Beware High Levels of Cortisol, the Stress Hormone

Cortisol, the Stress Hormone

We’ve all felt that surge of energy as we confront something threatening or startling. A barely avoided car accident. A call that your child has been hurt. The pressure to meet a deadline.

As your body perceives stress, your adrenal glands make and release the hormone cortisol into your bloodstream. Often called the “stress hormone,” cortisol causes an increase in your heart rate and blood pressure. It’s your natural “flight or fight” response that has kept humans alive for thousands of years.

Normal levels of cortisol also are released when you wake up in the morning or exercise. These levels can help regulate your blood pressure and blood sugar levels and even strengthen your heart muscle. In small doses, the hormone can heighten memory, increase your immune system, and lower sensitivity to pain.

“Stress is a lifestyle factor and a fact of life that we all face; however, reacting to stress in unhealthy ways can increase the risk of high blood pressure, heart attack and stroke,” says interventional cardiologist Dr. Sagger Mawri. The amount of stress we experience has increased since the COVID-19 pandemic, he adds. “Many people reacted to the stress of the pandemic with unhealthy weight changes, a decline in physical activity, and increased alcohol consumption. In fact, the average weight gain was 26 pounds among those who gained more weight than they wanted.” Widespread grief and other hardships caused by the pandemic have increased stress for many, Dr. Mawri adds.

If your body experiences chronic stress, you may begin to feel unpleasant and even dangerous effects, such as:

      • Fatigue
      • Irritability
      • Headaches
      • Intestinal problems, such as constipation, bloating, or diarrhea
      • Anxiety or depression
      • Weight gain
      • Increased blood pressure
      • Low libido, erectile dysfunction, or problems with regular ovulation or menstrual periods
      • Difficulty recovering from exercise
      • Poor sleep
      • Muscle pain or tension in the head, neck, jaw, or back

How Cortisol Works

When the adrenal glands release cortisol into your bloodstream, the hormone triggers a flood of glucose that supplies an immediate energy source to your large muscles. It also inhibits insulin production so the glucose won’t be stored but will be available for immediate use.

Cortisol narrows the arteries, while another hormone, epinephrine, increases your heart rate. Working together, they force your blood to pump harder and faster as you confront and resolve the immediate threat.

If your entire life is high-stress and always in high gear, your body may constantly pump out cortisol.

Hormone levels return to normal as you swerve to miss an oncoming car, find out that your child has only a few scrapes, or meet the deadline for your presentation.

Why Too Much of a Good Thing is Bad for You

If your entire life is high-stress and always in high gear, your body may constantly pump out cortisol. “This has several negative effects,” says Dr. Mawri.

      1. Increased blood sugar levels. Insulin typically helps the cells convert glucose to energy. As your pancreas struggles to keep up with the high demand for insulin, glucose levels in your blood remain high and your cells don’t get the sugar they need to perform at their best.
      2. Weight gain. As your cells are crying out for energy, your body may send signals to the brain that you are hungry and need to eat. Studies have demonstrated a direct association between cortisol levels and calorie intake in populations of women. False hunger signals can lead you to crave high-calorie foods, overeat and thus gain weight. Unused glucose in the blood is eventually stored as body fat.
      3. Suppressed immune system. Cortisol’s positive action to reduce inflammation in the body can turn against you if your levels are too high for too long. The elevated levels may actually suppress your immune system. You could be more susceptible to colds and contagious illnesses. Your risk of cancer and autoimmune diseases increases and you may develop food allergies.
      4. Digestive problems. When your body reacts to a threat, it shuts down other less critical functions, such as digestion. If the high-stress level is constant, your digestive tract can’t digest or absorb food well. It’s no coincidence that ulcers occur during stressful times and people with colitis or irritable bowel syndrome report better symptom control when they get their stress under control.
      5. Heart disease. Constricted arteries and high blood pressure can lead to blood vessel damage and plaque buildup in your arteries. They could be setting the stage for a heart attack or stroke.

How to Take Action

“Given the dramatic increase in stress in recent years, it is crucial that we all find healthy ways to cope with and manage the stress in our lives,” says Dr. Mawri. “Fortunately there are ways to do so and develop healthy behaviors that improve heart health.” He shares these tips from the American Heart Association:

      • If you are often stressed, learn the cause and constructive ways to deal with it.
      • Slow down and plan ahead to avoid feeling rushed.
      • Get 7 to 9 hours of sleep a night.
      • Let go of worry and take breaks.
      • Laugh more.
      • Make time to connect with friends and family and maintain a social support system.
      • Become more organized to stay on top of important tasks.
      • Practice giving back by volunteering and helping others.
      • Get exercise every day to relieve mental and physical tension.
      • Give up bad habits like excess alcohol, tobacco, and too much caffeine.
      • Lean into things that you can change, like a new skill or working towards a particular goal.
      • Learn to say no to things that are not a high priority.
      • Ask for help when you need it.

“If you have more stress than you can handle on your own, it’s a good idea to seek stress management counseling or speak to a mental health professional,” Dr. Mawri recommends.

Be aware of your own stress levels and takes steps to manage your stress. Simple practices such as getting enough sleep, exercising, meditating, deep breathing techniques, and scheduling leisure activities are a good start.

