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Hormones, Hysterectomy, and the Aging Brain

Published on April 7, 2022

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Everything slows down as we age. For some lucky folks, aging happens gracefully with nary a disease in sight. For others, the springs start popping off around 40 and by the time we reach ‘old age’ our bodies and brains are barely functioning. Arguably, diet and lifestyle have something to do with how well or how poorly we age, and of course, genetics contribute mightily, but beyond that, we really have no idea what’s happening with aging.

Sure, there are all sorts of physiological systems that become progressively less efficient over time. Wear and tear plays a huge role, but the relationships aren’t linear. There are always outliers. There are folks who, on a diet of smokes and scotch, live well into their nineties with all their faculties intact. Then there are the poor souls who are prodigiously healthy, who eat right and exercise, but yet, whose bodies seem set on wide-scale destruction, where the slightest change in lifestyle risks sending them into a morass of cascading illness. Somewhere in the middle, the rest of us live – sometimes healthy, sometimes not – aging in fits and spurts. What the heck?

From a physiological standpoint, aging is marked by two opposing factors: decreasing hormones and increasing inflammation. Where they intersect, age-related illnesses seem to accrue. Called endocrine senescence, researchers have long noted a relationship between declining hormones and declining immune function (marked by increased and inefficient inflammatory responses). Might there be some truth to the ever-young, hormone peddlers? Could hormones be the key to offsetting the age-induced inflammatory cascades? Possibly.

Hormones and Mitochondria

I just finished writing an extensive paper on acquired mitochondrial illness. Throughout the research, I stumbled upon a short essay linking mitochondrial structure and function to estradiol. More specifically, the rapid estradiol decline common post oophorectomy (ovary removal), fundamentally alters the shape, and ultimately, the function of mitochondria. Researchers found that a rapid decline in estradiol evokes significant damage in the brains (and presumably other organs) of female monkeys. Additional studies using estradiol starved mitochondria from female rodents showed similar shape alterations and consequent declines in brain bioenergetics. Interestingly though, with natural menopause, where estradiol declines more gradually, no such structural changes were observed. In fact, with the more gradual decline in estradiol, the mitochondria appear to increase their production of the lifesaving ATP as a compensatory reaction.

All Paths Lead to the Mitochondria

Recall, from previous posts, that mitochondria take dietary nutrients and oxygen, and change them into the chemical energy (ATP) that is used by every cell in the body. Without ATP, cell function grinds to a halt. So, anything that derails the mitochondria, imperils cell function and initiates cell death. Lack of nutrients, sedentary lifestyle, pharmaceutical, and environmental toxicants, all derail mitochondrial function. Cluster too much cell death together in one tissue or one organ and disease happens. Since mitochondria are in every cell of the body, mitochondrial damage induces disease broadly, but especially in regions with high energy demands like the brain, the heart, the muscles, and the GI system.

The cardinal symptoms of mitochondrial damage include fatigue, weakness, muscle pain, and depression. These are followed by dysregulated systems; a GI system, for example, that overreacts or under reacts or temperature dysregulation (hot flashes, cold insensitivity), insulin/sugar dysregulation, emotional volatility, migraines, seizures, syncope (fainting), and so on. It’s not a pretty picture.

In addition to providing the fuel for cellular respiration, e.g. life, mitochondria control a host of other functions, steroidogenesis is one of them. This means that if we fail to feed the mitochondria or hurl insults at them, hormone dysregulation is inevitable. Ditto for inflammation, as the mitochondria regulate inflammatory cascades. Every woman knows when her hormones are out of whack. Well, now we know that hormone dysregulation emerges from the mitochondria.

From a systems perspective, consider the mitochondria as central regulators of organismal health. Mitochondria both send and receive signals from all over the body and then adjust their functioning accordingly. With their role in hormone synthesis, we would expect there to be cross-talk between the mitochondria and circulating hormones. Indeed, there is. All steroid hormones have receptors on the mitochondrial membranes. When hormone concentrations increase or decrease, the mitochondria will initiate the synthesis of new hormones and send signals throughout the body to adjust other hormone-responsive systems as well.

No Estradiol Equals Misshapen Mitochondria: Donuts and Blobs

Removing the ovaries starves the mitochondria of one of its many feedback mechanisms and damages the brain mitochondria in the regions of the brain responsible for executive function and memory – the frontal cortex and the hippocampus. The mitochondria change shape, from spheres (healthy) to donuts and blobs, which represent early and late-stage mitochondrial damage, respectively. Misshapen mitochondria cannot provide the energy (ATP) needed to perform critical brain functions such as neural communication or the antioxidant tasks needed to clean up toxicants. Neurodegeneration ensues. In layman’s terms, and in the early stages, brain fog and memory loss. Researchers believe that it is this loss of functional mitochondria that contribute to the onset of neurodegenerative disorders like Alzheimer’s and other dementias. And, this loss of function is precipitated by an unnatural loss of estradiol.

Ovary Removal is Common with Hysterectomy – Now What?

For the millions of women who have had their ovaries removed with hysterectomy, this presents a problem. Amid the myriad of other side effects associated with ovary removal, and perhaps, the root cause of these effects, we can add mitochondrial damage and brain mitochondrial damage, specifically. The rapid decline of estradiol, and other hormones, places many women at risk for neurodegenerative disorders like Alzheimer’s. How could this be mitigated?

In animal research, hormone replacement with 17B – estradiol immediately after the ovaries are removed seems to temper the damage, at least in the short term. There are no long-term studies. Similarly, epidemiological studies in human women suggest hormone replacement immediately after open menopause and/or hysterectomy with oophorectomy reduces clinical symptoms associated with the diseases of aging – e.g. the cognitive decline of Alzheimer’s and other dementias. However, since the synthetic estrogens used pharmacologically are different compounds than those produced endogenously (and used in basic and animal research) and because there are no mitochondrial imaging or even mitochondrial function tests done with human females given hormone replacement, it is difficult to compare the two sets of literature.

Some data suggest that the use of synthetic estrogens damages mitochondria and further diminishes the synthesis of remaining endogenous estrogens (the adrenals continue to produce estradiol and other estrogens after the ovaries are removed). Women who have used synthetic estrogens such as those in oral contraceptives and hormone replacement therapies have lower concentrations of endogenous estradiol, estrone, androstenedione, testosterone, and sex hormone-binding globulin. Based upon the aforementioned research, the decline in endogenous hormones would suggest a commensurate derangement in mitochondrial structure and function, but there are no data either way. At the very least, caution is warranted when contemplating the use of synthetic estrogens, particularly in the current environment that is rife with estrogenic chemicals. There are no data on the use of ‘natural’ or ‘bioidentical’ hormones and human mitochondrial function. So, although the animal data are fairly clear, estradiol replacement begun early enough appears to offset the decline in endogenous estradiol, how this translates to human females is not known.

Other Hormones and Additional Pathways

A flaw common to most research in this field is the failure to address the other hormones involved in modulating health. Estradiol is but one of many estrogens produced endogenously. It is also one of many steroid hormones produced in the ovaries and regulated by mitochondrial function. How estradiol removal or add-back affects progesterone, the androgens, or even the glucocorticoids (cortisol) – is not known. Compensatory reactions are likely. Understanding how those reactions mediate mitochondrial function might determine a viable workaround for the depleted estradiol. The beauty of human physiology is a mind-blowing breadth and depth of compensatory reactions to maximize survival. So I would think, and this is purely speculative, that even if one has lost her ovaries, and even if estradiol treatment was not initiated immediately, or if synthetic estrogens were used instead, there should be other mechanisms to tap into and compensate for this loss. That is, there should be multiple pathways to help maintain mitochondrial function. What those are, I do not know, but they are worth exploring.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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This post was published originally in January 2015.

Digging Deeper into Mitochondrial Dysfunction

by Chandler Marrs, PhD

Published on April 5, 2022

20602 views

When you have a hammer, everything becomes a nail, or so they say. I worry about this as I dig deeper into mitochondrial dysfunction. Could all of these disparate symptoms and conditions have their roots in the mitochondria? Could it be that simple? Perhaps. More and more, as I search for explanations for the devastating symptoms that so many of our readers report, the research I find points to mitochondrial dysfunction. Sure, changes in gut microbiota and function are apparent and often related and certainly immune dysregulation is a component of these illnesses, but the underlying connection among these disturbances seems inevitably and inextricably linked to dysfunctional mitochondria as the central hub of illness. Heal the mitochondria, heal the body is quickly becoming my new mantra.

