Friday, January 11, 2013

Establishing the Overarching Implications of this Blog: Health, Disease, Energy Generation, and Refining the Concept of Stress

"what children inherit from their parents is not their longevity per se but rather their frailty that is, a set of susceptibilities and risk factors that alter their chances of death at different ages." - Vaupel 

The term “stress” conjures different meanings for people, even among researchers in the field who continuously study and think about it.  For the purpose of this blog, when I use the term "stress," I am referring to the Selye form of stress: broadly stated, the activation of the HPA axis by a stimulus or stimuli.1,2

But what exactly constitutes a stimulus?  And for that matter, what is a “good” stimulus, and what is a “bad” one?

A stimulus, more specifically a stressor, I suppose, could be conceived of as anything that puts demands on the body requiring an acute increase in energy generation that is attendant to a rise in the physiological factors of adaptation, all for the purpose of preserving the conditions of the body’s “internal milieu,” as the French physiologist Claude Bernard referred to it.3

Later on, the concept described by Bernard, that all adaptive mechanisms work to preserve the conditions of the “internal milieu,” was coined “homeostasis” by the American physiologist, Walter B. Cannon.4

Determining the nature of a stressor—good or bad—depends on two things.  First, the state of the individual: That is, his or her stress load, stage of life, immune status, early life experiences, and nutritional state.  These individual factors are, in turn, influenced by other factors, such as the time of day, season, and degree of light exposure.  And second, the nature of the stressor itself: namely its intensity and duration.

To bring this closer to home, if the demand placed on the body are not too great, and if we can learn from it, then we can deem a stressor as being good.  But we can deem a stressor that overwhelms our body’s capacity to safely respond to it as bad.

Equally important is what stress is not, and I wish I could summarize it as well as Selye did in his book; nonetheless, here are some of the most salient points.5

  • Stress is not something we can avoid, which is why statements like “he’s under stress” are meaningless and redundant.
  • Stressors are not unique in the reactions that they elicit in the body, because all stressors, regardless of the source, stimulate the HPA axis, increase energy demands, and affect the same organs.
  • Stress is not always bad; rather, they can be just as we perceive them to be.  The stress felt before a date and a passionate kiss, or before a performance that “keys” us up, for instance, are productive.

I am of the opinion that stress is the thread that runs through virtually every disease known to civilization.  Because, for the most part, infectious diseases and problems of food availability have been conquered, and considering the myriad of stressors we encounter daily–including ionizing radiation, air pollutants, and chemicals in the food supply–an area of research that deserves more attention is the contribution of each of these environmental stressors on influencing the progression of chronic diseases. 

But then again, what is disease?  And what really differentiates disease from vibrant health?  

First and foremost, we can conceive of disease and health to exist at two ends of the same continuum, with our resiliency to stress informing us of whereabouts we fit on it.  Diseases manifest as a consequence of progressively deteriorating adaptive mechanisms that is due to the damages incurred from pushing through the stresses encountered throughout a lifetime, without the energy reserves or adaptive mechanisms to do so.

These adaptive mechanisms—which are mediated by hormones, neurotransmitters, and cytokines, and thus coordinated by the endocrine, nervous, and immune systems—are life saving in the short-term without a doubt.  It’s just when they fall out of range, or persist in the blood too long, that degenerative processes become set in motion, as the damages incurred from these derangements are cumulative and decrease the body’s resistance to future stressors.  These degenerative processes manifest as, diabetes, hypertension, gastrointestinal ulcer, kidney disease, infertility, cardiovascular disease, and so on.

Chronic stress leads to the excessive secretion of ACTH, cortisol, GH, adrenalin, and glucagon, and this, in turn, results in the following biochemical derangements.

  • The accumulation of fat in places not designed for much of it
  • The influx of water into cells and cellular swelling
  • The preferential oxidation of fat and subsequent decrease in the efficiency of energy generation  
  • Oxidative stress
  • The impaired functioning of the mitochondrial respiratory chain
  • The deposition of calcium salts into soft tissue from the blood, manifesting as atherosclerosis, gallstones, kidney stones

Take for example cortisol, whose blood level is an independent risk factor for cardiovascular disease.6 When secreted in excess or chronically, pathology begins to set in, either from a collapse in our adaptive mechanisms or from direct damages caused by the hormone itself; whichever one comes first. 

Cortisol also leads to the preferential and excessive oxidation of fatty acids that promote the depletion of oxygen (hypoxia), thereby stimulating the proliferation of collagen secreting cells called fibroblasts.7 In a typical positive feedback fashion, this newly laid down collagen further depletes oxygen by increasing the distance that oxygen has to diffuse to reach cells, again, stimulating the proliferation of fibroblasts, collagen secretion, and so on.8 These processes could accelerate atherosclerosis, a major cause of heart attacks and strokes.