Source: ~ Image: Everyday Health

Dr. Israel Brekhman: “Father of Adaptogens” and His Energizing Adaptogen Blend

Dr. Israel Brekhman

It was 1960 when Russian scientist, Dr. Israel Brekhman, first had his work published in scientific literature. This first publication was a culmination of 15 years of previous research on adaptogens—a topic Brekhman dedicated the rest of his life. His continued research on adaptogens led to hundreds more publications and the discovery of the many health benefits of these protective agents. Brekhman was not only a world-renowned scientist and researcher, but also a medical doctor, teacher, and philosopher. Known as the “Father of Adaptogens,” he’s credited with introducing to the world formulas of adaptogens that promote health by helping people cope with everyday stress, maintain high levels of energy, and free the body from fatigue.

In a society plagued by chronic stress, a targeted solution to prime and protect the body from its harmful effects is necessary. Deemed “nature’s answer to stress,” Isagenix Ionix Supreme contains adaptogen compounds that work in the body by increasing its ability to adapt to stress while also improving physical and mental functioning under stressful conditions (1-2).

More specifically, and in one of his many research papers, Brekhman and his colleagues defined adaptogens as natural plant substances that:

    1. Increase the body’s ability to cope with internal and external stresses.
    2. Exhibit stimulating effects after both single-time use and prolonged use, leading to increased working capacity and mental performance under stressful and fatigue-inducing conditions.
    3. Normalize the functions of the body.
    4. Are entirely safe and have no negative side effects.

While all adaptogens are restorative to the body’s stress response and capacity to perform, certain combinations were studied by Brekhman for the exclusive purpose of boosting performance and fighting fatigue. With that purpose in mind, Isagenix has formulated the new e+ Natural Energy Shot with Brekhman’s own adaptogen formula coupled with naturally sourced caffeine—talk about the perfect pairing for energy and performance!

The first energy-boosting adaptogen in Brekhman’s formula, and now in e+ is Eleuthero (full name: Eleutherococcus senticosus). Eleuthero, also known as Siberian ginseng, is a thin, thorny shrub native to forests in southeastern Russia, northern China, Japan, and Korea.

The research behind Eleuthero has shown it to improve endurance exercise, oxygen uptake, and overall performance in athletes. One study published in 2010 echoed just that–college-aged male tennis players who supplemented with eleuthero for eight weeks had significantly enhanced endurance time and elevated cardiovascular functions (3).

Another adaptogen in e+, Rhodiola (full name: Rhodiola Rosea)—native to the arctic and mountainous regions throughout Europe, Asia, and America—also has scientific research behind it alluding to athletic improvement. A 2012 study conducted on cyclists found an improved heart rate response to exercise and a decreased perception of effort in subjects who took Rhodiola one hour before exercise (4).

The adaptogens in e+ not only can help power a workout but can also help you resist stress to stay mentally sharp after a hard day’s (or night’s) work. Rhodiola, for instance, has been found to reduce general and mental fatigue in doctors working night shifts (4).

One of the most recent reviews of adaptogens, published in October 2012, gives cause to always have e+ on hand when a pick-me-up is needed.  According to the review, adaptogens “induce increased attention and endurance in situations of decreased performance caused by fatigue and/or sensation of weakness” (5).

The bottom line is that adaptogens are plant substances that help the body to better handle external and internal stressors, they enhance the body’s ability to perform physically, and increase energy and mental alertness. Israel Brekhman spent his lifetime and career studying adaptogens and how we can use them to prime and protect the body. With e+, Isagenix is taking some of Brekhman’s best work and giving people the tool to take themselves and their health to the next level.


Technical and Clinical Aspects of Cortisol

Technical and clinical aspects of cortisol

Stress is now recognized as a universal premorbid factor associated with many risk factors of various chronic diseases. Acute stress may induce an individual’s adaptive response to environmental demands. However, chronic, excessive stress causes cumulative negative impacts on health outcomes through “allostatic load”. Thus, monitoring the quantified levels of long-term stress mediators would provide a timely opportunity for prevention or earlier intervention of stress-related chronic illnesses. Although either acute or chronic stress could be quantified through measurement of changes in physiological parameters such as heart rate, blood pressure, and levels of various metabolic hormones, it is still elusive to interpret whether the changes in circulating levels of stress mediators such as cortisol can reflect the acute, chronic, or diurnal variations. Both serum and salivary cortisol levels reveal acute changes at a single point in time, but the overall long-term systemic cortisol exposure is difficult to evaluate due to circadian variations and its protein-binding capacity. Scalp hair has a fairly predictable growth rate of approximately 1 cm/month, and the most 1 cm segment approximates the last month’s cortisol production as the mean value. The analysis of cortisol in hair is a highly promising technique for the retrospective assessment of chronic stress. [BMB Reports 2015; 48(4): 209-216]


Stress can lead to both physical and psychological health issues. Some stress can be beneficial at times by producing a boost that provides the drive and energy to help people get through situations like exams or work deadlines. However, an extreme amount of stress can lead to negative consequences and adversely affect the immune, cardiovascular, neuroendocrine, and central nervous systems . In particular, chronic stress can have a serious impact due to sustained high levels of the chemicals released in the “fight or flight” response, which involves the endocrine system releasing glucocorticoids .

