Volume 1 Issue 2
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ES Journal of Nutritional Health
A Proposal for Explaining Progression from Light/Moderate to Severe
Chronic Fatigue

Review Article

Anna Dorothea Höck*

Internal Medicine in Albertus-Magnus University in Cologne, Germany

Received: Apr 30, 2020; Accepted: June 09, 2020; Published: June 11, 2020

*Corresponding author: Anna Dorothea Höck, Internal Medicine in Albertus-Magnus University in Cologne, Germany

Copyright: © 2020 Anna Dorothea Höck. This is an open-access article distributed under the terms of the Creative Commons At-

tribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author andsource are credited.

Abstract
Background: Chronic mild to moderate fatigue is also called chronic idiopathic fatigue. Physicians at best consider
about psychotherapy for treatment. But most physicians do not view this condition as a real disease. In contrast,
debilitating chronic severe disease has been termed chronic fatigue syndrome (CFS), or if more severe, myalgic
encephalopathy (CFS/ME). Meanwhile published metabolic aberrations in CFS/ME suggest estimating these diseases
no longer as mere psychiatric diseases. The metabolic results inspire to further exploration of cell stress response
mechanisms, which are summarized in this paper. Interestingly, cell stress responses were tightly linked to vitamin D3mediated effects, such as homeostatic regulation of metabolism, energy and redox balance, as well as defense against
pathogens and toxins. Specific personality traits, prevalence of indoor activities, latitude and climate predispose tovitamin D3 deficiency, which is supposed to represent a missing link for a comprehensive model of disease progression
from mild chronic fatigue to most severe forms. By diagnosing vitamin D deficiency in early stages of chronic fatigue, theprogression to severe and debilitating chronic fatigue may be prevented. In more severe stages of chronic fatigue, suchas CFS/ME, resistance against mere vitamin D replenishment seems to be the rule. Some causal mechanisms for thisresistance and potential treatment options are shown.

Conclusion: Scientific insight to the biomolecular mechanisms of cell homeostasis helps to understand and treat allclinically manifestations associated with different stages of chronic fatigue.

Keywords

Chronic idiopathic fatigue; Chronic fatigue syndrome/myalgic encephalopathy; Nrf2, vitamin D3; Metabolic/energetic/redox balance; Cell stress defense mechanisms

Introduction
Meanwhile several recent and comprehensive papers
about metabolic alterations in chronic fatigue syndrome/
myalgic encephalopathy (CFS/ME) have been published,serving as an important step to a better understanding. The
patient-physician relation could take profit of these latest

findings. However busy physicians do not have time to go
in the depth of these results. They need a shorter overview
in order to support the needs of their patients. The aim of
this paper is to fill this gap.

Citation: Höck AD. A Proposal for Explaining Progression from Light/Moderate to Severe Chronic Fatigue. ES J Nutr Health. 2020; 1(2); 1008.

ES Journal of Nutritional Health
The more recent metabolic findings have incommon, that they report about a generalized metabolic
reprogramming with alteration of carbohydrate, aminoacid, lipid and nucleotide metabolism. The interdependence
between metabolic, energy, redox and immune regulationand the role of chronic oxidative stress, going along with
low-grade inflammation, altered mitochondrial function
and metabolic reprogramming, are pointed out [1-11].

