Adaptive Homeostasis Review PDF

Molecular Aspects of Medicine 49 (2016) 1–7 Contents lists available at ScienceDirect Molecular Aspects of Medicine...

Molecular Aspects of Medicine 49 (2016) 1–7 Contents lists available at ScienceDirect 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 Review Adaptive homeostasis Kelvin J. A. Davies a,b,* a Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center, The University of Southern California, Los Angeles, CA 90089-0191, USA b Division of Molecular and Computational Biology, Department of Biological Sciences, Dornsife College of Letters, Arts, & Sciences, The Uni- versity of Southern California, Los Angeles, CA 90089-0191, USA A R T I C L E I N F O A B S T R A C T Article history: Homeostasis is a central pillar of modern Physiology. The term homeostasis was invented Received 15 April 2016 by Walter Bradford Cannon in an attempt to extend and codify the principle of ‘milieu Accepted 15 April 2016 intérieur,’ or a constant interior bodily environment, that had previously been postulated Available online 22 April 2016 by Claude Bernard. Clearly, ‘milieu intérieur’ and homeostasis have served us well for over a century. Nevertheless, research on signal transduction systems that regulate gene ex- Keywords: pression, or that cause biochemical alterations to existing enzymes, in response to external Homeostasis and internal stimuli, makes it clear that biological systems are continuously making short- Adaptation Oxidative Stress term adaptations both to set-points, and to the range of ‘normal’ capacity. These transient Hormesis adaptations typically occur in response to relatively mild changes in conditions, to pro- Nrf2 grams of exercise training, or to sub-toxic, non-damaging levels of chemical agents; thus, Aging the terms hormesis, heterostasis, and allostasis are not accurate descriptors. Therefore, an operational adjustment to our understanding of homeostasis suggests that the modified term, Adaptive Homeostasis, may be useful especially in studies of stress, toxicology, disease, and aging. Adaptive Homeostasis may be defined as follows: ‘The transient expansion or contraction of the homeostatic range in response to exposure to sub-toxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events.’ © 2016 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction to homeostasis............................................................................................................................................................................................... 1 2. The importance of stress...................................................................................................................................................................................................... 3 3. Heterostasis and allostasis................................................................................................................................................................................................... 3 4. Hormesis.................................................................................................................................................................................................................................... 4 5. Adaptive homeostasis............................................................................................................................................................................................................ 4 6. Summary and conclusions................................................................................................................................................................................................... 5 Acknowledgements................................................................................................................................................................................................................ 6 References.................................................................................................................................................................................................................................. 6 1. Introduction to homeostasis * Leonard Davis School of Gerontology of the Ethel Percy Andrus The concept of milieu intérieur, or a constant interior Gerontology Center, The University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA. Tel.: (213)740-4200. bodily environment, was developed by the celebrated French E-mail address: [email protected]. physiologist Claude Bernard in 1865 (Bernard, 1865). The http://dx.doi.org/10.1016/j.mam.2016.04.007 0098-2997/© 2016 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 2 K.J.A. Davies / Molecular Aspects of Medicine 49 (2016) 1–7 word ‘homeostasis’ was coined by the Harvard Physiolo- gist, Walter Bradford Cannon in 1926 to describe and extend Bernard’s milieu intérieur concept (Cannon, 1926), and popu- larized (in 1932) in his highly successful and persuasive book, The Wisdom of the Body (Cannon, 1932). Cannon com- bined two words from Ancient Greek ο μος (hómos, ”similar”) + ιστημι (histēmi, ”standing still”)/stasis (from στάσις) into a Modern Latin form to invent his term homeostasis. Cannon wrote, “The constant conditions which are main- tained in the body might be termed