Mitochondria as Danger Sensors

Some researchers argue that the mitochondria are the danger sensors for host organisms; having evolved over two billion years to identify and communicate signs of danger to the cells within which they reside. The signaling is simple and yet highly refined, involving a series of switches that control cellular energy, and thus, cellular life or death. When danger is present, energy resources are conserved and the immune system fighters are unleashed. When danger is resolved, normal functioning can resume.

If the danger is not resolved and the immune battles must rage on, the mitochondria begin the complicated process of reallocating resources until the battle is won or the decision is made to institute what can only be described as suicide – cell death. Cell death is a normal occurrence in the cell cycle of life. Cells are born and die for all manner of reasons. But when cell death occurs from mitochondrial injury, it is messy, and evokes even broader immune responses, setting a cascade in motion that is difficult to arrest.

And, if the on the battlefield, the host army is understaffed and under-resourced, no matter how hard the immune fighters battle, the fight will be lost, maybe not immediately, but eventually. All sorts of mechanisms will be employed to reallocate and reinforce needed battlements, but they will be for naught, further depleting already scarce host resources, until the decision is made, within the mitochondria, to begin pulling back, withdrawing, and ultimately casting the final orders of cell death.

It’s not Autoimmunity, but Impaired Immunity

I never much liked the war model of health and disease, but it seems to work well as metaphor for immune functioning, as it is far more illustrative and useful than the self-versus non-self-characterization. Really, what army with two billion years of experience, one that contains all of the memories and skills of battles past, would misidentify itself and begin broad scale fratricide – kill itself and its brethren for no other reason but mistaken identity and do so for years on end? Sure, there can be errors, over compensation and other weaknesses in the immune system, but not continued aggression towards itself in some maladaptive response. That makes no sense and contradicts the very notion and function of an immune system – to keep the host organism alive and well. Indeed, when we consider the trillions of microbes – clear non-self entities – that live inside and upon us, the idea that the immune system evolved simply to kill the non selves seems laughable. And so, I reject the concept of autoimmunity, not because the patients who suffer from continued immune system activation are not ill, they are, but because the concept of autoimmunity belies the very nature of immune function and severely limits possible approaches to recovery.

The Naming of Things

Many of you might be thinking ‘what the heck does what we name things have to do with understanding illness?’ Well, the language and the characterization of disease impacts therapeutic choices. In a system where autoimmunity dominates the discussion, survival is predicated on suppressing the invading immune army. Consequently, most therapeutic options for autoimmune disease are immunosuppressant, and mostly they fail. In contrast, if one characterizes immune function by its ability to protect and sustain life by fending off dangers or threats to survival, be they self or non-self, it does not matter, then we can be open to finding causes for those failed battles. We can ask questions like: what resources are missing that would allow the immune army to fend off the danger once and for all or what could heal the damaged cells, scavenge toxicants and oxidants or re-calibrate mitochondrial energy production? When we re-frame the discussion in this way, we open the door to a deeper understanding of health and disease. It is from this perspective, one that says chronic immune activation is not a disease itself but a symptom of an on-going and failing immune battle, that we can get to the mitochondria as the central hub for chronic ill-health.

Evolution and the Mighty Mitochondria

Mitochondria are interesting little buggers, having evolved from the very parasites our immune system sought to protect us against. Called symbionts, the mitochondria were microbial intruders swallowed by the host. In a brilliant move of survival, they somehow convinced the host organism not only not to kill them but to let the mitochondria, a parasitic intruder, run the host’s energy supply. The mitochondria proved their utility and developed a symbiotic relationship with the cells within which they resided. Over time, mitochondria developed a myriad of intricate communication and resource allocation mechanisms to ensure not only their survival but that of their host organism. And so, in many ways, the mitochondria evolved as part of a cooperative and collaborative ecosystem; one in which they sense and communicate danger to the rest of the organism, and if need be, initiate the final death programs; something, they should be loath to do, since their survival depends entirely on host survival.

Clearly though, and from the very beginning, the mitochondria positioned themselves as the brains of the operation. Mitochondria control energy. There is no other resource more important to the living organism than energy. Consider the most consistent sickness behaviors across all illness include, lethargy, fatigue, sleepiness, often followed by muscle and body aches, anorexia or the loss of interest in eating. The reduction in energy is purely a function of mitochondrial resources. The achy muscles are moderated by mitochondrial retractions of energy and the loss of appetite too, mitochondrial diminishments – recall the orexin/hypocretin system. By whatever pathway, declining mitochondrial energy production arises when danger signals, or more appropriately, cell damage signals are communicated. It is then that the immune armies are activated and inflammation sequences unleashed.

What Does Mitochondrial Dysfunction Look Like?

Everything and nothing at the same time. Mitochondrial dysfunction doesn’t lead to one, clear cut disease, even when there are clear genetic markers, but predisposes one to everything. Where mitochondrial damage is felt and the subsequent immune events present is complex and dependent upon the interactions among the host organism’s innate predispositions, environmental exposures and nutritional status, with the latter two significantly influencing each other. The microbial composition of the host, especially in the gut, but also on the skin and the various mucous membranes that interface with the outside world, can also moderate or trigger the danger signals that lead to mitochondrial dysfunction. More often than not though, mitochondrial damage is felt where oxygen demands are greatest, the brain, the heart, the gut, the muscles. Diseases that are currently identified discretely might all have common symptoms – the mitochondria.

Certainly, chronic fatigue should be considered mitochondrial in nature. I don’t think there is a more clear-cut example of mitochondrial dysfunction than severe fatigue, muscle pain and weakness. The question becomes, from where does the dysfunction originate and how can it be fixed or healed?

Migraine, seizures, ataxias and other neurological disorders are emerging as mitochondrial, particularly was more work is done on the hypocretin/orexin system.

Autonomic dysregulation, recognized under the umbrella as dysautonomias are mitochondrial in nature.

Thyroid dysfunction is likely mitochondrial in nature; the interaction between thyroid hormones and mitochondria is direct. Given the mitochondria’s role in steroidogenesis, other hormone systems are likely modulated by mitochondrial functioning.

Research is emerging suggesting that gastrointestinal disturbances, particularly those of dysmotility like IBS, gastroparesis, constipation and pseudo obstruction but also anorexia are mitochondrial in nature. Indeed, the GI system has its own nervous system, called the enteric nervous system. Only 10-15% of GI motility is controlled from brain’s autonomic system. The rest is controlled on site by the enteric system, mostly from cells called the interstitial of cells Cajal – the smooth muscle cells that propagate contractility and rhythm and form the gut barrier between the inside contents and the rest of the body. The mitochondria control energy usage and production here. Mess with these cells, diminish oxygen usage, pull back energy production and all sorts of things go wrong. We can get ill-timed contractions or no contractions at all, making the movement of food stuffs through the GI impossible. Poor absorption and metabolism of nutrients, and increased permeability of the tight junctions allowing for the leaky gut scenario common in many chronic conditions, become prominent and are also symptoms of mitochondrial dysfunction. Even anorexia, the will to eat, can be disturbed significantly by mitochondrial damage.

And I suspect, although I have no evidence to support this claim, in women, mitochondrial damage can express itself in the reproductive organs, especially when oxygen demands are greatest, menstruation and pregnancy. Consider the increasingly painful muscle contractions for some women involved in shedding the uterine lining during menstruation, just as diminished oxygen and energy in other muscles begins the cycle of lactate production and buildup that initiates pain, so too might this happen in the uterus. As mitochondrial deficiencies persist, uterine dysfunction would grow and compensatory immune system mechanisms increase until the compensatory mechanisms take a life of their own. When we consider the mitochondrial influence on GI motility, their influence on uterine function is not difficult to imagine. I have an inkling that endometriosis, the excessive growth of endometrial cells first within the uterus and then in regions of the body where they ought not be, is a protective mechanism, albeit an aberrant and problem causing one, that indicates increased mitogenesis and cell growth as a compensatory reaction to some original mitochondrial inadequacy. How this might happen molecularly provides some intriguing possibilities.

