9. STRESS & FATIGUE Flashcards
This module covers: • Understanding stress. • Physiological effects of stress. • Stress in clinical practice. • Adrenals. • Natural approach to stress. • Understanding fatigue. • Mitochondria and fatigue. • Chronic fatigue and myalgic encephalomyelitis (ME). (98 cards)
1
Q
Define stress and the impact chronic stress can have on health
A
Stress is defined as a non-specific response of the body to any disturbance / demand - triggering the ‘stress response’.
If stress is extreme or chronic, the stress response can be overwhelming and harmful to any body system (this is ‘distress’).
2
Q
Name THREE causes of stress
A
- Poor nutrition: Nutritional deficiencies (e.g., highly-processed diets, high alcohol intake).
- Personal stress: Not feeling happy with oneself; financial problems; problems with family members, friends, at work.
- Poor body functions: Injury or illness e.g., allergy, skin conditions, thyroid disorders, chronic inflammatory disorders. Detoxification - slow or fast detoxification of certain NTs or hormones may result in imbalances in stress hormones (e.g., COMT / MAO).
- Environmental stressors: Radiation e.g., mobile phones, x-rays, microwaves; pesticides, industrial and household chemicals.
3
Q
What is the general adaptation syndrome?
Name its stages.
A
A term coined by the endocrinologist, Hans Selye, that describes the 3 stages of a stress response which are controlled and regulated by the adrenal glands.
Alarm phase, resistance phase and exhaustion phase.
4
Q
What happens during the alarm phase of the general adaptation syndrome?
A
Initial response, often referred to as ‘fight or flight’.
- Counteracts danger by mobilising resources for physical activity.
- Stressor → hypothalamus → sympathetic nervous system → adrenal medulla releases adrenaline and noradrenaline.
- Adrenaline activates inflammatory cytokines - ↑ oxidative stress.
- ACTH release (anterior pituitary) → cortisol release (adrenal cortex). Cortisol provides additional glucose, ↑ pain threshold and inhibiting immune responses.
ACTH - Adrenocorticotropic hormone
5
Q
What happens during the resistance phase of the general adaptation syndrome?
A
- Once the stressor has gone the alarm phase abates and the individual returns to a state of equilibrium.
- The first two phases (alarm and resistance) occur repeatedly in life and are part of evolving as human beings.
6
Q
What happens during the exhaustion phase of the general adaptation syndrome?
A
- If stress is prolonged or severe then equilibrium is not restored and exhaustion results.
- Prolonged release of stress hormones has negative health effects.
- Over time, cortisol levels especially decrease, leading to illness.
7
Q
Why can hyperactivation of the HPAA have widespread effects? Name THREE possible consequences.
A
Glucocorticoid receptors are expressed in most organs and tissues including several brain regions, sympathetic nerves and immune cells.
Repeated surges of cortisol can lead to cortisol dysfunction, resulting in unmodulated inflammation, and various sequelae including:
- pain
- depression
- GI issues
- increased risk of cardiovascular disease
- cancer.
8
Q
What are the proposed mechanisms underlying cortisol dysfunction and cortisol resistance?
A
- Glucocorticoid receptors are expressed in most organs and tissues. Prolonged or excessive cortisol secretion leads to desensitisation of glucocorticoid receptors to cortisol (cortisol resistance).
- Impaired binding disrupts negative feedback where cortisol would normally inhibit continued CRH release.
- CRH ↑ mast cell activation, release of noradrenaline (pro-inflammatory) and upregulates glutamate in the amygdala to promote a fear-based response to stress.
- High surges of cortisol increase its affinity to bind to mineralocorticoid receptors, where it has a pro-inflammatory effect.
CRH = corticotropinreleasing hormone
9
Q
The connection between stress and inflammation. What conditions is stress-induced inflammation implicated in?
A
Inflammation is a key driver in the physiological effects of stress. Stress in turn increases inflammation. It’s a vicious cycle.
- Stress-induced inflammation is implicated in: CVD, fibromyalgia, chronic fatigue syndrome, osteoporosis, rheumatoid arthritis, IBD, chronic back pain, TMJ dysfunction and more.
- Inflammation increases oxidative stress and free radical damage, cellular death, ageing and systemic tissue damage.
10
Q
TRUE or FALSE
The sympathetic stress response is pro-inflammatory, serving a purpose in the short term (destroys pathogens and foreign bodies).
A
True
In chronic stress situations, it contributes to the inflammatory state.
11
Q
Explain how prolonged cortisol secretion increase the risk of insulin resistance and Type 2 diabetes
A
- Cortisol increases gluconeogenesis and decreases glycogen synthesis. Prolonged elevations lead to hyperglycaemia.
- Cortisol also inhibits beta cell insulin secretion and impairs insulin-mediated glucose uptake.
12
Q
Explain how prolonged cortisol secretion leads to weight gain with central adiposity
A
- Cortisol stimulates appetite and intake of highly palatable foods.
- Impaired insulin response and consistently high blood glucose sends hunger signals to the brain leading to overeating.
- Causes redistribution / accumulation of fat in visceral fat cells.
