Hormesis

Hormesis…What doesn’t kill you makes you stronger. At least that is the theory. Hormesis is the paradoxical and potentially beneficial effect of low dose stressors.


In other words, everything can be useful or poisonous. It just depends on the dose. These are the basic theories underlying the hormetic model. How this concept applies to chronic disease is what matters to us and how do we leverage this idea?


Occasional exposure can actually generate an opposite effect compared to constant exposure. In some cases an initial contact with a stressor can also create an adaptive response that can be protective against future exposure. Certain stressors in early life can create resilience later in life, while a lack of stress can create a vulnerability.(1)


I am reminded of the story of the caterpillar’s struggle to emerge from its cocoon. This struggle is the way in which the natural world generates strength and resilience in an organism.


So let’s look at a few common human stressors and the biphasic curve that applies to them. One of the first examples of hormesis is radiation hormesis. In this scenario high-dose radiation promotes mutagenesis and carcinogenesis, but a low-dose ionizing radiation like X-ray for example has been shown to actually suppress tumor development.(2) Even chemical carcinogens like DTT a low doses can protect against DNA damage at higher dose subsequent exposures.(3)


Cigarette smoke, exercise and fasting are also all common examples of hormesis in humans. Cigarette smoke causes lung disease. That’s not really up for debate. However, nicotine actually has a neuroprotective effect. It exerts its activity through nicotinic acetylcholine receptors that can modulate neuroinflammation.(4) So believe it or not, epidemiological evidence shows a correlation between smoking and a lower incidence of Parkinson’s disease.(5)


Exercise is one of my favorite hormetic stressors. In healthy individuals moderate exercise both reduces the level of pro-inflammatory cytokines while also stimulating the production of anti-inflammatory cytokines. However intense exercise has the exact opposite effect. In fact exercise induced stress can even create shifts in the gut microbiome.(6)


A side note on inflammation. We always hear that inflammation is bad. I’m hoping that the theme of this article is teaching you that nature doesn’t waste energy and nothing is all bad or all good. Low levels of inflammation seem to be required for the recovery of exercise induced muscle mircotrauma. Post exercise treatments with NSAIDs caused a suppression of muscle satellite cell proliferation and a reduction in muscle protein synthesis.(7) So you see not all inflammation is bad.


Fasting is another one of my favorite hermetic examples. Intermittent fasting where food is restricted to an 8-12hr window can have beneficial effects on insulin sensitivity, lipid profiles and glucose tolerance. In mouse models of cancer alternate day fasting can inhibit the development of acute lymphoblastic leukemia.(8) However long bouts of fasting, AKA starvation, (2 weeks in rat models) can increase muscle wasting, stress-related corticosterone levels and impair cardiac output.(9)


Let me lastly touch on reactive oxygen species(ROS). Oxidative stress which is essentially high levels of ROS can cause damage to proteins, DNA and other components of a cell. The body has endogenous antioxidant defense systems in place to protect us because runaway, unrepaired ROS damage can be catastrophic for the cell and ultimately us! And yet antioxidant supplementation with things like vitamin E and C do not seem to prolong human lifespans and in some cases seem to lead to more disease and cancers.(10) It seems possible that low level ROS can function as a signaling molecule to initiate necessary biological processes to upregulate and therefore repair damage before it accumulates to a detrimental level. Making ROS not all bad.


This idea of hormesis is really just another way in which modern humans seek to explain biological phenomenon that have been developed over time for species survival. It seems counterintuitive at first until you zoom out and understand that the biological imperative of all organisms is in fact survival in a less than perfect environment. The Goldilocks zone is likely where we want to be to gain the benefits of stress and use it to our advantage. So being in tune with your body, understanding your allostatic load and working within that scope is your key to success.


References

1. Li X, Yang T, Sun Z. Hormesis in Health and Chronic Diseases. Trends Endocrinol Metab. 2019;30(12):944-958. doi:10.1016/j.tem.2019.08.007

2. Vaiserman A, Koliada A, Zabuga O, Socol Y. Health Impacts of Low-Dose Ionizing Radiation: Current Scientific Debates and Regulatory Issues. Dose Response. 2018;16(3):1559325818796331. Published 2018 Sep 19. doi:10.1177/1559325818796331

3. Fukushima S, Kinoshita A, Puatanachokchai R, Kushida M, Wanibuchi H, Morimura K. Hormesis and dose-response-mediated mechanisms in carcinogenesis: evidence for a threshold in carcinogenicity of non-genotoxic carcinogens. Carcinogenesis. 2005;26(11):1835-1845. doi:10.1093/carcin/bgi160

4. Quik M, Perez XA, Bordia T. Nicotine as a potential neuroprotective agent for Parkinson's disease. Mov Disord. 2012;27(8):947-957. doi:10.1002/mds.25028

5. Quik M. Smoking, nicotine and Parkinson's disease. Trends Neurosci. 2004;27(9):561-568. doi:10.1016/j.tins.2004.06.008

6. Clark A, Mach N. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes. J Int Soc Sports Nutr. 2016;13:43. Published 2016 Nov 24. doi:10.1186/s12970-016-0155-6

7. Peake JM, Markworth JF, Nosaka K, Raastad T, Wadley GD, Coffey VG. Modulating exercise-induced hormesis: Does less equal more?. J Appl Physiol (1985). 2015;119(3):172-189. doi:10.1152/japplphysiol.01055.2014

8. Lu Z, Xie J, Wu G, et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med. 2017;23(1):79-90. doi:10.1038/nm.4252

9. Lee SR, Ko TH, Kim HK, et al. Influence of starvation on heart contractility and corticosterone level in rats. Pflugers Arch. 2015;467(11):2351-2360. doi:10.1007/s00424-015-1701-9

10. Hercberg S, Kesse-Guyot E, Druesne-Pecollo N, et al. Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. Int J Cancer. 2010;127(8):1875-1881. doi:10.1002/ijc.25201

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