Standing on one leg - a life lengthening skill.
Standing on one leg - a life lengthening skill.
Large population study found the ability to balance on one foot for more than ten seconds was associated with a lower mortality rate. Metabolic Syndrome type Dx were more common in those who couldn't.
Balancing takes cerebellum interaction with the muscles and the inner ear vestibular system. It can be at risk to inflammation due to the fragile hair cells that are also found within the hearing area of the inner ear. The hair cells physically wave in a jelly like surrounding that cushion them from breakage with sudden motion or repetitive noise. Magnesium and adequate hydration are needed to form the protective jelly matrix.
An article about the study said it was not known why or how the ability to balance on one foot was impacting mortality rate but did mention the comorbid conditions being more common in those who couldn’t stand that long on one foot.
The article had no reasons to suggest from the researchers or other supporting information as to why being able to stand on one leg for longer than ten seconds might be correlated with reduced mortality rate, but the people who couldn't tended to have other diagnoses such as Type 2 Diabetes and poorer health.
"Those who failed the test generally had poorer health: a higher proportion were obese or had heart disease, hypertension, or dyslipidemia. Type 2 diabetes was three times as common in this group." (1)
In other words, . . . the people who were unable to stand on one foot for ten seconds had Metabolic Syndrome - hyperinflammation.
Risk Factors for Metabolic Syndrome:
Abdominal obesity. - obese with fat localized on the belly more than the thighs.
Atherogenic dyslipidemia. - vascular disease/high triglycerides or LDL cholesterol.
Raised blood pressure. - hypertension.
Insulin resistance ± glucose intolerance. - precursor /or Type 2 diabetes.
Proinflammatory state. - inflammation - cytokines and TN-fB.
Prothrombotic state. (12) - at risk for blood clots, heart attack or stroke.
Infection may also be a cause of cerebellar ataxia
Stress, whether from infection or for emotional or physical exertion reasons, can lead to inflammation which can lead to hyperinflammation if it continues long term and adequate replacement nutrients aren’t provided. Quality of life is impacted including balance and clear-headed thinking ability.
Can we balance on one foot in the dark? Or stumble around and find our way if we need to? Function is part of quality of life and practicing - simply using our muscles in full range of motion exercise, gentle if need be, helps us strengthen and maintain fitness and detoxify lymphatic fluid.
Self care is our number one job - if we aren't fit then we can't do any other job as well, or for as long a career possibly.
“Simple activities like balancing on one foot with your eyes closed will help make your cerebellum work better. Coordinated hand and foot movement also helps, as well as activities such as bouncing a ball to playing the piano.” (2)
Cerebellum Exercise: balance, coordination & fine motor skill.
Tracking a moving ball and having a hand ready to catch it, requires the interaction of our vision, cerebellum, and our muscles.
Cerebellum Exercises: Finger Pinchers - form an okay sign, then move thumb to each finger in succession, repeat back the other direction, Hand flips - arms out, palms up, then palms down, repeat, Tight rope stand - walk heel to toe or stand as if on a tight rope, One foot balance - stand on one foot for a few seconds, than the other, repeat. The article includes a brief description of each. (3)
If the balance exercises are too challenging initially, have a spotter nearby and use a gait belt if need be. Or try standing between two sturdy wooden kitchen chair type chairs with the backs towards you in the middle. Hold onto the chair backs as you briefly stand on one foot or the other. Simply hold the foot off the ground at first if putting it on your calf is too difficult. Starting somewhere, is a start, and a first step towards restoring brain networks that help maintain our balance.
Exercise that uses balance and coordination can help improve function and reaction time in case of an accidental fall. Learning to fall safely is a bonus of dance and some types of exercise classes. Roll with the fall onto your shoulders and back rather than instinctively trying to catch yourself with fragile wrists and hands.