13
Q
Explain how prolonged cortisol secretion suppresses reproductive function
A
- Normal function is inhibited by various components of the HPAA in chronic stress.
- CRH suppresses the secretion of GnRH, disrupting pulsatile release of FSH and LH and in turn, oestrogen, progesterone and androgens.
14
Q
Explain how prolonged cortisol secretion leads to impaired immune function
A
- Increases infection susceptibility.
- Decreases T-cell proliferation and downregulates T-helper cell receptor expression - necessary to induce Th1 immune response.
- Inhibits neutrophil, macrophage, NK cell and lymphocyte activity.
15
Q
Explain how prolonged cortisol secretion suppresses thyroid function
A
- HPAA activation and ↑ cortisol = ↓ TSH production.
- Glucocorticoids inhibit T4 - T3 conversion (↓ 5-deiodinase activity).
- Thyroxine is shunted into the ‘inactive’ rT3.
- In adrenal fatigue, low cortisol ↓ T3 receptor responsiveness.
16
Q
Explain how prolonged cortisol secretion suppresses gastrointestinal function
A
Ongoing stress leads to changes in the ‘gut-brain’ axis (this includes responses from the ANS and HPAA) causing:
- Altered GI motility (impairing digestion and elimination).
- Increased visceral perception.
- Changes in GI secretions - e.g., downregulates HCl production.
- Increased intestinal permeability to large antigenic molecules. It can lead to mast cell degranulation and colonic mucin depletion.
- Negative effects on microbiota and GI mucosal regeneration.
- Clinical consequences include GORD, peptic ulcers, IBD, SIBO etc.
17
Q
Explain how prolonged cortisol secretion downregulates the endocannabinoid (eCB) system and how it is connected to mood
A
- The eCB system has various homeostatic roles including
-modulation of neural plasticity,
-neuroprotection,
-immunity,
-inflammation,
-pain,
-emotional memory,
-hunger
-metabolism. - Suboptimal function of the eCB is linked with conditions such as
-depression,
-fibromyalgia,
-migraine
-IBS. - Circulating eCBs are used in the crosstalk between the intestinal microbiome and brain - specifically influencing mood.
18
Q
List FIVE typical symptoms and conditions linked to chronic stress
A
Examples of typical symptoms:
- Insomnia,
- fatigue,
- depression,
- irritability,
- headache,
- digestive disturbances.
Conditions linked to chronic stress include:
- Anorexia nervosa,
- asthma,
- autoimmunity,
- cancer,
- CVD,
- chronic fatigue syndrome,
- recurrent infections,
- mood disorders,
- Type 2 diabetes,
- IBS,
- ulcers,
- headaches,
- hypertension,
- menstrual irregularities,
- PMS,
- thyroid disorders.
19
Q
Persistent stress initially leads to hyperactivation of the HPAA. Continued stress results in hypo-activation of the HPAA. List the symptoms of both.
A
Hyperactivation
- depression,
- anxiety disorders,
- metabolic syndrome (hyperglycaemia, hypertension, lipid abnormalities and central adiposity).
Hypo-activation
- fatigue,
- irritability,
- pain and associated disorders including chronic fatigue syndrome, fibromyalgia and arthritis.
20
Q
What is the role of the androgen DHEA in the stress response?
A
- Alongside the release of glucocorticoids, noradrenaline and adrenaline, the androgen DHEA is also produced in larger amounts in response to stress.
- DHEA has been suggested to play a significant role in protection against the negative consequences of stress.
- Also protects against neurotoxic effects of chronically elevated cortisol on the hippocampus and reduces anxiety and depression.
21
Q
What can ongoing stress with prolonged DHEA and cortisol release lead to?
A
a depleted state (referred to as ‘adrenal exhaustion’) with an impaired stress response and loss of resiliency.
22
Q
Name SIX key signs and symptoms of adrenal ‘exhaustion’
A
- Fatigue and ↑ need for sleep,
- inability to cope with stress,
- anxiety,
- irritability,
- ↓ libido,
- lots of yawning,
- lower back pain,
- recurrent infections,
- sweet cravings,
- reactive dysglycaemia,
- sensitivity to cold and heat,
- lower body temperature,
- poor digestion,
- postural hypotension,
- unstable pupillary reflex.
23
Q
How can adaptogens be useful for adrenal ‘exhaustion’? Name TWO adaptogens.
A
Act as mild stressors to cells, priming them to be able to effectively respond to stress (analogous to repeated physical exercise).
Protect against adrenal exhaustion and assist recovery.
- ashwagandha,
- Siberian and Korean ginseng,
- rhodiola.
24
Q
General interpretation of adrenal stress index results:
- Normal levels of cortisol and DHEA
A
= normal (no stress)
25
General interpretation of adrenal stress index results:
* Raised cortisol and raised DHEA
= chronic stress
26
General interpretation of adrenal stress index results:
* Raised cortisol, normal DHEA
= normal short-term stress
27
General interpretation of adrenal stress index results:
* High cortisol, low DHEA
= first sign of adrenal ‘fatigue’
28
General interpretation of adrenal stress index results:
* Low cortisol, low DHEA
= adrenal ‘exhaustion’
29
General interpretation of adrenal stress index results:
* Low cortisol, normal DHEA
= start of recovery process
30
Nutritional approach to stress: discuss how an anti-inflammatory diet can be useful in reducing stress levels. Provide practical advice.