equilibria. That word, however, has come to have fairly exact meaning as applied to relatively simple physico-chemical states, in closed systems, where known forces are balanced. The coordi- nated physiological processes which maintain most of the steady states in the organism are so complex and so pecu- liar to living beings – involving, as they may, the brain and nerves, the heart, lungs, kidneys and spleen, all working co- operatively – that I have suggested a special designation for these states, homeostasis. The word does not imply some- thing set and immobile, a stagnation. It means a condition Fig. 1. Claude Bernard (1813–1878). The celebrated French physiologist – a condition which may vary, but which is relatively who developed concept of milieu intérieur, or a constant interior bodily constant.” environment in 1865 (Bernard, 1865). Image attribution: https:// upload.wikimedia.org/wikipedia/commons/e/e7/Bernard_Claude.jpg Claude Bernard (July 12, 1813–February 10, 1878), who is considered by many to have been the “father” of modern experimental physiology, is quoted as having said that, “The laboratory is the temple of the science of medicine.” (Schafer, 3 The regulating system that determines the homeo- 2009). Working at a time when cells were just beginning static state consists of a number of cooperating to be thought of as the basic structural unit of tissue and mechanisms acting simultaneously or successively. organ anatomy, Bernard was able to add an entirely new level 4 Homeostasis does not occur by chance, but is the result of functional integration. Bernard concluded that, “The con- of organized self-government (Fig. 2). stancy of the internal environment is the condition for free and independent life: the mechanism that makes it possible is that According to Arthur C. Guyton’s immensely influential which assured the maintenance, within the internal environ- Textbook of Medical Physiology (Guyton, 1991), “The term ment, of all the conditions necessary for the life of the elements.” (Bernard, 1974a, 1974b; Gross, 1998). An important biog- raphy of Claude Bernard has been written by Charles Gross (Gross, 1998) (Fig. 1). Prior to gaining his medical degree in 1900, Walter Cannon (October 19, 1871–October 1, 1945) was a student of Phys- iologist Henry Pickering Bowditch, who became Dean of Harvard’s Medical School. Bowditch, in turn, had studied in Paris with Claude Bernard in the late 1860s, after graduat- ing from Harvard College. It is clearly no accident that Cannon, who in 1906 became Higginson Professor and chair of the department of physiology at Harvard Medical School, went on to further clarify and classify Claude Bernard’s concept of milieu intérieur, presumably passed on via Bowditch, into his own terminology of Homeostasis (Cooper, 2008). No stranger to the concept of fluid metabolic states, Cannon had previously (in 1915) coined the term Fight or Flight to de- scribe an animal’s response to threats (Cannon, 1915). In The Wisdom of the Body (Cannon, 1932), Cannon listed four core concepts that defined his idea of homeostasis: 1 Constancy in an open system, such as our bodies rep- resent, requires mechanisms that act to maintain this Fig. 2. Walter Bradford Cannon (1871–1945). The Harvard Physiologist who constancy. coined the term Homeostasis in 1926 to describe and extend Bernard’s milieu intérieur concept (Cannon, 1926). Homeostasis was subsequently 2 Steady-state conditions require that any tendency toward popularized (in 1932) in Cannon’s highly influential book, The Wisdom of change automatically meets with factors that resist the Body (Cannon, 1932). Image attribution: https://upload.wikimedia.org/ change. wikipedia/commons/7/78/Walter_Bradford_Cannon_1934.jp  K.J.A. Davies / Molecular Aspects of Medicine 49 (2016) 1–7 3 In 1975 he created the International Institute of Stress and, in 1979, Selye and Arthur Antille started the Hans Selye Foundation. Behavioral Physiologists define stress as how Normal the body reacts to a stressor, real or imagined, a stimulus Range Mean or that causes stress. Acute stressors affect an organism in the Median short term while chronic stressors exert their effects over the longer term. General Adaptation Syndrome (GAS), de- veloped by Hans Selye (Selye, 1956), is a profile of how organisms respond to stress; GAS is characterized by three Time phases: a nonspecific mobilization phase, which pro- Fig. 3. A graphic depiction of the principle of homeostasis. According to motes sympathetic nervous system activity; a resistance Arthur C. Guyton’s Textbook of Medical Physiology (Guyton, 1991), “The term phase, during which the organism makes efforts to cope with homeostasis is used by physiologists to mean, maintenance of nearly con- the threat; and an exhaustion phase, which occurs if the or- stant conditions in the internal environment.” Any biological function or ganism fails to overcome the threat and depletes its measurement, therefore, will oscillate around a mean or median, within physiological resources. a range that is considered a ‘normal’ or physiological. Clearly, Selye was focusing on how the nervous system coordinates many behavioral and physiological responses to stress, often through the use of hormones (Timiras, 2004). homeostasis is used by physiologists to