“The stumbling gait of an intoxicated person is a result of decreased cerebellar function due to the alcohol. Improving your cerebellar function will not only improve your balance but also reduce your risk of injury. Some research has suggested that improved cerebellar function is even linked to improved brain function and the delay of cognitive decline associated with aging.” (2)
Movement also is improving the brain connections between the muscles, eyes, vestibular system, and other sensory organs that help us know where we are within our surroundings. Wearing a blindfold can help us notice more about what we are hearing, smelling, or the breeze blowing from an air conditioner or outdoors, as well as allowing us to tune into our muscle sensations. Which parts of the body are tight and want to be stretched? Which parts want to be shaken out? Is your back tight, would arching backward help? Bending or twisting side to side?
Lack of practice/exercise is not the only reason for poor balance, also: toxins, medications, alcohol, deficiencies,or trauma.
Toxins, medications, alcohol, or other drugs may affect balance and even cause stumbling. Extreme tiredness may also increase loss of balance. Various toxins or trauma can cause a severe loss of coordination called cerebellar ataxia.
Infection can also be a cause of cerebellar ataxia if the brain becomes inflamed - encephalomyelitis.
“Acute cerebellar ataxia (ACA) is a relatively common neurological disease in children. Most common types of ACA are acute post-infectious (APCA) and acute disseminated encephalomyelitis (ADEM). […] APCA is the most common cause of ACA in children, comprising about 30-50% of total cases. This is a report about an immunocompetent 4-yrs-old male affected by APCA, due to co-infection by human herpesvirus-6 (HHV-6) and adenovirus, with symptoms mimicking myositis [muscle inflammation - myocarditis is inflammation of heart muscle].” (16)
Cerebellar ataxia: “Sudden, uncoordinated movement of muscle due to disease or injury to the cerebellum.” It is seen in Multiple sclerosis and “It may be caused by: Alcohol, illicit drugs; Medicines, insecticides; or Trauma to head and neck.” (5)
Alcohol is where Retinoic Acid enters this post.
Ethanol, a type of alcohol, causes an increase in the enzyme that activates vitamin A or carotenoids to the active Retinoic Acid - and this is occurring in the cerebellum. (14)
“Several characteristics of fetal alcohol syndrome (FAS) are similar to the teratogenic effects of retinoic acid (RA) exposure. It has been suggested that FAS may result from ethanol-induced alteration in endogenous RA synthesis, leading to abnormal embryonic concentrations of this morphogen. We examined whether ethanol may interfere with RA synthesis in the postnatal cerebellum, as a region of the developing CNS particularly vulnerable to both ethanol and RA teratogenesis. It was found that astrocytes are the predominant source of postnatal RA synthesis in the cerebellum. They express both retinaldehyde dehydrogenase 1 and 2. In vitro cytosolic preparations of astrocytes, as well as live cell preparations, have an increased capacity to synthesize RA in the presence of ethanol.” (14)
Excess Retinoic acid is being produced by the astrocytes in increased amounts in the presence of ethanol. (14) Astrocytes are supporter brain cells that aid the nerve cells that send signals. (28) The excess Retinoic acid would activate mast cells leading to histamine excess and inflammatory cytokines, and during fetal development also acts as a morphogen, directing the pattern of tissue growth within the fetus’s growing body - and possibly wrong if in excess.
Visible birth defects are possible with Fetal Alcohol Syndrome (FAS) or excess Retinoic Acid during pregnancy. Low zinc at the same time as alcohol exposure prenatally can cause more severe effects from FAS. Zinc is needed in gene transcription. More severe internal skeletal differences were seen with more alcohol in ratio to zinc deficiency and more visible external birth defects were seen with more severe zinc deficiency and less excess alcohol, in an animal-based study. Resorptions - miscarriage or spontaneous abortion of a fetus in a pregnancy with multiple babies. The fetal body is absorbed as nutrients instead of being expelled, the rest of the litter is still developing normally. (29)
News to me - overactive production of retinoic acid may be a birth difference/defect that occurs during fetal development. It is associated with scoliosis in the infant and asymmetry in the left/right halves or organs of the body, (15) and coincidentally, or causally, both of which I have slightly. Both scoliosis and asymmetry, my left side seems weaker and less coordinated. I always bump into the left side of doorways when in klutzy, overstressed mode.