Inflammation drives stress and stress drives inflammation. Include:
‒ 8–10 portions of energetically balanced fresh fruit and vegetables, rich in vitamins, minerals and phytonutrients such as polyphenols, flavonoids and organosulphur compounds.
31
Nutritional approach to stress: discuss how stabilising blood glucose can be useful for chronic stress. Provide practical advice.
Drops in blood glucose trigger cortisol release; chronic stress increases hyperglycaemia risk:
– Complex carbohydrates - release glucose at a steady rate, high in fibre, rich in B vitamins e.g., whole grains and legumes.
32
Natural Approach to Stress: proteins.
Name THREE amino acids especially important for stress. Provide practical advice.
* 2–3 palm size portions of *high quality protein* e.g., legumes, nuts and seeds, whole grains, fish and eggs, to ensure amino acids required for neurotransmitter production.
* Especially **tyrosine** - adrenaline, noradrenaline, dopamine production e.g., *nuts, seeds, whole grains, legumes, fish*.
* **Tryptophan** - serotonin, melatonin precursor e.g., *brown rice, quinoa, oats, fish, eggs, bananas*.
* **Glutamine** - GABA (ensure B6, zinc, taurine) e.g., *cabbage juice, asparagus, broccoli, turkey, bone broth*. ↓ intestinal permeability. ½ cup cabbage juice or 1 cup bone broth daily.
33
Why is potassium to sodium ratio important for stress?
Provide practical advice.
* Ensure good intake of potassium-rich foods and reduce sodium intake.
* Stress hormones can cause reductions in serum potassium.
* Aim for a dietary potassium-to-sodium ratio greater than 5:1.
* Readily achieved with a diet rich in fruits and vegetables because most fruits and vegetables have a K:Na ratio of at least 50:1.
* Include 2 handfuls of dark green leafy veg daily (green smoothie).
34
How can we support microbiome during the times of stress?
Stress induces changes in the gut microbiota. Support this with:
* Prebiotic foods - dandelion greens, chicory, Jerusalem artichoke, garlic, etc.
* Probiotic foods - kimchi, sauerkraut, kombucha, kefir, yoghurt (cultured) etc.
* Polyphenol-rich foods (to feed commensals and support the mucosal barrier) - green tea, blueberries, cranberry, currants etc.
35
What foods/drinks should be avoided during stress?
* High fructose, artificial sweeteners, high-fat consumption especially damaged fats, high intake of animal and soy protein.
* Refined carbohydrates - alongside disruption to the microbiome, disturbs blood glucose regulation.
* Alcohol - a chemical stressor that impairs communication and processing pathways in the brain and contributes to mood and sleep disorders; depletes glutathione and Vitamin B1 - it is potentially neurotoxic.
* Caffeine - stimulates adrenaline and cortisol release, driving the stress response; blocks adenosine receptor activity inhibiting sleep.
36
Name herbal teas that relax the nervous system
- chamomile,
- lemon balm,
- passionflower,
- lime flower,
- hops.
37
Stress promotes a state of sympathetic nervous system dominance at the expense of digestion and rest. Provide practical advice on supporting digestion in a clinic.
* Encouraging *abdominal breathing techniques* before meals (↑ vagal stimulation as it passes through the diaphragm).
* Eating a fist-sized amount of *bitter foods* and *herbs* 15 minutes before meals e.g., rocket, dandelion greens, or use tinctures such as gentian. Bitters increase the release of gastric acid (vagal reflex) and prime pancreatic enzymes and bile. Apple cider vinegar - 1
tsp. in 100 ml water before main meals will have a similar action.
* *Mindful eating* focusing on aroma, texture and taste, and chewing food well shifts thoughts away from stress and improves digestion.
38
How can we support the eCB system?
* Increase dietary intake of **omega-3 fatty acids** - required for normal eCB signalling and act as regulators of the eCB system.
* **Polyunsaturated fatty acids** play a fundamental role in the eCB system.
* **Arachidonic acid** is needed in the biosynthesis of eCBs.
NOTE: a surplus of omega-6 fatty acids and inadequate omega-3 (common in Western diets), causes excess synthesis of eCBs.
This leads to desensitised and downregulated eCB receptors.
* **Prebiotics** and **probiotics** support the eCB system.
The eCB system interacts with the central and enteric nervous systems influencing gut motility, reducing GI inflammation and balancing the reaction to stress.
* *Black pepper, cinnamon, oregano, basil, lavender* and *rosemary* contain the phytocannabinoid beta-caryophyllene.
* *Cold water exposure* has been shown to increase eCB levels.
* *EVOO* has been shown to upregulate CB1 receptors.
39
# Nutrients to support stress
How does Vitamin C help with stress? Include dosage.
* *Key water-soluble antioxidant* in blood and tissues inclusive of CNS. Stress increases free radical damage.
* The CNS is especially sensitive to oxidative stress, which is in turn linked with ↑ psychosocial stress, anxiety and depression.