Cortisol, which is synthesized from cholesterol, is the main glucocorticoid in the zona fasciculate of the human adrenal cortex. Its secretion in response to biochemical stress contributes to the well-characterized suppression of the hypothalamic-pituitary-adrenal (HPA) axis on health and cognition events . Since the vast majority of cortisol actions rely on binding to cytosolic receptors, only a small fraction of unbound, free cortisol is revealed to be biologically active. It comes out of the mitochondrion and migrates out of the cell into the extracellular space and into the bloodstream. Due to its low molecular weight and lipophilic nature, unbound cortisol enters the cells through passive diffusion, which makes it feasible to measure the free cortisol in many body fluids .

In general, cortisol levels in the blood increase during the early morning (highest at about 8 a.m.) and decrease slightly in the evening and during the early phase of sleep . The timing of blood sampling is therefore very important. While its assessment in sweat or tears is only of theoretical importance and urinary cortisol is of decreasing interest, salivary cortisol may have some advantages over the assessment of cortisol in the blood . Since the hormone levels in biological fluids fluctuate on a daily basis, cortisol extracted from the hair fiber has been investigated . This review discusses on the methods involved in mass spectrometry-based metabolomic studies for the identification of biomarkers in chronic stress, which is more focused on hair cortisol. Comparative statistical analyses of crucial aspects are also included to facilitate the understanding of recent advances in the metabolic platform on mining biomarkers.


The two adrenal glands are located on top of the kidneys, and these glands produce hormones in response to stress. Each adrenal gland consists of a central area, called the medulla, and an outer area of the cortex (Fig. 1). In case of the apparent threat, the hypothalamus sends direct signals via the sympathetic nervous system to the adrenal glands, causing them to release a catecholamine and epinephrine (same as adrenaline). It leads to urgent action by stimulating faster breathing and heart rates. The adrenal medullar also secretes another catecholamine, norepinephrine, which works with epinephrine to stimulate liver cells to release glucose to make more fuel available for cellular respiration. These hormones have short-term effects as the nerve impulses are sent from the hypothalamus. Due to the short half-life of blood catecholamine, meticulous care must be taken to obtain blood samples consistently vis-à-vis the stress immersion experience .

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The differential stress hormones are secreted by the adrenal cortex and medullar. Catecholamines cause general physiological changes that prepare the body for physical activity (fight-or-flight response) in the short-term response. Some typical effects include increases in heart rate, blood pressure, blood glucose levels, and other general reactions of the sympathetic nervous system. Corticoids are involved in a wide range of physiological processes including chronic stress response, immune response, and regulations of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Data are taken from “”.

Finding a “gold standard” biomarker for chronic stress has been proven to be challenging, given its complex etiology and highly individual manifestations, while the biomarkers of acute stress have been well-defined and are primarily used to assess the release of catecholamine. Hormones secreted by the adrenal cortex provide a slower, longer-acting (chronic) response to stress. In this event, the hypothalamus secretes a releasing hormone which causes the anterior pituitary to secrete an adrenal-stimulating hormone, adrenocorticotrophic hormone (ACTH); and this signals the cells in the adrenal cortex to produce and secrete corticosteroids. Among them, mineralocorticoids, like aldosterone, can regulate water and sodium re-absorption in the kidneys. It also regulates the active secretion of potassium in the principal cells of the cortical collecting tubule and protons via proton ATPases in the luminal membrane of the intercalated cells of the collecting tubule, which results in an increase in blood pressure and blood volume. Glucocorticoids promote fat and protein breakdown and glucose synthesis. Cortisol is the major glucocorticoid, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions .


The term, stress, was originally adopted from engineering (a measure of the internal forces induced by the deformation of a body), but it is now referred to as ‘threats or anticipation of threats to an organism’s homeostasis’ . Thus stress events could be understood as any stimuli that cause alterations in homeostasis for adaptation to the environment. These changes in homeostasis are referred to as ‘allostasis’, which can be exemplified by increased heart rate or blood pressure and enhanced systemic metabolism. In general, allostasis can be adaptive or maladaptive depending on its degree or contextual relevance; mediators of allostasis, such as metabolic hormones, could contribute to healthy adaptation and pathophysiology . The concept of ‘allostatic load’ indicates an altered, ‘new set point’ of homeostasis, resulting from cumulative effects of allostatic responses which are chronic, excessive, or poorly regulated . For example, the increased serum glucose level is responsible for a single acute stressful event, which can be called as ‘allostatic response’. Also, diabetes (insulin resistance) resulting from repetitive chronic stress can be understood as an ‘allostatic overload’, in which the baseline fasting glucose level has been newly set to a higher level than before (Fig. 2). Therefore, the biomarkers of allostatic load, if available, could be used for measuring and predicting the cumulative biological risks of impending illnesses, and they are ideal indicators for detecting the ‘pre-phase’ of illnesses .