mean, maintenance of In fact, this nervous system and hormonal approach to the nearly constant conditions in the internal environment.” coordination of homeostasis was already part of Walter Can- The basic idea of homeostasis is shown in Fig. 3 below. non’s thinking when he proposed adrenaline as the common The Y axis of Fig. 3 can be any biological/physiological func- mediator for the regulation of both temperature and blood tion, such as blood pressure, heart rate, core temperature, sugar (of course, this was subsequently found to be incor- blood glucose, NAD+/NADH and NADP+/NADPH ratios, su- rect). Similarly, Cannon was also juggling both homeostasis peroxide dismutase and glutathione peroxidase levels and and stress responses when he developed his Fight or Flight activities, Proteasome and Lon levels and activities, or the theories (Cannon, 1915). capacity and effectiveness of DNA repair systems. The X axis is calibrated by time, whose units can be seconds, minutes, 3. Heterostasis and allostasis hours, days, weeks, or even years (if one considers aging). The classical homeostasis graph of Fig. 3 reveals that while Responding to a growing awareness of the body’s ability there is a mean value for any physiological attribute, we ac- to cope with toxic xenobiotics, Hans Selye proposed the new tually spend most of our time away from that mean, term heterostasis (‘heteros’ meaning other, and ‘stasis’ oscillating between a minimum ‘normal’ and a maximum meaning fixity) as a counterpart of homeostasis to de- ‘normal’ value. The span from low normal to high normal scribe a new state induced by excessive amounts of a toxin. is then considered the normal physiological or homeo- Selye wrote (Selye, 1975), “I propose to speak of heterostasis static range (Fig. 3). (heteros = other; stasis = fixity) as the establishment of a new steady state by exogenous (pharmacologic) stimulation of adap- 2. The importance of stress tive mechanisms through the development and maintenance of dormant tissue reactions.” Selye’s vision of heterostasis was It is, of course, many years since Bernard and Cannon of an entirely nonspecific reaction to toxic chemical stress- made their important contributions, and a great deal has ors. He wrote, “By chemical treatment this process induces the changed in our basic appreciation of how living organ- body to raise production of its own natural nonspecific (mul- isms function. When one considers, for example, that Watson tipurpose) remedies.” (Selye, 1980). and Crick (1953) published their three-dimensional Psychologists and behavioral physiologists have often pre- structure of the DNA double helix some 27 years after ferred the term Allostasis, also approximately meaning ‘other- Cannon proposed homeostasis, it is not difficult to imagine fixity’ or ‘other-sameness.’ Allostasis envisions responses to that certain aspects of the homeostatic principle might need a challenge and typically involves cephalic control or in- reconsideration or even revision. Indeed, looked at in that volvement in anticipating changing needs and, ultimately, light, it is quite remarkable that a 90-year-old theorem based restoring the homeostatic state (McEwen, 1998a; Sterling on 150-year-old observations has survived as a central and Eyer, 1988; Wingfield, 2003). Allostasis also adds the dogma of physiology. extra dimension of energy expenditure and Allostatic Load, Nevertheless, it could be argued that Hans Selye began which is the concept that responding to stress costs energy a reassessment in the 1950s, based on his observations of and that repeated or, especially, chronic incursions into the behavioral responses to stress. Selye was born in Vienna, then allostatic mode predispose individuals to chronic degener- part of the Austro-Hungarian Empire, on 26 January 1907. ative diseases (McEwen, 1998a; Sterling and Eyer, 1988; He grew up in Komárom, Hungary, and studied medicine Wingfield, 2003). and chemistry in Prague. In 1931 Selye moved to Johns Day (2005) has seriously criticized the entire idea of Hopkins University and then took a position at McGill Uni- allostasis and allostatic load as unnecessary and, even, in- versity in Montreal. In 1945, he was recruited by the correct usages of homeostasis. Day (2005) argues that, Université de Montréal, where he became professor and di- “Indeed, rather than clarifying the concept of stress, the primary rector of the Institute of Experimental Medicine and Surgery. effort seems to be directed at subsuming the concept of stress 4 K.J.A. Davies / Molecular Aspects of Medicine 49 (2016) 1–7 with the concept of allostasis, which has the inadvertent effect 5. Adaptive homeostasis of collapsing the study of homeostatic responses and stress re- sponses together.” Day (2005) goes even further to conclude Despite the somewhat idyllic picture of internal consis- that, “The attempt to subsume the concept of stress within the tency, painted by the concept of homeostasis, successful concept of allostasis is also counter-productive in that it dis- survival in the real world actually involves dealing with fluc- tracts stress researchers from the important task of developing tuating levels of both internal and environmental stresses; conceptual frameworks that allow us to tackle fundamental these threats include