Immune function and inflammatory reactions are directly controlled by mitochondrial signals of danger and so to the extent we see chronic inflammatory conditions, one can look towards mitochondrial resources and the ensuing danger signals for clues towards reducing these reactions. While much of the clinical research is nascent, more and more clinicians, often from disparate specialties and sometimes without recognizing the immune-mitochondrial connections, have made great inroads towards healing and restoring mitochondrial function through diet and nutritional supplementation paired with the reduction and removal of environmental and medical toxins and dietary inflammasomes.

Is Everything a Nail, When One has a Hammer?

Maybe, but I can’t help but thinking that this mitochondrial hammer might be the one to hit the nail on the head and finally make some inroads towards reducing the suffering and burden of chronic disease. Only time will tell. For the moment, however, this is a hammer that deserves more recognition and whether it turns out to be the final clue or not one thing is clear, mitochondrial health is critical for human health. Deny the mitochondria their due and chronic, complicated illness will persist.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

Image credit: OpenStax, CC BY 4.0, via Wikimedia Commons

This article was published previously on Hormones Matter in June 2014.

Thyroid Hormones, Mitochondrial Functioning, and Hair Loss

by Chandler Marrs, PhD

Published on January 3, 2022

38212 views

Hair loss is a common symptom of thyroid disease. In our research, hair loss, changes in color or luster, and skin changes are regularly reported as one of the first symptoms noticed in an emerging non-allergenic adverse reaction to a medication or vaccine. These symptoms often coincide with unexplained fatigue and muscle pain. Given that many patients who develop the more chronic, multi-symptom medication or vaccine reactions also develop thyroid disease and frequently exhibit signs of mitochondrial damage, I wondered if somehow the hair and skin changes could be early warning signs of diminished mitochondrial functioning. I also wondered if all of these variables were connected. It turns out that not only are they connected, but incredibly interdependent.

What are Mitochondria?

Recall from high school biology, the mitochondria are those bean-shaped organelles inside cells that are responsible for cellular respiration or energy production. Through a variety of pathways, the mitochondria provide fuel for cell survival. In addition to cellular energy production, mitochondria control cell apoptosis (death), calcium, copper, and iron homeostasis, and steroidogenesis. In essence, mitochondria perform the key tasks associated with cell survival, and indeed, human survival. Damage the mitochondria and cellular dysfunction or death will occur. Damage sufficient numbers of mitochondrion and chronic, multi-symptom illness arises.

How to Damage Mitochondria

Mitochondria are remarkably resilient given the proper nutrients, but without those nutrients, they can be highly susceptible to damage. Mitochondrial damage can be inherited via mutations in maternal DNA (mtDNA) or nuclear DNA and present at birth or remain latent until triggered later in life, as in the case of mitochondrial endocrinopathies. Mitochondria are also susceptible to epigenetic changes, which can be heritable and acquired and remain latent until triggered. Finally, mitochondrial impairment can derive from pharmaceutical or environmental exposures and nutrient or cofactor deficits. The sheer number of mechanisms that can influence mitochondrial functioning and heritability make diagnosing and predicting mitochondrial dysfunction difficult at best, particularly acquired or functional mitochondriopathies that are not evident from genetic or epigenetic testing. It is precisely those acquired mitochondriopathies, particularly those seemingly triggered by pharmaceutical reactions, that we are most interested in here at Hormones Matter. Indeed, acquired mitochondrial damage represents a nascent and emerging field in medicine, particularly in toxicology, as many drugs and vaccines damage mitochondrial functioning both directly and indirectly.

What Mitochondrial Damage Looks Like

Mitochondrial damage presents in a highly diverse, multi-organ, multi-symptom manner. On the surface, patients with mitochondrial dysfunction will appear to have multiple, unconnected diagnoses, from gastrointestinal distress to cognitive deficits, from cardiac arrhythmias to multiple sclerosis-like symptoms, and everything in between and beyond. According to Dr. Richard Boles, an expert on mitochondrial dysfunction:

“Mitochondrial dysfunction doesn’t really cause anything, what it does is predisposes towards seemingly everything. It’s one of many risk factors in multifactorial disease. It can predispose towards epilepsy, chronic fatigue, and even autism, but it doesn’t do it alone. It does it in combination with other factors, which is why in a family with a single mutation going through the family, everyone in the family is affected in a different way. Because it predisposes for disease throughout the entire system.”

This is partially because the human body contains over a billion mitochondria which are essential to cellular functioning in every cell of the body. Where the dysfunction emerges is dependent upon where the impaired mitochondria reside, by what mechanism the mitochondria are damaged, and how intervening variables, such as overall health, nutrition, and environment come into play. Given the mitochondrion’s role in energy production, highly energy-dependent tissues such as the brain, the heart, the liver, and even muscles, are most susceptible to direct mitochondrial damage. And considering the mitochondrion’s role in cellular energetics, fatigue is almost always present with mitochondrial dysfunction.

Hormone Synthesis and Mitochondrial Functioning

Adding yet another layer of complexity, mitochondria also control steroid production in the adrenal glands, ovaries, testes, and thyroid. Any impairment of mitochondrial functioning can have a significant influence on hormone production and regulation. Since hormones, like the mitochondria, also impact all facets of biological homeostasis, energy, and metabolism, damage to endocrine mitochondria can represent a double-hit and begin a cascade of endocrine ill-effects that are difficult to control. This is particularly true of the thyroid gland.

Thyroid Hormones and Mitochondrial Functioning

The cells within the thyroid gland are dependent upon proper mitochondrial functioning to maintain health and proper mitochondrial functioning is dependent upon thyroid hormones to manage cellular energy production. This reciprocal and interdependent relationship makes the thyroid especially susceptible to a mitochondrial spiral. Both thyroid and mitochondrial damage have been observed in our medication and vaccine adverse reaction populations.

Thyroid hormones regulate mitochondrial functioning. Triiodothyronine (T3) in particular is considered one of the major regulators of mitochondrial activity stimulating mitochondrial biogenesis (the birth of new mitochondria) both directly (genomic), indirectly (non-genomic), and epigenetically.

T3 is responsible for increasing cellular heat production and oxygen consumption, core activities of mitochondrial metabolism. In hypothyroid states, heat and oxygen are reduced, whereas, in hyperthyroid states, the two are increased. Here the intracellular patterns of heat and energy production correspond to the clinical symptoms of hypo- and hyperthyroid states. Other thyroid hormones along the hypothalamus – pituitary – thyroid axis (HPT) and the other iodothyronines within the thyroid hormone metabolic pathway influence mitochondrial functioning. Remove or reduce the presence of the thyroid hormones and mitochondria produce less energy and eventually die. With them, the cells in which they reside die too. Conversely, as mitochondria within the thyroid become less efficient, smaller concentrations of thyroid hormones are produced. With reduced thyroid hormones, mitochondrial efficiency continues to decline and so on, and so on.

Hair Follicles: Mini – HPTs

German researchers recently identified multiple mechanisms by which human hair follicles are responsive to thyroid hormones. Their research showed that human skin and hair follicles possess an equivalent peripheral HPT axis with all of the corresponding hormones such as the central HPT. It turns out that hair follicle mitochondria are differentially responsive to each of the thyroid hormones along that axis and are responsive to other iodothyronines not typically considered bioactive, such as diiodothyronine (T2).

An interesting finding, related specifically to the hair follicle, and perhaps other mitochondria, thyroid hormones were protective against reactive oxygen species (ROS) production via multiple mechanisms. ROS, also called free radicals or oxidants, are natural by-products of oxygen (energy) metabolism important to a number of basic cell and life processes, like signaling and the defense against pathogens, but ROS levels must be kept in strict balance. Too much or not enough ROS and health goes awry. In the case of adverse fluoroquinolone reactions, increased ROS production is implicated. According to the hair-follicle study, thyroid hormones protect against ROS production and regulate the enzymes that scavenge for and eliminate free radicals – our own internal antioxidants. If this function is conserved throughout the body, it provides one more reason to investigate and appropriately manage thyroid damage in medication adverse reactions.

