4 The Fundamental Role of Hormesis in Evolution

The Fundamental Role of Hormesis in Evolution Mark P. Mattson Abstract Hormesis can be considered a major mechanism underlying Darwin’s and Wallace’s theory of evolution by natural selection. The ability of organ- isms to respond adaptively to low levels of exposure to environmental hazards in a manner that increases their resistance to more severe similar or different hazards is fundamental to the evolutionary process. The organisms that survive and reproduce are those best able to tolerate or avoid environmental hazards while competing successfully for limited energy (food) resources. Therefore many of the genes selected for their survival value encode proteins that protect cells against stress (heat-shock proteins, antioxidant enzymes, antiapoptotic proteins, etc.) or that mediate behavioral responses to environmental stressors (neurotrans- mitters, hormones, muscle cell growth factors, etc.). Examples of environmental conditions that can, at subtoxic levels, activate hormetic responses and exam- ples of the genes and cellular and molecular pathways that mediate such adap- tive stress responses are provided to illustrate how hormesis mediates natural selection. Keywords Competition · Darwin · Ecology · Natural selection · Selenium · Stress resistance · Survival Introduction Life on Earth began in a hostile environment of limited (organic) resources and exposure to radiation, toxic metals, and other hazards (Williams, 2007). Today organisms also face many challenges that vary greatly, depending on the species M.P. Mattson (B) Laboratory of Neurosciences, National Institutes of Health, National Institute on Aging, Baltimore, MD 21224, USA e-mail: mattsonm@grc.nia.nih.gov 57M.P. Mattson, E.J. Calabrese, Hormesis, DOI 10.1007/978-1-60761-495-1_3, C© Springer Science+Business Media, LLC 2010 58 M.P. Mattson and its location and population density. The survival of the individual and its abil- ity to pass genes on to the next generation depends on phenotypic traits that allow it to avoid or resist environmental stressors and compete successfully for limited resources (food, shelter, mates, etc.). Simple organisms such as bacteria and proto- zoa may die from exposures to toxic metals, dehydration, and excessively high or low temperatures. Evolutionary adaptations that guard against such hazards include toxin-impermeable membranes and cell motility mechanisms. In humans, the most highly evolved species, the major causes of death prior to reproductive age are infectious diseases, starvation, accidents, and homicide. Sophisticated innate and humoral immune systems, agricultural methods, seat belts, and police forces are examples of evolutionary adaptations that improve the chances of survival and reproduction in humans. In this chapter I describe evidence and a rationale for a hormesis-centric view of evolution. The evolution of organic molecules, cells, multicellular organisms, and popu- lations of organisms is characterized by an increase in complexity. The purposes of these complex biological systems are, in large part, to protect the cells and organisms against environmental stressors. Hormesis is any process in which expo- sure of a cell or organism to a sublethal dose of a stressor (chemical, thermal, energetic, psychological, etc.) activates adaptive stress response pathways that pro- tect the cell/organism against more severe stresses of the same or different type (Fig. 1). In some situations hormesis pathways may be activated but ultimately fail to protect the cell or organism because of the severity and/or duration of the stress. In other situations (e.g., aging and disease states) the hormetic signaling pathways may be compromised. There are innumerable hormetic mechanisms that have evolved. For example, the development of lipid membranes with ion channels and pumps allowed cells to tightly control the intracellular ion concentrations and prevent toxic overloading with Na+ and Ca2+ (Gotoh et al., 2007; Thomas and Rano, 2007). The evolution of proteins with specific binding sites for metals such as iron, copper, Hormetic Zone Toxicity Zone Evolutionary Time Early Intermediate Recent Adaptation to Higher Amounts of a Toxin or Other Environmental Stressor Fig. 1 The hormetic dose zone for exposures to toxins shifts to higher levels of exposures as the result of the evolution of novel mechanisms for toxin resistance, thus allowing organisms to occupy more stressful environments. The Fundamental Role of Hormesis in Evolution 59 selenium, and zinc provided cells with a means of chelating these potentially toxic metals and also conferred new functional properties to the metal-binding proteins (copper/zinc superoxide dismutase, selenoproteins, ferritin, hemoglobin, and many others) (Crichton and Pierre, 2001). The evolution of nervous systems allowed organisms to respond to environmental hazards by activating simple (reflexive withdrawal from a