Otoxicity series - Introduction
Intro of my book format draft meets mitochondrial regulation of apoptosis with Prof. Naviaux, via El Senor Bio-hacker
I am working on a pdf/book format for the ototoxicity series but I got bogged down in the mind-blowing vitamin K2 information and the gut microbiome species involved in hearing risk is also complex. I have two long drafts that need better organization.
Here is the introduction so far:
Introduction
“Globally, around 360 million people have ear disorders leading to hearing loss, with children constituting around 32 million of the affected population. According to WHO, these ear diseases cost around 750 billion international dollars worldwide which is quite a burden economically [4]. Of all disorders involving the ear, otitis media (OM) is the most prevalent globally in both high and middle-income countries. Similarly, 60% of the hearing losses are due to preventable causes [5].” (Hamayal, et al., 2024)
Hearing loss and tinnitus may be early indicators of oxidative stress levels that are also damaging to the brain. The health of our mitochondria and gut microbiome are also negatively affected by oxidative stress and can add to it when dysfunctional or unhealthy species outnumber beneficial ones.
Alzheimer's needs to be prevented ideally because the hippocampus is already about ninety percent damaged at the time of diagnosis. Twenty years of damage seems to have accrued by the time diagnosis is made, and early onset Alzheimer's is being diagnosed starting at age 45 now. That means that 25-year old's need to protect their brains against hippocampal damage.
Mitochondrial support nutrients, sunshine, movement, water, good sleep.
Gut and Mouth Microbiome (and other areas of the body) - zinc, fiber and resistant starches in the diet, pomegranate or other polyphenol and bitter tasting phytonutrient foods or beverages, avoid a diet high in balance of fat to protein/carbohydrate calories. Above 60-70% shifts methylation cycles towards more inefficient and acid producing anaerobic use of energy sources.
Sunshine counts – for vitamin D (we need cholesterol and vitamin K2 too)
Regular movement and sunshine help both mitochondria and beneficial microbiome species. Sunshine is needed for us to create vitamin D from cholesterol, so Statins that reduce cholesterol too much are a risk factor to health, while may be somewhat protective of hearing if blood cholesterol is too high. Lack of vitamin K2 might be a causal factor in soft tissue calcification and add to risk of blood lipids being excessive. Cholesterol seems to be a side effect rather than a cause of soft tissue calcification. The body uses it to ‘spackle’ over electrically active calcium which is dangerous to cells. Lack of vitamin K2 and active vitamin D are combined risk factors as both are needed for our calcium binding proteins to function.
Transport proteins are like our body’s fleet of taxicabs or semi-trucks. Too much free calcium can cause cells to overwork to the point of cell death, that is called excitotoxicity and it can be a cause of inner ear or brain damage in addition to risk of blood vessel plaque formation and stiffening. Calcium binding proteins are critically important within the inner ear for the nerve signaling to happen. Uncontrolled calcium would be damaging risk though.
Movement counts
It seems, that both mitochondria and microbiome bacteria need us to be moving a little for them to remain in a symbiotic, mutually beneficial balance. Mitochondria are bacteria that colonized our ancestral mother a long, long time ago. When we stop moving, office bound or watching TV and inactive in general, it seems to signal something like a decomposition message - host is down, every microbe for itself now! Lack of activity and imbalanced growth of benign species into a negative problem is more likely - get moving and it seems to help restore balance. I may be correct. (Naviaux, 2020)
If too many toxins are present, the mitochondria can sense that and they are involved with signaling a need for a cell to be removed by white blood cells - a kind of a mercy killing called apoptosis in which the old cell is engulfed by a white blood cell and removed without leaving cellular debris that would risk nearby cells from too much oxidative stress or cell damage signaling chemicals. ATP is our cell’s energy ‘currency’ which mitochondria make for us. Outside of the cell though, it signals there is problems in the neighborhood which white blood cells need to clean up.
‘Perspective: Cell danger response Biology—The new science that connects environmental health with mitochondria and the rising tide of chronic illness’,
“The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis.” […]
“Mitochondria regulate the CDR by monitoring and responding to the physical, chemical, and microbial conditions within and around the cell. In this way, mitochondria connect cellular health to environmental health.” (Naviaux, 2020) via El Senor Bio-Hacker (x.com/AreciboCoqui *part of a Thread, click on through)
Any level of activity seems to help promote mitochondrial function (except strenuous exercise is inflammatory and too much oxidative stress is a negative for mitochondria - polyphenols before or after exercise helps the body cope with a hard workout). Helping a bedbound patient with full range body movement stretches or exercises is helpful for their general health and their mitochondria and gut microbiome.
How does inactivity add to cell damage response signaling?