heat stress, cold stress, exercise, oxi- issues such as how the organism differentiates stressful from dative stress, food deprivation, hypoxic or anoxic stress, non-stressful challenges.” chemical toxins, heavy metals, mechanical stress, salt, Basically, there appears to be very little difference alcohol, osmolarity, and even emotional and psychologi- between the terms heterostasis and allostasis, except for the cal stresses, as well as many more (de Nadal et al., 2011; introduction of allostatic load by the latter. To this inves- Kültz, 2005; Saunders and Verdin, 2009; Welch, 1992). A tigator, allostatic load is really just a hypothetical outcome sauna or spa can certainly be considered a heat shock or of repeated or lengthy deviations from homeostasis, rather stress, when one considers that temperatures of up to 104 °F than an actual physiological principle. Similarly, heterostasis (40 °C) are routinely encountered. Conversely, in the Mid- fails to account for specific, transient, and reversible adap- western United States, or Northeast Europe, or Northern tive changes in homeostasis. China, winter temperatures of −31 °F (−35 °C) must certain- ly be considered a cold shock or stress. Anyone who is involved in arc welding is exposed to significant oxidative 4. Hormesis stress in the form of the ozone (O3) generated, and various oxides that are partial combustion products (Liu et al., 2007). The term hormesis was suggested in 1943 by Southam Similarly, just driving on a busy freeway, expressway, or mo- and Ehrlich (1943) to describe the process by which sub- torway (or living next to one) exposes people to chronic lethal damage caused by small doses of a toxin or poison damage from thousands of free radical, partial combus- would produce an exaggerated repair response in which the tion products of carbon, oxygen, and nitrogen as well as organism actually becomes stronger than it was previ- oxidizing ultrafine particulates (Araujo et al., 2008; Zhang ously. The first recorded use of the term hormesis actually et al., 2012). Millions of people every year suffer ischemia/ occurred in 1941 in Chester M. Southam’s University of Idaho reperfusion injuries from cerebral strokes or heart attacks undergraduate thesis. In many ways, hormesis appears to that involve the transient stresses of hypoxia or anoxia and be a biological corollary of the famous pronouncement by reoxygenation (Tasoulis and Douzinas, 2016). Hunger (nu- German philosopher Friedrich Wilhelm Nietzsche (1844– trient deprivation shock) is, unfortunately, still hardly a 1900): “That which does not kill us makes us stronger.” stranger to much of the third world, and all human beings Hormesis has more recently been championed by Uni- suffer from transient emotional or psychological stresses at versity of Massachusetts at Amherst physiologist and some point in life. toxicologist, Edward J. Calabrese. Biphasic dose–response If we consider the ability to cope with these various cel- curves have formed the basis for much of Calabrese’s im- lular or organismal stressors, it is immediately clear that they pressive contributions to the toxicology literature. Calabrese can all rise, or fall, to levels that are not accommodated by has led a major effort to completely rethink the scientific the ‘normal’ homeostatic range of stress resistance. How then foundations of our risk assessment and environmental reg- do cells and whole organisms (including people) deal with ulation processes, and is also trying to gain acceptance for fluctuating levels of stress? hormetic principles in drug discovery and clinical treat- In the last several years, we have discovered that resis- ments (Calabrese, 2004; Calabrese and Baldwin, 2003; tance to multiple forms of stress is not a static property of cells, Mattson and Calabrese, 2014). Despite the apparent ubiq- tissues, or organisms. Indeed, multiple protective systems dem- uity of biphasic dose–response relationships, both the onstrate great transient plasticity in response to very small concept of hormesis and Calabrese’s attempts to revolu- changes in oxygen, oxidants, temperature, acid, alkali, salt, ex- tionize environmental and medical regulations have not been ercise, etc. In numerous well-documented examples, these are without their detractors (Axelrod et al., 2004; Kaiser, 2003). such small changes that they cause no damage at all (e.g. Cecia Nevertheless, Calabrese’s work (Calabrese, 2004; Calabrese et al., 2004; Demirovic and Rattan, 2013; Hohmann, 2002; and Baldwin, 2003; Mattson and Calabrese, 2014) has ef- Monge and Leon-Velarde, 1991; Perkins and Swain, 2009; fected a major change in our understanding of biphasic dose– Pickering et al., 2010, 2012, 2013; Zhang et al., 2015). Since responses, and the importance of hormetic reactions to these transient modifications of the homeostatic range are not damaging levels of various environmental and industrial examples of repair or restoration of damage to produce a stron- toxins. ger organism, they do not qualify as examples of hormesis. For the current discussion, however, the problem with Similarly, neither heterostasis nor allostasis, with their psy- hormesis is its association with repair or restoration of chological overtones and requirements for overall nervous damage, to produce a