In particular, the studies of Fluge et al., and Naviaux
et al., help to get a more comprehensive approach tometabolic alterations occurring in CFS/ME. Fluge etal., found increased messenger RNA expressions of thestress proteins “silent mating-type information regulator
protein 4” (sirtuin-4 or SIRT4), pyruvate dehydrogenasekinases 1, 2, and 4 (PDK1, PDK2, PDK4), and peroxisome
proliferator activator receptor 1 delta (PPARδ). SIRT4 andPPARδ gene up regulation correlated with disease durationand severity. They report also a functional inhibition of
pyruvate dehydrogenase complex (PDHC) and glutamate
dehydrogenase (GLDH) resulting in altered metabolic fluxin the tricarboxylic (TCA) cycle and decreased serum levelsof ketogenic and anaplerotic amino acids. The authors
describe also increased coupling between respiration and
ATP generation, and excessive lactate production underenergetic stress. Naviaux et al. report about a metabolic
reprogramming, termed “dauer” (german word for
persistence) in CFS/ME patients. “Dauer” resembles insome manner the hibernation reaction and is viewed as a
“unified hypometabolic cellular response, different fromacute stress response”. Similar to Fluge et al., the authors
describe as well an inhibition of PDHC. They emphasize ashortage of “central gauges of energy metabolism”, suchas flavin adenine dinucleotide (FAD) and nicotinamide
adenine dinucleotide (NAD). These metabolic studies
stimulate to more extensive exploration about generalprinciples of cellular stress responses.
Cell stress activates cell-protective metabolic-energyredox cascades

Cell stress response is mediated by a group of sensor
and simultaneously effector proteins which interact in ahighly cooperative manner [12-29]. The important protein
family of sirtuins (SIRTs) senses elevations of the oxidized/
reduced nicotinamide adenine dinucleotide (NAD+/ NADH)
ratio, which signals energy deficit and redox change [12].
Sirtuins contribute substantially to cell protection against
all sorts of cell challenge. Decreased sirtuin expression

is believed to be responsible for aging conditions andtumorigenesis [12-15]. Up to now, seven sirtuins are
known. SIRT1, SIRT6 and SIRT7 are primarily located in
the nucleus, SIRT2 in the cytoplasm, and SIRT3, SIRT4 andSIRT5 in mitochondria [13,16].

Sirtuins elicit changes of epigenetic, metabolic,energetic and redox functions by removing inhibitory
post-translational proteome modifications (PTMs), suchas acetyl, or acyl, or other moieties from histone proteins,transcription factors and cofactors, and further enzymes[12-17].
The best-studied stress response is that of SIRT1
activation [12,20,21]. SIRT 1 is a predominantly nuclear
stress protein, but acting also in cytoplasm. Starvation,
exercise, cold adaptation, and all sorts of cell stress, suchas pathogens, xenobiotics, and reactive oxygen species(ROS) generation trigger a coordinated and interacting
metabolic, energy and redox response by activating SIRT1
and further members of the stress response pathway, suchas 5’ adenosine monophosphate-activated kinase (AMPK)[18,19], a transcription factor termed nuclear factor
erythroid 2-related factor 2 (Nrf2) [21,24-27], peroxisome
proliferator activator receptor gamma co-receptor 1α(PGC-1α) [12, 22, 23] and forkhead box proteins (FoxO)[12,18]. All these proteins are most important for cellular
adaptation to an actual challenge and metabolic flexibility.

AMPK senses energy depletion in particular by a low
ATP/AMP ratio. It redirects metabolism to energy saving
and metabolic optimization, but in addition, mediates astrong anti-oxidant response by augmenting activity of
the highly redox-sensitive transcription factor, called Nrf2
[18,19,21]. Also Nrf2/PGC-1α co-expression is mediatedby AMPK [22]. PCG-1α enhances energy expenditure,
mitochondrial biogenesis, antioxidant defense, andmitochondrial unfolded protein response (UPRmt) [12,23].
The transcription factors forkhead box proteins, class O(FoxOs) are involved in both a potent anti-oxidation andmetabolic reprogramming, including promotion of glucose
supply for energy generation [18].
In particular, Nrf2 initiates a broad antioxidant andalso detoxifying response through induction of target
genes, such as the antioxidant machinery of glutathione/
thioredoxin systems, reductases, perioxidases, superoxide
dismutases 1 and 2, NAD (P) H:quinone oxidoreductase-1,
aldo-keto-reductases, drug metabolizing isoenzymes ofphase I and II, and multi-drug effusion pumps of phase III

