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February 4 - April 8, 2025
Epigenetics, which we covered briefly in Part Two, is the field dedicated to understanding what causes genes to turn on or off.
Throughout the day, genes are getting turned on or off in cells. This is constantly changing based on environmental circumstances and the needs of the body. In other words, the body is constantly adapting. Sometimes it needs to make a hormone, so those genes get turned on. Sometimes it needs to repair a cell, so those genes get turned on. Once done, these genes get turned off. Cells don’t waste resources.
Epigenetics provides a memory of what the body has been through.
One way is to modify the DNA itself by applying methyl groups to specific sites on DNA. These methyl groups then influence which genes get turned on or off. The methyl groups can be added or removed as needed,
Another way the body influences gene expression is through histones. These are proteins that DNA gets wrapped around. They, too, influence which genes get turned on or off.
What influences epigenetics? What triggers all these different factors to change gene expression? Almost all of them revolve around metabolism and mitochondria.
Factors thought to influence epigenetics include diet, exercise, drug and alcohol use, hormones, light exposure, and sleep—all related to metabolism and mitochondria (as you will soon learn). As a specific example, smokers tend to have less DNA methylation of the AHRR gene compared to nonsmokers.11 However, if they stop smoking, this change in methylation is reversible.
epigenetics as metabolic blueprints for cells.
The babies born during the famine were more likely to develop both metabolic and mental disorders later in life. This and other studies led to the thrifty phenotype hypothesis, which proposes that babies deprived of proper nutrition in utero are more likely to develop obesity, diabetes, and cardiovascular disease later in life. Unfortunately, this hypothesis overlooks or ignores the fact that these babies are also more likely to develop mental disorders.
Caregiver neglect and deprivation have profound effects on children for life. They include both metabolic and mental disorders. Epigenetic mechanisms play a role in all of this.
the passing of a metabolic factor from mothers to children in breast milk. One such molecule is nicotinamide adenine dinucleotide, or NAD. This is a critically important coenzyme that can be derived from vitamin B3 (niacin), or the body can make it using the amino acid tryptophan from protein. It is essential to mitochondria for energy production but also plays a role in the maintenance of DNA and epigenetics. Low levels of this enzyme are known to impair mitochondrial function and cause epigenetic changes, and have been associated with aging and many diseases.
The most widely studied phenomenon of how epigenetics relate to mental health is the intergenerational transmission of trauma.
Dr. Vivian Rakoff, noticed that children of Holocaust survivors appeared to sometimes have more severe forms of mental illness than their parents, even though it was the parents who spent time in the concentration camps.
Numerous studies followed and began to identify a pattern of parental trauma and poor mental health outcomes in their children—and even their grandchildren. But still, almost everyone assumed that this was due to upbringing.
People exposed to trauma—and their children—have different levels of sensitivity to glucocorticoids. In particular, exposure to high levels of cortisol in utero appear to “program” children, resulting in higher risk for developing mental and metabolic disorders later in life. With the genetic and epigenetic revolution came the discovery that many of these people have differences in methylation patterns of the glucocorticoid receptor and other DNA regions (promoter regions) associated with the stress response system.
even fathers might be passing on their traumatic experiences through epigenetic mechanisms in sperm, such as micro-RNA
In mice who are exposed to early stressful life events, these levels were dramatically reduced in sperm cells, and their male offspring also had these same low levels in their sperm cells, demonstrating transgenerational transmission of stress.
The timing of the stress appears to matter and can influence brain function in different ways.
Fetal exposure to a mother’s stress results in higher rates of learning impairment, depression, and anxiety later in life. In the first few years of life, separating a child from his/her mother can result in higher levels of cortisol throughout life, while severe abuse can result in lower levels of cortisol. Although paradoxical, both states take a metabolic toll and can be tied directly to mitochondria, given that mitochondria initiate production of cortisol.
We now know that there are usually not “abnormal” genes that cause mental illness. It’s much more likely that the transmission of mental illness from parents to children takes place through epigenetic mechanisms. The hopeful aspect of this insight is that most of these epigenetic mechanisms are known to be reversible!
The effects of in utero stress, micro-RNA levels, and levels of NAD are changeable, sometimes through lifestyle interventions alone. The other hopeful aspect of this is that people are not usually born with “bad genes”
neurotransmitters also go on to produce their own effects in target cells, resulting in stimulation or inhibition of mitochondria in those cells. This quickly becomes like a chain of dominoes, where metabolic disruption in one set of cells results in problems in other cells.
Many people talk about neurotransmitters as simple entities with simple functions. Serotonin makes us feel good. Dopamine drives psychosis and addiction. Norepinephrine helps us focus. Although there is some truth to these statements, these simplistic views of neurotransmitters and the disorders associated with them are almost farcical. The brain, neurotransmitters, and mental disorders are all much more complicated than that.
