Hormesis || Hormesis: What it is and Why it Matters

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  • Hormesis: What It Is and Why It Matters

    Mark P. Mattson and Edward J. Calabrese

    Abstract Hormesis describes any process in which a cell, organism, or group oforganisms exhibits a biphasic response to exposure to increasing amounts of a sub-stance or condition (e.g., chemical, sensory stimulus, or metabolic stress); typically,low-dose exposures elicit a stimulatory or beneficial response, whereas high dosescause inhibition or toxicity. The biphasic dose-response signature of hormesis is acommon result of experiments in the field of toxicology, but the low-dose data havebeen largely ignored, and the prevailing view is that it is important to reduce levelsof toxins as much as possible. However, in many cases, the toxins actually haveessential or beneficial effects in low amounts. Prominent examples of such beneficialtoxins are trace metals such as selenium, chromium, and zinc. Fundamental inter-and intracellular signals also exhibit hormetic dose responses, including hormones,neurotransmitters, growth factors, calcium, and protein kinases. Moreover, everydayhealth-promoting lifestyle factors, including exercise and dietary energy restriction,act, at least in part, through hormetic mechanisms involving activation of adaptivecellular stress response pathways (ACSRPs). ACSRPs typically involve receptorscoupled to kinases and activation of transcription factors that induce the expressionof cytoprotective proteins such as antioxidant enzymes, protein chaperones, andgrowth factors. The recognition and experimental utilization of hormesis is lead-ing to novel approaches for preventing and treating a range of diseases, includingcancers, cardiovascular disease, and neurodegenerative disorders.

    Keywords Adaptation Biphasic Environmental protection Evolution Preconditioning Stress Toxins

    M.P. Mattson (B)Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program,Baltimore, MD 21224, USAe-mail: mattsonm@grc.nia.nih.gov

    1M.P. Mattson, E.J. Calabrese, Hormesis, DOI 10.1007/978-1-60761-495-1_1,C Springer Science+Business Media, LLC 2010

  • 2 M.P. Mattson and E.J. Calabrese

    Hormesis Is a Fundamental Feature of Biological Systems

    A defining characteristic of hormesis is a biphasic dose-response curve, with ben-eficial or stimulatory effects at low doses and adverse or inhibitory effects athigh doses. Biphasic responses to increasing doses of chemicals have been widelyreported for a range of agents (mercury, arsenic, pesticides, radiation, etc.) andorganisms (bacteria, worms, flies, rodent, humans, and many others). In fact, toxinsmore often exhibit a hormetic dose response (low-dose stimulation or beneficialeffect, and high-dose inhibition or toxicity) than they do a linear dose response(toxicity proportional to the level of exposure). Calabrese has cataloged thousandsof examples of hormetic dose responses in the fields of biology, toxicology, andmedicine (Calabrese and Blain, 2005; Cook and Calabrese, 2006; and see the chap-ter in this book, Hormesis: Once Marginalized, Evidence Now Supports Hormesisas the Most Fundamental Dose Response). Examples of hormetic dose responseinclude the following: low amounts of cadmium improve the reproductive capac-ity of snails, whereas high doses are lethal (Lefcort et al., 2008); low doses ofradiation increase the growth rate of plants and can increase the lifespan of mice(Luckey, 1999); and chemicals that can cause cancer when consumed in highamounts can actually inhibit cancer cell growth when taken in low doses (Calabrese,2005).

    Paracelsus recognized four centuries ago that drugs are actually toxins that havebeneficial effects at low doses (Fig. 1). The biphasic dose-response relation is notlimited to exposures to environmental agents and drugs, however; it permeates biol-ogy, physiology, and the daily experiences of all organisms. Well-known categoriesof agents that exert biphasic effects on human health are minerals and vitamins.Selenium, a trace element obtained in the diet, is essential for health because it isnecessary for the proper function of at least 30 selenoproteins (Dodig and Cepelak,2004). However, high levels of selenium are toxic and can even cause death. VitaminD is critical for the growth and health of bones and for wound healing, among otherprocesses, but excessive intake of vitamin D can cause hypercalcemia and associatedpathologies in the kidneys and other organs (Vieth, 2007). Vitamin A is necessaryfor proper development of multiple organs and for maintenance of the health of theeye and other tissues in the adult; however, excessive intake of vitamin A can causeliver damage, may promote osteoporosis, and may also adversely affect the cardio-vascular system (Penniston and Tunumihardjo, 2006). Iron is essential for red bloodcell health and also serves important regulatory functions in other cell types, butexcessive iron intake can cause oxidative damage to tissues (Van Gossum and Neve,1998).

