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1 Q2 Review 2 3 Adaptive homeostasis 4 5 Q1 Kelvin J.A. Davies a,b,*

6 a Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA 7 Q5 90089-0191, USA 8 b Division of Molecular and Computational Biology, Department of Biological Sciences, Dornsife College of Letters, Arts, & Sciences, The Uni- 9 versity of Southern California, Los Angeles, CA 90089-0191, USA 10 11 12 ARTICLE INFO ABSTRACT 13 1514 Article history: Homeostasis is a central pillar of modern Physiology. The term homeostasis was invented 1716 Received 15 April 2016 by Walter Bradford Cannon in an attempt to extend and codify the principle of ‘milieu 1918 Accepted 15 April 2016 intérieur,’ or a constant interior bodily environment, that had previously been postulated 20 Available online 21 by Claude Bernard. Clearly, ‘milieu intérieur’ and homeostasis have served us well for over 2322 a century. Nevertheless, research on signal transduction systems that regulate gene ex- 2524 Keywords: pression, or that cause biochemical alterations to existing enzymes, in response to external 26 Homeostasis 27 and internal stimuli, makes it clear that biological systems are continuously making short- 28 Adaptation 3029 Stress term adaptations both to set-points, and to the range of ‘normal’ capacity. These transient 3231 Hormesis adaptations typically occur in response to relatively mild changes in conditions, to pro- 3433 Nrf2 grams of exercise training, or to sub-toxic, non-damaging levels of chemical agents; thus, 3635 Aging the terms hormesis, heterostasis, and allostasis are not accurate descriptors. Therefore, an 37 operational adjustment to our understanding of homeostasis suggests that the modiﬁed 38 term, Adaptive Homeostasis, may be useful especially in studies of stress, toxicology, disease, 39 and aging. Adaptive Homeostasis may be deﬁned as follows: ‘The transient expansion or 40 contraction of the homeostatic range in response to exposure to sub-toxic, non-damaging, 41 signaling molecules or events, or the removal or cessation of such molecules or events.’ 42 © 2016 Published by Elsevier Ltd. 43

44 Contents 45 46 1. Introduction to homeostasis ...... 1 47 2. The importance of stress ...... 2 48 3. Heterostasis and allostasis ...... 3 49 4. Hormesis ...... 4 50 5. Adaptive homeostasis ...... 4 51 6. Summary and conclusions ...... 5 52 Acknowledgements ...... 6 53 Uncited references ...... 6 54 References ...... 6 55 56 57 58 Q3 Q4 * Leonard Davis School of Gerontology of the Ethel Percy Andrus 1. Introduction to homeostasis Q6 64 59 Gerontology Center and Division of Molecular and Computational Biology, 65 60 Department of Biological Sciences, Dornsife College of Letters, Arts, & The concept of milieu intérieur, or a constant interior 66 61 Sciences, The University of Southern California, Los Angeles, CA 90089-0191, 62 USA. bodily environment, was developed by the celebrated French 67 63 E-mail address: [email protected]. physiologist Claude Bernard in 1865 (Bernard, 1865). The 68

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69 word ‘homeostasis’ was coined by the Harvard Physiolo- 70 gist, Walter Bradford Cannon in 1926 to describe and extend 71 Bernard’s milieu intérieur concept (Cannon, 1926), and popu- 72 larized (in 1932) in his highly successful and persuasive book, 73 The Wisdom of the Body (Cannon, 1932). Cannon com- 74 bined two words from Ancient Greek ο μος (hómos, 75 ”similar”) + ιστημι (histe¯mi, ”standing still”)/stasis (from 76 στα´σις) into a Modern Latin form to invent his term 77 homeostasis. 78 Cannon wrote, “The constant conditions which are main- 79 tained in the body might be termed equilibria. That word, 80 however, has come to have fairly exact meaning as applied 81 to relatively simple physico-chemical states, in closed 82 systems, where known forces are balanced. The coordi- 83 nated physiological processes which maintain most of the 84 steady states in the organism are so complex and so pecu- 85 liar to living beings – involving, as they may, the brain and 86 nerves, the heart, lungs, kidneys and spleen, all working co- 87 operatively – that I have suggested a special designation for 88 these states, homeostasis. The word does not imply some- 89 thing set and immobile, a