* Shown to improve recovery from mental stress.
* *Adrenal support* - is a co-factor in glucocorticoid synthesis.
* Vitamin C supplementation has shown to *reduce stress-induced cortisol release*. ↓ hyperactivation of the HPA-axis.
* *Enhances immune function* - upregulates natural killer cells, interferons and T-cells.
Dosage: 500 mg - 2 g daily.
40
# Nutrients to support stress
How does Vitamin B5 help with stress? Include dosage.
* As a precursor to *coenzyme A* plays an essential role in *adrenal cortex* function.
* Increases production of *glucocorticoids* and other adrenal hormones.
* Thought to reduce *secretion of cortisol* in times of stress.
Dosage: 100 - 300 mg / day.
41
# Nutrients to support stress
How does Vitamin B6 help with stress? Include dosage.
* Exerts modulatory effects on *GABA* and *serotonin*, neurotransmitters that regulate *anxiety, depression and pain perception*.
* Downregulates activity of *glucocorticoid receptors*, ↓ the physiological impact of corticosteroid release.
Dosage: 50 - 100 mg / day.
42
# Nutrients to support stress
How does B complex
vitamins help with stress? Include dosage.
* Co-factors in the Krebs cycle - needed for *ATP production*.
* Required to maintain *nervous system health* - B1 in particular enables the brain to utilise glucose.
* Vitamins B6, B9 and B12 have specific roles in methylation and decarboxylation processes
that support synthesis of *monoamine* and *catecholamine neurotransmitters*.
* B group vitamins taken as a complex have been shown to *improve mood* and *quality of life* in individuals experiencing depression and anxiety.
| High dose combination.
43
# Nutrients to support stress
How does Vitamin E help with stress? Include dosage.
* Acute and chronic stress increase free radical formation, especially in the CNS and adrenal cortex.
* As a *lipid-soluble antioxidant*, vitamin E protects neuronal cell membranes and myelin sheaths from oxidative stress.
* Has been shown to *protect the adrenal cortex from free radical damage* and decrease stress-induced release of cortisol.
* Supports immunity - increases phagocyte activity and promotes differentiation of immature T-cells in the thymus.
Dosage: 400–800 iu / day.
44
# Nutrients to support stress
How does Magnesium help with stress? Include dosage.
* Deficiency upregulates HPA activity, while supplementation attenuates activity with reductions in ACTH and cortisol.
* Is a co-factor for *GABA* synthesis, heightens GABAergic availability by reducing presynaptic glutamate release - net effect *anxiolytic*.
* Is a co-factor in the serotonin-melatonin pathway.
* Stress-related muscle tension - *breaks actin-myosin bond*.
* *Amino acid chelates* - taurate / glycinate: Taurine is a GABA agonist and glycine acts as an inhibitory neurotransmitter, so potentially even more useful.
Dosage: 100–400 mg / day.
45
# Nutrients to support stress
How does Phosphatidylserine help with stress? Include dosage.
* Normalises stress response.
* *Buffers HPAA response*, restoring normal ACTH and cortisol activity, allowing for better quality sleep, decreased anxiety and improved mood.
* The effect is believed to be mediated through the *normalisation of cortisol-binding globulin* (CBG).
Dosage: 200 - 400 mg / day.
46
# Nutrients to support stress
How does L-theanine help with stress? Include dosage.
L-theanine (N-ethyl-L-glutamine) is a major amino acid uniquely found in *green tea*. L theanine increases brain serotonin, dopamine, GABA levels, supporting cognitive function and aiding *relaxation*.
Dosage: 20 - 400 mg / day.
47
# Nutrients to support stress
How does Reishi mushroom help with stress? Include dosage.
* Regarded as an *adaptogen*.
* Triterpene constituents have a *sedative action*, calming the nervous system to support relaxation and sleep.
* Contains polypeptides that act as precursors to neurotransmitters and endorphins supporting the stress response.
* Assists the *immune system* at times of stress including the increased number and activity of NK cells, macrophages and T-lymphocytes.
Dosage: 3 - 9 g / day.
Use as a powder in tea, food, capsules.
48
Explain how herbs can be used as stress support. Provide the dosages.
Key herbal strategies are aimed at calming heightened nervous system activity and supporting resistance to stress.
* Herbs can be used as *infusions* - 2 teaspoons of dried herb infused for 10 minutes in just boiled water, 2–3 cups daily.
* For herbal products follow dosages as per label recommendations.
* *Nervine relaxants* and *mild sedatives* calm the nervous system and promote restful sleep.
* *Adaptogens* increase the body’s resistance to stress through modulation of hormone and neurotransmitter physiology.
49
# Herbal support for stress
Chamomile (Matricaria recutita) flowers
* Has *mild sedative and anxiolytic effects* and has demonstrated benefits in alleviating symptoms associated with generalised anxiety disorder.
* Relieves GI pain and spasms and is particularly helpful for GI complaints associated with stress.
50
# Herbal support for stress
Passionflower (Passiflora incarnata) aerial parts
* Has *anxiolytic* properties and promotes restful sleep.
* Shown to *increase resistance to stress* (i.e., ↑ resilience), with improvements in inner restlessness, fear, sleep disturbance and exhaustion.