Brave AI summary - (my eyes hurt, I’m doing what I can, monocularly, one eye closed) -
Inactivity and Cell Damage Signaling
Inactivity can contribute to cell damage response signaling through various mechanisms. When cells are inactive, they may experience increased oxidative stress, which can lead to DNA damage and activation of the DNA damage response (DDR) pathway. The DDR pathway is a complex signaling network that responds to DNA damage by initiating repair mechanisms, cell cycle arrest, and apoptosis (programmed cell death) if the damage is irreparable.
Prolonged inactivity can also lead to increased production of reactive oxygen species (ROS), which can damage cellular components, including DNA, proteins, and lipids. This can trigger the activation of stress-signaling pathways, such as the JNK and p38 MAPK pathways, which can lead to inflammation, cell death, and tissue damage.
Furthermore, inactivity can disrupt the normal functioning of cellular processes, including metabolism, protein synthesis, and degradation. This can lead to the accumulation of damaged or dysfunctional cellular components, which can trigger the activation of cell damage response signaling pathways.
In addition, inactivity can also lead to changes in the expression of genes involved in cell damage response signaling, including those involved in the DDR pathway, apoptosis, and inflammation. For example, studies have shown that prolonged inactivity can lead to increased expression of pro-inflammatory genes and decreased expression of anti-inflammatory genes, which can contribute to chronic inflammation and tissue damage.
Overall, inactivity can contribute to cell damage response signaling by increasing oxidative stress, disrupting normal cellular processes, and altering gene expression. This can lead to a range of negative consequences, including inflammation, cell death, and tissue damage, which can increase the risk of chronic diseases, such as cancer, cardiovascular disease, and neurodegenerative disorders.
Oxidative Stress: Increased production of reactive oxygen species (ROS) due to inactivity can damage cellular components and trigger cell damage response signaling.
DNA Damage Response: Inactivity can lead to increased DNA damage, which activates the DDR pathway, initiating repair mechanisms, cell cycle arrest, and apoptosis if the damage is irreparable.
Stress-Signaling Pathways: Prolonged inactivity can activate stress-signaling pathways, such as the JNK and p38 MAPK pathways, leading to inflammation, cell death, and tissue damage.
Cellular Processes: Inactivity can disrupt normal cellular processes, including metabolism, protein synthesis, and degradation, leading to the accumulation of damaged or dysfunctional cellular components and triggering cell damage response signaling.
Gene Expression: Inactivity can alter the expression of genes involved in cell damage response signaling, including those involved in the DDR pathway, apoptosis, and inflammation, contributing to chronic inflammation and tissue damage.
Brave AI Summary, (Hotamisligil and Davis, 2016; (openstax.org; Pateras, et al., 2015)
Follow up question - the “DDR” is not an interchangeable term with cell damage response, but they are similar, both signaling for apoptosis/death and removal of a damaged cell if needed. (Brave AI summary, more links with the search summary)
T-cell immunity requires movement - Chris Masterjohn has an explanation for us regarding part of the way motion is critically important to immune cell function - they are our clean-up crew for bad cells, infected, cancerous, or damaged. Interestingly, they don’t really respond to stuff floating around loose, they need a membrane surface to interact with, and the type of surface marker antigens is what they are responding or connecting to on a questionable cell. (open.substack.com/pub/chrismasterjohnphd; via a comment by MichaelT, thanks!) Too much motion or too little may increase risks of immune dysfunction or an increased risk of an autoimmune disease developing (a T-cell responding to a surface marker protein that is normal human, but excessive force may have led to a connection being made instead of slipping apart - roughly).
In a post linked in that one, Chris describes his own problems with tinnitus and hearing loss in the left ear. He traced it to an old injury to the tailbone that may have been causing uneven pressure all the way up the spine to the temporal bone on his left side. The temporal bone is part of the skull and the inner ear and vestibular system are housed within it. Chris recommends having a thorough body and posture analysis by a Physical Therapist to help identify problems in movement before they lead to degenerative damage. (open.substack.com/pub/chrismasterjohnphd)
Summary of factors involved in hearing besides loud noises or explosive air movement:
Movement helps move lymphatic fluid for cleansing and toxin removal.
Sunshine provides vitamin D and helps use up excess vitamin A, so it helps keep the two in balance. They are both are not really vitamins, being hormones when activated, and they both function as protein transcription factors and control which genes are transcribed into proteins. Activated hormone D is involved in bone and calcium metabolism but it is also essential for immune function along with activated vitamin A - Retinoic Acid or other retinoid forms.
Gut microbiome – beneficial species can make plenty of vitamin K2 for us and other nutrients too, and some also make mood calming serotonin. Within the colon, we need an anaerobic, oxygen free environment, which is based on our eating enough zinc and resistant starches to feed the anaerobic species what they need. SIBO, Small Intestine Bacterial Overgrowth can be related to the colon having an aerobic, oxygenated environment. We need the anaerobic bacteria to make butyrate and short chain fatty acids out of the resistant starches and undigested fiber. The colon cells feed on the fatty acids with anaerobic methods and butyrate also activates an immune supporting GP109 receptor.