“These findings suggest that human vertebral birth defects such as scoliosis, an abnormal left–right bending of the vertebral column, may be caused by a defect in RA signaling during somitogenesis [an early stage of fetal development].” (15)
My mom would give me cod liver oil by the spoonful in hope that it would help my eczema - it probably was making it worse. *The last post had more of my personal history with Retinoic acid excess - The Tale of Two Potato Chips. So the potentially causal factor would be excessive alcohol use by the father (possible) in the few days prior to or of the fetal conception - or alcohol use by the mother (unlikely). Well if I have some effects of FAS, it could have been worse, to put a positive spin on it.
ADHD may also be an effect of alcohol increasing retinoic acid levels during prenatal development as FAS can negatively affect the formation of the prefrontal cortex, cerebellum and brainstem, (34), and hippocampus, (35); and we know retinoic acid excess would be a risk to the hippocampus from previous posts. Hypoxia, also part of hyperinflammation, may be a causal factor in the damage from a retinoic acid increase, (more on this later), as it increases Hypoxia Inducible Factor - 1α. (36)
ADHD and FAS are frequently comorbid conditions. ADHD may have more severe impulse control problems and FAS may have more intellectual disability and physical differences in appearance. (37) It is fairly new information that a father’s alcohol use during the few days leading to conception can be a risk factor for FAS in addition to a mother’s use of alcohol throughout pregnancy.
“The most common identifiable cause of intellectual disability is FASD (relative risk 19 fold) [6]. FASD also appears to be the leading cause of ADHD as well. A diagnosis of FASD is associated with increased risk for ADHD (relative risk = 7.6; attributable risk 86.8 %). Conversely, a diagnosis of ADHD predicts increased risk for FASD (relative risk 13.28; attributable risk 92.5 %). Thus, ADHD and FASD represent an intersection of phenotype expression and complexity.” (37)
It is not known why there is a link . . . or why the negative effects of prenatal alcohol exposure seem to worsen as the child grows into later adulthood . . . and it is estimated that the majority cases are undiagnosed or misdiagnosed and largely only addressed during childhood, rather than screening adults too. (37) Sometimes being a human knockout mouse has advantages. I can experiment with a sweet potato chip challenge without having to consult an ethics committee.
This post was short until I added the Retinoic Acid and ROR sections - but now we know more about the connection between ADHD, FAS, and why older adults with FAS have worsened toxicity symptoms - they are likely overdosing on vitamin A and carotenoids on a daily basis which would add to the hyperinflammation positive feedback loop. Read on. . .and then please share, spread the word that some people may need to strictly limit vitamin A and carotenoids if they want to protect their brain and body from misfolded protein/fibrotic damage and other risks.
And lest anyone, in addition to me forgot the initial point - the ability to stand on one leg longer than ten seconds is associated with a reduced mortality rate - but they don’t know why. In this post I present medical research that suggests the inability to balance on one leg longer than ten seconds is an indicator of underlying hyperinflammation and the resulting cerebellum dysfunction or damage.
Modulators keep us in balance by up or down regulating as needed.
Deregulated retinal signaling, Retinoic acid out of balance, affects fetal heart development (cardiogenesis) leading to birth defects - Retinoic acid in excess or a deficiency can be a teratogen and cause organ dysfunction. (20) As a modulator, Retinoic acid may activate, inhibit, or modify how another chemical interaction progresses.
Example of a modulator - bidirectional regulation by the Retinoic Acid Receptor-Related Orphan Receptor-alpha (RORα) receptors - activate or inhibit, up or down regulate: “The regulatory mechanisms of RORα in many physiological processes are bidirectional.” (17)
What does Retinoic Acid do in the cerebellum?
