Around 250,000 people in the UK are currently thought to be affected by CFS/ME. The high level of disability that is often associated with this debilitating condition can be both physically and mentally challenging for patients and appears to stem from a combination of symptoms such as fatigue, pain, sleep disturbance, cognitive impairment, depression and, in many cases, symptoms mirroring those of irritable bowel syndrome. With no current cure and no validated, universally accepted, ‘one-size-fits-all’ approach to the treatment, many clients are seeking natural alternatives to conventional approaches. Taking a personalised and functional medicine approach, Dr Nina Bailey reviews the latest science on ME/CFS and the underlying mechanisms that can be targeted with nutritional interventions and explains how to ensure your therapeutic approach is right for your clients. Covered in the webinar: 1. CFS/ME background /causes/symptoms 2. Update on the mechanisms associated with CFS/ME: - Immune disturbances - Oxidative stress and inflammation - The kynurenine pathway and neurotransmitter dysregulation - Mitochondrial dysfunction and related mechanisms * Methylation * Detoxification * Glycolysis * Citric acid cycle/Krebs * Oxidative phosphorylation 3. An overview of current treatment options 4. Nutritional intervention – an evidence-based approach 5. Nutritional supplementation

1. Dr Nina Bailey BSc, MSc, PhD, RNutr
1
Managing CFS/ME: a clinical
approach

2. CFS/ME is a condition that causes fatigue severe enough to
interfere with a person’s normal life
According to the NHS, it’s estimated that approximately 250,000
people in the UK have CFS/ME
The high level of disability that is often associated with this
debilitating condition can be both physically and mentally
challenging for patients and appears to stem from a combination
of symptoms
With no current cure and no validated, universally accepted,
‘one-size-fits all’ approach to the treatment, many clients are
seeking natural alternatives to conventional approaches

3. Causes / triggers
• Viral / bacterial infections (e.g. glandular fever,
pneumonia)
• Immune dysfunction (e.g. Th2 dominance, reduced
NK-cells)
• Mental health problems (e.g. stress or emotional
trauma)
• Genetic predisposition
• Environmental factors (e.g. multiple chemical
sensitivity)
• Mitochondrial dysfunction

4. CFS/ME symptoms
• Severe fatigue that's not improved by rest and not explained
by other causes
• Post-exertional malaise, where symptoms get worse after
any physical or mental activity
• Loss of memory or concentration (brain fog)
• Unrefreshing sleep and/or insomnia
• Flu-like symptoms
• Muscle pain
• Frequent headaches
• Feeling sick/dizzy/palpitations

5. ‘energy currency’
Cellular respiration is a 4-stage process in which biochemical
energy from nutrients are converted into the energy currency adenosine
triphosphate (ATP)
ATP consists of an adenine nucleotide (ribose sugar, adenine base and phosphate
group, PO4
-2) plus two other phosphate groups
The bond that holds the third phosphate molecule is easily broken and when
phosphate is removed, energy is released and ATP becomes ADP which must then
be ‘recycled’ back to ATP

6. Pyruvate
Acetyl
CoA
Electron Transport Chain
& oxidative phosphorylation
Citric acid
cycle
Glucose
Pyruvate
Produces 2 ATP
Cytosol
Mitochondria
Lactate
Anaerobic
fermentation ATP
production stops
Chest pain &
muscle pain
Aerobic - moves
to mitochondria
Produces 2 ATP
Produces 34 ATP
The final product of glycolysis is pyruvate in aerobic conditions
and lactate in anaerobic conditions
Net yield aerobic = 38 ATP
Net yield anaerobic = 2 ATP
GLYCOLYSIS

7. Glycolysis occurs in the cytosol of the cell and produces pyruvate (from
glucose) which is transformed into acetyl-CoA
Pyruvate moves from the cytosol to the mitochondria and is converted to
acetyl-CoA by the enzyme pyruvate dehydrogenase complex (consisting of
three enzymes & five coenzymes)
The coenzymes are derived from water-soluble vitamins:
• Thiamine pyrophosphate (derived from thiamine)
• Nicotinamide adenine dinucleotide (NAD+ [derived from niacin])
• Flavin adenine dinucleotide (FAD [derived from riboflavin])
• Lipoic acid
• Coenzyme A (derived from pantothenic acid)
Pyruvate Acetyl CoAGlucose
Fat (b-oxidation)
Protein catabolism

9.  Mitochondria function to generate ATP (energy rich) from ADP (energy spent) and
CFS is characterised by slow recycling of ADP to ATP
 The reserves of ATP are generally very low and ADP to ATP ‘recycling’ has to be an
efficient process to keep the cell constantly supplied with energy
 If ATP is not available, then the body can use ADP instead (by spending one of its
phosphate groups) resulting in the production of AMP which, unlike ADP, cannot
easily be recycled (2 ADPs = 1 ATP + 1 AMP) meaning that the ADP ‘pool’ (for
making ATP) is reduced
 When patients overdo things and "hit a brick wall" this is because they have
inadequate levels of ATP and ADP