noxious agent) or complex (inventing seat belts and airbags to reduce the chances of injury and death in an auto- mobile accident) behavioral responses. In mammals the “flight-or-fight” response includes the robust activation of neuroendocrine signaling pathways involving the brain, hypothalamus, pituitary gland, and adrenal gland, as well as the autonomic nervous system (Kopin, 1995). The immediate result of this adaptive stress response is the mobilization of energy reserves in the liver for use by the musculoskeletal and cardiovascular systems. Two key hormones that mediate the latter physiological changes are cortisol and epinephrine, which are produced by cells in the adrenal gland. These changes maximize the chance that the animal evades or withstands the challenge (predator, forest fire, etc.). However, sustained activation of the neu- roendocrine stress response (as may occur under conditions of chronic psychosocial stress) can result in impaired hormesis and dysfunction and deterioration of tis- sues, resulting in pathological conditions such as cardiovascular disease, diabetes, osteoporosis, and psychiatric disorders (Chrousos, 2000). This example highlights the fact that both the magnitude of a stressor and its duration determine whether the organism is successful in responding to the stressor; a recovery period is often required for a hormetic response to be successful. The Biphasic Dose Response and Evolution Hormesis is a process in which there is a biphasic dose response to a natural or experimental perturbation of a cell or organism typified by a low-dose stim- ulatory or beneficial effect and a high-dose inhibitory or toxic effect (Calabrese et al., 2007; Mattson and Calabrese, 2008). The term hormesis is most widely used in the toxicology and biomedical fields, where investigators use it to describe bipha- sic dose responses of cells or organisms to toxins such as heavy metals, pesticides petrochemicals, and so on (Calabrese and Blain, 2005; Calabrese et al., 2007). Meta-analysis of data from research in the fields of toxicology, cancer biology, diet, neuroscience, drug development, and other areas have revealed the widespread existence of biphasic dose responses (Calabrese and Blain, 2005). The response of the cell or organism to the low dose of the toxin typically involves an adaptive compensatory process following an initial disruption in homeostasis. Thus, a short working definition of hormesis is “a process in which exposure to a low dose of a chemical agent or environmental factor that is damaging at higher doses induces an adaptive beneficial effect in the cell or organism.” Several different terms are commonly used to describe specific types of hormetic responses, including “precon- ditioning” and “adaptive stress response” (Calabrese et al., 2007). The prevalence in the literature of hormetic dose responses to environmental toxins has been reviewed comprehensively (Calabrese and Blain, 2005), as have the implications of 60 M.P. Mattson toxin-mediated hormesis for understanding carcinogenesis and its prevention (Calabrese, 2005). The biphasic dose response has rarely been considered as an important aspect of evolution. Nevertheless, Parsons (2001) described hormesis in the context of ecology and evolution. Parsons proposed that “Fitness varies nonlinearly with envi- ronmental variables . . . with maximum fitness at intermediate levels between more stressful extremes,” and that in the case of toxic agents, fitness is maximized at low concentrations. Parsons suggested that organisms inhabit environments for which they have evolved broad biological mechanisms to cope with the various stressors in that environment, so-called “hormetic zones.” At first approximation it would seem reasonable to assume that organisms would survive best in environments where stress levels are low and so the minimum amount of energy is expended in resisting stressors. However, because energy (food) resources are limited, the energy expended in competition for those energy resources may be greater than the energy expended in counteracting stressors in a harsher but less populated area. For exam- ple, the plant prince’s plume (Stanleya pinnata) accumulates high levels of the toxic element selenium, which protects it from caterpillar herbivory. However, an invasive species of diamondback moth (Plutella xylostella) has evolved a mechanism to with- stand the selenium toxicity and thrives on prince’s plume plants containing highly toxic selenium levels (Freeman et al., 2006), thus accessing a food source unavail- able to other insects. Similarly, certain species of proteobacteria exhibit resistance to high levels of selenite, tellurite, and other rare-earth oxides and so can survive in soils where other species die, and so benefit from reduced competition for energy resources in those environments (Moore and Kaplan, 1992). Thus, different species of organisms have evolved to survive and reproduce in