During fetal development it effects tissue development and too much can cause changes in body shape. Otherwise - I am not sure.
and what do Retinoic Acid Receptor-Related Orphan Receptor-alpha (RORa) receptors do in the cerebellum?
RORα are transcription factors which are proteins that regulate transcription of DNA to RNA by binding to specific sequences of DNA.
“The retinoic acid receptor-related orphan receptor alpha (RORα) belongs to the steroid nuclear hormone receptor superfamily and acts as a transcription factor through binding to the ROR responsive elements (ROREs) either as a monomer or homodimer in the regulatory region of target genes (Carlberg and Wiesenberg, 1995; Giguere et al., 1994; Jetten, 2009).” (23)
That did not help much . . . moving on. If they made this stuff easy, everybody would be reading it.
“Retinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks.” (17)
The transcription process - protein production or cessation of production by RORa is in response to circadian changes - so blackout curtains at night and full spectrum light in the morning or day would be helpful. Adequate melatonin would be helpful.
Figure 4 shows that the RORa may activate mast cells leading to inflammation and migraine. It also affects melatonin which can disrupt circadian cycles, further increasing the migraine risk. Melatonin can in return affect it so supplementing with melatonin and/or good sleep and light habits might help. (22-Fig 4, 22) Maybe RORa is related to the Retinoic Acid Receptor because it does similar things?
Regulators help keep us at an even balance, so a deficiency or an excess might cause similar symptoms. In the case of the cerebellum, dysfunction can lead literally to poor balance and an unsteady walk.
While I don’t know what Retinoic acid does in the cerebellum yet, or how the Retinoic Acid Receptor is related to the Retinoic Acid Receptor-Related Orphan Receptor-alpha (RORa), the RORa do have a lot to do with balance and walking steadily. (17)
A lack of the RORa gene/protein in mice due to a naturally occurring difference causes a staggering gait, hence their name '‘staggerer”. (17) A reduction in the number/expression of RORa has also been seen in people with autism spectrum disorder (ASD). (18) Cholesterol or cholesterol sulfate may be ligands or other small molecules. Two synthetic agonists are known and may have therapeutic benefits. (17, 19), helping with balance and steady walk. (17)
“Retinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks.” (17)
Regulating chemicals help keep us at an even balance, so a deficiency or an excess might cause similar symptoms. In the case of the cerebellum, dysfunction can lead literally to poor balance and an unsteady walk. Mice without a certain Retinoic Acid based gene and the receptor it transcribes, Retinoic acid receptor-related orphan receptor-α (RORα), are known as the “staggerer” mice. (17)
“The naturally occurring mutant mouse strain “staggerer” (also known as Rorαsg/sg)11 […] has a short lifespan. The defective phenotype of staggerer mice is due to deletion of the LBD region of the RORα gene, which causes a shift in the reading frame and prevents adequate translation [fewer of the RORα receptors are made]. These mice exhibit ataxia, motor deficiencies, irregular circadian rhythm, hyperinflammation, osteopenia, atherosclerosis, and muscle atrophy. Moreover, the similar phenotypes of RORα null-mutant (RORα−/−) 13 and Rorα sg/sg indicate that RORα is an essential regulator of PC differentiation and cerebellar function.
Furthermore, RORα is involved in various physiological processes, such as the circadian clock, inflammation, tumorigenesis, and metabolic diseases, and it is a tumor suppressor in many types of cancer. Its expression is downregulated in cancers of the skin, colon, prostate, liver, and breast, as well as in melanoma 14–19. Decreased RORα expression correlates with cancer aggressiveness, short overall survival, and poor prognosis.