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ES Journal of Nutritional Health[18,21,24-27]. Nrf2 is also involved in wound healing [25].
This Nrf2-related stress response contributes substantiallyto a metabolic switch resulting in enhancement of glucose
flow to the pentose phosphate pathway which promotes
cytosolic NADPH generation, used for anti-oxidative oroxidative defense, depending on cellular needs. Nrf2
promotes also serine and purine synthesis and metabolic
flux through the TCA cycle in order to provide energy
and metabolic intermediates [21, 26,27]. Serine is not
only used for glycine and nucleotide synthesis, but also
for synthesis of sphingolipid and phosphatidylserine
head groups in cell membranes [26]. On the other hand,Nrf2 regulates negatively pyruvate kinase and ATP-citratelyase, thus suppressing synthesis and storage of lipids[21]. Importantly, Nrf2 supports removal of defective
cell organelles and toxic proteins by enhancing cellular
autophagy/mitophagy and mitochondrial regeneration[21,26]. In addition, Nrf2 enhances gene expressionof all ferritin subunits and the iron-exporting protein
ferroportin, whereas suppressing gene expression of theiron transport-inhibitor hepcidin. Binding of hepcidin toferroportin induces ferroportin decay. Thus Nrf2 protects
potential toxic iron effects by supporting iron uptake,cellular exit and safe storage for use in erythropoiesis
or iron-dependent enzymes (24). Since Nrf2 activationand stabilization requires carbon monoxide (CO) andbiliverdin production through heme-oxygenase-1 (HO1),
and activated HO1 releases free iron, the iron-regulatory
function of Nrf2 seems to be most useful [24].
Though most actions of Nrf2 are highly cell protective,
excessive Nrf2 upregulation is reported to result in cancer
and other unwanted side effects, on the other hand [21,2427]. Of interest, many nutritional compounds are known to
induce Nrf2 activation by generating mild oxidative stress[24].

In summary, the cooperative gene expression andmutual activation of several stress-activated proteinspromote a most protective response which includes antiinflammation, anti-fibrosis, proteome, metabolic, energetic
and redox homeostatic flexibility, survival and longevity.
Nrf2 and SIRT1 are key components of this regulatory
network.
Cellular regulation depends on NAD+/NADH ratio, andcellular NAD pools

The amount of synthesis of the pyridine-nucleotide
containing molecules NAD+/NADH, and the phosphorylated

counterparts NADP+/NADPH are of paramount importancefor orchestrating cellular functions according to cellularneeds [16,28-32]. They are not only universal cofactors
for metabolic enzymes, but also cooperate with genetranscription and coordinate cellular metabolism,
energy and redox regulation. A high ratio of NAD+/
NADH signals decrease of energy and redox balance,
followed by activation of nuclear SIRT1 and mitochondrial
SIRT3, directing metabolism either to energy-saving andstress defense or to processes linked with more energy
expenditure. In contrast, a sufficiently high NADPH/
NADP+ ratio are necessary for adequate anti-oxidation,
detoxification, pathogen defense and biosynthesis.

However, not only the ratios of NAD (P)+/NAD(P)H are
important for cellular functions, but also the amount of NADpool in different cell compartments [12-15,28]. This pooldecreases through sirtuin-dependent deac(ety)lations,since the hydrolytic cleavage of NAD produces O-ac(et)ylADP ribose and nicotinamide [16]. Nicotinamide inhibits
SIRT1 and SIRT3, but can become rebuilt to NAD throughthe so-called salvage pathway which is an ATP-consuming
process. A more severe NAD consumption occurs throughactivation of the enzyme termed poly (ADP-ribose)polymerase transferase 1 protein (PARP1), acting either
as DNA-repair enzyme, but also as inhibitory poly-ADPribosylating enzyme in energy-regulation pathways[12,14,16,33,34]. Also enzymes called ADP-ribosylcyclases(CD38/CD157) contribute to NAD consumption [35, 36].
They produce ADP-ribose derivatives which enhance theactivity of calcium transporting ion channels [16,30,37]. Of
importance, decline of NAD-pools are reported to induce
SIRT4 up regulation [38], which is able to function as ADPribosyl transferase, thus consuming NAD by its own, andto compromise mitochondrial functions [33]. Nuclear NAD
decline has been found to disrupt nuclear-mitochondrialcommunication [39].
The difference between SIRT1/SIRT3 against SIRT4cell response