particular environments such that essentially all land and aquatic environments on Earth are now inhabited. Plants spread slowly across the landscape through dispersion of seeds and growth of root shoots. By virtue of selection for genes that enhance hormetic pathways, plants can over time inhabit soils and climates with levels of stressors that would have killed their ancestors. Because they are not motile and therefore cannot escape stressors such as heat and cold, drought, or herbivores, a large portion of the genome of plants encodes proteins involved in protecting them against environmen- tal extremes and consumption. For example, rice plants contain more genes than do humans, and many of the rice genes encode proteins that function in adaptive stress response pathways (Cooper et al., 2003). Microarray analyses of gene expression responses to various stressors have revealed conserved subcellular stress response pathways, as well as sets of genes that respond to certain types of stressor and not others (Hoffmann and Willi, 2008). Biphasic dose responses to a range of envi- ronmental factors have been documented in studies (Calabrese and Blain, 2008). The low-dose adaptive responses are likely mediated by evolutionarily conserved hormetic signaling pathways. In my view the future of human evolution is unclear in part because advances in technology have led to a reduction in exposures to challenges that stimulate adaptive cellular stress responses. Such challenges include exercise, dietary energy The Fundamental Role of Hormesis in Evolution 61 restriction, and exposures to hot and cold temperatures. It is now clear that many of the major diseases that result in premature death are caused, in part, by a seden- tary lifestyle combined with overeating. The chapter in this book entitled Couch Potato: The Antithesis of Hormesis elaborates on the downside of avoidance of hormetic challenges to the body and brain. However, at this point in human evolution (Table 1) the reduction in hormetic challenges appears not to be having a negative impact on reproduction, and one would therefore expect that selection for individu- als with superior adaptive stress response mechanisms may not occur. Consequently, the postreproductive health and longevity of humans may actually decrease in the future as deleterious mutations accumulate (Parsons, 2003). The greatest chal- lenges being faced by humans are largely psychological, and, accordingly, there has been an increase in the prevalence of psychiatric problems, including depres- sion and anxiety and bipolar disorders (Kessler et al., 2007). Of interest, emerging evidence suggests that there is a shared neurochemical/neuroendocrine mecha- nism underlying the psychiatric disorders and poor energy metabolism (i.e., insulin resistance and diabetes). The evidence is as follows: (1) depression and anxiety dis- orders, as well as metabolic syndrome and diabetes, are associated with reduced serotonergic signaling and decreased levels of brain-derived neurotrophic factor (BDNF) in the brain (Krabbe et al., 2007); (2) exercise and dietary energy restric- tion increase BDNF levels in the brain and improve glucose regulation (Mattson et al., 2004a; Yamanaka et al., 2008); (3) exercise improves symptoms in patients with depression, anxiety, and bipolar disorders (Barbour et al., 2007); and (4) antidepressants that increase serotonin and BDNF signaling (serotonin reuptake inhibitors) also improve glucose regulation (McIntyre et al., 2006). Thus, the neu- rotransmitter serotonin and the neurotrophic factor BDNF can be considered as key mediators of hormetic responses to exercise and antidepressants. Although increased levels of serotonin and BDNF often have beneficial effects on neurons, excessive activation of serotonin and BDNF receptors can adversely affect the plas- ticity and survival of neurons (McDonald et al., 2002; Capela et al., 2007), consistent with biphasic dose response effects of these two mediators of hormesis. Table 1 Examples of Toxic Substances, and the Adaptations That Cells and Organisms Have Evolved to Cope With or Utilize These Substances Substance Adaptation O2 Electron transport chain, antioxidant enzymes CO2 Respiratory exchange CO Guanylate cyclase, hemoproteins NO Guanylate cyclase Fe2+ Ferritin, transferrin Cu+ Ceruloplasmin Ca2+ Membranes, ion channels, transporters, binding proteins H2S Sulfide dehydrogenase UV radiation Pigments 62 M.P. Mattson Cellular and Molecular Hormetic Mechanisms To avoid extinction, organisms have developed complex mechanisms to cope with the environmental hazards they have encountered. Typically, such hormetic response pathways in cells involve proteins such as ion channels, kinases and deacetylases, and transcription factors that regulate the expression of genes that encode cytopro- tective proteins (Mattson and Cheng, 2006). Examples of such pathways include receptors for the neurotransmitter glutamate in neurons