"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 up different meanings for people, even among researchers in the field who study and think about the concept of stress day in and day out. For the purpose of this blog, when I use the term "stress," I am referring to the Selye form of stress: broadly, the activation of the HPA axis by a stimulus (Selye, 1946, 1998).
But what exactly constitutes a stimulus? And for that matter, what are “good” and “bad” stimuli?
A stimulus, or more specifically, a stressor, is anything that puts demands on the body, requiring an acute increase in energy generation, attendant to the rise in the physiological factors of adaptation, for the purpose of preserving conditions of the “internal milieu”, as the French physiologist, Claude Bernard, referred to it as (Bernard, 1957).
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 (Cannon, 1963).
Determining the nature of a stressor – good or bad – depends on two things. For one, the state of the individual, that is his or her stress load, stage of life, immune system 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 light exposure. And two, the stressor itself, namely its intensity and duration.
Nonetheless, if demands placed on the body are not too great, and if we can learn from it, we can conceive a stressor that fits this description to be “good.” Conversely, we can conceive a stressor that places demands on the body that are too great – such that it overwhelms the body’s capacity to safely deal with it – to be “bad.”
Equally important, in the interest of refining its definition, is what stress is not (Selye, 1957).
- For one, stress is not something we can avoid (This is why statements like “he’s under stress” are meaningless and redundant.)
- Two, 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.
- And three, stress is not always “bad”; rather, they can be just as we perceive them (e.g., the stress felt before a date or a passionate kiss, for instance, is productive.)
Stress is the thread that runs through virtually every disease known to civilization. Because, for the most part, infectious diseases and problems in food availability have been conquered, and the myriad of stressors we encounter daily nowadays – including from 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 impacting the progression of diseases.
But then again, what is disease? And what separates disease from vibrant health?
Foremost, we can conceive 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, which is due to the damages incurred, from pushing through the stresses encountered in one's lifetime, without the energy reserves or adaptive mechanisms to do so.
These adaptive mechanisms, mediated by hormones, neurotransmitters, and cytokines (and thus, coordinated by the endocrine, nervous, and immune systems) are life saving in the short-term. It’s when they fall out of range, or persist in the blood too long, that degenerative processes get 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, etc.
Biochemical derangements – brought about by stress resulting in an excess secretion of ACTH, cortisol, growth hormone, adrenalin, and glucagon – that underlie these degenerative processes entail:
- Lipid accumulation in tissues of organs not designed for it.
- The influx of water into cells and subsequent swelling.
- Preferential fat oxidation and decrease in energy generation.
- Oxidative stress (i.e., free radicals are produced in excess of the body’s anti-oxidizing potential).
- Impaired functioning of the mitochondrial respiratory chain apparatuses.
- The deposition of calcium salts into tissues from the blood, manifesting as atherosclerosis, tuberculosis, gallstones, and kidney stones.
Take for example, cortisol, whose blood concentrations are independent risk factors for cardiovascular disease (Yamaji et al., 2009). When secreted in excess or chronically, pathology sets in, either from a collapse in adaptive mechanisms or from direct damages caused by cortisol itself – whichever one comes first.
Discussed previously on this blog, cortisol leads to excessive fat oxidation, which depletes oxygen (hypoxia), and consequently, stimulates the proliferation of collagen secreting cells called “fibroblasts” (Siggaard-Andersen, Ulrich, & Gøthgen, 1995). In a typical positive feedback fashion, the newly laid down collagen further depletes oxygen by increasing the distance through which oxygen has to diffuse to reach cells, again, stimulating the proliferation of fibroblasts, collagen secretion, and so on (Sluimer & Daemen, 2009). These processes accelerate atherosclerosis – a major cause of heart attacks and strokes.
Hypoxia also promotes tumor growth, partly by limiting the rate of oxidative metabolism – rendering tumors capable of only generating energy via glycolysis, resulting in a high rate of lactate formation; lactate further impairs oxidative metabolism by favoring the shunting of pyruvate to LDH, rather than PDH (Braun, Lanzen, Snyder, & Dewhirst, 2001). PDH is activated by fructose(Park et al., 1992), insulin (Coore, Denton, Martin, & Randle, 1971), and, by decreasing the expression of HIF, oxygen(Papandreou, Cairns, Fontana, Lim, & Denko, 2006).