Hypoxia also promotes tumor growth, in part by limiting the rate of oxidative metabolism, thereby rendering tumors capable of generating energy only via glycolysis; this results in a high rate of lactate formation, and lactate further impairs oxidative metabolism by shunting pyruvate to the LDH enzyme, and away from the PDH complex.9 PDH is activated by fructose,10 insulin,11 and, by decreasing the expression of HIF, oxygen.12

Energy generation is at the core of our resiliency to stress, so the provision of support should start there.  Free linoleic acid (LA), for instance, can undergo decompose to lipid radicals and these lipid radicals, namely the lipid peroxides, epoxidize other lipids, such as cholesterol, phospholipids, and even other PUFA molecules.  Expoxized lipids uncouple oxidative metabolism, decreasing the efficiency of energy generation, and also binds DNA, promoting the development of tumors.13,14 So when PUFA are present in high amounts in tissues, these toxic effects are inevitable during intense bouts of stress.15

Support should also entail that for the consequences inherent in the excessive exposure to the adaptive hormones.  Aldosterone, for instance, which is secreted by the adrenal cortices and the fat tissue, depletes magnesium and calcium, necessitating the secretion of parathyroid hormone that, in turn, leads to a host of deleterious effects, especially in the cardiovascular system.16,17

The pioneering work of Bernard, Cannon, and Selye has laid down the groundwork for thinking about diseases in a holistic manner.  Selye, in particular, was adept at integrating data, seemingly disparate, into a unified and cohesive picture involving all systems in the body.  Nonetheless, I do think their discoveries are imperfect, as stress is represented by a much more complex picture that firmly incorporates the central role of energy generation.  The ideas introduced herein will be further explored in future posts.


1.       Selye, H. A syndrome produced by diverse nocuous agents. 1936. The Journal of neuropsychiatry and clinical neurosciences 10, 230–1 (1998).
2.       Selye, H. The general adaptation syndrome and the diseases of adaptation. The Journal of clinical endocrinology and metabolism 6, 117–230 (1946).
3.       Bernard, C. An introduction to the study of experimental medicine. 272 (Dover: New York, 1957).
4.       Cannon, W. The Wisdom of the Body. 340 (W.W. Norton & Company, Inc: 1963).
5.       Selye, H. The stress of life. 516 (McGraw-Hill: New York, 1957).
6.       Yamaji, M. et al. Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: the impact of oxidative stress. Circulation. Heart failure 2, 608–15 (2009).
7.       Siggaard-Andersen, O., Ulrich, A. & Gøthgen, I. H. Classes of tissue hypoxia. Acta anaesthesiologica Scandinavica. Supplementum 107, 137–42 (1995).
8.       Sluimer, J. C. & Daemen, M. J. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. The Journal of pathology 218, 7–29 (2009).
9.       Braun, R. D., Lanzen, J. L., Snyder, S. A. & Dewhirst, M. W. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. American journal of physiology. Heart and circulatory physiology 280, H2533–44 (2001).
10.     Park, O. J. et al. Mechanisms of fructose-induced hypertriglyceridaemia in the rat. Activation of hepatic pyruvate dehydrogenase through inhibition of pyruvate dehydrogenase kinase. The Biochemical journal 282 ( Pt 3, 753–7 (1992).
11.     Coore, H. G., Denton, R. M., Martin, B. R. & Randle, P. J. Regulation of adipose tissue pyruvate dehydrogenase by insulin and other hormones. The Biochemical journal 125, 115–27 (1971).
12.     Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell metabolism 3, 187–97 (2006).
13.     Chen, H. J., Gonzalez, F. J., Shou, M. & Chung, F. L. 2,3-epoxy-4-hydroxynonanal, a potential lipid peroxidation product for etheno adduct formation, is not a substrate of human epoxide hydrolase. Carcinogenesis 19, 939–43 (1998).
14.     Nair, J. et al. High dietary omega-6 polyunsaturated fatty acids drastically increase the formation of etheno-DNA base adducts in white blood cells of female subjects. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 6, 597–601 (1997).
15.     Gardner, H. W. Oxygen radical chemistry of polyunsaturated fatty acids. Free radical biology & medicine 7, 65–86 (1989).
16.     Block, G. A. et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. Journal of the American Society of Nephrology : JASN 15, 2208–18 (2004).
17.     Kamycheva, E., Sundsfjord, J. & Jorde, R. Serum parathyroid hormone levels predict coronary heart disease: the Tromsø Study. European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 11, 69–74 (2004).