Nuclear SIRT1 and also the mitochondrial equivalent,
SIRT3, function mainly as deacetylases and activate
the acute stress response cascade of AMPK, Nrf2, PGC1α, and FoxO proteins [12,14,40,41]. Activity-induced
glycolysis in muscle cells, mitochondrial electrontransport, nucleotide synthesis, overall cell defense,and flexibility of metabolic-energy-redox regulation
are promoted [12-15]. Furthermore, SIRT1 prevents

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ES Journal of Nutritional Healthadiposity and insulin resistance by inducing homeostasis
of fatty acid, lipid and cholesterol metabolism throughactivation of liver X receptor (LXR) [42]. Additionally,
SIRT1 interacts with the circadian regulatory machinery[43,44]. Interestingly, a link between circadian andmemory dysregulation has been reported [45].
Most importantly, SIRT1 antagonizes NAD-consuming PARP
1 activity through deacetylation [14,16]. In turn, PARP1
protein antagonizes SIRT1, since the PARP-dependent
decline of NAD pools inhibits SIRT1 activity [14]. Also free
radicals and high fat diet inhibit SIRT1 activation [46,47].

SIRT4 effects are less well studied than those of
SIRT1. SIRT4 regulates metabolism in a total differentmode compared to SIRT1 [36]. SIRT4 is highly expressedin muscle, kidney, testis and liver cells. SIRT1 and SIRT4
share some cell-protective effects, such as enhancementof NAD synthesis [17], suppression of the activationof pro-inflammatory nuclear factor kappa-lightchain-enhancer of activated B-cells (NFkB) [14,35],
and prevention of DNA damage [36]. Of note, SIRT4
becomes antagonized through high activity of SIRT1
and of mechanistic target of rapamycin (mTORC1),and also through abundant leucine availability [36].
In contrast to SIRT1, SIRT4 acts not predominately as histone
deacetylase, but mostly as deacylase, de-lipoamidase
and ADP-ribosyltransferase [36]. The activation of SIRT4
is promoted through the fed state, while inhibited in thefasting state [36,48]. SIRT4 represses mostly metabolic
enzymes, instead of enhancing them like the other sirtuins[49]. Unlike SIRT1, SIRT4 neither augments glucose uptake
and oxidation, nor promotes β-oxidation of fatty acids[36,50]. Instead, lipid synthesis is enhanced [48]. SIRT4
mediates reduced electron flow through the TCA cycle
through inhibitory de-lipoamidation of PDHC and also
through inhibitory ADP-ribosylation of GLDH [36,51]. As
a result, pyruvate and glutamine entry into the TCA cycle
is inhibited, followed by diminished α-ketoglutaric acidgeneration, thus inhibiting cell proliferation and tumor
growth [36]. SIRT4 also controls insulin secretion byenhancing the insulin-degrading enzyme and decreasing
leucine availability [15,36,48,50].

As the multiprotein enzyme complexes of PDHC,
α-ketoglutaric acid dehydrogenase (αKDGH) and branchedchain amino acid dehydrogenase (BCKDH) share thesame dihydrolipoyl-containing E2 and E3 subunits, thede-lipoamidase activity of SIRT4 might affect all threeof these mitochondrial dehydrogenases [51]. These