stagnation. It means a condition Fig. 1. Walter Bradford Cannon (1871–1945). The Harvard Physiologist who Q12 130 coined the term Homeostasis in 1926 to describe and extend Bernard’s 131 90 – a condition which may vary, but which is relatively milieu intérieur concept (Cannon, 1926). Homeostasis was subsequently 132 91 constant.” popularized (in 1932) in Cannon’s highly influential book, The Wisdom of 133 92 Claude Bernard (July 12, 1813–February 10, 1878), who the Body (Cannon, 1932). Image attribution: https://upload.wikimedia.org/ 134 93 is considered by many to have been the “father” of modern wikipedia/commons/7/78/Walter_Bradford_Cannon_1934.jp 135 94 experimental physiology, is quoted as having said that, “The 136 95 laboratory is the temple of the science of medicine.”(Schafer, 96 2009). Working at a time when cells were just beginning 3 The regulating system that determines the homeo- 137 97 to be thought of as the basic structural unit of tissue and static state consists of a number of cooperating 138 98 organ anatomy, Bernard was able to add an entirely new level mechanisms acting simultaneously or successively. 139 99 of functional integration. Bernard concluded that, “The con- 4 Homeostasis does not occur by chance, but is the result 140 100 stancy of the internal environment is the condition for free and of organized self-government (Fig. 1). 141 101 independent life: the mechanism that makes it possible is that 142 102 which assured the maintenance, within the internal environ- According to Arthur C. Guyton’s immensely influential 143 103 ment, of all the conditions necessary for the life of the elements.” Textbook of Medical Physiology (Guyton, 1991), “The term ho- 144 104 (Bernard, 1974a, 1974b; Gross, 1998). An important biog- meostasis is used by physiologists to mean, maintenance of 145 105 raphy of Claude Bernard has been written by Charles Gross nearly constant conditions in the internal environment.” 146 106 (Gross, 1998). The basic idea of homeostasis is shown in Fig. 2 below. 147 107 Prior to gaining his medical degree in 1900, Walter The Y axis of Fig. 2 can be any biological/physiological func- 148 108 Cannon (October 19, 1871–October 1, 1945) was a student tion, such as blood pressure, heart rate, core temperature, 149 109 of Physiologist Henry Pickering Bowditch, who became Dean blood glucose, NAD+/NADH and NADP+/NADPH ratios, su- 150 110 of Harvard’s Medical School. Bowditch, in turn, had studied peroxide dismutase and glutathione peroxidase levels and 151 111 in Paris with Claude Bernard in the late 1860s, after gradu- activities, Proteasome and Lon levels and activities, or the 152 112 ating from Harvard College. It is clearly no accident that capacity and effectiveness of DNA repair systems. The X axis 153 113 Cannon, who in 1906 became Higginson Professor and chair is calibrated by time, whose units can be seconds, minutes, 154 114 of the department of physiology at Harvard Medical School, hours, days, weeks, or even years (if one considers aging). 155 115 went on to further clarify and classify Claude Bernard’s The classical homeostasis graph of Fig. 2 reveals that while 156 116 concept of milieu intérieur, presumably passed on via there is a mean value for any physiological attribute, we ac- 157 117 Bowditch, into his own terminology of Homeostasis. No tually spend most of our time away from that mean, 158 118 stranger to the concept of fluid metabolic states, Cannon had oscillating between a minimum ‘normal’ and a maximum 159 119 previously (in 1915) coined the term Fight or Flight to de- ‘normal’ value. The span from low normal to high normal 160 120 scribe an animal’s response to threats (Cannon, 1915). is then considered the normal physiological or homeo- 161 121 In The Wisdom of the Body (Cannon, 1932), Cannon listed static range (Fig. 3). 162 122 four core concepts that defined his idea of homeostasis: 163 123 2. The importance of stress 164 124 1 Constancy in an open system, such as our bodies rep- 165 125 resent, requires mechanisms that act to maintain this It is, of course, many years since Bernard and Cannon 166 126 constancy. made their important contributions, and a great deal has 167 127 2 Steady-state conditions require that any tendency toward changed in our basic appreciation of how living organ- 168 128 change automatically meets with factors that resist isms function. When one considers, for example, that Watson 169 129 change. and Crick (1953) published their three-dimensional 170