51
# Herbal support for stress
Lavender (Lavandula officinalis) flowers, essential oil
* *Elevates mood*; useful for depression especially when accompanied by restlessness, insomnia or anxiety.
* The essential oil interacts with the *limbic system* (deals with emotion and memory).
52
# Herbal support for stress
Lemon balm (Melissa officinalis)
* *Mild sedative* and *antispasmodic* properties (relaxes smooth muscle) and is used traditionally for insomnia, anxiety, irritability, depression, colic, nervous dyspepsia.
* Effect thought to be by inhibition of *GABA transaminase* system, raising levels of GABA.
Dosage: 300–600 mg
53
# Herbal support for stress
Ashwagandha (Withania somnifera)
* Is both *adaptogen* and *tonic* - conserves energy and boosts energy reserves.
* In the CNS is *neuroprotective, sedative, anxiolytic (GABA agonist)*, and cognition enhancing.
* Shown to increase physical capability as well as improving psychological parameters.
54
# Herbal support for stress
Siberian ginseng (Eleutherococcus senticosus)
* Helps the body to counteract and adapt to stress.
* Improves mental and physical performance and minimises negative effects of stress.
* Enhances immunity, esp. NK cells and T-helper cells.
55
What lifestyle recommendation would you suggest to reduce stress?
* *Exercise*: Facilitates regulation of the HPAA, and influences neurotransmitters associated with mood such as dopamine and serotonin.
‒ Include regular physical activity (several times a week), e.g., walking, jogging, Pilates.
* *Natural therapies*: Acupuncture, aromatherapy, massage, reflexology, cranial osteopathy, Bach flowers, homeopathy etc.
* *Other ways*: Optimise sleep hygiene, avoid reading / listening to bad news, talk to a friend, go for a walk in daylight, reduce blue light, fulfil responsibilities you have.
* *Establish a purpose* / goal in life of your client (Japanese ikigai) - plays a major role in longevity. It acts as a buffer against stress and helps reduce overall inflammation.
56
What is fatigue and what leads to fatigue?
Fatigue = physical and mental exhaustion that is not relieved by rest.
* Fatigue is the *symptom experienced when energy demand exceeds energy delivery*. If more energy is spent than can be generated, it will lead to death!
* Thus, the body manifests uncomfortable symptoms to prevent this happening.
* While mild fatigue can be caused by a range of factors, moderate to severe persistent fatigue involves *cellular energy systems* - the hallmark of chronic fatigue syndrome and intractable fatigue states.
57
Mitochondrial energy production is the result of two closely coordinated metabolic processes - name them.
the Krebs cycle and the electron transport chain.
58
# Mitochondria function
What can be the outcome of slow mitochondrial function?
Mitochondria make over 90% of the body’s energy as ATP. This energy is crucial to sustain life and support organ function.
ATP cannot be stored - therefore, the mitochondria need to function continuously, every second of every day.
* If cells function slowly, then organs function slowly i.e., the start of organ failures such as heart failure and dementia.
* If the immune system functions slowly then healing and repair is slow, increasing risk of infection and cancer.
* If all cells in the body are affected, the clinical picture of *chronic fatigue syndrome* and *premature ageing* emerges.
59
Name FIVE factors associated with increased mitochondrial damage/dysfunction
Mitochondria are highly susceptible to nutrient deficiencies, environmental toxins and oxidative damage.
* **Environmental toxins** - mitochondria have very high metabolic activity so are particularly susceptible to toxin exposure.
* **Oxidative stress in cells** - the primary source of ROS are those generated by the mitochondria themselves, which leak out. Mitochondrial damage occurs when ROS outpaces antioxidant activity.
* **Hyperglycaemia** induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction.
* **Inflammatory mediators** such as TNF-α have been associated with mitochondrial dysfunction and increased ROS generation. Consider *why* inflammatory mediators are raised:
‒ intestinal mucosal degradation (LPS leakage),
‒ pro-inflammatory diet (high omega 6:3 etc.),
‒ glucose dysregulation,
‒ raised homocysteine (increases TNF-α expression),
‒ TNF SNP,
‒ smoking,
‒ obesity, etc
* Many **prescription drugs** e.g., antibiotics, aspirin, NSAIDs, statins.
* **Ageing** (accumulated oxidative damage to mitochondrial DNA).
* **Genomic susceptibility**.
60
What antioxidant enzymes and other nutrients protect mitochondria from oxidative stress?
‒ superoxide dismutase (manganese),
‒ glutathione peroxidase (selenium),
‒ glutathione reductase (B3),
‒ catalase (iron),
‒ Coenzyme Q10,
‒ vitamin E.