dehydrogenases generate high amounts of ROS, but are inturn ROS-sensitive, showing functional activation by low,
but auto-inhibition through high amounts of ROS [52]. Of
note, ROS-dependent activation of PDK1, PDK2, and PDK4
results in an additional inhibition of PDH through PDHC
phosphorylation, which is supposed to contribute as well
to TCA cycle obstruction [53].
On the one hand, SIRT4-dependent deacylation of
adenine nucleotide translocator 2 (ANT2) abolishes theuncoupling ability of ANT2, thus enhancing transportof ADP/ATP across the inner mitochondrial membrane,
resulting in facilitated ATP generation [36,54]. On the other
hand and in contrast to all other known sirtuins, SIRT4
mediates increase in ROS generation, and not decrease[46,54]. ROS levels become elevated through SIRT4dependent repression of SOD2 and GLDH [54], and throughenhanced angiotensin II activity [17]. The augmented
ROS-generation is thought to cause the observed exercise
intolerance and neuro-immunologic dysregulation in caseof SIRT4 overexpression [48,54].
Taken together, the knowledge that metabolic,energetic and redox regulation is interrelated throughseveral central and universal sensing and signaling tools,
such as NAD(P)+/NAD(P)H ratio, NAD pools, ROS andfree calcium levels, provides a comprehensive approachto diseases going along with chronic fatigue. NAD
consumption is supposed to be an important missing link
to explain metabolic reprogramming towards a SIRT4dependent pattern. Whereas SIRT4 appears to maintainlife and basal functions, the elevated basal ROS level anddecreased metabolic flexibility are supposed to explain
the striking exertional incapacity of CFS/ME patients. The
SIRT1-dependent cascade of stress defense and adaptation
appears to be suppressed due to low NAD pools. According
to Naviaux et al., “harsh conditions” induce the metabolic
switch to SIRT4-associated condition of “dauer”.
What “harsh conditions” may act on CFS/ME patients?

Listening to the reports of CFS/ME patients about
preceding life events, indeed stressful conditions can befound most frequently before disease outbreak, such as
infection, high workload, accidents, in particular if followed
by immobilization, operations, xenobiotic contact, orloss of a beloved person, besides other sorts of possible
triggers. However, such events belong more or less tocommon life course. So why recover many individuals andothers not? Difficult interpersonal problems, which would

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ES Journal of Nutritional Health

Figure 1: Proposed model for transition from idiopathic chronic fatigue to CFS/ME

CFS: Chronic Fatigue Syndrome; ME: Myalgic Encephalitis; NAD: Nicotinamide Adenine Dinucleotide; SIRT:
silent mating-type information regulator protein
explain persistent mental stress, are usually very rare inlife histories of CFS/ME patients, according to the author’s
own clinical experiences. Yet, there can be found a highprevalence of highly motivated and engaged personalities,
with high self-demands, and high-grade premorbid
functional capabilities. This might result in insidious NAD
consumption, which at first induces chronic idiopathic
fatigue. Their high motivation disposes these individuals
to neglect this condition mostly. Only after the second hit,
which is conceived as disease trigger, they realize thatthey are no longer able to cope with demands of theirusual life (Figure 1). Of note, the fact that most patients
report premorbid high physical and mental performance,
contradict the hypothesis, that inherited genetic
conditions might be responsible for disease development.
However, the existence of vitamin D3 deficiency, preceding
and accompanying these life stresses, would explain why
exactly these personalities progress to CFS/ME.
Vitamin D3 supports SIRT1-driven pro-survival andlife-span extension

Western world life style, prevalent indoor activities,
reduced outdoor leisure and diligent use of highly
protective sunscreen are usual factors promoting vitamin
D deficiency. Later-on after transition from idiopathic
fatigue to CFS/ME, the muscular weakness and light
hypersensitivity are the most potentiating factors forlack of sunlight. All this diminishes the synthesis of
25-hydroxyvitamin D3 (25OHD3), which is the precursor
molecule of the active 1α,25-dihydroxyvitamin D3[1,25(OH)2D3] [55,56]. Therefore vitamin D deficiency/
insufficiency is indeed a very common and mostly
overlooked condition in populations. As a rule, very
busy people are affected, but also all those who aredisabled through chronic health problems, including
those suffering already from CFS/ME/fibromyalgia.
1,25(OH)2D3 binds to and activates the dimeric protein
complex vitamin D receptor protein/retinoid X receptor α(VDR/RXRα), then acting as a transcription factor which
modifies the expression of up to 500 target genes [56-60].
Some plant ingredients such as curcumin, polyunsaturated
fatty acids, anthocyanidins, and in particular resveratrol,
initiate and augment VDR signaling [56]. On the contrary,xenobiotics and drugs, such as cortisone, anti-epileptics
and antiretroviral drugs can induce vitamin D3 deficiency,
by binding to the xenobiotic dimer receptor protein
pregnane X receptor/retinoic X receptor-α (PXR/RXR)[61]. As this dimer and the VDR/RXR dimer share thesame DNA-binding protein RXR, and additionally PXR
and VDR share about 60% structural homology in theirligand-binding domain, the mentioned drugs can bindaberrantly to VDR/RXR and induce gene expression of
the vitamin D-degrading enzyme cytochrome oxidase
enzyme 24 (CYP24), which promotes vitamin D3 deficiency