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in 1979, Selye and Arthur Antille started the Hans Selye 201 Foundation. Behavioral Physiologists define stress as how 202 the body reacts to a stressor, real or imagined, a stimulus 203 that causes stress. Acute stressors affect an organism in the 204 short term while chronic stressors exert their effects over 205 the longer term. General Adaptation Syndrome (GAS), de- 206 veloped by Hans Selye (Selye, 1956), is a profile of how 207 organisms respond to stress; GAS is characterized by three 208 phases: a nonspecific mobilization phase, which pro- 209 motes sympathetic nervous system activity; a resistance 210 phase, during which the organism makes efforts to cope with 211 the threat; and an exhaustion phase, which occurs if the or- 212 ganism fails to overcome the threat and depletes its 213 physiological resources. 214 Clearly, Selye was focusing on how the nervous system 215 coordinates many behavioral and physiological responses 216 to stress, often through the use of hormones (Timiras, 2004). 217 In fact, this nervous system and hormonal approach to the 218 coordination of homeostasis was already part of Walter Can- 219 non’s thinking when he proposed adrenaline as the common 220 171 Fig. 2. Claude Bernard (1813–1878). The celebrated French physiologist mediator for the regulation of both temperature and blood 221 172 who developed concept of milieu intérieur, or a constant interior bodily sugar (of course, this was subsequently found to be incor- 222 173 Q13 environment in 1865 (Bernard, 1865). Image attribution: https:// rect). Similarly, Cannon was also juggling both homeostasis 223 174 upload.wikimedia.org/wikipedia/commons/e/e7/Bernard_Claude.jpg and stress responses when he developed his Fight or Flight 224 175 theories (Cannon, 1915). 225 176 structure of the DNA double helix some 27 years after 226 177 Cannon proposed homeostasis, it is not difficult to imagine 3. Heterostasis and allostasis 227 178 that certain aspects of the homeostatic principle might need 228 179 reconsideration or even revision. Indeed, looked at in that Responding to a growing awareness of the body’s ability 229 180 light, it is quite remarkable that a 90-year-old theorem based to cope with toxic xenobiotics, Hans Selye proposed the new 230 181 on 150-year-old observations has survived as a central term heterostasis (‘heteros’ meaning other, and ‘stasis’ 231 182 dogma of physiology. meaning fixity) as a counterpart of homeostasis to de- 232 183 Nevertheless, it could be argued that Hans Selye began scribe a new state induced by excessive amounts of a toxin. 233 184 a reassessment in the 1950s, based on his observations of Selye wrote (Selye, 1975), “I propose to speak of heterostasis 234 185 behavioral responses to stress. Selye was born in Vienna, then (heteros = other; stasis = fixity) as the establishment of a new 235 186 part of the Austro-Hungarian Empire, on 26 January 1907. steady state by exogenous (pharmacologic) stimulation of adap- 236 187 He grew up in Komárom, Hungary, and studied medicine tive mechanisms through the development and maintenance 237 188 and chemistry in Prague. In 1931 Selye moved to Johns of dormant tissue reactions.” Selye’s vision of heterostasis was 238 189 Hopkins University and then took a position at McGill Uni- of an entirely nonspecific reaction to toxic chemical stress- 239 190 versity in Montreal. In 1945, he was recruited by the ors. He wrote, “By chemical treatment this process induces the 240 191 Université de Montréal, where he became professor and di- body to raise production of its own natural nonspecific (mul- 241 192 rector of the Institute of Experimental Medicine and Surgery. tipurpose) remedies.”(Selye, 1980). 242 193 In 1975 he created the International Institute of Stress and, Psychologists and behavioral physiologists have often pre- 243 ferred the term Allostasis, also approximately meaning ‘other- 244 fixity’ or ‘other-sameness.’ Allostasis envisions responses to 245 a challenge and typically involves cephalic control or in- 246 volvement in anticipating changing needs and, ultimately, 247 Normal restoring the homeostatic state (McEwen, 1998a; Sterling 248 194 and Eyer, 1988; Wingfield, 2003). Allostasis also adds the 249 Range Mean or extra dimension of energy expenditure and Allostatic Load, 250 Median which is the concept that responding to stress costs energy 251 and that repeated or, especially, chronic incursions into the 252 allostatic mode predispose individuals to chronic degener- 253 Time ative diseases (McEwen, 1998a; Sterling and Eyer, 1988; 254 Wingfield, 2003). 255 195 Fig. 3. A graphic depiction of the principle of homeostasis. According to Day (2005) has seriously criticized the entire idea of 256 196 Arthur C. Guyton’s Textbook of Medical Physiology (Guyton, 1991), “The term allostasis and allostatic load as unnecessary and, even, in- 257 197 homeostasis is used by physiologists to mean, maintenance of nearly con- correct usages of homeostasis. Day (2005) argues that, 258 198 stant conditions in the internal environment.” Any biological function or 199 measurement, therefore, will oscillate around a mean or median, within “Indeed, rather than clarifying the concept of stress, the primary 259 200 a range that is considered a ‘normal’ or physiological. effort seems to be directed at subsuming the concept of stress 260

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261 with the concept of allostasis, which has the inadvertent effect 5. Adaptive homeostasis 321 262 of collapsing the study of homeostatic responses and stress re- 322 263 sponses together.”Day(2005) goes even further to conclude Despite the somewhat idyllic picture of internal consis- 323 264 that, “The attempt to subsume the concept of stress within the tency, painted by the concept of homeostasis, successful 324 265 concept of allostasis is also counter-productive in that it dis- survival in the real world actually involves dealing with fluc- 325 266 tracts stress researchers from the important task of developing tuating levels of both internal and environmental stresses; 326 267 conceptual frameworks that allow us to tackle fundamental these threats include heat stress, cold stress, exercise, oxi- 327 268 issues such as how the organism differentiates stressful from dative stress, food deprivation, hypoxic or anoxic stress, 328 269 non-stressful challenges.” chemical toxins, heavy metals, mechanical stress, salt, 329 270 Basically, there appears to be very little difference alcohol, osmolarity, and even emotional and psychologi- 330 271 between the terms heterostasis and allostasis, except for the cal stresses, as well as many more (de Nadal et al., 2011; 331 272 introduction of allostatic load by the latter. To this inves- Kültz, 2005; Saunders and Verdin, 2009; Welch, 1992). A 332 273 tigator, allostatic load is really just a hypothetical outcome sauna or spa can certainly be considered a heat shock or 333 274 of repeated or lengthy deviations from homeostasis, rather stress, when one considers that temperatures of up to 104 °F 334 275 than an actual physiological principle. Similarly, heterostasis (40 °C) are routinely encountered. Conversely, in the Mid- 335 276 fails to account for specific, transient, and reversible adap- western United States, or Northeast Europe, or Northern 336 277 tive changes in homeostasis. China, winter temperatures of −31 °F (−35 °C) must certain- 337 ly be considered a cold shock or stress. Anyone who is 338 278 involved in arc welding is exposed to significant oxidative 339

279 4. Hormesis stress in the form of the ozone (O3) generated, and various 340 280 oxides that are partial combustion products (Liu et al., 2007). 