Hair Loss and Mitochondrial Damage

Skin and hair follicles are dense with mitochondria and highly regulated by thyroid hormones such that the mechanism for hair loss in some individuals can be attributed to either diminished thyroid hormones and/or damaged mitochondria. Since the relationship between thyroid hormones and mitochondria is reciprocal, it is difficult to tell which impairment comes first. However, given what we know about hair growth cycles and what we know about thyroid hormones and mitochondrial functioning, it is possible to speculate and backdate a chemical insult precipitating sudden and unexplained hair loss. For more incipient reactions, it is a bit more difficult. Regardless, however, it appears that unexplained hair loss is a sign of poor mitochondrial functioning.

Hair growth occurs in phases. The anagen phase is the growth cycle where hair follicles grow about 1 cm per day for 28 days. This growth phase lasts for 2-7 years. The exact time frame is genetically, or more specifically, epigenetically determined by factors associated with the health of the maternal grandmother. After the anagen phase, the hair follicles reach a transitional, quiescent period lasting approximately 2-3 weeks. This is then followed by the telogen phase where hair begins to fall out. At any given time, up to 90% of hair follicles are in the anagen or growth phase while the remaining follicles are either catagen (10-14%) or telogen phases (1-2%).

Chemo Induced Hair Loss: Answers in the Mitochondria?

With chemotherapy, hair loss begins 2-4 weeks after treatment begins and although multiple mechanisms have been investigated, none have been able to explain or treat effectively chemo-induced hair loss. I would suspect that given the time frame, the toxic insult of chemotherapy, the role of mitochondria in hair growth, and the connection to thyroid damage, that chemo-induced alopecia is representative of mitochondrial damage. The ability to maintain hair growth during chemo may be related to supporting mitochondrial and/or thyroid health.

In the case of other presumed less toxic or at least less directly toxic chemical insults such as medication or vaccine adverse reactions, the initial loss of hair that begins either in the weeks preceding the full onslaught of symptoms or coincident with those symptoms, marks a decline in mitochondrial functioning and likely an impending decline in thyroid functioning.

Hair Loss: A Reallocation of Mitochondrial Resources

Considering, that hair generation is an energy (read mitochondrial) intense process, sudden hair loss could be an early marker that mitochondrial resources are limited and being reallocated towards more critical operations like brain and heart functioning. When the components for proper mitochondrial functioning are absent, be it the thyroid hormones or the co-factors necessary for cellular energy (ATP) production, the first wave of resource allocation might be to cease non-essential activities. The non-essential activities would include hair growth (and wakefulness in general – read Medication and Vaccine Adverse Reactions and the Orexin – Hypocretin Neurons). Sudden or unexplained hair loss could indicate mitochondrial impairment. Backdate the hair loss 2-4 weeks and an illness, a medication, vaccine, or environmental exposure could be the culprit. Whatever the cause, the thyroid and mitochondrial health should be considered and treatment initiated accordingly because if the disease process continues, the symptoms will expand beyond the hair, potentially to every tissue and organ in the body. Concurrently, investigate and amend nutritional status. Mitochondrial functioning is critically dependent on proper nutrients. Deficits in important nutrients, like thiamine, can have severe repercussions.

Feed your thyroid. Feed your mitochondria.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

This article was first posted on Hormones Matter in May of 2014.

COVID Notes: “I Don’t See A Role For Mitochondria.” Say What?

by Chandler Marrs, PhD

Published on April 12, 2021

8307 views

covid notes mitochondria immune function

A persistent notion in medicine is that the only time mitochondria precipitate, or in any way influence illness, is when mDNA mutations are involved and/or with frank starvation. Absent those two events, the magical mitochondria will keep chugging along and there is no need to consider their impact on health or disease. This belief emanates partly from another all-too-persistent notion that holds tightly to a compartmentalized model of organismal function, suggesting that each bodily system and thus each disease process is unique and distinctly separate from everything else, and partly from the way most folks are taught about mitochondria – by rote memorization of the Krebs cycle. As a result and except in specific circumstances, most physicians and many researchers see no role for mitochondria in health or disease.

This is true with COVID as well. Even though COVID presents disparately across patient populations, is clearly not limited by body compartment or system, and not only does not fit within any diagnostic model to date but shatters everything we think we know about illness, folks are reticent, nay adamant, that mitochondria are not involved. COVID is not a mitochondrial illness, they proclaim. To that end, on a somewhat regular basis, I see posts, threads, and comments about just how unimportant mitochondria are to COVID and really, to health in general.

Stressed Mitochondria, Inflammation, and COVID

Some months ago, a gentleman argued that the chronic inflammation caused by COVID was related solely to altered immune function similar to that seen in conditions like rheumatoid arthritis or lupus. He went on to say that he did not see any role for mitochondria in this. Similarly, another gentleman was equally adamant that there was no known relationship between “mitochondrial health impacting which immune response or pathway will be activated.” He argued further that my suggestion of stressed mitochondria triggering the inflammatory responses seen in COVID-related blood pressure drops and cytokine storms was not possible per the tenets of modern immunology. It was foolhardy for me to consider otherwise.

Beyond the obvious faceplant response – ‘as if the immune system could function without the help of the mitochondria; as if anything could function without the mitochondria’ – there is an ample amount of research linking mitochondrial function to immune function predating COVID and a burgeoning body of research linking mitochondrial response to COVID severity. Indeed, some of the more recent research suggests that not only does SARS- COV2, the viral protein associated with COVID directly influence mitochondrial function like many other viruses do, but also that it is only the host variables e.g. mitochondrial fitness that determine how far the virus is allowed to progress. Mitochondria, it appears, are the determining factor of illness severity, something I have been saying since the beginning of this pandemic.

When this particular series of ‘COVID does not involve the mitochondria’ comments came up, I was speaking about the hijacking of the mTOR pathway by other viruses and speculating as to whether COVID might do the same. The mTOR pathway includes a set of enzymes that regulate cell and mitochondrial metabolism via multiple mechanisms. Though mTOR are not mitochondrial proteins, as they are located in the cytosol adjacent to another set of organelles called lysosomes, they provide critical signaling to mitochondria involving energy metabolism and stress response. In fact, mTOR coordinate mitochondrial energy consumption and production. They initiate these nutrient signals by binding or unbinding themselves to the lysosomes. Among those signals that mTOR respond to is protein or amino acid status. Low protein effectively inhibits mTOR enzymes. Absent outright starvation, which is entirely possible in critical illness, protein metabolism is dependent upon mitochondrial function. Specifically, protein catabolism and synthesis both require energy or ATP, which in turn requires an array of micronutrient co-factors to power mitochondrial enzymes, the machinery involved in these processes.

Returning to the claim that the COVID cytokine response was akin to the autoimmune diseases like arthritis or lupus, that claim is absolutely correct. The response is akin to one of an autoimmune disease process, but what most fail to recognize is that autoimmune disease process is itself tied to the mitochondria, through multiple channels, including mTOR. Since these conversations arose from a post on viral hijacking of mTOR and the inflammatory patterns observed with autoimmunity, let us dig into those relationships.

Th-17 Cells, mTOR and the Mitochondria

Common to both the severe and long COVID and autoimmune illness, are hyperactive pro-inflammatory Th17 cells with underactive anti-inflammatory Treg cells. Th17 modulation is tied to mitochondrial fitness. The Th17 response is thiamine dependent. Thiamine is the rate limiting co-factor to key enzymes involved in mitochondrial energy production, including those at the entry points for the glucose, fatty acid, and amino acid pathways and other enzymes within the TCA/Krebs cycle. Thiamine deficiency derails mitochondrial energy production, shifting it from oxidative phosphorylation and towards aerobic and eventually, anaerobic glycolysis. Even aerobic glycolysis, however, is thiamine dependent. These shifts in energy production are mitochondrial danger signals to the immune cells, including Th17 proinflammatory response. The mTOR proteins, are also involved. When oxidative phosphorylation, glutamine metabolism, and fatty acid synthesis, all which are thiamine dependent, are lagging and energy wanes (e.g. with insufficient thiamine or other mitochondrial nutrients), mTORs energy metabolism becomes anaerobic and pro-inflammatory – e.g. Th17s upregulate and the anti-inflammatory Treg cells downregulate.

Renowned mitochondrial researcher Robert Naviaux would tell us that in both autoimmunity, and in COVID, particularly Long COVID, the mitochondria are stuck in battleship mode; that they lack the energy not only to complete the tasks at hand, but to create more energy. Dr. Lonsdale would tell us that this is because the mitochondria lack the sufficient nutrients to convert food into energy, especially thiamine. From our book, notice how many times thiamine, vitamin B1, is required. Notice also, how many other micronutrients are required to convert food substrates, glucose, proteins, and fatty acids into ATP.