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ES Journal of Nutritional Health[61]. As vitamin D3 is reported to ensure genomic andphenotypic stability, as well as metabolic, energetic andredox homeostasis and “anti-aging”, this form of induced
vitamin D deficiency might play a substantial role forhealth problems in our population [55,56,62].

A bewildering multitude of 1,25(OH)2D3-mediatedmodulatory effects on genomic, non-genomic, epigenetic
and transcriptome functions are described meanwhile[57-59]. Beyond the well-known regulation of extracellular
calcium (Ca2+ec) and its effects on bone health, 1,25(OH)2D3
also regulates cellular calcium-signaling through diverse
mechanisms [55,56,60,62,63]. Vitamin D3-dependent
responses are often characterized by direct and indirect
induction of rather opposing effects. This seems counterintuitive at first sight, but is indeed most importantfor mediating effective functional balance. The cellularfunctions of all organ systems are favorably modulated
and orchestrated [55,56,58]. However, this homeostasis
depends on sufficient amounts of the precursor metabolite
25OHD­3.

In order to understand the role of vitamin D3 in metabolic,energetic, and redox regulation, it is helpful consideringthat VDR expression and vitamin D3 activation is elicited inmany cells through cell stress [55,56, 62]. In particular, gene
expression of two most important homeostatic proteins isenhanced by 1,25(OH)2D3. The first is the already discussed
key transcription factor Nrf2, which senses reactive
species and mediates a most effective stress response.
The second is a multi-functional protein, called α-klotho[55,56]. It is primarily a transmembrane protein which ishighly expressed in kidney and choroid plexus, but also inepithelia and neurons [56,64]. The transmembrane klotho
protein is cleaved by two metalloproteases, termed “adisintegrin and metalloprotease” 10 and 17 (ADAM10/17),
thus generating two truncated proteins, called soluble andsecreted α-klotho protein. These proteins act as humoral
co-factors on far distant cells and organs, and modulate awide array of signaling pathways and cellular processes.
Most importantly, α-klotho prevents vitamin D-dependent
potential calcium and phosphate toxicity [56,64]. Klotho
mediates calcium homeostasis through binding of α-klotho
to Na+/K+ ATPase, phosphate homeostasis through binding
to the fibroblast growth factor 23 receptor, and overallmineral homeostasis through binding to ion channels,
such as the “transient receptor potential protein 5” (TRP5),
and “renal outer medullary potassium channel” (ROMK1)[56,64]. Anti-oxidation is promoted through klotho-

dependent upregulation of anti-oxidant enzymes, such as
superoxide dismutase 2 (SOD2), catalases, peroxiredoxins,
and thioredoxin reductase [55,56,64]. Of note, α-klotho
expression becomes inhibited by ROS, NFkB, angiotensin
II, and by aging, and gene deletion of α-klotho reduces life
span through defective anti-oxidant reserve [55,64].