10. • The transporter facing outwards ('c-
state') ‘catches’ an ADP molecule
then inverts (‘m-state') to release the
ADP into the matrix
• An ATP molecule then moves into the
'empty' transporter which inverts,
transferring it to the cytoplasm (and
the process starts again)
• Mitochondrial synthesis of ATP requires ADP transport from cytosol into mitochondria
• Transport of ADP into the matrix is required to ensure that there is a level high
enough for ATPase to convert it to ATP. Once generated, ATP must then be transported
out of the matrix to the cytoplasm
• Both ADP and ATP are highly charged (ADP-3 & ATP-4) and cannot diffuse across the
membrane but must be actively transported across the membrane and the
mitochondrial ADP/ATP ‘transporter’ functions to exchange free ATP with free ADP
across the inner mitochondrial membrane (as ATP moves out, ADP moves in)

11. ADP/ATP transporter inhibition
• If this transfer is blocked then ATP and ADP cannot be exchanged
• Changes in the acid/base balance will affect the proton-motive force which drives
ATP synthesis, thereby reducing ATP synthesis
• Compounds which induce calcium efflux from calcium-loaded mitochondria
generally provoke membrane leakiness (exacerbated by low magnesium status)
• Low magnesium status, the presence of toxic metabolic products (byproducts of
viral or bacterial pathogens), cellular debris due to oxidative damage and some
environmental chemicals can inhibit the ADP/ATP transporter (explaining the
multiple chemical sensitivities experienced by some sufferers)
ADP/ATP transporter results in the compensatory activation of glycolysis to
pyruvate

12. Inflammation in CFS/ME
• Increased levels of inflammatory cytokines can induce /contribute to glutathione
depletion, which, in turn, may activate redox-sensitive transcription factors, such as NF-
κB (driving inflammation by triggering pro-inflammatory cytokine production)
• Poor sleep quality (common in CFS/ME) has been shown to be associated with greater
pro-inflammatory cytokine levels (e.g. IL-1β, IL-6 & TNF-α) and, in turn, greater fatigue,
fatigue-related interference with daily activities and more severe and frequent core
CFS/ME symptoms
• The subsequent ATP deficit together with inflammation and ROS/NOS are responsible for
the landmark symptoms of CFS/ME including post-exertional malaise
• Depletion of glutathione (high ROS) results in lowered Th1 activity and higher Th2 activity
Fletcher MA et al., Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12;7:96.
Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome.
Brain Behav Immun. 2010 Oct;24(7):1209-17.
Milrad SF et al., Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of
chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women. J Neuroimmunol. 2017 Feb 15;303:43-50
OXIDATIVE STRESS INFLAMMATION

13. Immune disturbances in ME/CFS
• ME/CFS patients routinely present with impaired Th1 function
(adaptive immunity critical to antiviral defence), a Th2 shift (innate
defence), pro-inflammatory cytokine up-regulation, increase in T-
regulatory (Treg) cells and down-regulation of important mediators
of cytotoxic cell function (natural killer cells [NK cells])
• Because NK cells play a role in the generation of Th1 immune
responses, the loss of NK activity might be related to the presence
of a Th2 bias and persistent viral activation and chronic infection
that is often seen in CFS/ME (explaining the frequent episodes of flu-
like symptoms)
Brenu EW et al., Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. 2011 May
28;9:81.
Rivas JL, Palencia T, Fernández G, García M.Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS). Front Immunol. 2018 May 9;9:1028.
Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory,
oxidative and nitrosative stress pathways. Metab Brain Dis. 2014 Mar;29(1):19-36

15. The mitochondrial permeability transition pore
• Opening of mPTP aids to eliminate dysfunctional mitochondria by mitophagy (the process by
which damaged parts of mitochondria are degraded as a protective mechanism to prevent
apoptosis)
• Opening of mPTP causes the collapse of the mitochondrial membrane potential which
interferes with the production of ATP
• This is because the mitochondria requires the electrochemical gradient to provide the driving
force for ATP production (pumping H+ through ATPase to provide the energy for the
phosphorylation of ADP to make ADP)
• Oxidative stress/inflammation/CoQ10 and (or) glutathione deficiency cause mPTP to open
• Magnesium also helps to keep the mPTP closed by competing with calcium for the binding
sites on the matrix and/or the cytoplasmic side of the mPTP (high calcium can open mPTP)
Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. Increased ventricular lactate in chronic
fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012
Sep;25(9):1073-87
Papucci, L., Schiavone, N., Witort, E., Donnini, M., Lapucci, A., Tempestini, A., Formigli, L., Zecchi-Orlandini, S., Orlandini, G., Carella, G., Brancato, R. and Capaccioli,
S., 2003. Coenzyme Q10 prevents apoptosis by inhibiting mitochondrial CoQ10 deficient-induced depolarization independently of its free radical scavenging
property. Journal of Biological Chemistry, 278(30), pp.28220–28228.