Mitochondria are critically important for inner ear function as they provide usable energy. Cell types with more work to do tend to have more mitochondria within each cell, and the inner ear hair cells have some particularly large mitochondria that cluster around right near the base of the hair cell, where nerve signaling would occur. Mitochondrial dysfunction, or lack of nutrients that they need, seems to be a large factor in inner ear symptoms or damage.
Other Risk Factors for Hearing Can Include:
Histamine excess and glutamate or aspartame/Neotame excitotoxicity are damaging to the hippocampus. Lack of magnesium and folate would worsen the problems. GABA, Serine and glycine and cysteine would be protective as glutathione precursor or calming neurotransmitters/signaling chemicals within the brain. Melatonin might be helpful.
Estrogen/progesterone/testosterone deficiency - hormonal balance helps. Genistein or Resveratrol or Turmeric might be helpful. Some people may be sensitive to Turmeric as a TRP channel activator - IBS/colitis might be flared by it. Turmeric is a Vitamin D receptor agonist/activator so it can provide immune system benefits similar to vitamin D. Genistein (from soy) and Resveratrol (grape skins/wine, other berries) are estrogen receptor agonists. Testosterone is a main male hormone and estrogen and progesterone are female hormones. Eating egg yolk or other cholesterol foods is needed as a precursor for us to make the steroid hormones or the secosteroid vitamin D.
Psychiatric or other medication use may be harmful to mitochondria directly or by depleting nutrients that they need and are needed for methylation cycle function. Many commonly used medications or pain-relievers are also ototoxic - harmful to hearing and that seems to be a co-risk or indicator for cognitive damage and later diagnosis of cognitive decline.
Long-term risk: Cognitive Decline may follow Hearing Loss/Tinnitus a few years later.
Hearing damage or tinnitus seems linked to risk for Alzheimer’s dementia or other cognitive conditions. Mitochondrial dysfunction and lack of nutrients needed to reduce oxidative stress would be shared risk factors.
Our brains are amazing in that we can function adequately in society with up to 90% of it damaged... but then we stop being able to function adequately and the decline may be rapid or gradual based on varied risks of diet, lifestyle, genetics, and attitude/mental coping. Social interaction also seems important and part of the risk of later cognitive decline from hearing loss and hair loss/alopecia or premature balding seems linked to reduced social interaction, not just body physiology.
It can take 20 years on average to reach that 90% damaged point.
The FAST scale developed for the Stages of Alzheimer’s Dementia:
1. Stage 1 - normal functional adult – no problems! (or is there early oxidative stress?)
2. Stage 2 - awareness of some decline,
3. Stage 3 - change in function to that of a older child of 12, diagnosis might occur.
4. Stage 4 - the adult now needs some help with daily self-care.
5. Stage 5 - more help getting dressed is needed with function now at a 5–7-year-old level.
6. Stage 6 - Care 24/7 is needed with function at 2-4 years of age.
7. Stage 7 - severe dysfunction at a newborn level, incontinence, wheelchair help.
How long a person takes to progress through the stages varies quite a bit and can last many years or might be more rapid.
Hearing loss is more closely linked to risk of cognitive decline than vision loss, although loss of both hearing and vision is linked to cognitive decline, disability, depression, and mortality. (Ilovehearing.com) Social interaction tends to be reduced with hearing or vision loss and that is likely a factor in cognitive decline. Quality of Life seems to decline with vision loss (not a big surprise). (Welp, et al., editors., 2016)
Nutrition and other support may help slow progression and may even improve or reverse some symptoms of decline. Supporting BDNF pathways may promote regeneration of hippocampal brain cells. We don't know what's possible without trying!
Social isolation doesn't help, and lack of stimulation or movement also worsens symptoms.
Glutamate and aspartame are excitotoxic and can kill hippocampus cells from overwork - spicy nachos are dopamine stimulating and addictive from the glutamate rich seasoning salt. Plain nacho chips and tomato salsa would be better unless there were a food sensitivity or Retinoid toxicity involved. Vitamin A and carotenoids are helpful unless being over-converted to the active form which thinks there is a flu to fight and gives you chronic fatigue or fibromyalgia like symptoms. It leads to histamine production and can add to a histamine problem.
Histamine excess can look like mania or severe paranoia and can lead to obsessive running away/moving away behavior, or it can lead to suicide or violent behavior. Histamine is a modulator normally. It provides brakes for our brain, or the transmission of a car to help us smoothly manage our moods. With an excess of histamine, hyperexcitability occurs and whatever mood the person is in can escalate to crazy levels, diagnosable as something psychiatric. Bipolar disorder, schizophrenia, agoraphobia, may be a diagnosis and ... needs meds – psychiatric medications would likely be prescribed but they wouldn't help unless it was an anti-histamine and those only help marginally.