In addition, RORα modulates cyclic expression of BMAL1, a key transcription factor (TF) that regulates circadian rhythms. RORα contributes to the inflammatory response, M1/M2 polarization, and the nuclear factor-κB (NF-κB) pathway 20–22 and regulates lipid and glucose metabolic gene expression, implying its involvement in energy homeostasis.” (17)
Fewer RORα have been found to be expressed in people with autism spectrum disorder (ASD) - fewer RORα present on cell membranes, and the genes that it affects were shown to be downregulated in ASD. (18)
“The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes.”
“Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior.” (18)
Retinoic acid is not the agonist, the activator, of RORa receptors. They are part of a group called orphan receptors because their ligand/agonist is not known. Cholesterol sulfate and/or cholesterol intermediates are suspected. (17)
“Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ . The retinoic acid receptor-related receptors (RORs) are members of the nuclear receptor (NR) superfamily of transcription factors. Several NRs are still characterized as orphan receptors because ligands have not yet been identified for these proteins.” (19)
“In addition to natural ligands, SR3335 and SR1078 constitute developed inverse agonists of RORα. Selective synthetic SR3335 inhibits expression of RORα target genes, such as the gluconeogenic enzymes G6pc and Pepck6, and effects of SR1078 on p53 regulation, adipose tissue inflammation, renal ischemia, and allergic asthma have been studied 7–10.” (17)
The RORa modifies the immune response of T-cells in a way that is anti-inflammatory, inhibiting the NF-kB hyperinflammation pathways and helping stop cancer cell growth. (17)
“Under ROR-mediated NF-κB target gene suppression, the functions of damaged cells are restored to reduce hyperinflammation. The anti-inflammatory roles of RORα further induce effective cytotoxic function in CD8+ T cells, resulting in cancer cell death. Activation of RORα with selective agonists, such as SR1078 and cholesterol sulfate, result in stimulatory effector responses of CD8+ T cells.” (17)
Cholesterol Sulfate - a ligand of RORα.
In Rheumatoid arthritis the alpha ROR down regulates inflammation, and the gamma upregulates it. Cholesterol sulfate or SR1078, a synthetic ligand for RORa were beneficial for RH arthritis. (24) The RORα are also anti-inflammatory in inflammatory bowel disease. (17)
“Retinoic acid receptor-related orphan receptor alpha (RORα) is a negative regulator of inflammatory responses, [down regulator] whereas RORγt, another member of the ROR family, is a Th17 lineage-specific transcription factor. [Th17 T helper cells are associated with autoimmune disease]
Here, we investigated the immunoregulatory potential of RORα in collagen-induced arthritis (CIA) mice, an experimental model of RA. Cholesterol sulfate (CS) or SR1078, a ligand of RORα, inhibited RORγt expression and Th17 differentiation in vitro. […] We found that RORα overexpression in CIA mice attenuated the clinical and histological severities of inflammatory arthritis. The anti-arthritic effect of RORα was associated with suppressed Th17 differentiation and attenuated mTOR-STAT3 signaling in T cells.” (24)
Epsom salt soaks, magnesium sulfate, are a good source of bioactive sulfate. Cholesterol in a vegan diet though - that is a lack. My diet is vegan for presumed autoimmune albumin antibodies and it turns out also for vitamin A reasons. This article suggests including the precursor saturated fats, (coconut oil, cocoa butter, or palm oil), in meals in moderation so your body will make the cholesterol you need. (26)
It would be interesting to redo the standing on one foot study (1) but first screen the participants for cholesterol levels, or cholesterol sulfate levels. My hypothesis would be that there would be a significant association between inability to stand on one leg and low cholesterol/sulfate levels. Screening for other Metabolic Syndrome biomarkers would also be helpful.
We hear so much about how bad cholesterol is for the heart and we need statin drugs - but most everyone probably missed this headline: “Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study.” (27) We need cholesterol for survival - news to know.
Statin medications would probably be a negative for cerebellar function as they reduce cholesterol levels, sometimes too low for health. We need some cholesterol and can make it ourselves if statins are not used. Modulation by different forms of cholesterol or other small molecules means that the receptors can do different things based on what types of cholesterol metabolites or other ligands are present.
