals (Martin et al., 2006). CR has shown to remedy the age dependent decrease of PGC-1, thereby potentially increasing lifespan (Kayo, Allison, Weindruch, & Prolla, 2001; Weindruch, Kayo, Lee, & Prolla, 2002).

 FoxO transcription factors

            FoxO proteins are gene regulators that regulate the expression of proteins related to energy metabolism (Martin et al., 2006). Examples of FoxO function are glucose metabolism (Nakae, Kitamura, Silver, & Accili, 2001), cell death through the Fas ligand, reactive oxygen species (ROI) detoxification and DNA repair. ROI detoxification as a result of FoxO activation works through the expression of catalase and manganese superoxide dismutase (Kops et al., 2002). The DNA repair functions through damage-inducible protein 45 and damage-specific DNA-binding protein 1(Tran et al., 2002). Insulin receptor stimulation reduces FoxO activity by resulting in its phosphorylation and consequent removal from the nucleus (Martin et al., 2006). CR reduces overall insulin levels, and IF has periods of extreme low insulin levels. Both therefore increase FoxO regulatory activity.

Concluding summary

Many beneficial effects of intermittent fasting and caloric restriction have been observed in different species. They include the beneficial upregulation of stress responses, without the initial damage of the stressors. Which results in a higher resistance to environmental and metabolic stress. CR and IF have also been shown to have neuroprotective effects potentially capable of warding Parkinson’s and Alzheimer’s. Cytoprotective effects have also been observed. The glucose and insulin systems of the body also show marked improvement in IF and CR regimes. The cytokine activity as a result of this dietary pattern also has neuroprotective effects. Leptin and adiponectin levels also mediate neuroprotective effects. The sirtiun gene family and the corresponding proteins have a wide variety of health and longevity enhancing effects. Their expression is increased by CR and IF. As a result improved levels of PPAR-gamma and PGC-alpha also become apparent. The SIRT1 sirtuin upregulates FoxO, as does the reduced insulin activity that is a consequence of CR and IF. These transcription factors regulate a series of metabolic and protective mechanisms in the cell. There are many findings that strongly suggest intermittent fasting to have health and longevity effects. However, more studies need to be done to confirm the workings of these systems in humans.


I put them on a different page because there are so many.