The neuroendocrine theory of aging: minimizing chronic stress to prevent the degenerative diseases of age.
When Dilman first proposed that neuroendocrine factors were involved with aging, it was a pioneering theory. Dilman and Dean built the foundation for the theory, and now researchers are filling in the gaps and expanding upon it. The reason that this theory is appealing and why we wanted to write about it is because it gives us a lens to look at the human body as a symphony put on by all the members of the orchestra. If we only focus on the brass or the strings, we're missing the bigger picture. In the same way, all the systems of the body work in harmony, and any disharmony in any part of the bodily cycles causes us health challenges.
There are too many components to the neuroendocrine theory of aging to discuss them all in one article; therefore, here we're going to discuss one aspect: stress. More specifically, we're going to discuss what Dilman called the adaptive homeostat, the system that the body uses to cope with stress. But first, let's briefly talk more about the neuroendocrine theory of aging overall.
An Explanation for Why We Age
The main line of thought behind the neuroendocrine theory of aging is that as we age, receptors in the body begin to ignore the effects of hormones and other messenger substances. Normally, when the body is overproducing a hormone or other substance, there are mechanisms established to shut off the overproduction. However, when receptors become desensitized to those signaling substances that tell them to stop overproducing, more and more of those signaling substances are needed for the receptors to understand the message. It's the same concept as an elderly person who is hard of hearing. When they were younger they could hear a whisper. But now, people may have to talk really loudly or even shout for that elderly person to hear them. Thus, when your receptors become desensitized, your hormones and signaling substances must increase their "volume" more and more for the cells to understand the directions that they are being given. At some point, the cells may become completely deaf to the message that the hormones and signaling substances are sending.
This process is what Dilman referred to as loss of hypothalamic and peripheral receptor sensitivity. When there is a loss of this sensitivity, your body's homeostasis--its balance--begins to shift in a way that is unfavorable to your health. The resulting imbalanced levels of hormones, neurotransmitters, and cell signalers contribute to aging and degenerative diseases. (2)
Stress: Not Always the Villain
Balanced cortisol levels are healthy. Cortisol, when released in high amounts in short spurts, acts as an antiinflammatory. It helps make glucose and fatty acids available to produce energy and nourish many bodily tissues.
Thus, we need some stress in order to survive. Stress results in a number of reactions that give us an advantage in times of danger. It's what helped our ancestors survive their encounters with a saber-toothed tiger.
When our ancestors encountered danger, it was often short lived. Cortisol levels rose to help them deal with the danger and then returned to normal after it was over.
However, when we are exposed to chronic stress such as the emotional demands of work deadlines, financial challenges, raising children, and countless other stressors, our cortisol levels tend to rise, and to remain elevated longer than normal. These types of stressors are "the saber-toothed tigers" of our time.
There's no doubt that chronic stress is often an aging accelerator. Just look at how much older the president of the US appears after eight years in one of the most stressful jobs that anyone can have.
During chronic stress, cortisol levels stay high. When the body overproduces cortisol for an extended time, it becomes harmful. At some point, after extended periods of producing too much cortisol, the adrenal glands may even become exhausted and stop producing cortisol altogether, which also leaves the body vulnerable to disease and fatigue.
The Neuroendocrine Theory and Stress
The neuroendocrine theory of aging proposes a reason why stress ages us and causes disease. The theory also lays out solutions for minimizing the effects of stress. Based upon Oilman's theory, stress-related damage occurs due to dysfunction in the adaptive homeostat, the hypothalamus-pituitary-adrenal (HPA) axis.
When you're stressed, it normally causes the hypothalamus to release corticotropin-releasing hormone (CRH). The release of CRH triggers pituitary production of adrenocorticotropic hormone (ACTH), which then triggers the adrenal cortex to produce DHEA and the glucocorticoid cortisol and the adrenal medulla to release epinephrine and norepinephrine, typically called "fight or flight" hormones.
During stress, as cortisol levels rise, this signals the hypothalamus and pituitary to slow the output of CRH and ACTH. On the other end of the spectrum, falling cortisol levels cause an increase in hypothalamic activity, which stimulates the production of CRH while ACTH production once again increases in the pituitary, causing the adrenal cortex to increase levels of cortisol. And so the cycle continues, ensuring that the adaptive homeostat works in a balanced manner.