“Reports showing that cholesterol and cholesterol sulfate, as well as a series of other small molecules, were able to bind the LBD of RORs and modulate its transcriptional activity indicated that RORs function as ligand-dependent transcription factors [2, 25, 32, 33]. Recently, several intermediates of the cholesterol biosynthetic pathway were reported to act as endogenous agonists of RORγ [34, 35]. These studies revealed that RORγ transcriptional activity and the physiological processes it regulates, can be controlled by changes in the intracellular pool of these sterol intermediates. In addition, these discoveries raised the possibility that ROR ligands might be valuable in the development of new therapeutic strategies for diseases in which RORs are implicated, including various inflammatory and metabolic diseases and neuropsychiatric disorders.” (19)
Sulfate nutrients from foods or Epsom salt, magnesium sulfate, has been found beneficial for people with autism, ASD. Prenatally, the drinking water of women was tested for sulfate. It was found that regions that had lower levels of sulfate in the water had more infants develop autism and with more severe symptoms on average. (30) Speculation - if the mothers had too little cholesterol sulfate and too little RORα function than the developing infant would have had more risk of hyperinflammation resulting from too little RORα activity.
The androgen receptor may have a role to play, as the RORa receptor is differentially regulated by male and female hormones and there is a difference seen in the risk of autism between males and females (males being more frequently affected).
“Retinoic acid-related orphan receptor-alpha (RORA) is a new autism candidate gene that has been shown to be differentially regulated by male and female hormones. Previous studies have shown deregulation of its expression in the prefrontal cortex and the cerebellum of ASD patients.” (21)
“Deregulation of its expression” - too few or too many of the transcription factor receptors are being made in the decision making (prefrontal cortex) and movement control (cerebellum) centers of the brain. (21)
Genetic differences in the RORα sequence seem to be a factor in ASD and migraines.
The T allele, or TT: “rs4774388-TT”, one of “two functional polymorphisms in the RORA gene”, (21), was found significantly more often in patients with ASD compared to the control group. (21)
“The rs4774388-TT genotype was significantly higher in patients compared with controls and was associated with ASD risk…” (21)
In patients with migraines, the CC allele, “rs4774388-C/C”, (22), was present significantly more than the TT allele, “rs4774388-TT” compared to control groups. (22)
Figure 4 shows that the RORa may activate mast cells leading to inflammation and migraine. It also affects melatonin which can disrupt circadian cycles, further increasing the migraine risk. Melatonin can in return affect it so supplementing or good sleep and light habits might help. (22-Fig 4, 22)
RORa expression is elevated in hypoxia in keratinocytes.
Hypoxia is part of the symptom set of COVID19. Migraine pain involves localized hypoxia and vascular constriction. That RORα is elevated in keratinocytes in hypoxic conditions is interesting but may not be directly related. Keratinocytes are the outermost skin cells and form a semi-impermeable barrier against the outer world, The paper like cells develop in layers with the outer layers of dead cells protecting newly growing inner layers of cells. The outer cell layers will remain for a while before sluffing off.
“The expression level of RORα is significantly elevated under hypoxia in both human and murine keratinocytes. Gene silencing of RORA attenuates hypoxia-stimulated expression of genes related to late differentiation and epidermal barrier function, and leads to an enhanced apoptotic response.” (23)
Hypoxia and inflammation are related - the Hypoxia inducing factor is activated when there is a lack of oxygen but also can be activated by other inflammatory signals including TNF-alpha or the NF-kB pathway. Which if it continues, may create a positive feedback loop, as NF-kB can in turn lead to more activation of the HIF.