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Stress, allostasis, and allostatic load. Stress is any stimulus inducing either adaptive or maladaptive allostasis (changes in homeostasis) of stress mediators, which constitute the autonomic nervous system (blood pressure, catecholamines), metabolic hormones (cortisol, insulin), and pro- & anti-inflammatory cytokines. If stress stimuli are excessive and repetitive, recovery to the original homeostatic levels may be incomplete (indicated by the second blue arrow). As a result, chronic stress can make a body system anticipate, as if such a new (stressful) environment would persist, demanding a newly defined set point for future adaptation. Thus, the difference between the new and old set points can be understood as a ‘cumulative burden of adaptation to stress’- i.e., allostatic load. Examples of allostatic load may be found in the primary mediators (hypercortisolemia, increased inflammatory cytokines), secondary outcomes (elevated blood pressure, overweight, insulin resistance), or tertiary outcomes (hypertension, diabetes, obesity, coronary heart disease, neurodegenerative disorders). For more details, see reference # 6.

Mediators of allostasis constitute the autonomic nervous system (catecholamines), metabolic hormones, and various cytokines . Among these, cortisol is the one that has been paid great attention based on the concept of the ‘glucocorticoid cascade hypothesis’ . This hypothesis explains how and why the cortisol actions could be related to pathophysiology upon an overload of stress. Psychological and physical stresses increase the circulating cortisol levels. In the acute state, increased cortisol induces adaptive responses via enhancing catabolic processes to supply more energy to the body. In general, increased cortisol levels return to the basal levels by feedback inhibition mechanisms through the hypothalamus, prefrontal cortex, and most importantly, hippocampus . When stressful stimuli are repeated chronically, circulating cortisol is maintained at higher levels over a prolonged period. Chronically elevated cortisol levels now cause damage on hippocampal and cortical neurons , which are the main regions where feedback inhibition starts. As a result, even when stress stimuli disappear, cortisol levels could be maintained at higher levels beyond the physiologically normal range due to a vicious cycle caused by the already damaged feedback mechanism.

Consequently, a great number of studies have explored the potential of utilizing cortisol as a biomarker for various chronic illnesses or their pre-disease states . Currently, it seems that such the role of cortisol, as one of the biomarkers for the allostatic load, may be largely accepted . However, there are still controversial issues regarding the sampling and measurement methods of these hormones that are fluctuated by environmental contexts as well as by the circadian cycle. However, the most important issue might be the possibility that the level measured once at a current point could reflect the past history of an individual’s stress load, just as HbA1c indicates the degree of ‘glucose load’ for the past 3 months. The level of cortisol in scalp hair is now considered a promising biomarker for assessing the average level of one’s past stress burden during a given period, and it will be further discussed in this paper. Its utility has been demonstrated across diverse clinical settings from neonates to old age, indicated by associations of hair cortisol levels with babies’ stress in the neonatal intensive care unit , children’s stress at school entry , and various metabolic and neuropsychiatric disorders including acute myocardial infarction , heart failure , metabolic syndrome , and post-traumatic stress disorder .


Because more than 90% of circulating cortisol in human serum is protein-bound, changes in the binding proteins can alter the levels of serum total cortisol without influencing the free concentrations of cortisol. Total cortisol could be misleadingly lower than anticipated, resulting in the incorrect interpretation that adrenal function is impaired. This is important because the current standards for defining normal adrenal functions are based on healthy people who have normal levels of binding proteins. Measuring serum-free cortisol levels in critical illnesses may help to prevent the unnecessary use of glucocorticoid therapy . Although the free cortisol hypothesis has been widely used, it has also been suggested that cortisol-binding globulin (CBG)-bound cortisol may have physiological effects on target tissues .

There is a high correlation between salivary cortisol levels and unbound cortisol in plasma and serum, which remains high during the circadian cycle and under different dynamic tests such as ACTH stimulation . Since free cortisol represents the biologically active hormone fraction, salivary cortisol measures have early been considered a better method than serum cortisol for the evaluation of adrenocortical function . Recently, late-night salivary cortisol has been showing a superior diagnostic performance as the primary biochemical diagnostic test for Cushing’s syndrome . Cortisol in biological fluids has been extensively evaluated with cortisone, which may reveal the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) by mass spectrometry-based metabolite profiling techniques . These analytical methods have shown acceptable analytical sensitivity and selectivity in trace amounts of biological samples such as urine and serum. However, the methods have still been hampered by incorrect physiological levels of adrenal steroids, including cortisol, due to the sampling problems with a circadian variation. In general, acute cortisol levels fluctuate markedly depending on many physiological factors including circadian rhythmicity, and it may provide a rather poor reflection of normal, chronic cortisol secretion .

In contrast to the biological fluids, hair can provide biological information about long-term exposure because its growth rate is about 1 cm/month (Fig. 3). The hormones are mainly delivered from the blood circulation to the capillaries of the dermal papilla, which is located in the hair follicles . This phenomenon enables retrospective examination of cortisol production at the times when a stressor is most salient, without needing to take a sample right at that time. Alternatively, it can provide a baseline cortisol assessment for a time period during which the stress has not yet occurred. In addition, its non-invasive nature in sampling and easy storage at room temperature has been highlighted as an advantage in clinical applications . In hair analysis, steroid hormones are extracted by solubilization or digestion of the hair matrix with alkaline hydrolysis for androgen and estrogens . Also, acid hydrolysis or methanol extraction can enable an analysis of corticoids in hair due to their insufficient chemical stability . When 62 biologically active steroids were analyzed by an optimized extraction technique, only 20 hair steroids, including cortisol and cortisone, were quantitatively detectable .