61
Key nutrients required for ATP production (other than oxygen) for Glycolysis
‒ Magnesium
‒ vitamin B3
62
Key nutrients required for ATP production (other than oxygen) for Acetyl CoA formation
‒ Vitamin B1
‒ alpha-lipoic acid
‒ vitamin B5
63
Key nutrients required for ATP production (other than oxygen) for Krebs cycle
‒ Magnesium
‒ manganese
‒ iron
‒ B1
‒ B2
‒ B3
64
Key nutrients required for ATP production (other than oxygen) for Electron Transport Chain (ETC)
* vitamin B2 and sulphur (complex I)
* CoQ10 (complex II - transports high energy electrons
* Iron (complex I and III)
* copper (complex IV)
65
Key nutrients required for ATP production (other than oxygen) for β-oxidation of fats
Carnitine to transport fatty acids is most crucial
66
Key nutrients required for ATP production (other than oxygen) for Energy carriers
* **Vitamin B3** (or tryptophan & aspartic acid) - NAD
* **Vitamin B2** - FAD
67
Name key strategies to improve mitochondrial function
* Optimise *nutrients* required for ATP production and antioxidant properties to protect the mitochondria from oxidative stress.
* Focus on *blood sugar regulation* (prevent chronic hyperglycaemia).
* *Reduce levels of inflammatory mediators* - optimise intestinal health, anti-inflammatory foods, optimise weight etc.
* *Decrease toxin exposure* e.g., consume organic food, avoid plastic packaging, carefully select cleaning products, cosmetics and personal care items; avoid alcohol and pharmaceuticals.
* *Strength training* - increase muscle mass to increase mitochondria number and function.
68
# explain mode of action and include dosage
Essential nutrients for mitochondrial function: Coenzyme Q10
* *Transports high-energy electrons in the ETC* supporting mitochondrial function and energy production.
* Deficiency reduces ATP production and increases electron loss causing increased oxidative damage and fatigue.
* Production of ROS, which can damage cellular lipids, proteins and DNA, is a direct consequence of the ET process.
* CoQ10 is an *efficient intra-mitochondrial antioxidant*, playing a vital role in neutralising ROS.
* Ability to produce CoQ10 strongly correlates with longevity.
Dosage: 100–300 mg / day (solubilised)
69
# explain mode of action and include dosage
Essential nutrients for mitochondrial function: Alpha lipoic acid (ALA)
* Is a *co-factor for several mitochondrial enzymes* involved in glucose oxidation and ATP generation.
* As an antioxidant, protects mitochondrial structures.
Dosage: 300–600 mg / day.
70
# explain mode of action and include dosage
Essential nutrients for mitochondrial function: Acetyl L-carnitine.
* Essential for the *transport of long-chain fatty acids across the mitochondrial membrane* for subsequent β-oxidation and generation of ATP.
* Increases mitochondrial oxidative phosphorylation, thereby increasing ATP production and reducing mtROS.
Dosage: 500–2000 mg / day.
71
# explain mode of action and include dosage
Essential nutrients for mitochondrial function: Magnesium (as citrate or malate).
* Plays a fundamental role in energy production where it *transfers phosphate groups between ADP and ATP*.
* Magnesium insufficiency or deficiency can result in a symptom picture reflective of chronic fatigue syndrome.
* Malic acid is a Krebs cycle cofactor, so magnesium malate may be better, and is researched to improve fibromyalgia.
Dosage: 200 ‒ 400 mg / day.
72
# explain mode of action and include dosage
Essential nutrients for mitochondrial function: B complex vitamins - High dose combination.
* **B1** is needed in the *Krebs cycle*.
* **B2** - energy carriers *FAD, FMN*
* **B3** - coenzymes *NAD, NADP*.
Required for Krebs cycle and for conversion of fatty acids to ATP.
* Possibly consider even higher even dose B2/B3 - 100mg+
73
What is the difference between CFS (chronic fatigue syndrome) and ME (myalgic encephalomyelitis)? What are some of the common symptoms?
CFS and ME are terms often used interchangeably though ME is sometimes defined as CFS + inflammation.
* Characterised by long-term physical and cognitive fatigue, not alleviated by rest.
* Other symptoms include:
‒ post-exertional malaise,
‒ muscle and joint pain,
‒ unrefreshing sleep,
‒ flu-like symptoms with sore throat and tender lymph nodes,
‒ mood disturbances.
74
CFS and ME proposed aetiologies
* **Infectious organisms** - in particular EBV (high antibody titres in patients with symptoms indicative of CFS). Other: Human herpes virus-6, Borrelia burgdorferi (Lyme’s).
* **Immunological** - e.g., increased cytokines, NK cell abnormalities, decreased CD8 suppressor cells. Imbalances that collectively suggest chronic, low-level activation of the immune system.
* **Abnormal HPAA functioning** - association with hypocortisolism.
* **Mitochondrial dysfunction** and **high oxidative stress** - associated with ↓ GPO, SOD and melatonin (sleep dysregulation).
* **Serotonin dysregulation**.
‒ Increased 5-HT autoimmune activity is associated with activation of inflammatory pathways and increased bacterial translocation. A reduction in 5 HT neurons has been noted.
‒ Proposed upregulation of the serotonin transporter (5-HTT) in astrocytes, reducing extracellular serotonin (5-HT) levels.
75
Explain the connection between CFS / ME and intestinal health
A breakdown in the bidirectional communication between the *brain and the gut* mediated by bacteria and their metabolites. CFS / ME are commonly associated with GI symptoms.