However, cortisol levels don't stay the same throughout the day. They're usually at their peak in the morning and lower in the afternoon and evening. These daily fluctuations in cortisol are governed by changes in CRH and ACTH production and by alterations in the sensitivity of the hypothalamus and the central nervous system to cortisol. Normally, between 3 to 6 a.m., when ACTH levels increase, this results in an increase in cortisol. Throughout the day, cortisol levels fall until at night they are at their lowest. If the adaptive homeostat is working properly, basal morning cortisol levels should be twice those of nighttime. (2)
Age Is Not the HPA's Friend
Being exposed to high levels of cortisol for long periods of time can tip the scales in favor of disease. This is what Dilman called hyperadaptosis. Chronic high cortisol levels are linked to diabetes, hypertension, suppressed immunity, gastric ulcers, headaches, osteoporosis, cardiovascular concerns, and death of brain cells. This is similar to what is seen in people who have Cushing's syndrome, a disease marked by high cortisol levels. In these patients, the high cortisol levels lead to insulin resistance and obesity. It is a vicious circle, because high cortisol levels cause the loss of more hypothalamic cortisol receptors, making the body even less sensitive to the effects of cortisol. (2)
All of these effects appear to worsen with age. Dilman proposed that as we grow older, the hypothalamic receptors become less sensitive to high levels of cortisol. This means that it is more difficult for the receptors to understand when to shut off or slow cortisol production. Increasingly higher and higher levels of cortisol are needed to stop production of cortisol and return the body to a balanced state. (2)
Dilman's original research on this subject has been confirmed by recent studies. In one study published in August 2014, researchers looked at how bereavement affected the cortisol:DHEAS ratio and immunity in younger and older adults. The study included 41 subjects with a mean age of 32 years and 52 older adults with a mean age of 72 years, and compared bereaved and nonbereaved study participants. The researchers found raised stress hormone levels (a higher cortisol:DHEAS ratio) in the older bereaved participants compared with their age-matched controls. By contrast, the younger subjects had a low cortisol:DHEAS ratio even though, like all the bereaved subjects in the study, the younger ones were suffering from symptoms of depression and anxiety. The neutrophils (immune cells) of younger bereaved subjects also functioned effectively, whereas in the older bereaved subjects, there was weakened neutrophil function. (3)
Hyperadaptosis can actually alter physical appearance. Dilman noted that in many people who are over age 40, hyperadaptosis is characterized by a moonlike appearance to the face and the buildup of visceral fat in the waist.
How Stress Affects Testosterone
Throughout Chris Meletis's clinical career working from the foundational base of the neuroendocrine theory of aging, he has postulated a concept that he terms the NeSID (neuroendocrine stress-induced dysfunction) effect, which incorporates the role of stress on both the 5-alpha reductase and COMT pathways. Stress elevates levels of 5-alpha reductase, the enzyme that converts the androgen testosterone to dihydrotestosterone (DHT) as well as serves to help break down cortisol to its metabolites: allo-tetrahydrocortisol (5[alpha]-THF) and 11[beta]-hydroxyandrosterone (OHAN) and corticosterone to allo-tetrahydrocorticosterone. Receptors for androgens have a greater sensitivity for DHT than they do for testosterone, and testosterone breaks apart from the receptors more easily than does DHT. This is not advantageous to health because DHT is linked to male pattern baldness, benign prostatic hyperplasia (BPH), and prostate cancer. (4)
It has been shown in studies of obese patients--both male and female --that 5-alpha reductase levels rise in response to the development of insulin resistance and that the rise in the 5-alpha reductase levels is associated with inactivation of cortisol levels in the liver. It is believed that this rise in 5-alpha reductase is a compensatory mechanism to protect against cortisol levels' rising too high. Although this increase in 5-alpha reductase protects against cortisol, it leaves the body wide open for the other negative effects of the DHT produced. (4,5)
The Genetic Link
Everyone has a different tolerance for stress. What is stressful for one person may not bother someone else. Researchers are now discovering that the activity of an enzyme called catechol-O-methyltransferase, which is encoded by the COMT gene, may explain why some people are more resilient to stress than others.