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A proposed mechanism of cortisol incorporation into hair and retrospective reflection of its chronic secretion. Cortisol may be incorporated into hair via passive diffusion from (A) blood capillary, (B) sweat, and (C) sebum, as well as from (D) external sources. Data are taken from reference #12.


Because more than 70% of diseases are believed to be stress-related, the prediction of chronic stress is an important step in reducing the incidence of chronic illnesses. Hair cortisol may provide an objective measurement of stress over time rather than just a ‘day in the life’. The symptoms of the metabolic syndrome resemble those of Cushing’s syndrome, a disease that is characterized by hypercortisolism. One of the questions raised is whether chronically elevated cortisol concentrations play a role in the development of obesity and metabolic syndromes. The increased hair cortisol levels are also associated with children’s obesity caused by long-term activation of the HPA-axis , which is in accordance with the urinary levels of cortisol in obese children . The risk of cardiovascular disease (CVD) is associated with an increase in hair cortisol levels by 2.7 times, which was similar to the risk associated with hypertension or obesity. This suggests that high cortisol levels in a long term might be an important risk factor for CVD .

Mitotane, an anti-neoplastic agent for adrenocortical cancer (ACC), increases CBG and induces CYP3A4 activity, which leads to high doses of hydrocortisone; however, there has been no efficient biomarker to evaluate this therapy. Hair cortisol levels were higher in ACC patients compared to healthy individuals, and they were associated with body mass index . However, there was no correlation between hair cortisol levels and hydrocortisone doses. As a measure of long-term cortisol exposure, the hair cortisol analysis in patients receiving glucocorticoid replacement therapy may be a useful tool. Also, the hair cortisol content is correlated with hydrocortisone dose in the patients with adrenal insufficiency, who had significantly higher subjective stress scores than the control subjects .


The main benefit of the metabolomic strategy is the high likelihood of identifying unpredicted changes in metabolic profiles cued by abnormal conditions . In particular, the metabolomic information may offer novel diagnostic indicators and therapeutic targets in clinical applications , as well as in mechanistic studies heading to elucidate metabolic modules that can regulate dysfunctional processes in disease statuses .

Among dysfunctional health conditions, chronic diseases are mostly composed of subtle and long-term dysregulations of cellular and physiological functions that are often not measurable even during disease onset . The stress-inducing abnormal status is chronically developed with an unpredictable combination of various types of etiological factors. Therefore, the molecular characterization, as well as clinical definition, may not be clear in specific disease courses and it may not be homologous across individuals . The diversity of pathological traits induced by chronic stress makes it even harder to properly diagnose the abnormality and classify the progress stage. Most of the studies are mainly focused on a targeted single molecule and one-point interaction, which may be insufficient to reflect the dynamics and systematic effects of chronic stress . In this context, metabolite profiling can be an effective tool for biomarker discovery and understanding of the molecular mechanism, particularly for cases where a diagnostic/prognostic indicator is unknown and the molecular mechanism remains veiled. Recently, a chronic unpredictable mild stress in an animal model showed aberrant profiling of amino acids that were grouped into neurotransmitters and branched-chain amino acids . The metabolic signatures under acute and chronic stress in a rat models and the biochemical cues are also closely associated with behavior and physiological readouts .


To capture disease-specific metabolic signatures, many studies, including the case studies described above, primarily explored the multiple molecular constituents (metabolites), robustly managed variability and heterogeneity of disease progression, and defined the individuality of metabolic contents, which could lead to well-defined diagnoses and prognoses. In this context, multivariate statistics such as principal component analysis (PCA) or partial least squared algorithm is a useful data mining tool that can distinguish different groups with minimized loss of information . By this nature, unidentified variation sources caused by transient (time-course) or individual specificity can be handled within the reconstructed statistical model, which in turn offers more robust candidates for diagnostic/prognostic information in clinical cases (Fig. 4).

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Reconstructed metabolic network for systematic screening of therapeutic target point. The re-modeled metabolic structure is composed of metabolites, which consist of node (e.g. metabolite) and edge (e.g. correlation, structural similarity). The model may be extended to protein information via reaction pair that has already been built in the assembly, which could unravel “hidden” or veiled metabolic modulation, particularly in chronic disease. In this example, node color and size indicate significant differences and fold change compared to control (e.g. disease vs control), while edge presents two layers of information on structural similarity and reaction likelihood, which leads to automatic rearrangement as seen in the figure indicating proximity of biochemical module.

In many studies, the metabolomic approach has been limitedly applied to biomarker discovery with either a single target or a group of metabolites. Yet, an ideal exploratory use of the technology would not only be able to capture the metabolite changes associated with pathology, but it would also elucidate the molecular mechanism responsible for the dysfunction and propose the logical candidate for regulating the abnormality. Pathway (enrichment) analysis, a systematic approach for data mining from metabolite sets, can provide metabolic pathway-wise information rather than the readouts of an individual or few metabolite contents . This bioinformatics tool, which is rooted in gene ontology enrichment analysis, assigns groups of metabolites at the level of the metabolic pathway. The analysis provides a P value that presents significant differences at the levels of metabolic pathways and information on pathway centrality (pathway importance), which demonstrates how much connectivity is formed surrounding the metabolites of interest in the pathway . The output can be further investigated for a mechanistic understanding of the disease, and it can be applied for targeting and controlling the functional points of the disease process. However, although metabolic signatures can be identified at the level of either single molecule, groups of metabolites, or metabolic pathways, metabolite assessment cannot by itself provide a complete understanding of the disease process. To gain comprehensive causality and mechanism in given experimental designs, the integrative analysis should be accompanied by other molecular information such as mRNA expression levels and protein abundances . Since metabolomics joins systems with biology, mRNA has been the first partner for integrative analysis mainly due to the well-establishment of technical platforms and advancements in statistical analysis. However, the expression level of mRNA showed a low correlation with enzyme activity and protein expression levels, which is a direct molecular companion with metabolites, the substrate, and products. Thus protein information is the more suitable counterpart of metabolite readout .