– High relative abundance of bacterial species such as *clostridium* and *ruminococcus* in CFS / ME; decreased *faecalibacterium* abundance.
– Metabolic endotoxaemia as a driver for CFS / ME.
Microbes that cause dysbiosis can alter the immune system and dysregulate mitochondrial function.
Further, CNS manifestations are thought to relate in part to increases in neurotoxic ammonia and D-lactic acid-producing gut bacteria.
76
Natural approach to CFS / ME - what to avoid
* *Caffeine* (coffee, tea, chocolate, energy drinks). Temporarily counters fatigue, but the effect is short-lived and places strain on the adrenal glands exacerbating an already fatigued body.
* *Sugar* - an immune system depressant. Destabilises blood glucose causing peaks and troughs in energy.
* *Artificial sweeteners* - interact with sweet receptors to trigger insulin release (destabilise blood glucose). Aspartame contains excitotoxins (e.g., aspartates) and methanol, which converts to formic acid - a neurotoxin. Can worsen neurological symptoms.
* *Alcohol* - worsening of symptoms, depletes the body of nutrients.
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Natural approach to CFS / ME - what to include
* Good quantities of **essential fatty acids**:
– Omega-3 is especially important for the activity of the mitochondrial membrane. *EPA* - anti-inflammatory properties and increases mitochondrial growth, size and distribution.
*DHA* - essential for the structure of ETC complexes.
Benefits: improvements in cognitive function and a reduction in relapse frequency.
* Sufficient **protein** to allow for immune cell restoration and function.
* **Immune support** (e.g., anti-microbials, vitamin C etc.)
* **GI support** (e.g., digestive bitters, pro and prebiotics etc.).
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What are the principles of nutritional ketosis?
Nutritional ketosis in CFS / ME is considered a beneficial dietary strategy for supporting mitochondrial function.
* Total carbohydrate intake < 50 g / day (or whatever is needed to get into ketosis).
* Moderate protein intake, around 1.5 g / kg bodyweight per day.
* Fuel as ketones come from fat AND the fermentation of fibre in the large bowel to short-chain fatty acids.
* Typical macronutrient ratio - 75% fat, 20% protein, 5% carbohydrate.
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What are the benefits of a ketogenic diet in CFS / ME?
* While excess levels of mitochondrial ROS (mtROS) are associated with mitochondrial dysfunction, low concentrations of mtROS can act as signalling molecules, *upregulating mitochondrial capacity and antioxidant defence* - known as mitohormesis.
* Ketosis causes a significant shift in energy metabolism increasing reliance on mitochondrial respiration - this induces mitohormesis.
* Further, in addition to their role as energy substrates, ketones (esp. *β hydroxybutyrate*) act as signalling molecules increasing *expression of antioxidant enzyme systems*.
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What is mitohormesis?
low concentrations of mitochondrial stress increase health and viability within cells.
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Name ONE herb (including its mode of action and dosage) that can be beneficial in CFS / ME.
*Liquorice* - Glycyrrhiza glabra
1‒2 tsp powder daily.
* Suboptimal HPAA function and low cortisol is a common feature of CFS / ME. Liquorice is an adrenal cortex restorative, supporting cortisol production and ↓ fatigue.
* Anti-inflammatory activity - research indicates inhibitory effects on ROS-induced tissue inflammation and the COX, LOX and NF-κB inflammatory pathways.
*Astragalus* - Astragalus membranaceus
2.5‒3.5 g dry herb.
* An adaptogen and tonic indicated for debility and CFS.
* Regulatory effect on immune function; supports aspects of innate immunity while promoting Th1 / Th2 balance.
* Reduces abnormal cytokine production.
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Describe the connection between chronic stress and CFS and ME
Chronic stress effectively ‘kicks’ mitochondria unrelentingly but:
* Eventually *mitochondria will fatigue* either because they run out of raw materials and / or there is no proper ‘shut down’ during sleep for healing and repair.
* If they become unable to respond to the unrelenting adrenaline kick, it results in the clinical picture of *chronic fatigue syndrome*.
* If the immune system lacks energy, then it cannot deal with an infection efficiently so the infection may become chronic.
* The above mechanisms result in the clinical picture of *myalgic encephalomyelitis*.
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Name the effects of poor energy delivery to the body
* Physical fatigue, poor stamina.
* Post-exertional malaise (akin to over-training in athletes).
* Loss of muscle power - muscles heavily rely on ATP!
* Muscle pain - because of an early switch into anaerobic metabolism with production of lactic acid.
* Variable blurred vision - the ciliary body muscles required for focusing tire easily.
* Subnormal core temperature.
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Name the effects of poor energy delivery to the brain
* Mental fatigue with *brain fog* - the brain weighs 2% of body weight but consumes 20% of total energy.
* Light and noise intolerance.
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Name the effects of poor energy delivery on mental symptoms
* Low mood.
* Feeling stressed.
* Procrastination.
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Name the effects of poor energy delivery to the heart
* Hypotension - in severe cases this manifests with orthostatic intolerance and POTS.
* Angina described as ‘atypical’ (from lactic acid).
| POTS = postural orthostatic tachycardia syndrome
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Name the effects of poor energy delivery to the immune system
* *Susceptibility to infection*, unable to run a good fever.