Now consider the high calorie, low nutrient composition of the modern American diet, the metabolic dysfunction associated with the severity and chronicity of COVID, and the range of inflammatory disorders afflicting many of the patients who develop severe and/or long COVID. These are connections that must be recognized.

We know that absent sufficient mitochondrial nutrients, energy wanes. When energy wanes, inflammatory cascades remain unchecked; among them, hyperactive pro-inflammatory Th17 and underactive anti-inflammatory Treg cells. We have to consider also that although pharmaceutical interventions may abrogate that inflammation superficially and temporarily, they do nothing resolve the underlying issue, which is micronutrient deficiency. Since most, if not all, medications damage mitochondria by one mechanism or another, their use, while necessary in some instances, ultimately imperil mitochondrial capacity and exacerbate any underlying energy deficiency as well. So, when we look at folks most at risk for the more severe cases of COVID and/or those who develop symptoms consistent with Long COVID, it is important address the inflammatory response caused by the lack of sufficient energy.

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COVID Notes: Considering Drug Induced Mitochondrial Damage

by Chandler Marrs, PhD

Published on March 15, 2021

6703 views

COVID notes drug induced mitochondrial damage

Much has been written about the associations between COVID severity, chronicity, and pre-existing conditions. Top among those conditions include cardiovascular disease and diabetes, likely type 2, but both are lumped together. What has not been discussed is why this would be the case. On a basic level, fighting two illnesses takes more energy than fighting one. This is obvious. What is not obvious is that many modern illnesses, especially cardiovascular disease and type 2 diabetes, begin in the mitochondria as a consequence of diet and lifestyle. Statistically, 80% of cardiovascular disease and 78-83% of type 2 diabetes can be traced back to longstanding dietary, lifestyle and environmental issues* that effectively diminish mitochondrial energetic capabilities and disrupt metabolic flexibility; and the remainder that did not originate from diet and lifestyle are certainly affected by these variables.

To function effectively and to convert the foods we eat into energy or ATP, the mitochondria require sufficient vitamins and minerals, 22 of them, in fact. Western diets, while high in calories, are woefully low in these micronutrients, even when fortified, creating what we refer to as high calorie malnutrition. Against this dietary backdrop, reduced ATP then leads to a constant, low level molecular hypoxia. This is not a hypoxia of obstruction or exertion, but more fundamental. For without proper nutrients, mitochondria can neither utilize oxygen effectively to create ATP, nor do they have sufficient ATP to traffic the O2 into the hemoglobin where it can be pumped into circulation to feed tissues and organs. It is a subtle desaturation, at least initially, but one that initiates all sorts of compensatory reactions to mitigate risk; reactions that are necessary and lifesaving in the short term but become increasingly harmful as time passes.

With insufficient ATP, inflammatory and immune reactions become disrupted and even seemingly chaotic; hormone and electrolyte regulation becomes imbalanced and organ and brain function diminishes. We get disrupted autonomic function (dysautonomia), which cycles back and further disrupts everything else. Depression, anxiety and other mental health issues are also common. This underlying mitochondrial distress is part of the reason why patients with comorbid conditions are at increased risk of not only developing but succumbing to COVID, or really, any virulent pathogen. Their mitochondria are already taxed. They are already carrying low-level hypoxia and, in a very real way, they simply do not have the energy to mount or manage a successful defense.

Now, to add insult to already injured mitochondria, we prescribe medications to manage these conditions rather than correct the root cause, which remember is mitochondrial distress. These medications, while they effectively provide the semblance of health, likely cause more damage to an already damaged system. That is, we get more normal labs, or in the case of antidepressants or anxiolytics, we may feel better, but they do nothing to correct the problem. They only exacerbate it further.

An Unappreciated Factor in COVID Severity and Chronicity

A little appreciated fact in medicine, all pharmaceuticals damage mitochondrial function by some mechanism or another. I have published extensively on this topic here on HM and in our book. Sometimes they deplete critical micronutrients and other times they directly distress, damage and/or deform the mitochondrial membrane by forcibly overriding the regulation of key enzymes involved in ATP production. This, of course, is often compounded by poor nutrition and nearly continuous exposures to chemical toxicants in the environment. It is a perfect cycle of destruction. Poor nutrition causes poorly functioning mitochondria, which decreases ATP while increasing cell level hypoxia, which then initiates inflammation and alters immune reactivity, and rather than correct this, we prescribe medications to override what are necessary reactions to poor nutrition and environmental exposures. These medications then elicit additional damage, further decreasing mitochondrial efficiency and ATP, which necessitates extra nutrients to maintain ATP and stave off more damage.

When we consider the association between COVID severity and comorbid health issues, it must be against the backdrop of nutrition and pharmaceutically and environmentally induced mitochondrial damage. The only variables we can control directly are nutrition and pharmaceutical exposures. We can add more nutrition and we can apply medications more cautiously, but more often than not, we choose to do neither. We ignore nutrient status and stack medications on top of each other endlessly, all the while wondering why the patient’s health continues to decline.

Common Drugs Block Vitamins B1, B9, B12, and CoQ10

To illustrate the state of drug-induced mitochondrial hypoxia that plague so many of the patients threatened by COVID, let us look one common medication that as of 2017, 78 million Americans were taking: metformin. Metformin damages the mitochondria by multiple mechanisms that ultimately lead to reduced ATP, entrenched molecular hypoxia, inflammatory cascades and altered immune reactivity. This, of course, is in addition to the neurological sequelae.

Perhaps the most critical nutrient for in mitochondrial health is thiamine. Thiamine, is blocked by metformin. Metformin blocks vitamin B1 – thiamine – uptake by multiple mechanisms. When metformin is present, a set of transporters that normally bring thiamine into the cell to perform its task as a cofactor in the machinery that converts carbs to ATP, brings metformin into the cell instead, replacing thiamine altogether. The transporters involved are the SLC22A1, also called the organic cation transporter 1, [OAT1] and the SLC19A3. Metformin also blocks the lactate pathway and acetyl coenzyme A carboxylase (an enzyme necessary to process fatty acids into fuels). Thiamine is critical for mitochondrial function and its position as gateway substrate into the each the of the pathways leading to the electron transport chain, means that insufficient or deficient thiamine limits ATP production, induces cell level hypoxia and all of the inflammatory cascades that go with this process.

Metformin also depletes vitamins B12 and B9, which are responsible for hundreds of enzymatic reactions and particularly important in central nervous system function including myelination (how many cases of diabetic neuropathy or multiple sclerosis are really vitamin b12 deficiency?) One study found almost 30% of Metformin users were vitamin B12 deficient. For the US alone, that’s 26 million people who could be vitamin B12 deficient and likely do not know that they are deficient. What happens when one is B12 deficient? Inflammation increases, along with homocysteine concentrations, which is a very strong and independent risk factor for heart disease (the very same disease metformin is promoted to prevent). What else happens when B12 is deficient? Poor iron management, better known as pernicious anemia.

Metformin tanks CoEnzyme Q10 which effectively cripples mitochondrial ATP production even further, by as much as 48% in muscles. Imagine having to function in such a reduced capacity. Now imagine having to fight a deadly virus or recover from one. Finally, if the reductions in nutrients and ATP weren’t sufficiently troubling, metformin also interferes with the body’s innate toxicant metabolism pathways, the P450 enzymes, rendering those who use this drug less capable of effectively metabolizing a whole host of other medications and environmental toxicants.

This is one medication. Very few adults who go down this pathway are prescribed just one medication. With metformin, one is likely also to have a statin, perhaps a blood pressure medicine, and if the patient is a women, some form of birth control or hormone replacement. Many are also on antidepressants or anxiolytics. Statins, for example, severely deplete CoQ10, further crippling the electron transport chain. Synthetic hormones deplete a whole host of nutrients (thiamine, riboflavin, pyridoxine, folate, vitamin B12, ascorbic acid, and zinc) while damaging mitochondria via multiple mechanisms.