Neurotransmitters and mitochondria are in a feedback cycle with each other.
Mitochondria also have receptors for some important neurotransmitters directly on their membranes, such as benzodiazepine and GABA receptors.
Mitochondria also have one important enzyme known to most psychiatrists: monoamine oxidase. This enzyme is involved in the degradation and regulation of some very important neurotransmitters, such as dopamine, epinephrine, and norepinephrine.
It is known to control appetite, digestive tract functions, and metabolism of nutrients broadly. About 90 percent of the serotonin in the human body is actually located in the digestive tract, not the brain. Recent research has demonstrated a direct role of serotonin in regulating the production and function of mitochondria within cortical neurons, enhancing their production of ATP and decreasing oxidative stress.
Serotonin is converted into melatonin, an important hormone in the regulation of sleep, which plays a powerful role in metabolism as well. Serotonin is also the product of an important metabolic pathway, the kynurenine pathway, that involves the fate of the amino acid tryptophan. When people eat protein that contains tryptophan, it has many possible fates. Two important ones are getting converted into serotonin or kynurenine.
medications that affect serotonin levels will have a direct impact on metabolism and mitochondria through all these mechanisms.
medications that increase GABA activity, such as Valium, Klonopin, and Xanax, produce a calming, anti-anxiety effect. However, abnormalities of GABA neurotransmission have also been found in other disorders, including schizophrenia and autism. Mitochondria directly influence and sometimes control GABA activity.
mitochondria actually sequester GABA inside themselves, thereby directly controlling its release.
GABA doesn’t just affect mental functions, it also plays a role in metabolic disorders like obesity.
Problems with GABA signaling in this type of fat result in mitochondrial calcium overload and metabolic abnormalities often found in people who are obese.5
dopamine is directly involved in the regulation of glucose and metabolism.
dopamine D2 receptors aren’t located just in the brain, they are also found in the pancreas and play a critical role in the release of insulin and glucagon.
Valium was working by activating another area of the brain called the ventral tegmental area (VTA), which sends dopamine to the NAc. This dopamine increases mitochondrial function in the NAc, resulting in higher ATP levels, and this leads to reduced anxiety and enhanced social dominance. When the researchers blocked the effects of dopamine, this therapeutic effect was lost.
a paradox: some medications appear to improve mitochondrial functions while others impair mitochondrial functions.
direct correlation between markers of impaired mitochondrial energy metabolism and the symptoms of TD.
When a cell is hyperexcitable, there are two ways to reduce symptoms: 1.Improve mitochondrial function and energy production so that the cell can repair itself and function normally again.
Manage these cells by shutting them down—in
A treatment that can help in the short run might make things worse in the long run. Unfortunately, the dilemma of hyperexcitability isn’t even this simple.
All cells are likely not impacted in the same ways. Recall that cells have different inputs.
Even if medications impair mitochondrial function broadly, we need to consider the consequences of not treating the person.
What is clear already, however, is that suppressing mitochondrial function long-term is not a path to healing. At best, it’s a path to reducing symptoms.
The theory of brain energy answers numerous questions that the mental health field has been unable to answer to date. It outlines why medications that target serotonin, norepinephrine, and dopamine can all be used to treat depression. They all enhance the function of mitochondria.
if one brain region is metabolically compromised, it will impact the other brain regions, just like a traffic jam in one part of the city slowly backing up traffic in other parts of the city. Metabolic problems are connected and can spread.
The drug classes included “statins” for cholesterol (hydroxylmethyl glutaryl coenzyme A reductase inhibitors), blood pressure medicines (L-type calcium channel antagonists), and diabetes medicines like metformin (biguanides). Across the board, these medications had an impact on the “mental” metrics, especially in reducing self-harm. The brain energy theory offers explanations for why these might help.
On the surface, it’s understandable how Jane ended up on so many medications. However, several of them are known to impair mitochondrial function. This means that they can help in the short run, but they come with the risk of making matters worse in the long run. That appears to be what happened to Jane. By the time I saw her, whatever caused her initial delirium had probably passed, and she was delirious because of the treatments she was receiving.
Hormones are chemical messengers that are produced in one type of cell and then travel through the body to impact other cells. The human body produces numerous hormones. All of them affect mitochondrial function and cause epigenetic changes in their target cells. Hormones change the metabolism of cells. In turn, they can play a role in both mental and metabolic disorders.
There are many regulators of metabolism and mitochondrial function beyond hormones and neurotransmitters. They include things like neuropeptides, mitokines, adipokines, myokines, RNA molecules, and other messengers. Why so many factors? Because they all control different aspects of metabolic function in different cells under different circumstances.
