Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 2 • February 2013

Feeling Burned Out?

Reduced Sensitivity to Glucocorticoid Feedback Regulation of Inflammatory Cytokines in Vitally Exhausted Men

In our article on leptin and increased body fat (Durk & Sandy Life Extension Newsletter, Oct. 2012), we noted that leptin, a negative feedback adiposity signal, is less effective in the presence of inflammatory conditions.A One source of inflammation is stress.1,2 Researchers found that male industrial employees suffering from vital exhaustion (a combination of unusual fatigue, loss of energy, and irritability) have high levels of inflammatory cytokines such as IL-1beta, TNF-alpha, IL-6, and C-reactive protein (CRP).1 In another study,2 researchers reported that daily social interactions that are negative and competitive are associated with increased proinflammatory cytokine activity. Under these inflammatory conditions, one would expect leptin signaling to be impaired, resulting in weight gain and reduced satiety.

The authors of the paper on vital exhaustion in men1 report that the increased inflammatory responses of activated monocytes are generally normalized by glucocorticoid feedback regulation, but there is a reduced release of endogenous cortisol in individuals with vital exhaustion. Hence, these individuals, because of inadequate glucorticoids, do not adequately downregulate inflammatory responses and, thus, have increased plasma levels of inflammatory cytokines, such as those listed in the paragraph just above. As the authors of paper #1 explained, “... more dexamethasone [a glucocorticoid] was required to suppress IL-6 release in response to the same LPS stimulus in highly exhausted subjects as compared with nonexhausted individuals.” Inadequate shutting down of monocyte release of proinflammatory cytokines in response to LPS (lipopolysaccharide, a bacterial cell wall component that strongly stimulates immune system activation) can result in a chronic inflammatory state such as is associated with obesity and an increased risk of cardio­vascular disease.

Consumption of Hydrogen (in Water) Prevents Stress-Induced Impairments in Hippocampus-dependent Learning in Mice

We continue our Hydrogen Therapy Series here with a paper that found protection by hydrogen against stress-induced learning impairments in mice.

A recent paper3 reports that mice subjected to 4 to 8 weeks of chronic physical restraint stress had a variety of cognitive impairments and significantly increased oxidative stress in the brain, which is a known inducer of inflammation. Consistently with increased inflammation, there was a decline in the proliferation of neural progenitors (neurogenesis) in the stressed mice.

Treating the stressed mice with hydrogen-saturated water was able to restore neurogenesis and improve their performance in passive avoidance learning, novel recognition test, and in the Morris Water Maize test (where the mice have to find a hidden platform in a tank of water to avoid having to continually tread water).

Supplementation with long chain oligosaccharides (a form of inulin) is one way to provide a food that humans cannot digest for consumption by resident bacteria in the lower intestine that they can use to produce hydrogen. Data indicate that hydrogen is produced and released over a longer period of time than when hydrogen is ingested in water or saline or when hydrogen is inhaled as a gas. Some of the hydrogen is consumed by other resident bacteria, but most diffuses out of the lower intestine and throughout the body, passing through the blood-brain barrier and even reaching into mitochondria, before being exhaled out from the lungs.

We are particularly impressed by the ability of hydrogen to reach into cellular compartments (especially mitochondria, subject to considerable oxidative stress) that many antioxidants are unable to do. Many other supplements have been reported to have potent antiinflammatory effects, though not necessarily including data on the ability to pass into mitochondria; a few examples are foods such as fruits,4 berries,4 whole grains,4 and fatty fish,4 as well as nutrients such as choline5 and betaine,5 and herb/spice constituents including curcumin,6 epigallocatechin gallate (EGCG),7 and cinnamon.8


A. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med. 12(4):425 (2006).
1. Wirtz et al. Reduced glucorticoid sensitivity of monocyte interleukin-6 production in male industrial employees who are vitally exhausted. Psychosomatic Medicine. 65:672-8 (2003).
2. Chiang et al. Negative and competitive social interactions are related to heightened proinflammatory cytokine activity. Proc Natl Acad Sci USA. 109(6):1878-82 (2012).
3. Nagata et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 34:501-8 (2009).
4. Wu and Schauss. Mitigation of inflammation with foods. J Agric Food Chem. 60:6703-17 (2012).
5. Detopoulou et al. Dietary choline and betaine intakes in relation to concentration of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 87:424-30 (2008).
6. Shehzad et al. New mechanisms and the anti-inflammatory riule of curcumin in obesity and obesity-related metabolic diseases. Eur J Nutr. 50:151-61 (2011).
7. Kumaran et al. Attenuation of the inflammatory changes and lipid anomalies by epigallocatechin-3-gallate in hypercholesterolemic diet fed aged rats. Exp Gerontol. 44:745-51 (2009).
8. Kim et al. Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. Biogerontology. 8:545-54 (2007).

Restoration of Glucocorticoid Sensitivity to Downregulation of Monocyte Release of Pro-Inflammatory Cytokines in Patients with COPD and Asthma

As explained above, in vitally exhausted men, monocytes are insensitive to glucorticoid-induced downregulation of proinflammatory cytokine secretion. Interestingly, histone deacetylase-2 (HDAC2), “a critical component of corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity.”9 “... curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity by either CSE [cigarette smoke extract] or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.”9 The similarity of this mechanism to the glucorticoid insensitivity to suppressing proinflammatory cytokine release in monocytes of men with vital exhaustion hints (but does not prove) that HDAC2 may be involved in the glucocorticoid insensitivity that was found in vital exhaustion and, therefore, curcumin may be able to restore glucocorticoid sensitivity in that disorder as was found in COPD patients.

Another activator of HDAC2 is sulforaphane (found in cruciferous vegetables, such as broccoli). It has been reported to reactivate HDAC2 in alveolar macrophages via activation of Nrf2 (a major regulator of antioxidant genes) and thus restore sensitivity to corticosteroid downregulation of proinflammatory cytokine release.10

Another paper11 reports that “[l]ow subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics.” The authors note that although curcumin and low-dose theophylline “appear to restore corticosteroid [antiinflamatory] function and may initially provide therapeutic potential, they lack specificity [e.g., they affect other chemical pathways] and the mechanism of their action is unknown.”

9. Mela et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 39(3):312-23 (2008).
10. Malhotra et al. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticoid sensitivity in macrophages from COPD patients. J Clin Invest. 121:4289-302 (2011).
11. Marwick et al. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets. 11(6):745-55 (2007).

Acute Psychological Stress in Men: Higher Body Mass Index Associated with Reduced Glucocorticoid Inhibition of Inflammatory Cytokines

“Our data suggest that with increasing BMI, glucocorticoids are less able to inhibit TNF-alpha [tumor necrosis factor-alpha, a proinflammatory cytokine] production following stress. This might suggest a new mechanism linking BMI with elevated risk for adverse cardiovascular outcomes following stress.”12

A recent paper reports on reduced ability of glucocorticoid feedback signaling to inhibit inflammation (as assessed by monocyte TNF-alpha production) following experimental stresses (the Trier Social Stress Test, which is a combination of a mock job interview and mental arithmetic task) in 42 male subjects aged 21-65.12 This is a lot less stress than vital exhaustion (as discussed above), but the decrease in glucocorticoid feedback signaling against inflammation (as indicated by reduction of monocyte TNF-alpha production) was similar. Although increased BMI was associated with reduced effectiveness of glucocorticoid suppression of TNF-alpha production under conditions of stress, baseline gluco­corticoid sensitivity was not associated with BMI.12 “... mental stress might increase cardiovascular risk in overweight persons by lowering the capacity of GCs [glucocorticoids] to down-regulate monocyte cytokine release.”12 A likely mechanism is leptin resistance, which, as noted above, is increased under proinflammatory conditions and also in obesity, which would link inflammation with increased adiposity and BMI. However, leptin was not discussed in this paper.12

12. Wirtz et al. Higher body mass index (BMI) is associated with reduced gluco­corticoid inhibition of inflammatory cytokine production following acute psychosocial stress in men. Psychoneuroendocrinology. 33:1102-10 (2008).

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