Fatigue - Lecture 9

Question 1

What can cause mitochondria dysfunction?

Answer 1

• 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 production 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. When the immune system is activated inflammatory mediators are activated or when someone has allergies or AI.
  ‒ Consider why inflammatory mediators are raised, e.g., 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.

Question 2

Nutrients for mitochondria function

Answer 2

Antioxidant = superoxide dismutase (manganese), Glutathione Peroxidase (selenium), B3, iron

CoQ10, Vit E, Vit D, Vit K, Melatonin, Vit C

Question 3

Factors associated with mitochondrial damage ?

Answer 3

ROS
Ageing
Genomic susceptibility
Toxic metals
Prescription drugs

Question 4

Key nutrients required for glycolysis?

Answer 4

Magnesium and B3

Question 5

Key nutrients required for Acetyl CoA

Answer 5

B1, B5 and alpha lipoid acid

Question 6

Key nutrients required for Krebs cycle

Answer 6

Magnesium, Vita D, Mangenese, Iron, B1, B2, B3, CoQ10

Question 7

Key nutrients required for ETP

Answer 7

iron, B2, sulphur, CoQ10, Copper

Question 8

Key nutrients required for beta oxidation of fats

Answer 8

carnitine

Question 9

Key nutrients required for energy carriers

Answer 9

b3, b2

Question 10

Key strategies to optimise mitochondria functions?

Answer 10

• 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  can damage mitochondria (aluminium for example)
• Strength training — increase muscle mass to increase mitochondria number and function.

Question 11

CoQ10 dose and usage

Answer 11

Coenzyme Q10
Dosage: 100–300 mg / day

• 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.
• As we age we should all take coq10

Question 12

Alpha lipoic acid (ALA) dosage and use

Answer 12

Alpha lipoic acid (ALA)
Dosage: 300–600 mg / day.

• Is a co-factor for several mitochondrial enzymes involved in glucose oxidation and ATP generation.
• As an antioxidant, protects mitochondrial structures.
• Glutathione is similar – both multitasking tool. As we age and in any disease process very helpful for patients

Question 13

Acetyl L- carnitine dosage and use

Answer 13

Acetyl L- carnitine.
Dosage: 500–2000 mg / day.

• 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.
• Is very rich in meat (if patient can digest meat properly), if patient id vegetarian or vegan high chance they will need L-carnitine

Question 14

Magnesium dosage and use

Answer 14

Magnesium
(as citrate or malate).
Dosage:200 ‒400 mg / day.

• 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.

Calcium and magnesium compete with each other and takin a lot of calcium deplete of magnesium. Dairy products are 10x calcium for 1x magnesium and that is why dairy products are a risk factor for heart disease

Question 15

B complex vitamins dosage and use

Answer 15

B complex vitamins High dose combination.

• B1 is needed in the Krebs cycle. B2 (energy carriers FAD, FMN) and B3 (coenzymes NAD and NADP). Required for Krebs cycle and for conversion of fatty acids to ATP.
• Possibly consider even higher even dose B2/B3 — 100mg+

Question 16

CFS = chronic fatigue syndrome. ME = myalgic encephalomyelitis.

Signs and characteristics

Answer 16

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.
* While mitochondrial dysfunction is recognised as a key player, there are a number of proposed contributing factors.
* Post exertion malaise (do something one day and pay for it the next)
* Inflammation can be joint pain, neck pain, fibromyalgia, feeling ill (malaise)
* Mitochondrial health is central to both

Question 17

Proposed aetiologies of CFS and ME

Answer 17

• 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 and SOD. Also low melatonin (sleep dysregulation).
• Serotonin studies have concluded:
  ‒ 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.
• 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 (see next slide).
• The key to that is to ensure a good connection between the gut and the brain
• Findings in relation to intestinal health and CFS:
  – 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.

Question 18

Natural approach to CFS and ME - what to avoid / what to include?

Answer 18

Natural approach to CFS / ME — 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 body of nutrients

Natural approach to CFS / ME — 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.
* Sufficient protein to allow for immune cell restoration and function.
* Individualised immune support (e.g., anti-microbials, vitamin C etc.) and GI support (e.g., digestive bitters, pro and prebiotics etc.).

Question 19

Nutritional ketosis in CFS / ME how to?

Answer 19

Nutritional ketosis in CFS / ME — 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.
* Changes the body’s primary fuel source from glucose to ketones.
* Ketones enter the mitochondria of body tissues for ATP production.

Question 20

Benefits of a ketogenic diet:

Answer 20

• 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 (mitohormesis = low concentrations of mitochondrial stress increase health and viability within cells).
• Ketogenic diet is also anti-inflammatory  without a keto diet you won’t get rid off the fermented gut  and won’t be able to absorb nutrients needed for the mitochondria.
• Further, in addition to their role as energy substrates, ketones (especially β-hydroxybutyrate) act as signalling molecules increasing expression of antioxidant enzyme systems.

Question 21

Liquorice in CFS dosage and use

Answer 21

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.