Most importantly, in order to have molecular information (mRNA, protein, and metabolite) located at the cornerstone of clinical application, various types of molecular levels should be linked to physiological traits (e.g. clinical parameters) in a statistically sound manner. This has been mainly done by ‘qualitative’ assessment in which the final readout of molecular behaviors is linked to logical phenotypes of disease. For example, aberrant glycolytic activity can be associated with tumor metabolism, in which glycolytic intermediates and key enzymes are overexpressed in tumor cells. But in the case of chronic disease, we may not be able to detect “the standardized feature” like cancer metabolism case. Alternatively, we can track and correlate the quantitative traits of pathology with molecular dynamics, which can bear the variability caused by individuality and differential disease progress. One relevant statistical approach is canonical correlation analysis (CCA), which has been often applied in psychological, climate, and ecological studies to enumerate the correlations between two distinct data sets measured on identical experimental units . These statistics can analyze significant relations between two different datasets (e.g. metabolite contents and the associated clinical parameters). It is similar to PCA, in the way that CCA seeks linear combinations of the variables to reduce the dimension of the data sets; but at the same time, it explores to maximize the correlation between the two variates .


Because single cortisol assessments are strongly affected by the acute context of the measurement situation (time of day, day of the week, and other circumstances such as distress for blood sampling), the assessment of long-term cortisol secretion from the biological fluids, such as blood, urine, and saliva, is highly labor-intensive and rather difficult to be implemented in physical and psychological studies. Hair growth patterns also vary across different regions of the scalp, and the precise mechanisms of substances incorporating into hair are still incompletely understood. But a growing observation supports the notion that hair cortisol analysis provides a valid and reliable reflection of long-term cortisol secretion . We mainly discussed about the advantages of hair analysis as an index of chronic cortisol response. Due to their association with various aspects of biochemical stress in adrenal steroids and other steroid metabolites, the advantages of hair analysis may not only be restricted to cortisol . Further research on establishing the reference values of hair cortisol may be needed to enhance the current knowledge on particular aspects of chronic stress and other metabolic changes in many endocrine diseases.

Source: ~ By: Do Yup Lee, Eosu Kim, and Man Ho Choi ~ Image:

Newsletter, 8/2/22 Telomeres

Are Telomeres the Key to Aging and Cancer

Inside the nucleus of a cell, our genes are arranged along twisted, double-stranded molecules of DNA called chromosomes. At the ends of the chromosomes are stretches of DNA called telomeres, which protect our genetic data, make it possible for cells to divide, and hold some secrets to how we age and get cancer.

Telomeres have been compared with the plastic tips on shoelaces because they keep chromosome ends from fraying and sticking to each other, which would destroy or scramble an organism’s genetic information.

Yet, each time a cell divides, the telomeres get shorter. When they get too short, the cell can no longer divide; it becomes inactive or “senescent” or it dies. This shortening process is associated with aging, cancer, and a higher risk of death. So telomeres also have been compared with a bomb fuse. READ MORE

Save Your Telomeres

Since their discovery more than 75 years ago by the Nobel Laureate geneticist Hermann Müller, telomeres have attracted worldwide attention among scientists investigating the aging process.

Telomeres are the protective caps on the ends of chromosomes composed of short DNA sequences protecting our DNA and genetic material from damage. Another Nobel Laureate, Elizabeth Blackburn, likened telomeres to the little plastic caps on the ends of shoelaces (aglets).

Under normal conditions, when a cell divides, telomeres shorten. If they grow too short, they reach what’s known as the Hayflick limit (named after the esteemed gerontologist Leonard Hayflick), and the protective capacity of the telomere decreases. Real-world relevance of telomere shortening can be observed during the aging process in humans when comparing the length of telomeres from newborns (8,000 base pairs) to adults (3,000 base pairs) to elderly individuals (1,500 base pairs). READ MORE

IsaGenesis: Plant-Based Ingredients for Youthful Aging

Telomeres are the protective DNA sequences at the end of each chromosome. They are essential to maintaining genome stability within the cells, and researchers have honed in on telomeres as a marker of biological aging.

Over time, our telomeres begin to gradually shorten, which is naturally associated with normal aging. Early telomere shortening is linked to lifestyle factors such as poor diet, stress, and exposure to environmental toxins, which can lead to negative consequences for health (1-5).

Think of telomeres like the plastic caps on the end of your shoelaces. With time, they will inevitably get worn down. If you take care of your shoes, you can protect your shoelaces from splitting and fraying faster than they naturally would.