The COMT gene directs the body to produce two versions of catechol-O-methyltransferase. One version--membrane-bound catechol-O-methyltransferase (MB-COMT) --is a longer form and is primarily produced in the brain's nerve cells. A shorter version of catechol-O-methyltransferase --soluble catechol-O-methyltransferase (S-COMT)--is produced in the liver, kidneys, and blood and plays a role in regulating levels of some hormones. (6)
Catechol-O-methyltransferase plays an important role in the inactivation of catecholamine neurotransmitters (dopamine, epinephrine, and norepinephrine) in the brain. The type of genotype of the COMT gene that a person possesses dictates how well he or she can adapt to stress. In a study of 321 healthy college volunteers, male participants with the COMT Metpresent genotype were significantly more resilient to stress than those with the Val/Val genotype. (7)
Increasing activity of COMT may also unfavorably influence metabolism of estrone, one of three major endogenous estrogens found in humans along with estradiol and estriol. Estrone is converted in fat tissue from estradiol and adrenal androstenedione. Estrone has a higher affinity for an estrogen receptor found in breast cancer cells, the estrogen receptor alpha. Estrone can be procarcinogenic in women and also is linked to hypertension, leg cramps, and breast tenderness. (8) In men, estrone is linked to erectile dysfunction. (8)
Epigenetic Effects on the Adaptive Homeostat
Epigenetics refers to changes in gene expression that involve the process of methylation, which acts like a switch to turn genes on and off. Studies have shown that epigenetic changes to the gene for the type II glucocorticoid receptor (NR3C1) are a likely mechanism explaining the neuroendocrine effects of chronic stress (for example, having a stressful childhood). In fact, adults who have a history of childhood adversity have been found to show reduced cortisol responses to a standardized neuroendocrine challenge test. This reduced cortisol response was found to be due to epigenetic changes. (9)
How Stress Causes Weight Gain
Obesity is responsible for many of the diseases of our time. The neuroendocrine theory offers an explanation as to how obesity--especially weight gain around the abdomen--causes disease. The theory also provides a basis for effective weight management solutions and may explain why conventional weight-loss programs are often ineffective.
Obesity is known to cause changes in the hypothalamus. Furthermore, in obese humans and animals, there is evidence of neuronal injury in the hypothalamus, a brain area involved in body weight control. (10) Additionally, chronic stress, primarily by disrupting the hypothalamic-pituitary-adrenal axis, encourages visceral fat accumulation. (11) Visceral fat tissue is a key endocrine organ that helps regulate insulin action and plays a role in insulin resistance. (12) One study found that in depressed women, stress was responsible for almost 11 pounds per year of weight gain. The explanation for this goes beyond the fact that people tend to eat more--and eat more unhealthful foods--when they're stressed. The bodies of people who are stressed actually react differently to a high-fat meal. Depressed subjects who are under more stress have lower post-meal resting energy expenditure and higher insulin levels compared with subjects who are not stressed. (13)
The weight gain that occurs after chronic stress also involves disrupted cortisol levels. Higher cortisol levels have been found in obese subjects compared with nonobese subjects. (14)
Further supporting the connection between stress and weight gain is the link between cortisol and the metabolic syndrome, a cluster of risk factors for heart disease. Metabolic syndrome is characterized by the accumulation of visceral fat, which is also a characteristic of cortisol excess. Studies have associated abnormalities of cortisol secretion and metabolism with the development of metabolic syndrome. (15)
Natural Solutions for Hyperadaptosis
Oilman's work showed that the way to restore optimal function of the adaptive homeostat, relieve hyperadaptosis, and ultimately reduce the damaging effects of stress is to restore hypothalamic (and peripheral) receptor sensitivity and to use hormone replacement therapy to restore hormone levels to what they were when the body was younger. This can be accomplished by using a number of natural substances.
A combination of herbs known as adaptogens can be used effectively to resensitize the hypothalamus and restore the adaptive homeostat. These include:
* Siberian ginseng (Eleutherococcus senticosus) (16)
* Manchurian thorn tree extract (2)
* hawthorn extract (17)
* Echinopanax elatum (18)
* schisandra (19)
* Rhaponticum carthamoides (20)
* Ajuga turkestanica (2)
* Aralia mandshurica (21)
* Rhodiola rosea (16)
* myricetin (22)
* Magnolia officinalis (23)
* Phellodendron amurense (23)
* Ashwagandha (24)
Each of these adaptogens has been studied extensively and used clinically for its ability to protect the body from stress. Many clinicians have used these adaptogenic botanicals in clinical practice with great success.
New research continues to be published on these adaptogens, building upon and lending even more support to Dilman's theory. For example, an animal study published in August 2014 showed that Schisandra chinensis reduced serum cortisol and blood glucose levels in rats undergoing stress. (19) According to the researchers, "It appears to protect the cell structure of the adrenal cortex, and offset the negative effects of psychological stress and strenuous exercise related to immune dysfunction."