    Another example of hormesis centers on glutamate, an amino acid neurotrans-mitter that is critical for the transfer of electrical activity from one nerve cell toanother in the brain. The relatively low amounts of glutamate released at the synapsewhen the brain is engaged in activities such as reading and writing activate adaptivecellular stress response pathways (ACSRPs) that benefit the nerve cells, promot-ing their growth and survival (Fig. 2). However, excessive amounts of glutamatecan damage and kill nerve cells in a process called excitotoxicity that occurs during

  • Hormesis 3

    All things are poison and nothing is without poison, only the dose permits something not to be poisonous -Paracelsus

    Fig. 1 Paracelsus was aSwiss-born alchemist andphysician who pioneered theuse of chemicals and mineralsin medicine. He recognizedthe importance of the dose ofchemicals in determiningwhether they are therapeuticor toxic, and essentiallypredicted the prevalence ofthe biphasic nature of thedose-response curve astypical of all medicines





    Glutamate Dose

    Adaptive Response


    Carbon Monoxide (CO) Level


    in F



    CO producedwithin the brain Inhaled CO





    Fig. 2 Hormetic dose responses of nerve cells to the neurotransmitter glutamate and the gaseousmessenger carbon monoxide (CO). Low to medium doses of glutamate mediate synaptic trans-mission and plasticity, learning and memory, and other behaviors. High amounts of glutamate cancause excessive calcium influx into neurons, resulting in neuronal damage and death; this occursin epilepsy and stroke and may also occur in Alzheimers, Parkinsons, and Huntingtons diseases.Carbon monoxide is produced by cells in the brain and plays important roles in signaling withinand between neurons and in blood vessel cells. Inhaled CO can result in levels in blood and tissuesthat, if sustained, can cause asphyxia and death

  • 4 M.P. Mattson and E.J. Calabrese

    severe epileptic seizures, as well as in Alzheimers and Parkinsons diseases. Carbonmonoxide also exerts hormetic effects on cells and organisms. Carbon monoxideis widely known as a toxic gas present in the exhaust of combustion engines, butcarbon monoxide also is produced by cells in the body, where it serves importantsignaling functions promoting blood vessel relaxation and communication betweennerve cells (Kaczorowski and Zuckerbraun, 2007; Fig. 2).

    Another class of hormetic molecules in cells comprises oxygen free radicals,notorious for their ability to damage DNA, proteins, and membrane lipids. Free rad-icals are believed to play major roles in the aging process and in various diseases,including cardiovascular and inflammatory diseases, cancers, and neurodegenera-tive disorders (Giacosa and Filiberti, 1996; Mattson and Liu, 2002). Recent researchhas clearly shown, however, that low amounts of some free radicals serve importantfunctions in cells that involve the activation of ACSRPs (Ridnour et al., 2006; Valkoet al., 2007. One example is superoxide anion radical (O2.), which is produced bythe activity of the mitochondrial electron transport chain as a byproduct of oxidativephosphorylation (the process that produces adenosine triphosphate [ATP], the majorcellular energy substrate). Superoxide is normally detoxified by the actions ofsuperoxide dismutases, which convert O2. to hydrogen peroxide; hydrogen perox-ide is then converted to water by the actions of catalase and glutathione peroxidase.Thus, levels of O2. are normally kept low. However, high amounts of O2. canoccur in certain conditions (e.g., with reductions in levels of antioxidant enzymes)and can damage cells by conversion to more highly reactive free radicals, includ-ing hydroxyl radical and (by interaction with nitric oxide) peroxynitrite (Mattson,2004). In response to physiological signals such as neurotransmitters, cytokines,and calcium fluxes, O2. is produced and mediates the activation of kinases and tran-scription factors (Camello-Almaraz et al., 2006; Kishida and Klann, 2007). Reactiveoxygen species such as O2. also mediate responses of immune cells. For exam-ple, in response to exogenous (allergens) and endogenous (molecules released fromdamaged cells) factors, mast cells generate O2. and other free radicals that inducedegranulation, leukotriene secretion, and cytokine production (Suzuki et al., 2005).Free radicals also play important roles in signaling processes that regulate vascularendothelial cell function and blood pressure (Wolin, 1996). Mitochondria normallyproduce O2. in bursts or flashes (Wang et al., 2008), and one possible func-tion of such O2. flashes is to activate adaptive cellular stress response signalingpathways.

    Hormesis Is a Manifestation of a Fundamental