Why IsaGenesis? A growing body of scientific literature suggests that antioxidant nutrients along with select plant extracts and herbal ingredients can support telomeres and defend against the harmful effects of oxidative stress known to accelerate the cellular aging process (6). READ  MORE

The 27 Best Anti-Aging Tips of All Time

Prevent fine lines, wrinkles, sagging, dark spots, and other visible signs of aging with these proven strategies…

1) Skip the Straw

2) Seriously, Don’t Smoke

3) Eat Your Antioxidants

4) Fill Up on Fermented Foods

5) Pack on the Protein… READ MORE


Cleansing Your Way to Better Health

Basic nutritional re-balance in your body and understanding the principles of inflammation -disease-manifestation are the cornerstones to improving your overall health. It is of no real benefit to masking the symptoms without removing the original causes. On the contrary, such an approach robs the body of its ability to fight its own problems and may lead to permanent health damage and may unfortunately lead to dependency on drugs/treatments that often have devastating side-effects.

The following may shed some light on why people develop inflammation – diseases, which when analyzed properly, can turn out to be no diseases, but appropriate, natural responses by the body to protect itself against the conscious or unconscious abuse on the body. Depending on constitutional status, dietary habits, excessive lifestyles, ability to deal with stressful situations, environmental factors, and existing predisposed weaknesses in the body, the symptoms may vary from person to person, but the mechanisms of inflammation – disease manifestation are similar.

One person may develop fibromyalgia, another respiratory weakness, a third, chronic fatigue- stress, yet they are all suffering from severe intestinal trouble and resulting lymphatic congestion and nutritional imbalance -undernourishment. Wherever the blockage occurs, symptoms show up. And wherever the blockage is removed, the symptoms disappear. It is up to each person suffering from health problems to help himself/herself.

The following are a few examples of conditions affected by inflammation, since these conditions can be chronic in nature, that is, they are constantly re-created by the afflicted person making the same mistakes over and over again. Many conditions caused by inflammation can be reduced if with body cleansing: elimination of cellar waste and detoxification.


Fibromyalgia can be a painful condition that affects the connective tissue responsible for holding muscular cells in place and feeding them with nutrients. The symptoms may vary, in some patients the pain is felt all over the body. In others, it appears in localized areas, for example in the shoulder (frozen shoulder) or the elbows (tennis elbow). Fibromyalgia s considered to be a form of rheumatism with the difference that it affects the softer tissues of the muscles rather than the harder tissues of the joints.

Although there may be a number of causes involved, many of them lead to one common underlying factor — acidification of the body’s connective tissues, toxicity. Many patients are told that excessive, regular, and one-sided use of muscle groups causes the death of muscle cells because the increased oxygen requirement cannot be met. This then results in the accumulation of dead muscle cells, leading to a thickening and hardening of the connective tissue.


It is much more likely that when the respiratory functions are already impaired through congestion and insufficient drainage of lymph/waste from the lung and bronchial areas, the oxygen demands of the body cannot be met. Most respiratory weakness is due to lack of enough ‘fresh’ air, not enough exercise, allergies acid-forming foods such as milk and dairy products, meat, sugars, soft drinks, coffee, cigarettes, alcohol, and/or irregular sleeping patterns. Suppressing emotional issues is another major contributing factor to respiratory difficulties.

Those parts of the body where waste removal through the lymphatic ducts is obstructed creates havoc in your lungs. For muscle cells to die and remain trapped in the connective tissue it takes much more than just repeated strenuous physical movements. Thickened and acidified connective tissue does not permit sufficient amounts of oxygen and nutrients to make their way through to the cells. Among the above reasons responsible for causing poor respiration, diet and digestion assert the greatest influence. Regular consumption of animal proteins, dairy food, refined and hardened oils and fats, as well as most processed foods are notorious for causing such acidity-related problems. Most factory-made processed food products are deprived of all living substance, and are considered “non-physiological”, that is inflammation – disease-generating.

Processed foods, no longer being in their natural form, rob the body of vital nutrients and can damage the probiotic flora of essential bacteria located on our skin and mucous lining along the intestinal and respiratory tracts. It is vital to have these highly useful bacteria, they are our first line of defense against any harmful substances and adverse invading organisms. Once the flora has been damaged, these acidic food compounds find entry into the connective tissues creating havoc throughout the body. Consequently, just to neutralize these substances, the muscle, bone, and organ tissues must give up some of their own oxygen, minerals, vitamins, trace elements, etc. Once this second line of defense is exhausted, too, the connective tissue becomes increasingly filled and saturated with cellular debris, metabolic waste, and toxic compounds and it thickens to a gel-like consistency. Microbes start coming on the scene, attacking the accumulated waste matter, which leads to inflammatory cascade.

Hampering proper lymph drainage and reducing the clearing of all naturally occurring metabolic waste products, results in stagnation causing overused and tense muscle groups in the body. This lends to malfunction and battle cry for attention and the battle to fight inflammation begins.  Most of the people who are affected in this way have no idea; however, the regular intake of sugars, stimulants such as coffee, cigarettes, sodas, alcohol, dairy products, fast foods and junk foods, may have something to do with their muscular rheumatism. They may also not realize that the pain syndrome in their body indicates the presence of a deeper metabolic imbalance that affects the entire organism.