A study published in August 2013 investigating 56 stressed human subjects showed that a combination of magnolia and phellodendron reduces cortisol exposure and perceived daily stress, while improving mood, reducing fatigue, and increasing vitality. (23)
Other Ways to Restore Cortisol Receptor Sensitivity
In addition to adaptogens, there are other substances that can increase the body's ability to deal with stress. One of those substances is phosphatidylserine. Supplementation with phosphatidylserine normalizes the dysregulations of the hypothalamus-pituitary-adrenal axis caused by stress. (25)
Dean has also used the drug metformin (Glucophage) to restore cortisol receptor sensitivity as well as metformin's nutritional relatives, berberine and mulberry. It is also important to note that goat's rue (Galega officinalis) is the herbal progenitor upon which metformin is based. All four of these substances are known for their ability to improve insulin sensitivity and reduce insulin resistance. (26-29) There is an intricate interplay between cortisol and insulin. Cortisol opposes the blood-sugar balancing effects of insulin and is responsible for the development of hyperglycemia (high blood sugar). Cortisol also blocks the peripheral utilization of glucose, thereby contributing to insulin resistance. Therefore, any substance that can restore insulin sensitivity also has the potential to restore cortisol receptor sensitivity.
Natural Hormone Replacement Therapy
To rejuvenate the adaptive homeostat, Dilman also advocated supplementing with natural hormones to restore them to their youthful levels. Melatonin, DHEA, and pregnenolone are three hormones that fall with age and which also play a critical part in the body's stress response.
Melatonin is produced by the pineal gland of the brain, primarily after exposure to darkness. Although best known for its ability to promote sleep, melatonin is a regulator of regulators and plays a critical role in maintaining the diurnal rhythm of many body processes. Melatonin also counteracts stress and is a powerful adaptogen due to its ability to suppress the release of cortisol. In stressed animals, nighttime melatonin administration significantly reduced the memory problems and depression that typically occur after chronic stress. (30) In human studies, after exposure to light at night, cortisol levels rise as melatonin levels drop. (31)
Dosages of melatonin from 750 meg to 6 mg per day, taken before bed, can be effective at restoring melatonin levels.
DHEA, which originates in the adrenal glands, is another hormone that declines with age and chronic stress. Depending on the results of a salivary hormone test, supplementing with 12.5 to 50 mg of DHEA per day in the morning can help your adrenal glands adjust to stress. Women usually need less DHEA than men.
Pregnenolone also is produced by the adrenal glands and is important in regulating the adaptive homeostat. In one study, researchers investigated the effects of DHEA sulfate or pregnenolone sulfate in mice introduced into an environment where they had previously received an electric shock to their feet. Normally, these mice would halt in fear when exposed to this environment. However, when the mice were given DHEA and pregnenolone sulfate, the animals' usual fear response was reduced. (32)
As part of his adaptive homeostat protocol, Dean recommends 10 to 100 mg of pregnenolone per day, taken in the morning.
Support for Adrenal Exhaustion
As noted earlier, when the adrenal glands overproduce cortisol due to exposure to chronic stress, over time, they can become burned out and stop producing cortisol. When this happens, it's necessary to replenish cortisol levels in one of two ways. First, if an adrenal function salivary hormone test indicates that your cortisol levels are depleted, with a doctor's supervision you can try low-dose hydrocortisone treatment.
Another option to nourish exhausted adrenals is to supplement with adrenal glandular and/or glycyrrhizin, which is extracted from licorice. Glycyrrhizin affects cortisol metabolism and can raise cortisol levels, giving exhausted adrenals a much-needed break. (33) Glycyrrhizin should be taken for 1 or 2 weeks at a time, alternating with 2 or 3 weeks of nonuse, to eliminate the risk of adverse effects and to maximize its beneficial properties.
One component of the neuroendocrine theory of aging, the adaptive homeostat, provides us with many solutions for protecting our bodies from the damaging effects of stress. Thanks to Dilman and Dean's work, we have a blueprint we can follow for balancing cortisol levels and restoring hypothalamic sensitivity, thereby inhibiting the diseases of aging.
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Dr. Chris D. Meletis is an educator, international author, and lecturer. His personal mission is "Changing America's Health One Person at a Time." He believes that when people become educated about their bodies, that is the moment when true change and wellness begin. Dr. Meletis served as dean of naturopathic medicine and chief medical officer for 7 years at National College of Natural Medicine (NCNM) and was awarded the 2003 Physician of the Year award by the American Association of Naturopathic Physicians. www.DrMeletis.com.
Kimberly Wilkes is a freelance writer specializing in health, science, nutrition, and complementary medicine. She has written more than 300 articles covering a variety of topics from the dangers of homocysteine to sugar's damaging effects on the heart. She is the editor of Complementary Prescriptions journal and enjoys scouring the medical literature to find the latest health-related science.
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|Author:||Meletis, Chris D.; Wilkes, Kimberly|
|Date:||Dec 1, 2015|
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