Question 22

Astragalus in CFS dosage and use

Answer 22

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.

Question 23

Effect of Poor energy delivery to the body:

Answer 23

• Physical fatigue, poor stamina.
• Post-exertional malaise (akin to over-training in athletes)  if you have to pay for your action the next day.
• Loss of muscle power — muscles heavily rely on ATP!
• Muscle pain — because of an early switch into anaerobic metabolism with production of lactic acid. If you cannot produce ATP efficiently. Anaerobic respiraction produces 2 ATP + Lactic Acid and then you need to suppress the Lactic Acid and need 6 ATP to do it  if you don’t have the ATP in the tank you have muscle pain
• Variable blurred vision — the ciliary body muscles required for focusing tire easily.
• Subnormal core temperature.

Question 24

Poor energy delivery to the brain:

Answer 24

• Mental fatigue with brain fog — the brain weighs 2% of body weight but consumes 20% of total energy.
• Light and noise intolerance  demands a lot of energy the retina demands 10x energy more than the brain
• All the early symptoms of dementia

Question 25

Mental symptoms which inhibit energy expenditure:

Answer 25

Low mood.
* Feeling stressed  brain knows that the body does not have energy to get things done
* Procrastination.
* Depression / isolation because no energy

Question 26

Poor energy delivery mechanisms involve the following which can be described using the car analogy:

Answer 26

– Diet (fuel)  ketones
– Mitochondria (engine).
– Thyroid (accelerator pedal).
– Adrenals (gear box)  gives energy in the ST, then cortisol (gives energy for a few hours) then DHEA for longer period of energy demand

Question 27

what is the 3 step approach to CFS and ME?

Answer 27

To improve energy delivery mechanisms, all aspects must be addressed. They must also be addressed in the correct order.
1. Fuel in the tank (paleo-ketogenic diet, basic package of nutritional supplements and good gut function).
2. Mitochondrial engine — servicing and repair (quality and quantity of sleep).
3. The control mechanisms:
a. Thyroid accelerator pedal.
b. Adrenal gear box.

Question 28

1. Fuel in the tank — paleo-ketogenic diet (PK Diet):

What to incl what to avoid?

Answer 28

• Mitochondria evolved to use ketones from fat and fibre for energy.
• Increases expression of energy-producing genes — energy output is increased.
• Decreases inflammatory end-products and the toxic load on the mitochondria.
• Ketosis protects mitochondria from damage
• Cut out dairy, grain and yeast

AVOID
* 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 — this is why a ketone breath meter is so helpful  to show you are in ketosis  if you have any amount of ketones, your blood sugar will be fine.
* 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.

Question 29

How to determine you are in ketosis — three types of ketones:

Answer 29

• 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.  good in the early days of ketosis
• 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. Measured in part per millions (ppm) – same technology as testing alcohol. You have a false positive you have a fermenting gut and a false negative if you have just eaten.
• When sufficiently low in carbs, expect to blow 2–6 (ppm) of ketones. ppm = parts per million

Question 30

What can cause high ketone up to 10 ppm?

Answer 30

Very high ketones (up to 10 ppm) may occur because:
* When stressed, an outpouring of adrenaline stimulates fat burning.
* Fasting — even on a PK diet you consume some carbohydrates! With fasting you get ALL your calories from fat, so ketones are higher. This illustrates the point that even in mild ketosis
you will be using some sugars as a fuel — that is fine!
* Over-dosing with thyroid hormones may cause high levels.

Question 31

What can cause a false positive when in ketosis?

Answer 31

How to determine you are in ketosis — false positives:
* The mechanism used to measure ketones is the same as that for measuring alcohol. You may see a positive if you have consumed any alcohol in the past 24 hours (depending on how much!)
* If you have SIBO, this too produces alcohol.
* Any products containing alcohol may give a positive result e.g., an alcohol wipe to clean the mouthpiece.
* The meter measures parts per million — it is very sensitive! Only a tiny amount of contaminant can upset the result.
* Many household cleaners contain volatile organic compounds which may register on the meter!

Question 32

2. Mitochondrial engine => what nutrients?

Answer 32

• CoQ10 100‒300 mg.
• Magnesium 300 mg (absorption enhanced by vit. D 10,000iu / day).
• Niacinamide 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

Question 33

Factors that inhibit mitochondrial function:

Answer 33

Lactic acid * Pace activity carefully.

Products of the ‘fermenting gut’ – incl. alcohol make us feel fatigue because block mitochondria. * 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.
Superoxide dismutase (zinc, magnesium copper)
Glutathione peroxidase (selenium, CoQ10)
Vit D, B vitamins
Vitamin C

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.

Question 34

3. THE CONTROL MECHANISM in CFS and ME

Answer 34

3. The control mechanisms — balance the thyroid (accelerator pedal) and adrenal glands (gear box).
   * The thyroid and adrenal glands allow energy delivery to be matched closely with energy demands.
   * They are also essential for circadian rhythms.