So Nrf2 and α-klotho are key gene products which
contributeextensively
to
1,25(OH)2D3-mediatedhomeostasis.
Furthermore,
1,25(OH)2D3 enhances
substantially the cell-protective SIRT1-driven stressresponse [55,56,65-67]. A cooperative stress-induced
interplay exists between SIRT1 and 1,25(OH)2D3. SIRT1
deacetylation and hence activates VDR, Nrf2, FoxOs, and
PCG1α [55,65-67]. The deacetylation of VDR enhances
gene expression of vitamin D-dependent targets, anddeacetylation of Nrf2 and FoxO proteins promotes a more
reducing nuclear environment which favors also VDRdependent gene expressions [68,69]. Of note, besides
the deacetylation of PCGα, a successful cooperation
between VDR/PCGα, important for mitochondrial
fate, is also dependent on sufficient amounts ofmethyl donors, such as folate and vitamin B12 [70].
Similar to Nrf2, 1,25(OH)2D3 enhances also the oxidative
part of the pentose phosphate pathway (PPP) [71]. Similar
to SIRT4 it restricts glutamine entry in the TCA cycle, though
by a different mechanism which favors glutamate export
from the cell [72]. Therefore cytosolic NADPH generationand context-dependent antioxidant or oxidant actions
are favored, yet preventing excessive use of NADPH for
biosynthesis and malignant cell proliferation, thus opposing
malignancy. It is noteworthy that key metabolic pathways,
inhibited by SIRT4, are enhanced by 1,25(OH)2D3, such as
PDHC activity, fatty acid oxidation and TCA cycle flux [73,74].
In summary, vitamin D3 is a most important and contextdriven enhancer of stress adaptation which is importantfor homeostasis and longevity. Vitamin D-deficiency
diminishes this adaptation. Then even minor or “normal
stress” is presumed to be turned into critical NAD pooldecline, resulting in SIRT1 inhibition and increased ROS
generation, followed by decreased PARP inhibition andfurther NAD-consumption.

Discussion

Considering vitamin D3 deficiency as a substantial
causal factor for disturbed stress tolerance allows amore comprehensive approach to CFS/ME patients. The
here presented data tell, that cell stress effects become

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ES Journal of Nutritional Healthsubstantially augmented through vitamin D- deficiency.
This explains why patients often report about having
not recovered from an infection, xenobiotic burden, an
operation, or physical trauma which resulted in longterm immobilization. All these events, and of course also
severe mental stressors, could explain the transition
from the everyday-condition chronic idiopathic fatigue to
CFS/ME which is then associated with a very high grade
global stress intolerance. Vitamin D-resistance in the wakeof elevated ROS burden, elicited by any specific cause, ispresumed to impede recovery by fixing up a vicious cycleof metabolic, energetic and redox imbalance and chronic
pro-inflammation. Vitamin D3 resistance would explain thepersistent downhill disease course observed in late stagesof CFS/ME. The model would explain the multitude of CFS/ME symptoms, such as flu-like post-exertional malaise,
protracted wound-healing, chronic widespread pains, theparadox of chronic fatigue and difficulty sleeping, andfunctional dysregulations in all organ systems. The often
contradictory switches in distinct functional responses
with unusually large amplitudes could become interpreted
as compromised homeostasis. The decreased defense
against pathogens, toxins, xenobiotics, and any sort ofcell stress would potentiate NAD consumption up to a
critical extent, thus fixing cellular regulation in a SIRT4driven cell response, and resulting in decreased metabolic
flexibility, higher ROS burden, and pro-inflammation.
Another, at first sight enigmatic symptom in patients
suffering from CFS/ME, is latent iron deficiency. Usually,
patients show low normal ferritin levels, however
without overt anemia. The trial of iron substitution
reduces fatigue only minimally, and increases ferritin
levels only very moderately. After termination ofsubstitution, ferritin levels rapidly fall to base line. A
possible explanation could be the reduction of Nrf2
expression, resulting in decreased production of ferritin
and ferroportin, but augmented production of hepcidin.
Of note, latent iron deficiency in CFS/ME should beprotective against iron-induced oxidative stress.
An unresolved puzzle, however, is the report of McGregor
et al. about metabolic alterations during post-exertional
exhaustion, going along with hyper-metabolism, hypoacetylation and purine deregulation in CFS/ME [5].
Hypo-acetylation and hyper-metabolism appear to beinconsistent with the reported low deacetylation activityof SIRT4. It remains an open question, if exertion induces
activation of SIRT3, which is the mitochondrial deacetylase
equivalent of SIRT1. However in any case, any further SIRT-