“While the [Hypoxia Inducing Factor] HIF pathway primarily responds to hypoxia, HIF expression is also increased in response to non-hypoxic stimuli, including bacterial lipopolysaccharide (LPS) [LPS is worsened by chimeric spike], tumor necrosis factor-α (TNF-α), reactive oxygen species, hepatocyte growth factor, and interleukin (IL)-18 via crosstalk with the nuclear factor-κB (NF-κB) pathway (Figueroa et al., 2002; Zhou et al., 2003; Frede et al., 2006; Taylor, 2008).
The NF-κB transcription factor is a master regulator of inflammation.
NF-κB is kept localized in the cytoplasm by inhibitory IκB proteins (Lawrence, 2009; Oeckinghaus and Ghosh, 2009), which thereby inhibit DNA binding by NF-κB (Beg and Jr, 1993; Mitchell et al., 2016). In response to inflammatory stimuli and microbial products, the IκB kinase (IKK) complex phosphorylates IκB, leading to IκB ubiquitination and proteasomal degradation (Israël, 2010). With the degradation of IκB, NF-κB can translocate to the nucleus and upregulate key downstream inflammatory pathways (Hayden and Ghosh, 2004; Perkins, 2006; Mitchell et al., 2016; Figure 1).
The NF-κB pathway can also upregulate HIF-1α (BelAiba et al., 2007). NF-κB subunits bind to the NF-κB binding element within the HIF-1α gene promoter region and induce HIF-1α mRNA expression (Van Uden et al., 2008).” (31)
NF-kB, hyperinflammation and positive feedback loops - flashback:
With increased NF-kB, a positive feedback loop can occur because it can increase inflammatory signaling too, perpetuating the chronic inflammation - unless stopped by both removing inflammatory triggers and adding Nrf2 promoting foods and other anti-inflammatory nutrients like methyl B vitamins, choline, vitamin C, CoQ10, EPA/DHA omega 3 fatty acids, cholesterol and magnesium sulfate, other trace minerals in balance, including zinc, copper, boron and manganese.
Hold the presses - a dietitian recommending cholesterol? In adequate amounts it is promoting longevity, or reducing mortality rate, and as a reminder, vitamin D supplements if not needed are simply broken down into the precursor cholesterol. Mega doses of vitamin D are likely converted into cholesterol in part. Vegans may need to make cholesterol from saturated fats in their diet. Coconut or palm oil, or dark chocolate products are vegan sources of saturated fats. *Note that cocoa beans are a source of oxalates and excess can be a dietary cause of inflammation, calcium adequacy is helpful.
Hypoxia damages the cerebellum, hippocampus and parieto-occipital lobes in earlier stages and can lead to cerebellar ataxia. (32, viewable at 33) Retinoic acid increases Hypoxia Inducible Factor and also can lead to damage in the prefrontal cortex, cerebellum, and hippocampus in earlier stages of chronic inflammation and can cause damage to the brainstem and overall brain tissue in later stages. (35, 36)
“Different CNS cell populations are selectively vulnerable to hypoxia, possibly as a function of their metabolic rates. The neurons of the hippocampus, parieto-occipital lobe, and cerebellum are particularly sensitive. As hypoxia becomes more severe, damage extends to the entire cerebral cortex and deep nuclei and ultimately to the brainstem.”
“If anoxia has lasted for a couple of minutes, confusion or stupor may occur on return of consciousness and irreversible damage may begin after 2 to 4 minutes. If the individual survives, longer periods of anoxia usually lead to permanent sequelae such as memory deficits, myoclonic and generalized seizures, extrapyramidal disorders, and cerebellar ataxia.” (32, viewable at 33)
Nutrients that may be deficient or supplements that may be helpful.
WebMD search provided links for supplements of “5-HTP, ashwagandha, choline, and Coenzyme Q10” as having some evidence, but “insufficient,” for treatment of cerebellar ataxia. (4) Ashwagandha is a nootropic - an herb thought to help brain function.