16. CoQ10, mitochondrial function & ATP
• CoQ10 deficiency decreases the numbers of healthy mitochondria
– CoQ10 is an essential cofactor for the enzyme dihydrooratate dehydrogenase
(DHODH) involved in de novo pyrimidine synthesis that is required for the
generation of mitochondrial DNA
– reduced gene expression related to mitochondrial biogenesis (related to fision
and fusion)
• CoQ10 deficiency triggers the opening of the mitochondrial permeability transition
pore (mPTP) leading to increased ROS
• Opening of mPTP causes the collapse of mitochondrial membrane potential and
lowers the production of ATP (mitochondria require an electrochemical gradient to
provide the driving force for ATP production) triggering mitophagy
• Excessive mitophagy induces ATP-dependent apoptosis (cell death) thereby
exacerbating ATP depletion with the potential to induce further production of pro-
inflammatory cytokines
Rodríguez-Hernández A, Cordero MD, Salviati L, Artuch R, Pineda M, Briones P, Gómez Izquierdo L, Cotán D, Navas P, Sánchez-Alcázar JA. Coenzyme Q
deficiency triggers mitochondria degradation by mitophagy. Autophagy. 2009 Jan;5(1):19-32.

17. • ATP production is accompanied by production of ROS as a ‘normal’ by-product through
leakage of electrons from the electron transport chain
• Low levels of ROS are directly removed by antioxidants (such as ubiquinol) within
mitochondria
• Because of their role in metabolism, mitochondria are very susceptible to ROS damage
and excessive accumulation of ROS during stress damages mitochondrial components
including mitochondrial DNA, protein and lipids, which further exacerbates ROS
production and mitochondrial dysfunction
• Normal mitochondria will eventually accumulate oxidative stress and poor quality
mitochondria may enhance cellular oxidative stress, generate apoptosis signals and
induce cell death
• Owing to their bacterial origin, mitochondria have their own genome and can
autoreplicate via ‘mitochondrial biogenesis’
ROS and mitochondria

18. ROS leads to damaged
mitochondria
Fission (dissection)
Selection
Mitophagy (elimination)
Autophagosome
ROS production also activates
pathways to prevent detrimental
consequences of ROS by activating
pathways and transcription factors
that regulate mitochondrial
biogenesis
Mitochondrial biogenesis
Fusion
Biogenesis

19. Biogenesis
AMPK: AMP-activated protein kinase; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α
AMPK acts as an energy sensor and
regulator of biogenesis activating PGC-1α
the “master regulator”
Fusion of the outer mitochondrial membrane is
mediated mitofusins (Mtf 1 & 2), and fusion of
the inner membrane mediated by Opa1
mtDNA transcription and
replication (e.g. nuclear respiratory
factors Nfr1 & Nfr2)
Fission is regulated by
dymin-1-like protein (Drp1)
Mitochondrial bioenergetics
and dynamics (balancing
fission with fusion)

20. Biogenesis
AMPK: AMP-activated protein kinase; SIRT-1: sirtuin-1; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α
AMPK acts as an energy sensor and
regulator of biogenesis activating PGC-1α
the “master regulator”
Fusion of the outer mitochondrial membrane is
mediated mitofusins (Mtf 1 & 2), and fusion of
the inner membrane mediated by Opa1
mtDNA transcription and
replication (e.g. nuclear respiratory
factors Nfr1 & Nfr2)
CoQ10 deficiency and mitochondrial bioenergetics
Low mitochondrial fusion proteins result
in increased mitochondrial fragmentation
(high numbers of low quality
mitochondria)
Low mtDHA can also be caused by low CoQ10
which is also an essential cofactor for the
enzyme dihydroorotate dehydrogenase
(DHODH) involved in de novo pyrimidine
synthesis
Depleting cells of Drp1 leads to
mitochondrial dysfunction
(mitochondria cannot fragment),
leading to an increase in cellular ROS
levels, loss of mtDNA which is
accompanied by a drop in cellular ATP
levels, a proliferative arrest and
apoptosis
Fission is regulated by
dymin-1-like protein (Drp1)

21. Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in
patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301-7.
Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries CG. Response to vitamin B12 and folic acid in myalgic encephalomyelitis
and fibromyalgia. PLoS One. 2015 Apr 22;10(4):e0124648. doi: 10.1371/journal.pone.0124648. eCollection 2015.
Glutathione Depletion-Methylation Cycle Block
Homocysteine is a natural by-product of the methylation cycle and can be
remethylated to methionine or directed to the transsulfuration pathway
Sulfur containing amino
acids (e.g. methionine and
cysteine) are extremely
sensitive to almost all
forms of ROS/RNS which
can have direct impact on
methylation processes
Increased concentrations of homocysteine have been found in the
cerebrospinal fluid in patients with ME/CFS/FMS

22. Methionine
recycling
Methionine
Homocysteine
SAM
SAH
Methionine
synthase
5-methyl THF
Increased oxidative stress in CFS can cause a partial
block of the methylation cycle through inhibition of
methionine synthase with a subsequent negative
impact on glutathione
FOLIC ACID
CYCLE
Disrupts gene expression
Decreased neurotransmitter function
Decreased myelination
Disrupted cellular energy transfer
Disrupted fatty acid metabolism
Increased allergic reactions
Cystathionine
Reduced
detoxification
of toxins and
heavy metals
Cysteine
Glutathione
Metallathionines
Affects potent metal-
binding and redox
capabilities
Cysteinesulflinic acid
Phenol sulfur-
transferase
Poor phenol
processing
Poor
digestion
Sulphate
Sulphite
Taurine
Production of
bile salts
SULPHATIONTRANSSULFURATION
METHYLATION
Gut and blood brain
barrier integrity
compromised
Poor
detoxification
Inactivates
MAT and
decreases
SAM synthesis
Villi flatten
and lose
function
Reduced
antioxidant
function
Th1 decreases
Th2 increases
S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH); methionine adenosyltransferase (MAT); tetrahydrofolate (THF)
THF
Glutathione levels
drop, ROS
increases, with a
shift from Th1 to
Th2 that leaves the
patient immune
compromised
Chronically impaired
detoxification leads to
xenobiotic accumulation,
increased ROS and
inflammation

23. Increase glutathione levels
Up-regulate glutathione-related enzymes including glutathione reductase and
glutathione S-transferase
Anthocyanins are members of the flavonoid group of phytochemicals, a group
predominant in teas, honey, wine, fruits, vegetables, nuts, olive oil & cocoa
Cruciferous vegetables such as broccoli, kale and cabbage contain antioxidants
that increase the production of detoxifying enzymes in the body
Sulphur-rich foods such as onions and garlic, cauliflower, eggs, Brussels sprouts &
broccoli
Cysteine-rich foods: soya beans, egg white, oats & tofu, providing the body with
the balance of nutrients that make (glutathione = L-cysteine + L-glutamic acid
+ glycine)
Increasing glutathione helps keep the mPTP ‘closed’ and by doing this, supports
the proton-motive force required to drive ATP synthesis

24. Inflammation and oxidative stress
(IFN-g, TNF-a, IL-1, IL-6 & cortisol)
increase the activity of the
enzyme IDO which catalyses the
oxidation of tryptophan to
N-formylkynurenine, kynurenine
and the downstream QA
Kynurenine
Quinolinic acid
(QA) NMDA receptor
Tryptophan
Symptoms
Sleep disturbance
Depression
Low libido
Fatigue
Brain fog
Cognitive dysfunction
IDO
The NMDA receptor is important for controlling
synaptic plasticity and memory function.
Magnesium supplementation plays a ‘calming’
role in the regulation of NMDA by acting as a
gatekeeper and preventing overstimulation
Glutamate
(excitatory neurotransmitter)
GABA
(inhibitory neurotransmitter)
Requires vitamin B6 and
magnesium
Omega-3 EPA &
ubiquinol can all
reduce the
conversion of
tryptophan to QA
glutamate decarboxylase
QA promotes glutamate release and blocks its reuptake leading to
overstimulation of NMDA receptors.
QA inhibit glutamine synthetase that breaks down glutamate to glutamine.
While glutamate is the primary excitatory neurotransmitter, gamma-
aminobutyric acid (GABA) is the chief inhibitory neurotransmitter derived
from glutamate and that serves to balance glutamate.
QA also inhibits the activity of glutamate decarboxylase - an enzyme that
catalyses the decarboxylation of glutamate to GABA.
QA can decrease the activity of antioxidant enzymes thereby promoting
oxidative stress and generating lipid peroxidation.
QA inhibits the activity of mitochondrial complexes required for ATP
production

25. While glutamate is the primary excitatory neurotransmitter, gamma-aminobutyric acid
(GABA) is the chief inhibitory neurotransmitter that serves to balance glutamate .
Therefore both neurotransmitters work together to control many processes, including
the brain's overall level of excitation.
Magnesium and GABA
In addition to low magnesium status, an imbalance between GABA and glutamate is
exacerbated by dietary factors, stress & inflammation.
Glutamate decarboxylase
catalyzes the decarboxylation
of glutamate to GABA (requires
pyridoxal-5-phostaphate and
magnesium as cofactors).