dependent deac(et)ylation and/or ADP-ribosylation will
aggravate decrease of NAD pools in addition. Furthermore,decrease of methyl donors, such as folate and vitamin
B12, in concert with NAD depletion and elevated ROS
will compromise VDR/PGC1α interaction, resulting in
diminished mitochondrial function and regeneration [70].
This also might contribute to post-exertional malaise.

According to own clinical experience, Vitamin D3
supplementation cures idiopathic fatigue promptly. On theother hand, CFS/ME, diseases which are supposed to beaccompanied by long-lasting vitamin D deficiency, proved
to be less easily treatable, presumably due to vitamin D
resistance. Often the 25OHD3 levels remained strikingly
low in spite of a daily dosage of 10,000 IU (250µg) per
day. Maybe the mechanism for drug- and xenobioticinduced vitamin D deficiency, reported by Holick, plays
a role [61]. As vitamin D deficiency goes along with
deficiency and dysregulation of calcium and phosphate,
this might also contribute to resistance. A presumably
upregulated CD38/CD157 activity due to calcium
deficiency might exacerbate NAD consumption in addition.
Of interest, some more recent papers report about pain
reduction through treatment with vitamin D3 and calcium[75-78].

Conclusions

Vitamin D deficiency should be considered in allsorts of chronic fatiguing illnesses as a causal andaggravating factor. This would complete the actual modelof homeostasis disruption, recently presented by Naviaux[79]. If physicians would be able to prevent the transition
to higher grade chronic fatigue through colecalciferol
substitution, it would be of great importance for worldwide health systems. Symptoms of CFS/ME and theburden of disease would be understood more easily, thus
relieving the mutually strained and stressful relationships
which still exist between patients and their physicians.
Physicians could be stimulated to revise their treatment
regimens by omitting all interventions which induce
further redox stress and xenobiotic burden. The drug
and chemical intolerances of CFS/ME patients call for
only minor dosages of pain and psychoactive substances.
Instead, restoration of effective VDR activity should betargeted. This is assumed to stabilize a SIRT1/Nrf2driven stress response. This might be achieved by plantbased diets and/or supplementations, such as thoserecommended by Naviaux et al. [8], and Xiao W 2018 [31],Citation: Höck AD. A Proposal for Explaining Progression from Light/Moderate to Severe Chronic Fatigue. ES J Nutr Health. 2020; 1(2); 1008.

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ES Journal of Nutritional Healthincluding all B vitamins, and by supplements of vitamin
D3 and minerals, which include calcium and magnesium,in particular. Phosphate deficiency through long-standing
vitamin D deficiency should be considered as well. Due topresumed vitamin D3 resistance and to distinct genomic
and translational vitamin D3 responses, personalized highdoses such as 250 mcg cholecalciferol and up to 2400 mg
calcium per day should be applied [57,58]. Careful clinicalobservations should clarify the potential reversibility ofvery severe and long-standing CFS/ME stages. In any case,any sort of stressful challenge, such as xenobiotics, drugs,
nutrient additions, microwaves, and psychosocial stress,
should be avoided as much as possible.

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Acknowledgements

14. Jęśko H, Strosznajder RP. Sirtuins and their interactions withtranscription factors and poly(ADP-ribose) polymerases. Folia
Neuropathol. 2016; 54: 212-233.

I am grateful to Martin L Pall PhD for his suggestionthat functional disorders can be understood through theactions of Nrf2. This inspired me to write this paper

16. Jokinen R, Pirnes-Karhub S, Pietiläinen KH, Pirinen E. Adipose tissue
NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases- important players in mitochondrial metabolism and metabolic
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