that are coupled to cal- cium influx and activation of the transcription factors CREB and AP1 (Marini et al., 2008); receptors in muscle cells for acetylcholine that are sodium chan- nels that when activated depolarize the plasma membrane, resulting in calcium influx (Booth, 1988); insulin receptors in liver cells coupled to the PI3 kinase–Akt kinase–FOXO transcription factor pathway (Matsumoto et al., 2006); increased pro- duction of reactive oxygen species (superoxide and hydrogen peroxide), resulting in the activation of the transcription factor Nrf-2 (Kang et al., 2005); and a reduction in cellular energy (ATP and NAD+) levels, resulting in the activation of AMP kinase and inhibition of mTOR kinase (Martin and Hall, 2005). These pathways can be affected by behavioral responses involving the nervous system (exercise, neuroen- docrine stress response activation, etc.) (McEwen, 2007), by ingestion or exposure to a noxious chemical (including chemicals in fruits, vegetables, and other plants) (Mattson and Cheng, 2006), or by reduced energy intake (Martin et al., 2006). The genes induced by hormetic stressors include those encoding several cat- egories of stress resistance proteins, including protein chaperones such as the heat-shock proteins, antioxidant enzymes such as superoxide dismutases and glu- tathione peroxidase, and growth factors such as insulin-like growth factors (IGFs) and brain-derived neurotrophic factor and BDNF (Mathers et al., 2004; Mattson et al., 2004 ; Young et al., 2004). Protein chaperones bind to other proteins, thus pre- serving their structure and protecting them against oxidative damage. For example, heat-shock protein (HSP-70) protects neurons against ischemic injury by stabi- lizing and enabling the function of antiapoptotic proteins such as Bcl-2 (Yenari et al., 2005). Other studies have shown that HSP-27 protects cells against oxida- tive stress by increasing glutathione levels and reducing levels of intracellular iron (Arrigo et al., 2005) (Fig. 2). Aerobic exercise results in the activation of mitogen- activated protein (MAP) kinases and the transcription factor NF-κB, which induces the expression of the antioxidant enzyme manganese superoxide dismutase (Kramer and Goodyear, 2007). NF-κB mediates hormetic responses to a variety of insults, including traumatic injury, infections, and oxidative stress (Mattson and Meffert, 2006). An evolutionarily conserved mechanism by which cells under stress warn adjacent cells of worsening conditions involves the production of one or more growth factors by the stressed cells. The growth factors typically activate receptor tyrosine kinases coupled to the PI3 kinase–Akt or MAP kinase pathways, resulting in the activation of transcription factors that induce the expression of cytoprotec- tive proteins. For example, during a stroke, brain cells produce fibroblast growth factor (FGF), IGF-1, and BDNF, all of which act on neurons so as to increase the resistance of the cells to the metabolic and oxidative stress associated with The Fundamental Role of Hormesis in Evolution 63 *Fe2+, Cu+ ETC Ca2+ PN NO SO H2O2 OH H2O2 MnSOD g R tk GF L R NOS Ca2+ calm MLP HNE MBP GSH * * * * * * CBP Mitochondria Nucleus Kinases TFs CREB, NF-kB AP1, FOXO DNA Hormetic Proteins HSPs,AOEs Ph1 and Ph2 enzymes CBPs,MBPs NT H2O Cat GPx Fig. 2 Cells are continuously exposed to endogenous toxins that also serve important physio- logical roles, and so the cells have evolved mechanisms to limit the level of the toxins within a hormetic range of concentrations. Examples of toxic substances (marked with an asterisk) include Fe2+, Cu+, Ca2+, superoxide (SO), hydroxyl radical (OH), nitric oxide (NO), peroxynitrite (PN), and 4-hydroxynonenal (HNE). Hormetic mechanisms include proteins that bind the toxins, such as glutathione (GSH), metal-binding proteins (MBP), and calcium-binding proteins (CBP); antioxi- dant enzymes, such as manganese superoxide dismutase (MnSOD), catalase (Cat), and glutathione peroxidase (GPx); the activation of receptors for neurotransmitters (NT), growth factors (GF), and ligands (L) for G protein–coupled receptors, resulting in the activation of kinases and transcription factors (TFs), which induce the expression of cytoprotective proteins, including heat-shock pro- teins (HSPs), antioxidant enzymes (AOEs), phase 1 (Ph1) and phase 2 (Ph2) enzymes, CBPs, and MBPs. calm, calmodulin the ischemia (Mattson et al., 2002, 2004; Yamanaka et al., 2008); without these growth factors many more nerve cells would die from the stroke (Mattson et al., 2000; Arumugam et al., 2009). Age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases may, in part, result from impaired hormesis signaling mechanisms, including decreased production or activity of neurotrophic factors such as BDNF. The chapter in this book entitled Hormesis and Aging describe how a decrease in “homeodynamic space” (adaptive response capabilities) may be a fundamental aspect of aging.