26. Fatigue
Inflammation/ROS/RNS
Mitochondrial
dysfunction
Impaired ETC and oxidative phosphorylation
• Reduced citrate synthase activity (an essential enzyme in the citric acid cycle)
• Reduced levels of succinate reductase (Complex II) and cytochrome-c oxidase
(Complex IV)
• Reduced CoQ10 levels
Impaired energy production
• Dysfunctional ADP/ATP concentration
• Low quality mitochondria
• Dysfunctional ATP recycling
Increased oxidative stress
• Low antioxidants (e.g. glutathione, superoxide dismutase, catalase, GSH
peroxidase, GSH reductase)
• Increased oxidative stress (e.g. ROS/RNS, malondialdehyde, F2-isoprostanes)
Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of Mitochondrial Dysfunction and Fatigue: A Review of
the Literature
Maes M, Twisk FN.Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and
oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-
93. Review.

27. Inflammation, leaky gut and CFS/ME?
• NF-kB, proinflammatory cytokines and oxidative and nitrosative stress
(ROS/RNS) can lead to a disruption of epithelial tight junctions in the intestine,
allowing translocation of gram-negative bacteria, containing lipopolysaccharides,
into the circulation, stimulating TLR4 mediated pathways (hypersensitive
microglia often appear in ME/CFS/FMS)
• Prolonged and /or excessive stimulation of membrane-bound TLR4 results in the
further production of pro-inflammatory cytokines and ROS/RNS
• Increasing levels of ROS/RNS damage mitochondrial lipids and proteins leading
to dissipation of the mitochondrial membrane potential and inhibition of the
electron transport chain
• This leads to compromised oxidative phosphorylation and to the further
production of ROS, making another major contribution to the inflammatory
milieu related to fatigue
Filler K, Lyon D, Bennett J, McCain N, Elswick R, Lukkahatai N, Saligan LN. Association of Mitochondrial Dysfunction and Fatigue: A Review of
the Literature.BBA Clin. 2014 Jun 1;1:12-23.
Schulzke JD, Ploeger S, Amasheh M, Fromm A, Zeissig S, Troeger H, Richter J, Bojarski C, Schumann M, Fromm M. Epithelial tight junctions in
intestinal inflammation. Ann N Y Acad Sci. 2009 May;1165:294-300.
Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis
(ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85.

28. Improving gut health – improve nutrient absorption
Several probiotic strains such as Lactobacillus Bacteroides thetaiotaomicron,
Bifidobacterium longum and Lactobacillus rhamnosus, Bifidobacterium infantis,
Lactobacillus plantarum shown to have beneficial effects on tight junction - and intestinal
barrier function
 Increasing zonula occludens-1 (ZO-1)
 Increased transcription of occludin and cingulin genes
 Decreased faecal zonulin levels (a marker indicating enhanced gut permeability)
 Decreased proinflammatory cytokines
 Short-chain non-digestible carbohydrates (inulin-type fructans, fructo-
oligosaccharides (FOS) and galacto-oligosaccharides (GOS)) are the quintessential
prebiotics (occurring naturally in cereals, fruits and vegetables) and the target
bacterial groups are typically Bifidobacterium and Lactobacillus
 Fermented foods like sauerkraut, kimchi, yogurt, kefir
 L-glutamine, vitamins A & D (SigA)
Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC Regulation of tight junction permeability by intestinal bacteria and dietarycomponents.
Nutr. 2011 May;141(5):769-76.
Lamprecht M, Bogner S, Schippinger G, Steinbauer K, Fankhauser F, Hallstroem S, Schuetz B, Greilberger JF
Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. J
Int Soc Sports Nutr. 2012 Sep 20;9(1):45.

29. Current treatments include
 Pain killers (e.g. NSAIDS, COX-2 inhibitors)
 Antidepressants (e.g. SSRIs)
 Exercise therapy/pacing (balancing activity and rest)
 Lightening process® (a combination of osteopathy, life-
coaching and brain training)
 Cognitive behavioural therapy (CBT)
 Lymphatic massage (Perrin Technique)

30. Tests?
• Homocysteine (methylation)
• Magnesium (RBC)
• B12 (RBC)
• Tryptophan/kynurenine ratio
• Omega-3 (inflammation)
• ATP-profile (mitochondrial function)
• Leaky gut