CoQ10 deficiency due to a gene difference led to cerebellar ataxia (13) and it is associated with progressive nerve degeneration. While I haven’t returned to finish the page, CoQ10 is one of the nutrients that may help myelin degeneration which is a precursor or part of Multiple sclerosis and other conditions that lead to loss of movement abilities. See page G12. Demyelination, (effectivecare.info). Lack of phospholipids/cannabinoids, and general malnutrition or excess calorie/ deficient trace-nutrient malnutrition, may be factors also.
Choline, actylcholine, nAChRs and movement.
Choline is a precursor for acetylcholine and 5-HTP is a precursor for serotonin, both are neurotransmitters.
“Acetylcholine appears to be a primary transmitter in the vestibulocerebellar pathways at several levels, which may account for the potent effects of muscarinic antagonists in diminishing vestibular vertigo in humans.” (6)
The balance area of the cerebellum has a concentration of cells that make the enzyme needed to form acetylcholine.
“A subset of cerebellar mossy fibres is rich in choline acetyltransferase, the rate-limiting enzyme for the synthesis of acetylcholine. These choline acetyltransferase-positive mossy fibres are concentrated in the vestibulocerebellum and originate predominantly from the medial vestibular nucleus.” (7)
Nicotinic acetylcholine receptors are also prevalent in the cerebellum. In addition to the “homomeric α7 subtype,” six distinct types were found in an animal based study, “including α3α4β2 and α3α4β4 nAChRs”. (8) An excess of nicotine can affect balance. Cholinergic blocking agents such as Conotoxin, snake venom toxin, and the S1 subunit of the chimeric spike protein are paralytics due to the inhibition of nAChR receptors.
Having low acetylcholine levels has been found to be more common than average in conditions of “Dementia, Alzheimer’s dementia, Parkinson’s Disease, Myasthenia Gravis, Schizophrenia, Glaucoma, and Autism”. (9)
Excessive supplementation of choline may be over stimulating for some people. A 250 mg supplement along with a methyl B complex may be helpful. CoQ10 is generally available in 100-200 mg supplements.
St. John’s Wort may be a more effective way to promote good serotonin levels as it modulates breakdown more than providing the precursor. Waking up regularly around 4 am and not being able to go back to sleep until 6-7 am can be a symptom of serotonin deficiency. Taking 5-HTP or St. John’s Wort supplements in the evening may be helpful.
Niacin deficiency or low protein, lack of tryptophan, may be factors.
Lack of niacin can be an underlying factor in serotonin deficiency as tryptophan is a precursor for serotonin which is used up more excessively when there is a lack of niacin. Higher dose niacin has also been found very beneficial for the treatment of schizophrenia. (11) See the post: Niacin & Early Treatment in general for SARS-CoV-2 is sensible, reduces hospitalization and mortality rate. (transcendingsquare.com)
“Tryptophan is used by the body to make niacin, a B vitamin that is important for digestion, skin and nerves, and serotonin. Serotonin is a brain chemical that plays a large role in mood) and can help to create a feeling of well-being and relaxation.
"When levels of serotonin are high, you're in a better mood, sleep better, and have a higher pain tolerance," says Elizabeth Somer, MA, RD, author of numerous nutrition books, including her latest, Eat Your Way to Happiness.
Tryptophan is needed for the body to produce serotonin. Serotonin is used to make melatonin, a hormone that helps to control your sleep and wake cycles.” (10)
Tryptophan is an amino acid that is rich in turkey meat which may be why Thanksgiving dinner is associated with sleepiness afterwards. (10)
The sleepiness might be an excess of food too. Moderation is easier with small portions of the many things you want and maybe skipping the roll or carb side dish that you care less about. Eating light or not snacking in the evening can help the body later to focus on cleanup and repair - nightshift, and no indigestion to trouble sleep!
Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
Reference List
Mortality Risk Linked With Balance on One Leg. MedPageToday, https://www.medpagetoday.com/primarycare/generalprimarycare/99350
How your cerebellum affects your life. northwestwellnessscentre.com, https://northwestwellnesscentre.com/how-your-cerebellum-affects-your-life
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