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Molecular Aspects of Medicine ■■ (2016) ■■–■■

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Molecular Aspects of Medicine

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / m a m

1 Q2 Review
2
3 Adaptive homeostasis
4
5 Q1 Kelvin J.A. Davies a,b,*
a
6 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 A R T I C L E I N F O A B S T R A C T
13
14
15 Article history: Homeostasis is a central pillar of modern Physiology. The term homeostasis was invented
16
17 Received 15 April 2016 by Walter Bradford Cannon in an attempt to extend and codify the principle of ‘milieu
18
19 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
22
23 a century. Nevertheless, research on signal transduction systems that regulate gene ex-
24
25 Keywords:
pression, or that cause biochemical alterations to existing enzymes, in response to external
26 Homeostasis
27
28 Adaptation
and internal stimuli, makes it clear that biological systems are continuously making short-
29
30 Stress term adaptations both to set-points, and to the range of ‘normal’ capacity. These transient
31
32 Hormesis adaptations typically occur in response to relatively mild changes in conditions, to pro-
33
34 Nrf2 grams of exercise training, or to sub-toxic, non-damaging levels of chemical agents; thus,
35
36 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, &
61 Sciences, The University of Southern California, Los Angeles, CA 90089-0191,
The concept of milieu intérieur, or a constant interior 66
62 USA. bodily environment, was developed by the celebrated French 67
63 E-mail address: kelvin@usc.edu. physiologist Claude Bernard in 1865 (Bernard, 1865). The 68

http://dx.doi.org/10.1016/j.mam.2016.04.007
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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 (histēmi, ”standing still”)/stasis (from
76 στάσις) 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
restoring the homeostatic state (McEwen, 1998a; Sterling 248
Normal and Eyer, 1988; Wingfield, 2003). Allostasis also adds the 249
194
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-
198 stant conditions in the internal environment.” Any biological function or
correct usages of homeostasis. Day (2005) argues that, 258
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
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