341 281 The term hormesis was suggested in 1943 by Southam Similarly, just driving on a busy freeway, expressway, or mo- 342 282 and Ehrlich (1943) to describe the process by which sub- torway (or living next to one) exposes people to chronic 343 283 lethal damage caused by small doses of a toxin or poison damage from thousands of free radical, partial combus- 344 284 would produce an exaggerated repair response in which the tion products of carbon, oxygen, and nitrogen as well as 345 285 organism actually becomes stronger than it was previ- oxidizing ultrafine particulates (Araujo et al., 2008; Zhang 346 286 ously. The first recorded use of the term hormesis actually et al., 2012). Millions of people every year suffer ischemia/ 347 287 occurred in 1941 in Chester M. Southam’s University of Idaho reperfusion injuries from cerebral strokes or heart attacks 348 288 undergraduate thesis. In many ways, hormesis appears to that involve the transient stresses of hypoxia or anoxia and 349 289 be a biological corollary of the famous pronouncement by reoxygenation (Tasoulis and Douzinas, 2016). Hunger (nu- 350 290 German philosopher Friedrich Wilhelm Nietzsche (1844– trient deprivation shock) is, unfortunately, still hardly a 351 291 1900): “That which does not kill us makes us stronger.” stranger to much of the third world, and all human beings 352 292 Hormesis has more recently been championed by Uni- suffer from transient emotional or psychological stresses at 353 293 versity of Massachusetts at Amherst physiologist and some point in life. 354 294 toxicologist, Edward J. Calabrese. Biphasic dose–response If we consider the ability to cope with these various cel- 355 295 curves have formed the basis for much of Calabrese’s im- lular or organismal stressors, it is immediately clear that they 356 296 pressive contributions to the toxicology literature. Calabrese can all rise, or fall, to levels that are not accommodated by 357 297 has led a major effort to completely rethink the scientific the ‘normal’ homeostatic range of stress resistance. How then 358 298 foundations of our risk assessment and environmental reg- do cells and whole organisms (including people) deal with 359 299 ulation processes, and is also trying to gain acceptance for fluctuating levels of stress? 360 300 hormetic principles in drug discovery and clinical treat- In the last several years, we have discovered that resis- 361 301 ments (Calabrese, 2004; Calabrese and Baldwin, 2003; tance to multiple forms of stress is not a static property of cells, 362 302 Q7 Hormesis: What it is and why it matters, 2014). Despite the tissues, or organisms. Indeed, multiple protective systems dem- 363 303 apparent ubiquity of biphasic dose–response relation- onstrate great transient plasticity in response to very small 364 304 ships, both the concept of hormesis and Calabrese’s attempts changes in oxygen, oxidants, temperature, acid, alkali, salt, ex- 365 305 to revolutionize environmental and medical regulations have ercise, etc. In numerous well-documented examples, these are 366 306 not been without their detractors (Axelrod et al., 2004; such small changes that they cause no damage at all (e.g. Cecia 367 307 Kaiser, 2003). Nevertheless, Calabrese’s work (Calabrese, et al., 2004; Demirovic and Rattan, 2013; Hohmann, 2002; 368 308 2004; Calabrese and Baldwin, 2003; Hormesis: What it is Monge and Leon-Velarde, 1991; Perkins and Swain, 2009; 369 309 Q8 and why it matters, 2014) has effected a major change in Pickering et al., 2010, 2012, 2013; Zhang et al., 2015). Since 370 310 our understanding of biphasic dose–responses, and the im- these transient modifications of the homeostatic range are not 371 311 portance of hormetic reactions to damaging levels of various examples of repair or restoration of damage to produce a stron- 372 312 environmental and industrial toxins. ger organism, they do not qualify as examples of hormesis. 373 313 For the current discussion, however, the problem with Similarly, neither hereostasis nor allostasis, with their psy- Q9 374 314 hormesis is its association with repair or restoration of chological overtones and requirements for overall nervous 375 315 damage, to produce a stronger organism. Instead, we now system control, seem adequate to describe transient varia- 376 316 have numerous examples of situations in which the ho- tions in the homeostatic range that occur as discrete 377 317 meostatic range for multiple functions is transiently responses to (non-damaging) changes in the levels of in- 378 318 expanded or contracted, without any damaging initiating ternal or environmental factors. 379 319 stimulus and, therefore, with no repair process, as will be It is now clear that cells and whole organisms make tran- 380 320 explained in the next section. sient and reversible adjustments to their stress resistance 381