31. Mitochondrial Function Test (Acumen Laboratory)
ATP profiles (3 tests)
•Measure the rate at which ATP is recycled in cells (magnesium dependent)
•Measure the efficiency with which ATP is made from ADP via the oxidative
phosphorylation process (can be linked to magnesium deficiency and/or low levels of
Co-enzyme Q10 and/or low levels of vitamin B3 and/or low levels of acetyl L-carnitine)
•Measure the efficiency for the transfer of ATP from the mitochondria into the cytosol
where it can release its energy as needed
Additional tests
•Nicotinamide adenine dinucleotide (NAD+/functional B3) – metabolic cofactor
•Superoxide dismutase (SODase) - superoxide free radical scavenger
•L-carnitine – transports long-chain fatty acids into the mitochondria
•Cell-free DNA – a marker of tissue injury
•Glutathione peroxidase – major endogenous antioxidant
•Coenzyme Q10 – antioxidant and critical component of the electron transfer chain
Booth NE, Myhill S, McLaren-Howard J.Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20.
Myhill S, Booth NE, McLaren-Howard J.Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.

32. Nutritional interventions for CFS/ME can target:
Mitochondrial dysfunction in CFS/ME
• Deficiency in substrate
• Inhibition of function
Mechanisms related to mitochondrial function/dysfunction
• Methylation
• Detoxification
• Glycolysis
• Citric acid cycle/Krebs
• Electron transport chain
• Oxidative phosphorylation
• ADP/ATP transporter
• Mitochondrial permeability transition pore (mPTP)
Mitochondrial biogenesis
• Changes in mitochondrial numbers, size and/or shape
Booth NE, Myhill S, McLaren-Howard J.Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20.
Myhill S, Booth NE, McLaren-Howard J.Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16.

33. Interventions for CFS/ME
Remove the trigger
Restore function (nutrition)

34. Increase mitochondrial biogenesis
Activating pathways and transcription factors (e.g. AMPK, SIRT1
& PGC-1a) via diet and exercise increases mitochondrial
biogenesis and controls mitochondrial DNA (mtDNA) replication
Exercise
Nitric oxide
NAD+
Cold treatment
Ubiquinol
EPA, DHA & CLA
Calorie restriction/intermittent fasting
Polyphenols (e.g. resveratrol, EGCG & curcumin)
AMPK: AMP-activated protein kinase; SIRT-1: sirtuin-1; PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α

35. Enzyme function (many involved in energy)
ATP-Mg (as the primary source of energy in cells, ATP must be bound to a magnesium ion to be biologically
active)
Protein kinase B (plays a crucial role in multiple cellular processes such as glucose metabolism, apoptosis, cell
proliferation, transcription and cell migration
Hexokinase (glycolysis)
Creatine kinase (plays a major role in the production of energy)
Protein kinase (involved in phosphorylation –’switching on’)
ATPases & GTPases (involved in de-phosphorylation – ‘switching off’)
Na+ /K+-ATPase (involved in sodium/potassium regulation)
Ca2+-ATPase (involved in calcium regulation)
Adenylate cyclase (intracellular signalling – catalyses ATP into the secondary messenger cAMP)
Guanylate cyclase (involved in vasodilation [and therefore blood pressure regulation])
Phosphofructokinase (activated by magnesium and then phosphorylates fructose 6-phosphate in glycolysis
and therefore ATP production)
Creatine kinase (catalyzes the conversion of phosphocreatine, the energy reservoir for regeneration of ATP)
5-Phosphoribosyl-pyrophosphate synthetase (converts ribose 5-phosphate into phosphoribosyl
pyrophosphate (PRPP) which provides the ribose sugar for the synthesis of purines and pyrimidines, used in
the nucleotide bases that make up DNA & RNA)
ATP, adenosine triphosphate; GTP, guanosine triphosphate; K, potassium; Mg, magnesium; Na, sodium; Ca, calcium.
Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kidney J. 2012 Feb;5(Suppl 1):i3-i14.
Restore magnesium

36. • ADVANCED TRIPLE MAGNESIUM BLEND:
combining magnesium citrate, taurate and
bisglycinate enhances magnesium absorption by
utilising multiple magnesium uptake pathways,
avoiding saturation. Taurine and glycine are highly
effective carriers for magnesium.
• FULLY REACTED FORMULA: only fully reacted (not
blended or buffered) magnesium forms are free
from poorly absorbed magnesium oxide. The
enhanced solubility of these fully reacted
magnesium forms optimises absorption potential.
• MULTIPLE HEALTH BENEFITS: magnesium supports
normal energy release, muscle function, electrolyte
balance, nervous system function and normal
psychological function.
• CONSISTENT PRODUCT QUALITY GUARANTEED:
manufactured in the UK in GMP-accredited
facilities.