If histamine excess symptoms are present than strictly reducing histamine sources or trigger foods from the diet can help. Avoiding flickering lights may also be a need as that also triggers allergy mast cells which then release more histamine and other inflammatory chemicals. The body thinks there is something for the immune system to fight. Symptoms would also feel like seasonal allergies with itchy watery eyes and a drippy nose.
If you are waving around a flame thrower daily, and throwing one bucket of water on the flames to put it out, then the place is still going to be burning down. Every day the place would be burning down with insufficient nutrients for detoxifying the oxidative stress chemicals produced by normal daily living, or in excess when there are food sensitivities, loud noise, bad smog air, or other risk factors adding to our inflammatory load. A person with excess histamine can get used to feeling unwell and they may think they are just 'anxious' or whatever was diagnosed, just a Bipolar disorder person who should take their psych meds… That is disinformation, a negative nocebo message though, because a low histamine diet can return the person to a normal modulated state of mind - and they would no longer be so anxious, or they might only have a reasonable amount of anxiety. The psychiatric medications also tend to deplete mitochondrial nutrients and lead to worsening cognitive health and more severe diagnoses.
Frequently seen Dx pathway: “anxiety” or “depression” diagnosis >> Bipolar Disorder or Schizophrenia >> Alzheimer’s Dementia. Tinnitus or hearing symptoms might be occurring during the early stages of inflammation, the “anxiety” or “depression” stage. Increased inflammation is likely an underlying problem combined with a lack of magnesium and vitamin D and K2 for coping with electrically active calcium or other oxidative stress chemicals.
Helpful things - Pure Maple Syrup - so rich in manganese that you shouldn't have more than 1/4-1/2 cup per day. So balanced in trace minerals and magnesium that a 1/4 cup in a liter of water it can be used as a sports rehydration beverage.
Catechins from Pomegranate/peel and Persimmons - seriously worth trying and using more often. They have similar catechin phytonutrients as green and black tea, pomegranate/peel, goji berries, sumac powder, and red raspberries. The leaves of persimmon are made into tea and it is a source of the catechins too. Pomegranate leaves could be used similarly.
Sumac powder is used to make a lemony sweetened beverage which is served cold in hot areas of the Middle East, or in indigenous communities of America. Sumac, the red berry type, has edible vitamin C rich berries that are powdered and sprinkled in tiny amounts on food in Middle Eastern areas. Zaatar spice mix contains sumac powder. Sumac with white berries is toxic, don't consume.
Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.
Reference List
(Hotamisligil and Davis, 2016; (openstax.org; Pateras, et al., 2015) Hotamisligil GS, Davis RJ. Cell Signaling and Stress Responses. Cold Spring Harb Perspect Biol. 2016 Oct 3;8(10):a006072. doi: 10.1101/cshperspect.a006072. PMID: 27698029; PMCID: PMC5046695. https://pmc.ncbi.nlm.nih.gov/articles/PMC5046695/
(Naviaux, 2020) Robert K. Naviaux, Perspective: Cell danger response Biology—The new science that connects environmental health with mitochondria and the rising tide of chronic illness, Mitochondrion, Vol 51, 2020, pp40-45, ISSN 1567-7249, https://doi.org/10.1016/j.mito.2019.12.005. https://www.sciencedirect.com/science/article/pii/S1567724919302922
(openstax.org), openstax.org, Biology for AP® Courses, 9.3 Response to the Signal, https://openstax.org/books/biology-ap-courses/pages/9-3-response-to-the-signal
(Pateras, et al., 2015) Pateras IS, Havaki S, Nikitopoulou X, Vougas K, Townsend PA, Panayiotidis MI, Georgakilas AG, Gorgoulis VG. The DNA damage response and immune signaling alliance: Is it good or bad? Nature decides when and where. Pharmacol Ther. 2015 Oct;154:36-56. doi: 10.1016/j.pharmthera.2015.06.011. Epub 2015 Jul 3. PMID: 26145166. https://pubmed.ncbi.nlm.nih.gov/26145166/
(Welp, et al., editors., 2016) National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on Public Health Approaches to Reduce Vision Impairment and Promote Eye Health; Welp A, Woodbury RB, McCoy MA, et al., editors. Making Eye Health a Population Health Imperative: Vision for Tomorrow. Washington (DC): National Academies Press (US); 2016 Sep 15. 3, The Impact of Vision Loss. Available from: https://www.ncbi.nlm.nih.gov/books/NBK402367/
Wow! Great research and companion notes for bodily Heath and fitness. Many thanks
Your substack is amazing. Jam-packed with important info and stats. Grateful for all of this. Thank you!