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382 or resilience, in response to ﬂuctuating metabolic and en- Most of the Nrf2 target genes are involved in providing cel- 443 383 vironmental conditions, and to exercise. These adjustments lular protection against damage by electrophilic or oxidizing 444 384 in stress resistance can either have a biochemical, post- toxicants. Naturally, early studies of the Keep1–Nrf2 signal 445 385 translational basis, or can depend on alterations in gene transduction pathway focused on its role in response to toxic 446 386 expression. Based on the principle that one should largely exposures to electrophiles and oxidants (Kensler et al., 2007; 447 387 discuss the subjects one knows best, and about which one Ma, 2013; Zhang, 2006). Subsequently, it has become abun- 448 388 has most expertise, I will use protein turnover and oxida- dantly clear that entirely sub-toxic, non-damaging levels of the 449 389 tive stress as my exemplars for the following discourse. Thus, same electrophiles or oxidants is suﬃcient to activate the 450 390 using the need to control and regulate protein turnover as pathway (Pickering et al., 2012, 2013; Zhang et al., 2015). Es- 451 391 an example, and using signaling by oxidants as a model, sentially, sub-toxic, non-damaging levels of Nrf2-inducing 452 392 we have found that the proteolytic enzymes Proteasome agents or conditions act as priming doses to activate path- 453 393 and Lon can undergo biochemical alteration to differen- ways and enzymes that would provide protection, should it 454 394 tially modify the cellular proteome. The nuclear form of subsequently become necessary. Thus, the Keep1–Nrf2 signal 455 395 Proteasome, for example, undergoes post-translational ADP- transduction pathway can effect transient but powerful changes 456 396 ribosylation by poly ADP-ribose polymerase in response to in the homeostatic range of cellular defenses against 457

397 signaling by oxidants such as H2O2, and this modification electrophiles and oxidants, yet it is not an example of 458 398 increases nuclear Proteasome’s ability to degrade histone heterostasis, allostasis, or hormesis. 459 399 proteins (Ullrich et al., 1999). Mitochondria have no I propose that the term Adaptive Homeostasis more ad- 460 400 Proteasome, but they do contain the Lon protease which is equately and appropriately describes this important cellular 461 401 involved in both protein quality control in the matrix, and capability. How then could we define the term Adaptive Ho- 462 402 mitochondrial DNA maintenance and mitochondrial pro- meostasis? I suggest that Adaptive Homeostasis be defined 463 403 liferation. Normally, Lon is bound in the D-loop of the as follows: ‘The transient expansion or contraction of the 464 404 mitochondrial genome, where it is required for DNA main- homeostatic range in response to exposure to sub-toxic, non- 465 405 tenance and mitochondrial proliferation (Lu et al., 2007; damaging, signaling molecules or events, or the removal or 466 406 Matsushimaa et al., 2010). Following signaling by (non- cessation of such molecules or events.’ This definition allows 467

407 damaging) nanomolar to low micromolar amounts of H2O2, us to predict and explain the transient expansion of the ho- 468 408 Lon is actually released from the mitochondrial DNA (at- meostatic range that occurs upon exposure to nanomolar, 469 409 tached to the inner surface of the inner mitochondrial even picomolar, levels of agents that would only be dam- 470 410 membrane) and migrates to the matrix where it can selec- aging or toxic in the millimolar range: Positive Adaptive 471 411 tively degrade soluble mitochondrial proteins (Bota and Homeostasis. Similarly, the contraction of the homeo- 472 412 Davies, 2002). static range that occurs many hours after initial expansion 473 413 Although post-translational homeostatic adaptations can is understandable as Negative Adaptive Homeostasis, oc- 474 414 produce extremely rapid responses to changing environ- curring as a result of removal or metabolism of the initiating 475 415 ments, transient adaptive responses in gene expression agent. Negative Adaptive Homeostasis can also describe a 476 416 proﬁles can allow cells and organisms to cope