37. • FULL TRANPARENCY: unlike many of our
competitors who combine two or more
magnesium sources without disclosing the
ratios (which can mislead consumers into
thinking a product is high in a specific
magnesium), we list the bulk and elemental
amounts of each of our magnesiums.
• NO UNNECESSARY FILLERS: we choose to
encapsulate our magnesium to avoid the use of
bulking agents commonly found in tablets.
• SPLIT DOSING FOR ENHANCED UPTAKE: as the
relative absorption of magnesium is inversely
related to the ingested dose, magnesium
absorption is significantly improved by taking
smaller doses throughout the day.
• WE DELIVER 52 % RI: because it’s not how
much you take, but how much you retain.
Excess magnesium cannot be stored and our
ethos is to focus on efficacy of delivery by
tripling our magnesium with the most
absorbable and synergistic ‘carriers’ that target
multiple, unopposed uptake pathways.

38. ‘RESTORE’
pure EPA
‘MAINTAIN’
EPA, DHA and GLA
Minimum 3-6 months
 AA to EPA ratio
 Inflammatory regulation
 Symptoms of inflammatory illness
 Optimum brain, cell, heart, immune
and CNS function
 Optimum wellbeing
 Omega-3 index
 AA to EPA ratio
 Long-term general and cellular health
 Heart, brain and eye health
 Reduce risk of chronic illness and help
protect against inflammatory disease
Therapeutic role of Pharmepa®
RESTORE & MAINTAIN™

39. Primary structural function &
anti-inflammatory
docosanoid production
Resolvins
Protectins
Anti-inflammatory eicosanoid
production
REDUCED INFLAMMATION
Series-3 prostaglandins
Series-3 thromboxanes
Series-5 leukotrienes
Hydroxy fatty acids
Resolvins
DHA
Anti-inflammatory
eicosanoid production
REDUCED INFLAMMATION
Series-1 prostaglandins
Series -1 thromboxanes
DGLA
GLA
LA
EPA
ETA
SDA
ALA
Delta -6 desaturase
Elongase/
desaturaseDelta -5 desaturase
Cyclooxygenase (COX)/lipoxygenase (LOX)
Elongase
Pro-inflammatory eicosanoid
production
INFLAMMATION
Series-2 prostaglandins
Series-2 thromboxanes
Series-4 leukotrienes
Hydroxy fatty acids
AA
COX/LOX
COX
Pro-resolving Lipoxins
Omega-6 Omega-3
Elongase enzyme requirements
Niacin (B3)
Pyridoxial-5-phosphate (B6)
Pantothenic acid (B5)
Biotin (B7)
Vitamin C
Desaturase enzyme requirements
Flavin adenine dinucleotide (FAD)
Riboflavin (B2)
Niacin (B3)
Pyridoxial-5-phosphate (B6)
Vitamin C
Zinc
Magnesium

40. Astaxanthin inhibits oxidative stress-induced
mitochondrial dysfunction
Kim SH, Kim H. Inhibitory Effect of Astaxanthin on Oxidative Stress-Induced Mitochondrial Dysfunction-A Mini-Review. Nutrients. 2018 Aug 21;10(9)
Pashkow FJ, Watumull DG, Campbell CL. Astaxanthin: a novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am J
Cardiol 2008;101(suppl):58D-68D
Kidd P. Astaxanthin, cell membrane nutrient with diverse clinical benefits and anti-aging potential. Altern Med Rev. 2011 Dec;16(4):355-64. Review

41. INGREDIENTS:
Cold-pressed extra-virgin olive oil; AstaPure® from Haematococcus
pluvialis (H. pluvialis) microalgae (10% astaxanthin); capsule shell (gelatine,
glycerol, beta-carotene, caramel E150a).
Astaxanthin’s ROS-scavenging capacity has been shown to be 6000x more than
vitamin C, 800x more than coenzyme Q10, 550x more than vitamin E, 200x more
than polyphenols, 150x more than anthocyanins, and 75x more than alpha lipoic
acid - the majority of the research to date used between 2 mg and 24 mg of
astaxanthin daily
Nishida Y., Yamashita E., Miki W. Quenching activities of common hydrophilic and lipophilic antioxidants against singlet oxygen using chemiluminescence detection
system. Carotenoid Science. 2007;11(6):16–20.
Nutritional information Per capsule
AstaPure® Haematococcus pluvialis
microalgae (10% astaxanthin complex)
42 mg
of which astaxanthin 4 mg
of which lutein 36 mg
of which canthaxanthin 20 mg
of which zeaxanthin 3 mg
of which violaxanthin 0.5 mg