Long COVID and Medication

Just as the use of medications leading up to and during the illness impact the functioning of one’s mitochondria, the use of medications across time, as one recovers from the infection, will negatively impact mitochondrial capacity as well. This, of course, is in addition to the demand COVID itself places on mitochondrial energy capacity. Data suggests that at least 10% and upwards of 80% of COVID survivors have lingering symptoms. Among the most common are fatigue, brain fog, muscle pain and weakness, and breathing difficulties along with an array of dysautonomias. These are classical indicators of ailing mitochondria and yet common treatment protocols involve more of the same medications and none of the nutrients needed to support them. As we go forward and recover from the COVID pandemic, I think it is incumbent upon us to look at mitochondrial health more closely.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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*Environmental issues should be considered as the totality of chemical exposures from environmental, agricultural, industrial, and pharmaceutical sources. Environmental exposures damage mitochondria and should not be excluded as contributing factors to illness.

COVID Notes: Mitochondrial Hypoxia

by Chandler Marrs, PhD

Published on October 28, 2020

7541 views

I began writing this post in April of 2020 as a part of a much larger post on COVID and never finished it. I am publishing it now in its unfinished state in the hopes that others might be inspired to pick up where I left off. Although the current hypothesis regarding COVID morbidity and mortality involves micro-coagulopathies believed to emanate from platelet dysfunction, based upon my research, I contend that mitochondrially driven hypoxia cascades are still responsible. I will publish some thoughts on this in a subsequent post. For now, consider the role of molecular hypoxia as a key component of COVID complications.

Mitochondrial Energy Failure

When one has a hammer, everything becomes a nail. My hammer, my framework for understanding every illness, is mitochondrial function. Mitochondria, because they produce cellular energy (ATP), the single most important, non-negotiable requisite for survival, sit at the nexus of health and disease. Absent the ability to produce sufficient ATP, death is imminent. We are seeing this play out on a large scale with the coronavirus (COVID-19). The progression and patterns of illness reported associated with COVID mortalities share striking similarities with what might be deemed an energy failure, where mitochondria initiate every tool in their armament to fight the battle but have not the resources to contain the threat or manage the consequences of such a brutal battle, and so instead, are forced to withdraw, shut down, and slowly die off.

The key pathology of COVID, acute respiratory distress syndrome (ARDS), the one responsible for all of the morbidity and much of the mortality associated with COVID, can be linked directly to mitochondrial failure, as can many of the associated pathologies attributed to the COVID disease process itself. Inasmuch as these same processes also develop with other viral, bacterial, or fungal agents, it suggests that while COVID is undoubtedly unique in its structure, its mechanisms, and its virulence compared to other pathogens, this uniqueness may not be the only variable to address. If entirely different pathogens or stressors can cause similar response patterns, then perhaps it is not the uniqueness of the pathogen that matters as much as the strength and agility of the individual response. That is, perhaps the host response contributes, if not more, at least equally, to pathogenicity. Perhaps distinctions in host response offer more salient clues about surviving this or any other threat than the endless taxonomy of distinctions between threats. And finally, perhaps the use of mechanical ventilation as the treatment option has become medicine’s hammer for too many nails.

Ever since this pandemic began, I have suspected that the respiratory distress syndrome developing with COVID was related more to mitochondrial failure than any mechanical problems with respiration for which the ventilators are designed. Indeed, I suspect that given the high mortality rates associated with mechanical ventilation of any cause, 30-45% according to pooled data, in a good portion of these cases, we have missed a key variable. I think at the root of these deaths and the severity of COVID is molecular hypoxia. Molecular hypoxia emanates not from obstruction, though obstructive fibrosis and fluid build-up may develop later, but from the bottom up; from the inability to utilize O2 in the mitochondria, and thus, efficiently produce ATP. This then initiates a host of self-reinforcing cascades that lead to poor blood oxygenation, sometimes perceived as ‘air hunger’ by patients and often correspondent to an altitude sickness-like effect.

I believe that molecular hypoxia is also responsible for the deregulated immune and inflammatory responses noted in COVID and in a long list of other conditions, many of which impact COVID severity. I believe that molecular hypoxia is both the cause and consequence of disrupted iron homeostasis, as well as the seemingly chaotic autonomic response, the progressive fibrotic and fluid build-up in the lungs, and finally, death by either by a sepsis-like syndrome that leads to multi-organ failure or cardiac arrest. With regard to heart function, it should be noted that disparate or inconsistent ATP availability affects rate and rhythm both in the cardiomyocytes themselves but also via the brainstem with chaotic autonomic nervous system (ANS) signals. In other words, with mitochondrial collapse, death happens by a thousand possible cuts.

What Causes Mitochondrial Collapse?

We like to think of mitochondria as these magical black boxes that provide sufficient ATP no matter what we throw at them. Most of us were taught, absent outright starvation or ‘rare’ mitochondrial disorders, that mitochondria would happily and efficiently do their thing – produce sufficient ATP to meet the demands of living. That is just not the case. Any number of toxicants will damage mitochondria, including pharmaceuticals. That is why what is in one’s diet matters as much or more than the calories in, calories out equation recognizes, and why genetic mitochondrial disorders are not as rare as once believed.

Mitochondria require micronutrients, which many of our diets are starved of, to breathe, to consume O2, and utilize it to convert to ATP. With insufficient micronutrients, even in the face of sufficient or abundant macronutrients, hypoxia develops and with it, each of the cascades noted in COVID, albeit on a lesser scale, are enacted. The metabolic disarray plaguing much of the western world is a direct result of chronic, mitochondrially-driven hypoxia, which is a direct result of micronutrient malnutrition coupled with a continuous onslaught of chemical toxicants. This means that comorbid conditions linked to COVID severity and mortality, share common origins and that COVID, as unique as it is in its delivery of viral pathogenesis, in many ways, enacts exactly the same mitochondrial pathways as everything else but perhaps unlike other viral pandemics, is developing against the backdrop of longstanding, often epigenetic, mitochondrial insufficiency e.g. pre-existing hypoxia cascades.

So while COVID is a particularly virulent pathogen, its virulence is increased exponentially by our own ill-health; by a lifetime (or many lifetimes, if we consider the epigenetic consequences of these chemicals and dietary choices) of accumulated mitochondrial damage. With COVID, it is as if we are asking our bodies to run a marathon while starving and dodging bullets. Many of us simply do not have the energy to make it through because we are already hypoxic, starved for nutrients, and generally, exhausted. And while with age comes mitochondrial decline, age is not the defining variable. The defining variable is mitochondrial health, which if prescription data are any indicator, is progressively declining across all age groups, but most notably, among the young.

If this hypothesis is correct, then how do we survive? By going old school. By supporting the mitochondria so that they have the energy to manage and contain the threat. Oxygen is vital for life. Mitochondria are vital for proper oxygenation. Nutrients are vital for functioning mitochondria. Support the mitochondria and perhaps our capacity to withstand this virus will improve.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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Adult Onset TMAU: Intense Fishy Body Odor Syndrome

by Charlie M.

Published on July 7, 2020

27181 views

I am 24 year old male from the UK who has developed trimethylaminuria (TMAU). TMAU is a condition where the liver enzyme called Fm03 fails to oxidize the smelly chemical compound trimethylamine (TMA), resulting in a smell of rotting fish, fecal material, and rotting eggs combined that leaves the body via breath and bodily fluids. I learned recently that I am heterozygous for this condition and although the research suggest only those who are homozygous develop symptoms, I believe that my poor diet and lifestyle that included heavy alcohol use, recreational drugs, a variety of prescription drugs, including potent antibiotics, long term antacids and a brief stint with anabolic steroids, combined to trigger this disease process. TMAU is rare disorder and there are no clear treatments. I am writing this in the hopes that someone can help me to put my life back together.

Early History: Setting the Foundation Ill-health

My diet for young lad was not great. I ate a lot of processed foods. I don’t believe I had any childhood illnesses, but I got my doctors medical records and I believe I was on and off antibiotics as a young infant. I have a hiatal hernia but that came later on around 19 years of age. My lifestyle wasn’t great either. Growing up I smoked a lot of weed daily, and on the weekends I would drink. I thought I was healthy though. I had a good life growing up no worries in the world, played high level sports, and had some good friends.

