Chronic fatigue syndrome is a growing concern in the UK, affecting at least 1 in 250 people and this figure is likely to be wildly underestimated. With the incidence of long covid increasing and becoming a major driver of long-term fatigue, it is an important time to support energy levels.

Energy levels may seem, perhaps, slightly trivial to some. However, low energy levels contribute to multiple conditions including depression, obesity and poor cognitive function and can increase the risk of cardiovascular disease, diabetes, and dementia. Our energy powerhouses, the mitochondria (more on these later), are seen to be dysfunctional in many chronic diseases and are an important focus for conditions of fatigue.

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Dr Sarah Myhill suggests that depression is a symptom of fatigue, as a way of preserving energy as it makes us apathetic, unmotivated, and lethargic, hence the body deliberately depresses our energy levels to conserve it.¹ Supporting energy is not just essential for those experiencing long-term fatigue but also for the preservation of normal cellular function, which when disrupted, contributes to chronic disease. Therefore, there needs to be a stronger focus on overcoming the symptoms of chronic fatigue to help support long term wellness and quality of life.

CFS Pathophysiology

While the cause or causes of CFS are still unknown, evidence supports a combination of factors that are thought to contribute to the development of this illness. These may include²:

• Infection – some, but not all, patients develop CFS following an acute viral-like illness e.g., Epstein Barr, Candida, coronaviruses, mycoplasma, and retroviruses. This is also pertinent for infection from Covid19.
• Physical or emotional trauma – some patients report experiencing an accident, trauma, immobilization, surgery, or significant emotional stress prior to the onset of symptoms.
• Genetics – CFS has been observed within some families. This suggests either a possible genetic link or a common environmental exposure (infectious or toxic).
• Environmental factors – exposure to mould or toxins has been suspected as a trigger for CFS.

These triggers are likely to initiate pathological dysfunctions which can lead to persistent fatigue including³;

Immune system abnormalities – impaired natural killer cell function and/or T cell function, chronic higher production of inflammatory cytokines, and in some cases slight increase in some autoantibodies (rheumatic factor, anti-thyroid antibodies, anti-gliadin, anti-smooth muscle antibodies, and cold agglutinins).

Mitochondrial Dysfunction – impaired ability to produce energy from the usual “fuel” that cells use to produce energy: oxygen, glucose, fatty acids, and amino acids. Exercise studies in adults have revealed impaired oxygen consumption and activation of anaerobic metabolic pathways in the early stages of exercise.

Neuroendocrine disturbances – some people report physical or emotional stress before they become ill, which can lead to dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis). Some patients with CFS have flattened diurnal cortisol profiles compared to healthy people, but their cortisol levels are still within the normal range. CFS is also strongly associated with a depressed nervous system and therefore the dysfunction of neurotransmitters including serotonin, dopamine and GABA should be considered.

Blood pressure or heart rate regulation abnormalities – some people with CFS, particularly adolescents, experience symptoms of orthostatic intolerance. Patients with orthostatic intolerance develop a worsening of symptoms with quiet upright posture and improvement (though not necessarily full resolution) of symptoms with recumbency.

What appears to be consistent in the above triggers of CFS is that they initiate excessive amounts of inflammation and oxidative stress, which has a direct impact on mitochondrial function.

Role of Mitochondria

Whether it is a symptom of other pathological dysfunctions or is the main cause is not understood and may differ among individuals, but mitochondrial dysfunction is a consistent factor of chronic fatigue syndrome and is a main focus of ameliorating symptoms. The mitochondria are the powerhouses of the cell and the site of the most efficient form of energy production, aerobic respiration.

Mitochondria possess their own DNA, which is much more susceptible to damage and oxidation due to the lack of protection by the nucleus that nuclear DNA benefits from. Although much of mitochondrial function is encoded in nuclear DNA, mitochondrial DNA plays an essential role in normal function. The increased vulnerability to oxidative stress means that when oxidative damage risk is increased by stress, inflammation, and toxicity, and antioxidant systems are under pressure, the mitochondria can struggle to function effectively, meaning that energy production is reduced. The persistence of mitochondrial DNA damage ultimately leads to mutations in the mitochondrial genome and gives rise to further mitochondrial dysfunction, which induces and aggravates conditions of fatigue.²

This is coupled with the fact that the mitochondria are one of, if not the most, common source of free radical production. Oxidative stress from free radicals is normal and, in moderate amounts, essential for mitochondrial function. However, when the mitochondria are damaged, the electron transport chain (an essential aspect of energy production) become increasingly “leaky” which allows more electrons to “escape” which causes further damage and less efficient energy production.⁴

During normal aerobic respiration, 2% of electrons leak out of the electron transport chain (ETC)*. During normal aerobic respiration, 2% of electrons leak out of the ETC. This transports electrons directly to oxygen and therefore leads to the creation of the superoxide free radicle. It has been estimated that the steady-state concentration of superoxide (a potent free radicle) in the mitochondrial matrix is 5-to-10- fold higher than in the cytosol. Hence, adequate antioxidant systems are essential. The antioxidant systems, superoxide dismutase and glutathione, are vital in protecting and preserving the integrity and function of the mitochondria.