The organs of elimination and detoxification become heavily overtaxed, which forces the body to dump the waste matter elsewhere, such as in the connective tissue of muscles. Also energy levels drop, and emotional well-being is disturbed. All this can cause multiple symptoms, including headaches, constant tiredness, reduced ability to concentrate, fluid retention, abdominal pain and diarrhea, etc.

The most thorough and fundamental treatment program for these and many other health problems consists of cleansing the major organs and systems of elimination and detoxification, including the liver, kidneys, large intestine, small intestine, lymphatic system, lungs and skin. Unless they are cleared of any obstructions such as gallstones in the gallbladder and bile ducts of the liver, stones or grease in the kidneys, hardened deposits of undigested foods in the intestinal tract, layers of accumulated protein in the walls of blood vessels, etc., the body will continue to absorb toxic wastes in the connective tissues. Once the absorption capacity is exceeded, the waste spills over into the body’s orifices, e.g., eyes, ears, nose, mouth, skin pores, causing congestion and impairing sensory functions.

When these organs and systems are cleansed and begin to function more efficiently again, the body systematically retrieves and neutralizes the deposits of toxic wastes in the connective tissues. As a result, the symptoms of inflammation – pain begin to disappear. This is easy to understand since pain arises only when ducts, pathways, vessels, etc. become obstructed. Respiratory weakness and many other inflammation areas of the body may not be considered to be diseases, but they could be a signal the body generates in order to warn its owner of the imminent danger and to deal with the existing toxicity crisis in the best possible way.


Chronic fatigue is a sign of major imbalance on all levels of living, physiological, psychological, and sociological. Its main cause, however, is overuse of the body’s energy resources. Since waste elimination is suppressed, there may be multiple symptoms of congestion, swellings, headaches, pain in joints and muscles, enlarged lymph nodes, etc.

Many professional athletes, for example, suffer from this condition later in life, especially when drugs were used to increase performance. There is a certain amount of life-energy available that is supposed to last for the entire natural lifespan. If used up within a few years, there is not much left for the later years.

But not only athletes tend to abuse their energy systems. Many people over-stimulate their body unnecessarily, just to derive sensory pleasure. Excessive travel to different time zones, chronic exposure to stressful activities can lead to the same depletion of energy that athletes can suffer. Even the overuse of the sense of sight, by watching too much TV for example, can cause major energy depletion. The nervous system must use vast amounts of energy, vitamins, and water in order to keep up. If this over-stimulation, prompting a constant release of the stress hormone adrenalin, becomes too strenuous for the body, it goes into exhaustion and may fall asleep — a common experience especially among the elderly. Also, regular exposure to low frequency electromagnetic fields, radiating from TV sets, computers, car engines, and household appliances, are another major source of energy depletion.

Perhaps the most important cause of chronic fatigue is many years of over-stimulation through food and beverages. Foods that are non-physiological, have no real value for the body, rob the body of its energy reserves. Since they don’t provide energy to the body, the body is forced to give up its own resources to deal with them. Typical foods and drinks that have such an effect on the body are isolated sugar, cakes, candy, pastries, all stimulants such as caffeine in coffee, tea, chocolate, soft drinks, preservatives, coloring agents, emulsifiers and other chemical food additives, pesticides, hormones, and antibiotics contained in meat, milk, and other foods, meat, and basically all factory-produced foods.

Many modern foods and drinks literally trigger a fight-or-flight response in the body — a system of survival that is only to be used in emergency situations, such as facing an immediate danger from an approaching car. All stimulants trigger this survival response. Constant stress, and irregular sleeping habits, of course, do the same. A typical adrenalin release uses up a vast amount of energy in the body. Fatigue results when a number of these factors, combined with a longstanding weakness of the digestive functions, lead to the exhaustion of almost all energy reserves in the body. Since digestion is impaired there is not much energy left to fill up the complex sugar reserves.

Stress always goes hand in hand with severe congestion occurring in many parts of the body. This applies particularly to the lymphatic system, where thickened lymph fluid filled with metabolic waste products, toxins from foods and environment block the small and large lymph ducts and cause lymph node swelling or lymph edemas. Once lymph flow is continuously inhibited the surrounding tissue turns into a pool of toxins, which in turn can have a detrimental effect on nutrient and energy supply to the cells, organs and systems in the body.

The body, being a composite of ducts, channels, vessels, biochemical and electrical pathways, can only be energetically self-sufficient, when it is free of any abnormal obstructions. The various symptoms of inflammation simply reflect the location and degree of congestion and toxicity. In the case of chronic fatigue, the degree of congestion in these ducts and vessels is very high. Water, oxygen, glucose, and other essential substances are increasingly hindered from entering the cells.Consequently, cellular energy production remains too low to meet the body’s high demands for energy.

Since the liver serves as the main energy distribution center in the body, a series of body cleanses usually alleviates the situation greatly and in fact often fully restores normal energy levels.

In closing, to restore normal energy levels, remove pain and other symptoms of inflammation it is necessary to open all congested areas in the body through simple body cleansing. Diet and lifestyle must be adjusted to support the body in restoring its complex energy reserves and to deliver nourishment to all organs and systems. A body that is cleansed and free of congestion has no need to generate pain signals; instead it is a constant source of happiness, freedom and rejuvenation.

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