Things slowly started changing for me when I was 17 or 18 years of age. I noticed my stomach was in bad pain 24/7 especially in the morning, and would throw up and be sick after eating. I got acid reflux pretty bad as well. I saw my doctor, and of course, they did no investigating. They just shoved me on acid reducing drugs (proton pump inhibitors –PPIs). I took PPIs for two years approximately, and they did wonders for my reflux, so I thought they were pretty good. I clearly failed to realize the importance of stomach acid in the body.

I developed chronic constipation. I wouldn’t have bowel movements for at least a week at a time. I had inflamed hemorrhoids that seemed to prolapse. I got major brain fog, and after eating, I would become extremely tired and would bloat. I also developed bad breath, and after exercise or anytime I would need to use my muscles for lifting heavy objects at work, I would get painful radiating aches all in my joints, especially elbow and shoulders. I knew things weren’t right but I was so uneducated about everything that I didn’t even realize any importance of gut health. Becoming sick was the only reason I stumbled across this unknown world.

The Decline

When I was 19 years old, I had an infected tooth. I ended up having a root canal and the tooth extracted. I took strong antibiotics at that point. I don’t remember which ones. Before it healed though, I went on a lads’ holiday and drank heavily. Thinking back, I can’t believe how stupid I was.

I also took strong antibiotic several times for reasons I cannot remember, including metronidazole (Flagyl) and amoxicillin. Sometime between the ages of 18-20, I also had inflamed ball/tonsil on one side of my throat and ended up having that removed for reasons I cannot remember. Just looking back at everything, it is clear that I put my body under major stress.

Fast forward a year, I split up with my girlfriend of three years. This was a very stressful time. I took it upon myself to take some steroids as my close mate at the time was doing it and seeing results in the gym. So stupidly, I organized and put it upon myself to experiment. I thought I had nothing to lose as I was already feeling sorry for myself. The anabolic steroid I was taking was Anavar. I was 22 at this point and I took the steroids for only a month, but looking back, this may have been the last straw. While I was taking them, I carried on my normal activities of drinking on the weekends with these steroids still in my system.

By taking these steroids, my breath odor got worse by tenfold. People two meters away from me would cover their noses when I spoke. I was shocked and baffled on how this could actually happen. It was humiliating. By this time my hair started falling out and thinning. It still happens to this day. I finally did some research, and boom. I found that if one is predisposed to the male pattern baldness and take steroids, the baldness gene is activated early. The conversion of testosterone to the hormone DHT, attacks your hair follicles. At age 22, I had bad breath, severe stomach issues and was going bald.

After I found the steroid hair loss connection, I spent the next few months vigorously searching for answers. I scoured the internet, and fell into a depression. I overwhelmed myself into trying to figure out what was going on inside my body. The stress of this was crippling as I wanted to avoid everybody. Things got even worse as my breath odor slowly transformed into body odor as well, especially after sweating.

Intense Body Odor: A Clear Sign of TMAU

I first noticed after a long 90 minute football match, people were avoiding me, and holding their breath when they walked past me. I could not understand why. I’ve not long come out the shower, surely it can’t be me? Can it? My head became a complete mess. I thought I was going crazy. Fast forward a few months, and my friends asked me to go to a music festival. I reluctantly accepted as I had been cooped up in my bedroom for too long. I was very stressed over my socially debilitating situation, so desperately purchased some Chlorella supplements from Holland and Barrett, as I found a small print on the internet that they freshen you from the insides.

During this festival I ended up taking around 12 tablets of chlorella whilst I was there, hoping for some sort of reduction of symptoms. Since being at a festival, I drank and took some narcotics. A few hours passed and then I suddenly realized people around me was “reacting” to me. I started to part crowds like the river Nile. As the horrible cold feeling of me becoming a human sewage tank dawned over my whole body. I couldn’t smell a single bad thing off me, but the way everyone was holding their noses and pointing at me confirmed the nightmare is actually happening and I’m living it. The ONLY positive thing about this awful situation is the fact it confirmed for me that all this isn’t in my head and it’s actually happening. I wanted the ground to swallow me up I couldn’t take the humiliation and degrading feeling anymore. I ended up running two miles out the festival and locked myself in my hotel room in a flood of confusion and tears.

I noticed that I was making people cough, and clear their throats and also made peoples noses run. So whatever my body was emitting was obviously an irritant to everyone else. Whilst I lay there in my bed trying to get my head around this disturbing nightmare I’m living in, people in the next room were coughing profusely and shouting what is that smell. So whatever I was emitting was penetrating through walls and causing people to have allergic reactions.

Finding the Strength to Discover a Cause

By the time I made it home, I had completely hit rock bottom. I became a hermit, I never wanted to leave the house, I had no one to speak to, and no doctor wanted to listen. Suicidal thoughts raced through my mind every day and the thought of death felt pleasant, as I would not have to continue living this nightmare. I somehow found the determination to dive my head into overwhelming research. My eyes wouldn’t leave my laptop screen throughout the day. It became an obsession, and I would wake up and go to bed with my head dived into the internet. All this information got way too much for me to handle and started to take a step back.

I ended up obtaining certain tests to help paint a picture of what the hell is going on. I spent a bit of money on these tests what I will list here.

Organic acid test (Oat)
GI map test
23andme genetic test
SIBO
Candida test
Heavy metal test

I noticed on the GI map tests, it shows gut dysbiosis. I had low good bacteria and high bad or opportunistic bacteria. I also had H Pylori, leaky gut and low IgA levels. The heavy metals showed high arsenic levels and the OAT test showed that everything was out of balance.

The Source of the Foul Smell: Trimethylaminuria or TMAU

With research, I discovered the condition called trimethylaminuria -TMAU. TMAU is a condition where the liver enzyme called Fm03 fails to oxidize the smelly chemical compound trimethylamine (TMA), resulting in a smell of rotting fish/fecal and rotting eggs and more to leave the body via breath and bodily fluids. TMA is produced in the gut. I always thought I could not have this condition because you are born with it, and I most definitely didn’t think I was born with this. So this is where the genetic test came into play. I looked at what genetic variants are associated with TMAU, and I found that I had the genetic variants, but they were highlighted in yellow, meaning I only have them from one parent.

Genetic TMAU 1 is diagnosed by receiving both faulty genes from both parents. I am thinking that maybe I have an underactive enzyme, that works at maybe 50 percent, but that is overridden by the excess TMA in my gut and which it cannot keep up. Also, I would like to refer back to the steroid period. As I stumbled across a research article on doctors injecting mice with the hormone DHT and it was said that it reduced the FM03 enzyme by 90 percent, and it seems very coincidental this condition peaked while taking steroids.

Where I am Now

A year has passed since the festival, and my life has never been the same since. The only emotions I have felt are sadness, anxiety and hopelessness. Everyone treats me like a piece of trash, the constant comments I hear behind my back, and having to stand there in a group of people noticing them silently taking the piss out of me takes its toll. I can no longer go and exercise or play football with a group of people because of this condition and I used to play semi-professional. The days I muster up the strength to go to work as a plumber if end up sweating, I get reactions and comments making me feel like I don’t deserve to even be there.

Everything in this life what I used to take for granted, and also what around 80 percent of the population do, are the small things: socially meeting up with your friends, speaking to people face to face without having crippling social anxiety, going out for meals, bonds of friendships and relationships what have now been destroyed with TMAU. This condition has taken everything away from me. It has taken my dignity, my confidence, my motivation, my happiness, my self-esteem, my football what lived for, and now it is destroying any strong bonds I had.

My mum has been diagnosed with cancer, and this hit me hard, and she is the main reason why I am writing this post. I cannot bare for her to look at me anymore wasting my life in sadness. I believe I may have been a catalyst in her cancer, diagnosis as I definitely put her under a lot of stress over the years due to this sudden onset of this condition; and she is the reason I have motivation to try and tackle this, and seek any sort of help. It is my last ditch attempt at trying to beat TMAU. I will not let her live the rest of her remaining precious years watching me in the gutter. I need her to see me back to my old self and back on my feet. I need for her to see me succeed.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

Are Your Mitochondria Stuck in Battleship Mode?

by Chandler Marrs, PhD

Published on May 18, 2020

10346 views

As part of my work here, I am regularly confronted with desperately ill individuals who have seen dozens of physicians over the course of many years only to have their health continue to decline. Among the more frustrating aspects of this work is the failure of these physicians to assess and address the most basic aspects of health and healing. Namely, they fail to ask what the body needs to be healthy and whether the patient is getting those things. Of course, since evaluating these aspects health comes down to nutrition and exercise it does not align well with the practice of medicine, and if we are honest with ourselves, it is not something many of us want to deal with either. We want to eat what we want to eat and do what we want to do without regard to our health. Conventional medicine has capitalized on those sentiments, arguing persuasively for decades that a disease process is not real if all it requires to resolve is nutrients. Real illness requires medication, we now believe, having forgotten the very real nutrient deficient scourges like beriberi, Wernicke’s, pellagra, rickets, scurvy, and such.