Having said that, it is essential that if mitochondria are dysfunctional, they go through mitophagy, the process of breaking down and dismantling dying off mitochondria. This prevents increased reactive oxygen species created by “sick” mitochondria that are limping on, and allows for mitochondrial biogenesis, the production of new mitochondria. It’s almost a salvage operation. The balance between mitophagy and mitochondrial biogenesis occurs in healthy people and is known as mitochondrial homeostasis.

If mitochondrial homeostasis is impaired, there is an excess of inefficient mitochondria producing poor amounts of energy and increased oxidation, which is a major contributor to fatigue. Therefore, supporting mitochondrial homeostasis is important^5-7.

Mitophagy

Mitochondrial homeostasis is preserved by the fine co‐ordination between two opposing processes: generation of new mitochondria, by mitochondrial biogenesis, and the removal of damaged mitochondria, by mitophagy.

The term "mitophagy" was in use by 1998. Mitophagy is key in keeping the cell healthy. It promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria, which can lead to cellular degeneration

Mitochondrial biogenesis

Mitochondrial biogenesis induction is associated with activation of transcription factors and enzymes that act on mitochondrial genes and with the up‐regulation of local translation of mitochondrial proteins to stimulate the production of new mitochondria.  These include NRF2, SIRT, AMPK, PGC-1, and PPAR. Interestingly, most of these molecules are also associated with longevity and fat burning. Their production has been shown to be stimulated in response to several natural products, including⁵;

NRF2	SIRT	AMPK	PGC-1	PPAR
Garlic Curcumin Green Tea Extract Resveratrol Sulfuraphane DHA	Resveratrol Rhodiola Spirulina	Tangeretin (flavonoid) Ginger Saffron Spirulina	Tangeretin Spirulina	Thai Black ginger

Lifestyle factors have also been shown to stimulate mitochondrial biogenesis and putting the body in a slight, reversible state of stress is beneficial for maintaining mitochondrial homeostasis. These lifestyle factors include:

• Caloric restriction
• Cold exposure
• Exercise
• Meditation
• Fasting

Fasting, in particular, has much supporting research for the stimulation of mitochondrial biogenesis⁶:

• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) is a fasting-induced transcriptional coactivator that mediates mitochondrial biogenesis, activates when the body receives a signal that it needs more cellular energy, and increases in expression during fasting.
• Nuclear factor (erythroid-derived) factor 2 (Nrf2) is a transcription factor that regulates ROS production by mitochondria. Studies suggest that Nrf2 is associated with mitochondrial biogenesis and may be involved in mitochondrial quality control systems. A 2019 study evaluated the impact of Ramadan intermittent fasting on the expression of antioxidant genes, including Nrf2, and results suggested that fasting improved the expression of the antioxidant regulatory genes^12.

Intermittent fasting- try to go for 12 hours (overnight) without eating, this significantly reduces insulin levels and therefore helps blood sugar regulation. I.e. do not eat between 7pm and 7am. If you can stretch this to 14 or 16 hours, it can be really useful. Other options are 5:2 (only consuming 500 calories on 2 days of the week). For further information see our blog: Time restricted eating.

Nutrients that support chemical energy production by the mitochondria^{1, 9-11}:

Thiamin (B1) – cofactor in the essential step which converts pyruvate in to acetyl CoA

Riboflavin (B2) – also known as FAD, accepts electrons and donates to the ETC in order to produce ATP (energy)

Niacin (B3) – also known as NADH (similar to FAD) accepts and donates electrons to the ETC in order to produce ATP.

Pantothenic Acid (B5) – carrier of Coenzyme A, essential for Acetyl CoA and therefore energy production

CoQ10 (Ubiquinol) – utilised as a carrier in complex II of the ETC. CoQ10 also has antioxidant properties and is found in high concentrations in heart and brain. It therefore plays an essential role in cognitive and cardiovascular function as well as in normal energy production, all of which are implicated in CFS.

Alpha Lipoic Acid – a coenzyme of pyruvate dehydrogenase and a-ketoglutarate; enzymes responsible for reactions involved in the breakdown of fat and carbohydrate within the mitochondria

Magnesium – binds to ATP and affects its structure, making energy more easily available.

All of the above nutrients are directly involved in metabolism reactions which occur in the mitochondria in order to produce energy. Any deficiencies of the above nutrients can affect the rate of energy production.

There are other nutrients that are not directly involved in the chemical pathways of metabolism but are important for energy production and maintaining mitochondrial function such as;

L-Carnitine – plays a vital role in fatty acid metabolism and transporting fatty acids into the mitochondria to be converted into energy. Again, a deficiency can lead to reduced energy production.