* Slow healing and repair.
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Mitochondrial disorders manifest in the short term with poor energy delivery mechanisms. Name the energy delivery mechanisms and the order in which they need to be addressed.
1. **Diet** - fuel in the tank (paleo-ketogenic diet, basic package of nutritional supplements and good gut function).
2. **Mitochondria** (engine) - servicing and repair (quality and quantity of sleep).
3. **The control mechanisms**:
- *Thyroid* (accelerator pedal).
- *Adrenal* (gear box).
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What foods should be avoided in the first PK diet stage and why?
Avoid gluten and all dairy except butter (almost 100% fat).
* **Gluten** - Non-coeliac wheat sensitivity (NCWS), identified in a subset of individuals with CFS / ME, is linked with increased intestinal permeability and systemic immune activation.
*Other grains* are permitted so long as ketosis is maintained.
* **Dairy** - at least 30% of people are allergic; lactose may be fermented; milk protein contains growth promoters (risk for cancer); high Ca / Mg ratio which induces Mg deficiency, increased risk of osteoporosis; milk protein increases blood viscosity.
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How to determine you are in ketosis? Name three types of ketones
* **Beta-hydroxybutyric acid** - is present in the blood and can be measured in the blood. This is the most accurate measure, but testing strips are expensive.
* **Acetoacetate** - is excreted in the urine. Testing is cheap and easy with urine keto-stix but as the body becomes more efficient at matching ketone production to demand, urine tests may show false negatives.
* **Acetone** - is exhaled and can be measured with breath testing. This can easily be tested after every meal to ensure you have not overdone the carbohydrates.
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What can provide false negatives in a breath test for ketones?
* Any **alcohol** if consumed in the past 24 hours (same mechanism to measure ketones and alcohol).
* **SIBO** (produces alcohol).
* **Any products containing alcohol** may give a positive result e.g., an alcohol wipe to clean the mouthpiece - a tiny amount of contaminant can upset the result.
* Many **household cleaners** contain volatile organic compounds which may register on the meter.
* **Eating or drinking** anything other than water in the preceding 20 minutes may affect the test e.g., a sip of **coffee** can = a negative reading.
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# Mitochondrial engine
Name FOUR raw materials (nutrients) that mitochondria need daily for enzyme systems to work
* **CoQ10** 100‒300 mg.
* **Magnesium** 300 mg (absorption enhanced by vit. D 10,000iu / day).
* **Niacinamide** (B3) 1500 mg daily.
* **Acetyl L-carnitine** 500‒2,000 mg (vegetarians and vegans are often deficient).
* **Vitamin B12** 1‒5 mg daily.
* **D-ribose** 5‒15 g daily - but has to be part of the PK diet carb count -it is a sugar! Use as a rescue remedy to shorten recovery time if the patient has overdone his / her activity.
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Name THREE factors that inhibit mitochondrial function
**Lactic acid**
- Pace activity carefully.
**Products of the ‘fermenting gut**’
- PK diet.
- Vitamin C to bowel tolerance.
**Diamino compounds** e.g., hair dye.
- Avoid.
**Malondialdehdye** - a result of poor antioxidant status.
- Improve antioxidant status esp. with vitamin B12 and C to bowel tolerance.
**Parabens, polybrominated biphenyls** (e.g., in fire retardants), pesticides, mercury and other *toxic metals*.
- Avoid and eliminate, e.g., with heating regimes such as with saunas.
- Detoxify with multi-minerals and glutathione 250 mg daily.
**Mycotoxins** and **viral proteins**.
- Look for infectious cause.
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The control mechanisms.
Why is balancing the thyroid (accelerator pedal) and adrenal glands (gear box) important in treating CFS / ME?
* The thyroid and adrenal glands allow energy delivery to be matched closely with energy demands.
* They are also essential for circadian rhythms.
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The control mechanisms.
Explain the connection between the thyroid, adrenals and circadian rhythm.
* Light (sunshine is best) switches off melatonin production.
* Darkness triggers melatonin production from the suprachiasmatic nuclei in the pineal gland, following signalling from the retina.
* As *melatonin* rises TSH production is stimulated - spiking at 12am.
* The thyroid gland increases the output of *T4* which spikes at 4am.
T4 is converted to *T3* which spikes at 5am.
*T3 stimulates the adrenals* and so adrenal hormones, including cortisol and DHEA, spike at 6-7am; this wakes you up.
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What is the connection between thyroid, adrenal function and the body's core temperature?
The combined effects of the fuel in the tank, the mitochondrial engines, the thyroid accelerator pedal and the adrenal gear box are reflected by our core temperature.
Assuming the fuel and engines are correct:
- The average core temperature reflects thyroid function.
- The fluctuations reflect adrenal function.
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Correcting temperatures - adrenals: what to do if the core temperature wobbles by more than 0.6 degrees (i.e., 0.3 above and below average).
Adrenal glandulars may be needed (such as adrenavive).
Alternatively, adrenal herbs / nutrients can be implemented here.
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Correcting temperatures - thyroid: what to do if the average temperature is low
A thyroid glandular such as metavive may be needed