Like most physicians, we have bought into the corresponding notions that fortification of foodstuffs assures that nutrient requirements are met and that in the land of plenty, where obesity reigns, malnutrition is rare. Neither is true of course, but belief in those myths absolves us of looking more closely at the chemistry of health and disease. For when we look at that chemistry, when we follow each of the altered signal transduction pathways, when look at the various patterns of deranged protein expression, and the myriad of genetic and epigenetic markers, we inevitably land at starving, inefficient mitochondria and the simple truth that they require nutrients to function; nutrient requirements that cannot be met by fortification alone and nutrient requirements, that if not met, lead to disease. When we dig a little deeper, we are also faced with a rather inconvenient truth that not only will pharmaceuticals not recover these deficiencies but they damage the mitochondria further. This does not accord well with the practice of conventional medicine and certainly does not fit into our busy, convenience-based lifestyles.

The Capacity to Survive

Among the more remarkable aspects of human physiology, however, is the capacity to survive all manner of illnesses and insults. We are supremely adept at adapting and surviving. We may not be living healthy, but we live. Mitochondria mediate these survival functions. They are responsible for converting the foods we consume and the oxygen we breathe into cellular energy (ATP). With that energy, they regulate all aspects of basic survival at the molecular level, including survival itself – cellular respiration – but also things like inflammation, immune function, steroid hormone production, cellular life and death cycles, and whole bunch of other stuff. As one might expect, each of these functions is energy dependent.

Decrements in cellular energy, thus, elicit those survival mechanisms. If they are not resolved appropriately, when the threat persists, and/or when there is limited energy to face the threat, these normal responses lead to all sorts of tissue and organ dysfunction. It is this mismatch between the energy available and the energy required that leads to the persistence of not only the original illness, but because of the chronically activated survival cascades, leads to new and more complicated illnesses. On the one hand, decrements in ATP lead to things like inflammation and immune system activation – the normal, programmed and encoded survival cascades – but on the other hand, the survival cascades themselves lead to decrements in ATP, which in turn leads to more inflammation and immune reactivity. Without resolution, these cascades can easily become ingrained and ultimately lead to death. This suggests that energy availability is the key to health, or more specifically, that insufficient mitochondrial energy, and thus, impaired mitochondrial function leads to illness.

From Power Plant to Battleship: Mitochondrial Healing Cycles and the Necessity of Sufficient ATP

A recent paper suggests this is true. Just last month, one of the leading experts in mitochondrial function, put forth a compelling synthesis of research delineating what he called the mitochondrial healing cycles. Specifically, he demonstrated by what systems level mechanisms mitochondria maintain health or initiate and maintain disease. Dr. Naviaux argues that chronic illness is initiated by the “biological reaction to an injury and not the initial injury or the agent of injury itself.” He uses melanoma as an example, illustrating how it is not caused by the sun per se, but our biological, or more specifically, our metabolic (mitochondrial) response, to the sun. Chronic illness, he argues, becomes chronic only when there is incomplete healing of the original injury and/or when secondary injuries occur before primary injuries have healed. Illness, he suggests, is a multi-hit proposition.

To Naviaux, illness begins and ends in the mitochondria. Mitochondria are responsible for enacting what he terms the ‘cell danger response’ (CDR), the survival mechanisms that I spoke of earlier. There are three phases of the CDR:

The initial inflammatory/immune response: “activation of innate immunity, intruder and toxin detection and removal, damage control, and containment.” He aptly describes this phase as a shift in mitochondrial energetics and function from power plant to battleship. ATP has to be diverted to fight the threat, initiate and maintain the characteristic inflammatory response. The reduction in ATP results in the characteristic fatigue we all experience at the beginning of an illness.
Once the damage from the initial injury is contained, phase 2 begins. This involves replacing the dead and damaged cells as well as walling off any remaining damaged tissue that was not completely cleared in phase 1. Here stem cells are recruited and enter the cell cycle. Mitochondria in stem cells are critical for this phase, supplying the stem cells with ATP as well as key substrates to help with healing process. An interesting aspect of this phase, is that cell – cell communication ceases. There is no metabolic cooperation between cells as they are continuing grow and migrate. It is only when growth is complete and migration ceases that cell-cell communication reemerges.
In phase 3, we get a return to “cell differentiation, tissue remodeling, adaptive immunity, detoxification, metabolic memory, sensory and pain modulation and sleep tuning”. Once the cells have been fully differentiated and re-educated, cell-cell communication reinstates and healing is complete.

The healing cycles are linear, sequential and ATP intensive. Each must be completed before the next can begin, before a secondary injury takes place, and each requires a continuous supply of ATP. Too many hits and/or too little ATP will derail healing. When we consider mitochondrial metabolism as the root cause of persistent disease, it is difficult not to ask what constrains the availability of energy and thus blocks the body’s ability to progress across each healing cycle.

Recovering Mitochondria: The Role of Nutrition

To answer this question, one has to look at how we produce ATP. Absent outright starvation, to get from food to ATP we need a few things: macronutrients and micronutrients or proteins, fats and carbohydrates along with vitamins and minerals. That’s it. Nothing fancy or complicated, just basic nutrition.

When we look at macronutrient consumption, one of the leading problems in western cultures is the high consumption of junk, carbohydrate-based foods. These foods, though they are often fortified with vitamins and minerals, come with far more sugar and other toxicants than the body can handle. Rather than being a net gain in energy, ultimately, become a net loss, both in macro, but especially, in micronutrients. Without sufficient micronutrients, none of the enzyme machinery, whether in the cytosol of the cell or in the mitochondria themselves, can perform the required functions that moves the macronutrient through the factory and produces ATP. Indeed, even the consumption of molecular oxygen requires the presence of vitamins and minerals. Absent those vitamins and minerals, a sort of cellular hypoxia sets in; one that activates inflammatory pathways, and ultimately, the shift in tale tell shift energy production associated with cancer known as the Warburg effect.

Conversely, because of decades-long advertising campaigns, most folks, but women especially, consume insufficient quantities of protein and fat. This skewed consumption of macronutrients places a high demand on the OXPHOS (oxidative phosphorylation) pathway of the mitochondria to produce ATP, while simultaneously not providing sufficient micronutrients to fuel the enzyme machinery to produce this ATP. It also increases the need for detox, while again, failing to provide adequate substrates to do. Moreover, if the diet is high in the staple sweetener high fructose corn syrup, in addition to everything else that becomes dysregulated at the mitochondrial level, the ability to covert fatty acids into energy, can be shut down entirely, conferring a metabolic inflexibility that is common in western cultures.

Along with issues with macronutrient consumption, large percentages of the population are deficient in one or more of the micronutrients required for healthy mitochondria. Individuals with chronic illness are severely deficient. The mitochondria require 22 vitamins and minerals in varying concentrations to convert the food we eat and the air we breathe into cellular energy or ATP (Figure 1.). Absent sufficient concentrations of one or more of those nutrients, mitochondrial function deteriorates and healing will not progress. Survival mode is all that can maintained.

With Naviaux’s framework, it becomes clear that healing is an energy intensive process. The only way to boost energy is via good nutrition. Sure there are compounds that can override certain pathways within the mitochondria and, at least temporarily, provide additional energy, but if the core requirements for optimal mitochondrial health are not met, it is only a matter of time before initial benefits become problematic. (I should note that exercise is also critical for healing the mitochondria. Exercise forces mitochondrial biogenesis among other important processes.) The questions that physicians and individuals with chronic illness should be asking are:

What is required for health?
Is this patient or am I getting those things?

Unless and until those aspects of health are addressed, chronic illness will persist because the mitochondria simply do not have the resources to progress through the healing cycles. There are no short cuts here.

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Image credit: ImgFlip, Template ID: 24838763

This article was published originally on October 17, 2018.

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