with a far transient contraction of the homeostatic range in re- 477 417 greater range of conditions. Many such adaptive altera- sponse to a negative signaling molecule or event. For 478 418 tions to the homeostatic range are mediated by discrete example, production of amino acid synthetases is turned off 479 419 signal transduction pathways that transiently alter transiently if organisms consume a diet very rich in all amino 480 420 transcription/translation (Efeyan et al., 2015; Fossett, 2013; acids (Negative Adaptive Homeostasis) and the homeo- 481 421 Holmstrom and Finkel, 2014; Huang et al., 2012; Lee, 2001; static range of amino acid synthesis capacity is transiently 482 422 Lloyd, 2013; Shadel and Horvath, 2015). A good example decreased (Fig. 4). 483 423 of such pathways is the Keep1–Nrf2 system (Kensler et al., Of course, transient adaptation is also seen in condi- 484 424 2007; Ma, 2013; Pickering et al., 2012, 2013; Zhang, 2006; tions where cells or organisms are exposed to toxic levels 485 425 Zhang et al., 2015). Nrf2 (nuclear factor erythroid 2-related of agents, or to damaging conditions, unless the toxicity or 486 426 factor 2) is a basic leucine zipper protein, with a Cap “n” damage is so great that irreparable harm or even death 487 427 Collar (CCC) structure. Nrf2 is normally found in the cyto- occurs (Wiese et al., 1995). Such conditions may actually 488 428 plasm of mammalian cells, where it is bound to the Keep1 include genetic or metabolic responses to actual damage, 489 429 (Kelch ECH associating protein1), an E3 ubiquitin ligase that i.e. hormesis. A few examples of such truly hormetic re- 490 430 actually polyubiquitinylates Nrf2 and targets it for proteo- sponses are well-characterized in the literature, such as the 491 431 lytic degradation by the 26S Proteasome. This process keeps induction of DNA repair capacities in response to frank DNA 492 432 cellular Nrf2 levels low, and prevents Nrf2 translocation to damage (Bin-Bing et al., 2000). In most cases, however, tran- 493 433 the nucleus where it would have signaling effects. In re- sient changes in protection or repair capacities can clearly 494 434 sponse to a wide variety of electrophiles and oxidants, Nrf2 be seen as the outcome of signal transduction pathways that 495 435 avoids proteolytic digestion, undergoes phosphorylation, and are activated by very low, even trace, levels of initiating 496 436 translocates to the nucleus where it binds to Electrophile agents, or conditions: i.e. they are true examples of Adap- 497 437 Response Elements (EPREs) which are also called Antioxi- tive Homeostasis. 498 438 dant Response Elements (AREs) within target gene 499 439 sequences. Binding of Nrf2 to a gene’s EPRE or ARE (along 6. Summary and conclusions 500 440 with other proteins, such as MafG) causes increased ex- 501 441 pression of that gene for a limited period: a transient Our understanding of transient adaptive changes in ho- 502 442 increase in homeostatic levels. meostatic capacities has been irrevocably altered by the 503

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Acknowledgements 550 551 KJAD was supported by grant #ES003598 from the Na- 552 tional Institute of Environmental Health Sciences of the US 553 National Institutes of Health. 554 555 Uncited references Q14 556 557 Cooper, 2008, Mattson, Calabrese, 2014 558 559 References Q10 560

Araujo, J.A., Barajas, B., Kleinman, M., Wang, X., Bennett, B.J., Gong, K.W., 561 et al., 2008. Ambient particulate pollutants in the ultrafine range 562 promote early atherosclerosis and systemic oxidative stress. Circ. Res. 563 504 Fig. 4. A graphic representation of adaptive homeostasis. Here, in addi- 102, 589–596. 564 505 tion to the normal or physiological range, are added both positive and Axelrod, D., Burns, K., Davis, D., von Larebeke, N., 2004. Hormesis – an 565 506 negative adaptive ranges that can be transiently induced via signal trans- inappropriate extrapolation from the specific to the universal. Int. J. 566 507 duction pathways in response to sub-toxic, non-damaging, stimuli. Thus, Occup. Environ. Health 10, 335–339. 567 508 for example, a signal given by nanomolar levels of H2O2 can act via the Bernard, C., 1865. 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