42. CoQ10 is a powerful, fat-soluble, vitamin-like substance
• Two main functions:
• Energy production – cellular respiration
• Antioxidant/antioxidant recycling
CoQ10 – ubiqinone vs ubiquinol
 Ubiquinone – oxidised form
 Ubiquinol – reduced form
96% of CoQ10 within the body is in the form of ubiquinol
Ubiquinol is considered the active form of CoQ10
Ubiquinol wasn’t available in supplements until 2006 - not only is it more
absorbable than ubiquinone but may also exhibit better neuroprotective
effects than ubiquinone
Langsjoen PH, Langsjoen AM. Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone. Clin
Pharmacol Drug Dev. 2014 Jan;3(1):13-7

43. VESIsorbTM
Oil-based
Time (hours)
AUC(0-10hours)mg/mL*h
PlasmaCoQ10(mg/mL)
VESIsorbTM
Therapeutic level
VESIsorbTM delivered CoQ10 is absorbed
FASTER, reaching concentrations that are
STRONGER and stays in the body
LONGER than generic delivery methods
 Fully reduced form of CoQ10
 VESIsorb® technology for enhanced
bioavailability and tissue distribution
 100 mg therapeutic dose
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
7.5
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Oil-based
Cmax
Tmax

44. • CoQ10 synthesis is a complex, multi-step process, requiring several
vitamin cofactors (including vitamin B2 [riboflavin], vitamin B3
[nicotinamide], vitamin B5 [pantothenic acid], vitamin B6 [pyridoxal-5-
phosphate], vitamin B9 [folic acid], vitamin B12 [methylcobalamin] and
vitamin C) as well as several trace elements
• A deficiency in, or low intake of, any of these nutrients has the potential
for negative impact on CoQ10 levels
• The first step in CoQ10 synthesis is biosynthesis of the quinone nucleus of
CoQ10 from the amino acid tyrosine, a step requiring vitamin
B6 (specifically in the form of pyridoxal-5-phosphate)
• It is well established that this initial step is dependent on vitamin B6 and
that low vitamin B6 status has a direct negative impact on blood levels of
CoQ10
Willis R, Anthony M, Sun L, Honse Y, Qiao G. Clinical implications of the correlation between coenzyme Q10 and
vitamin B6 status. Biofactors. 1999;9(2-4):359-363

45. Nutritional information Per dose % RI*
Vitamin C (ascorbic acid) 160 mg 200
Vitamin B3 (niacin) 48 mg 300
Vitamin B5 (pantothenic acid) 36 mg 600
Vitamin B1 (thiamine ) 20 mg 1818
Vitamin B6 (pyridoxal-5-phosphate) 20 mg 1429
Vitamin B2 (riboflavin-5-phosphate 14 mg 1000
Vitamin B12 (methylcobalamin) 900 mg 36000
Folate ([6S]-5-methyltetrahydrofolate) 400 mg 200
Vitamin B7 (biotin) 300 mg 600
*Reference Intake; Quatrefolic® is a registered trademark owned by Gnosis S.p.A.
Methylation support
BIOAVAILABLE FORMS: Super B-Complex delivers maximum levels of key nutrients:
​Quatrefolic® provides the body-ready form of folate, as [6S]-5-methyltetrahydrofolate
the active form of riboflavin, riboflavin-5-phosphate
vitamin B6 as pyridoxal-5-phosphate with cofactor activity
vitamin B12 as methylcobalamin, for enhanced uptake
HIGH DOSE B6, B12 & folate support efficient homocysteine metabolism and methylation pathways,
for heart health & brain function
SPLIT DOSE FOR ENHANCED ABSORPTION: vitamin B12 uptake is optimised by taking tablets twice
daily, morning & evening
SUSTAINED RELEASE: offers longer-lasting action

46. Protocol summary
 Increase mitochondrial biogenesis
 Reduce inflammation
 Reduce oxidative stress
 Support methylation
 Support detoxification
 Improve energy via ATP production

47. Dosing guide
The Opti-O-3 biomarker test is highly effective when used in conjunction with
our therapeutic range of supplements. By identifying the actual dose required
to achieve an omega-3 index of ≥8% and an AA to EPA ratio of 1.5-3:1, it offers
the ideal solution to personalised nutrition.
Product Dose Duration
Pharmepa RESTORE* 4 x 1 capsule daily 6-12 months
Pharmepa MAINTAIN* 3 x 1 capsule daily Follow on from RESTORE
Super-B Complex 2 x 1 tablet daily 6 months minimum
VESIsorb® Ubiquinol 2 capsules daily 6 months minimum
Triple Magnesium Complex 3 x 1 capsule daily 6 months minimum
Astaxanthin 1 capsule daily 6 months minimum
*Suggested minimum doses when it is not possible to use the Opti-O-3 biomarker test.
Capsules and tablets should be taken as a split-dose and with food for
optimum absorption and to improve bioavailability

48. Extra reading?

49. Get in touch!
Dr Nina Bailey
Head of Nutrition
ninab@igennus.com
Twitter @DrNinaBailey