Omega 3 Fatty Acids – can be incorporated into the mitochondrial membrane, which aids fluidity of the membrane and therefore signalling. Omega 3 fatty acids are also very important for cell and mitochondrial membranes and hence their stability.

We can also help to protect our mitochondria by ensuring that we are consuming adequate levels of antioxidants. The antioxidant of particular importance for the mitochondria is glutathione, which is our own intrinsic intracellular antioxidant. Although we are able to manufacture our own glutathione, when oxidative stress is in excess, it can become overwhelmed. Or,  if nutrients that are required to manufacture it are deficient, this can lead to reduced levels. Nutrients that support the production of glutathione include;

Liposomal Glutathione - this bypasses degradation within the gut and is absorbed directly across the digestive lining and can cross the blood-brain barrier.

N-Acetyl Cysteine – regulates synthesis of and is an effective precursor to glutathione.

Alpha Lipoic Acid – has the ability to induce enzymes required for glutathione synthesis.

Selenium – constituent of glutathione.

Vitamin C – an antioxidant in its own right but also has the ability to regenerate glutathione. Vitamin C also an essential nutrient for adrenal funciton, adrenal dysfunction is considered to be a major driver of fatigue issues including CFS.

Other antioxidants have the ability to reduce oxidative stress by neutralising free radicles and could be considered to support mitochondrial function in doing so. These include carotenoids, flavonoids, vitamin E, vitamin A and zinc -  this list is not exhaustive. You can ensure that you are obtaining good levels of antioxidants in the diet by:

• Eating a rainbow (different colours of fruit and vegetables contain differing phytonutrients which have antioxidant properties)
• Consuming herbs and spices including turmeric, garlic and ginger.
• Including polyphenols  - found in olives, 70%+ dark chocolate (1-2 squares) and small quantities of red wine.
• Consuming antioxidant containing teas such as green tea and rooibos.

Nicotinamide riboside (a form of vitamin B3 that functions as a precursor to NAD) - has shown similar benefits to caloric restriction and may support mitochondrial biogenesis. It is a rate limiting co-substrate for the family of sirtuin enzymes – increasing levels of the co-substrate NAD increases the activity of these enzymes; and oral supplementation with nicotinamide riboside has been shown to increase levels of NAD.¹⁵
D-Ribose – may be useful to support ATP production by encouraging re-phosphorylation, particularly within muscle, including cardia muscle. It is used effectively in chronic fatigue patients and can also improve exercise tolerance.

It is also important to consider the way in which excess oxidative stress occurs and therefore reducing sources of oxidation can be useful.

Factors that contribute to oxidative stress include:

• Smoking
• Obesity
• Inflammation
• High stress levels
• High sugar diet
• Consumption of trans and hydrogenated fats
• Pollution
• Chemicals from household products, toiletries and cosmetics

Other considerations for CFS:

It is also important to investigate other factors that may be either driving mitochondrial dysfunction or causing energy depletion:

These may include:

• Inflammation
• Immune dysfunction
• Adrenal fatigue/stress
• Thyroid dysfunction
• Poor sleep
• Depression

Although mitochondrial function is an essential focus for therapies for CFS, it is also important to address the driving forces that are contributing to pathophysiological dysfunction and energy depletion.

*Electron transport chain - a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H⁺ ions) across a membrane. Many of the enzymes in the ETC are membrane-bound.

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If you have questions regarding the topics that have been raised, or any other health matters, please do contact our team of Nutritional Therapists. nutrition@cytoplan.co.uk 01684 310099

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References

1. Myhill, S (2021) The Energy Equation
2. Textbook of functional medicine. 2008. Institute for Functional Medicine.
3. Etiology and Pathophysiology | Presentation and Clinical Course | Healthcare Providers | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | CDC
4. Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. Mitochondrial proton and electron leaks. Essays Biochem. 2010;47:53-67. doi:10.1042/bse0470053
5. Popov LD. Mitochondrial biogenesis: An update. J Cell Mol Med. 2020;24(9):4892-4899.
6. https://www.ifm.org/news-insights/fasting-mitochondrial-health/
7. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003 Feb;24(1):78-90.
8. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013 Jul 25;8(21):2003-14
9. Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006 Oct 27;163(1-2):94-112.
10. Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006 Nov;12(9):857-62. doi: 10.1089/acm.2006.12.857. PMID: 17109576.
11. Belenky, P. et al. (2007) ‘Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/MeuI pathway to NAD+’. Cell, 4, 129, 3, 473-84
12. Madkour MI, T El-Serafi A, Jahrami HA, Sherif NM, Hassan RE, Awadallah S, Faris MAE. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. 2019 Sep;155:107801. doi: 10.1016/j.diabres.2019.107801. Epub 2019 Jul 26. PMID: 31356832.