Energy generation is at the core of our resiliency to stress, so the provision of support should start there. For instance, referenced previously on this blog, liberated PUFA undergo epoxidation, and the resulting products thereafter can uncouple oxidative metabolism, decreasing energy generation (Also, epoxidized PUFA can bind DNA, initiating tumor development [Chen, Gonzalez, Shou, & Chung, 1998; Nair et al., 1997].) When PUFA are present in tissues in high concentrations, this toxic effect on energy generation is inevitable during stress (Gardner, 1989). Support includes rigorously excluding PUFA from the diet.
Support also entails that for sequelae resulting from excessive exposure to the adaptive hormones. For instance, aldosterone – secreted by the adrenal cortex and fat tissue – depletes magnesium and calcium, necessitating the secretion of parathyroid hormone (PTH), and PTH itself, in turn leads to a host of adverse consequences, especially in the cardiovascular system (Block et al., 2004; Kamycheva, Sundsfjord, & Jorde, 2004). Extra calcium and magnesium should, at the very least, be supplied.
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, their discoveries are imperfect, as stress is represented by a much more complex picture that firmly incorporates the central role of energy generation (This will be the topic of a future post.)
References
Bernard, C. (1957). An introduction to the study of experimental medicine (p. 272). New York: Dover.
Block, G. A., Klassen, P. S., Lazarus, J. M., Ofsthun, N., Lowrie, E. G., & Chertow, G. M. (2004). Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. Journal of the American Society of Nephrology : JASN, 15(8), 2208–18. doi:10.1097/01.ASN.0000133041.27682.A2
Braun, R. D., Lanzen, J. L., Snyder, S. A., & Dewhirst, M. W. (2001). Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. American journal of physiology. Heart and circulatory physiology, 280(6), H2533–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11356608
Cannon, W. (1963). The Wisdom of the Body (p. 340). W.W. Norton & Company, Inc.
Chen, H. J., Gonzalez, F. J., Shou, M., & Chung, F. L. (1998). 2,3-epoxy-4-hydroxynonanal, a potential lipid peroxidation product for etheno adduct formation, is not a substrate of human epoxide hydrolase. Carcinogenesis, 19(5), 939–43. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9635886
Coore, H. G., Denton, R. M., Martin, B. R., & Randle, P. J. (1971). Regulation of adipose tissue pyruvate dehydrogenase by insulin and other hormones. The Biochemical journal, 125(1), 115–27. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1178031&tool=pmcentrez&rendertype=abstract
Gardner, H. W. (1989). Oxygen radical chemistry of polyunsaturated fatty acids. Free radical biology & medicine, 7(1), 65–86. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2666279
Kamycheva, E., Sundsfjord, J., & Jorde, R. (2004). 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(1), 69–74. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15167209
Nair, J., Vaca, C. E., Velic, I., Mutanen, M., Valsta, L. M., & Bartsch, H. (1997). 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(8), 597–601. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9264272
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell metabolism, 3(3), 187–97. doi:10.1016/j.cmet.2006.01.012
Park, O. J., Cesar, D., Faix, D., Wu, K., Shackleton, C. H., & Hellerstein, M. K. (1992). 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. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1130852&tool=pmcentrez&rendertype=abstract
Selye, H. (1946). The general adaptation syndrome and the diseases of adaptation. The Journal of clinical endocrinology and metabolism, 6, 117–230. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21025115
Selye, H. (1957). The stress of life (2nd ed., p. 516). New York: McGraw-Hill.
Selye, H. (1998). A syndrome produced by diverse nocuous agents. 1936. The Journal of neuropsychiatry and clinical neurosciences, 10(2), 230–1. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9722327
Siggaard-Andersen, O., Ulrich, A., & Gøthgen, I. H. (1995). Classes of tissue hypoxia. Acta anaesthesiologica Scandinavica. Supplementum, 107, 137–42. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8599267
Sluimer, J. C., & Daemen, M. J. (2009). Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. The Journal of pathology, 218(1), 7–29. doi:10.1002/path.2518
Yamaji, M., Tsutamoto, T., Kawahara, C., Nishiyama, K., Yamamoto, T., Fujii, M., & Horie, M. (2009). Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: the impact of oxidative stress. Circulation. Heart failure, 2(6), 608–15. doi:10.1161/CIRCHEARTFAILURE.109.868513