stronger organism. Instead, we now system control, seem adequate to describe transient varia- have numerous examples of situations in which the ho- tions in the homeostatic range that occur as discrete responses meostatic range for multiple functions is transiently to (non-damaging) changes in the levels of internal or envi- expanded or contracted, without any damaging initiating ronmental factors. stimulus and, therefore, with no repair process, as will be It is now clear that cells and whole organisms make tran- explained in the next section. sient and reversible adjustments to their stress resistance  K.J.A. Davies / Molecular Aspects of Medicine 49 (2016) 1–7 5 or resilience, in response to fluctuating metabolic and en- Most of the Nrf2 target genes are involved in providing cel- vironmental conditions, and to exercise. These adjustments lular protection against damage by electrophilic or oxidizing in stress resistance can either have a biochemical, post- toxicants. Naturally, early studies of the Keep1–Nrf2 signal translational basis, or can depend on alterations in gene transduction pathway focused on its role in response to toxic expression. Based on the principle that one should largely exposures to electrophiles and oxidants (Kensler et al., 2007; discuss the subjects one knows best, and about which one Ma, 2013; Zhang, 2006). Subsequently, it has become abun- has most expertise, I will use protein turnover and oxida- dantly clear that entirely sub-toxic, non-damaging levels of the tive stress as my exemplars for the following discourse. Thus, same electrophiles or oxidants is sufficient to activate the using the need to control and regulate protein turnover as pathway (Pickering et al., 2012, 2013; Zhang et al., 2015). Es- an example, and using signaling by oxidants as a model, sentially, sub-toxic, non-damaging levels of Nrf2-inducing we have found that the proteolytic enzymes Proteasome agents or conditions act as priming doses to activate path- and Lon can undergo biochemical alteration to differen- ways and enzymes that would provide protection, should it tially modify the cellular proteome. The nuclear form of subsequently become necessary. Thus, the Keep1–Nrf2 signal Proteasome, for example, undergoes post-translational ADP- transduction pathway can effect transient but powerful changes ribosylation by poly ADP-ribose polymerase in response to in the homeostatic range of cellular defenses against signaling by oxidants such as H2O2, and this modification electrophiles and oxidants, yet it is not an example of increases nuclear Proteasome’s ability to degrade histone heterostasis, allostasis, or hormesis. proteins (Ullrich et al., 1999). Mitochondria have no I propose that the term Adaptive Homeostasis more ad- Proteasome, but they do contain the Lon protease which is equately and appropriately describes this important cellular involved in both protein quality control in the matrix, and capability. How then could we define the term Adaptive Ho- mitochondrial DNA maintenance and mitochondrial pro- meostasis? I suggest that Adaptive Homeostasis be defined liferation. Normally, Lon is bound in the D-loop of the as follows: ‘The transient expansion or contraction of the mitochondrial genome, where it is required for DNA main- homeostatic range in response to exposure to sub-toxic, non- tenance and mitochondrial proliferation (Lu et al., 2007; damaging, signaling molecules or events, or the removal or Matsushimaa et al., 2010). Following signaling by (non- cessation of such molecules or events.’ This definition allows damaging) nanomolar to low micromolar amounts of H2O2, us to predict and explain the transient expansion of the ho- Lon is actually released from the mitochondrial DNA (at- meostatic range that occurs upon exposure to nanomolar, tached to the inner surface of the inner mitochondrial even picomolar, levels of agents that would only be dam- membrane) and migrates to the matrix where it can selec- aging or toxic in the millimolar range: Positive Adaptive tively degrade soluble mitochondrial proteins (Bota and Homeostasis. Similarly, the contraction of the homeo- Davies, 2002). static range that occurs many hours after initial expansion Although post-translational homeostatic adaptations can is understandable as Negative Adaptive Homeostasis, oc- produce extremely rapid responses to changing environ- curring as a result of removal or metabolism of the initiating ments, transient adaptive responses in gene expression agent. Negative Adaptive Homeostasis can also describe a profiles can allow cells and organisms to cope with a far transient contraction of the homeostatic range in re- greater range of conditions. Many such adaptive altera- sponse to a negative signaling molecule or event. For tions to the homeostatic range are mediated by discrete example, production of amino acid synthetases is turned off signal transduction pathways that transiently alter transiently if organisms consume a diet very rich in all amino transcription/translation (Efeyan et al., 2015; Fossett, 2013; acids (Negative Adaptive Homeostasis) and the homeo- Holmstrom and Finkel, 2014; Huang et al., 2012; Lee, 2001; static range of amino acid synthesis capacity is transiently Lloyd, 2013; Shadel and Horvath, 2015). A good example decreased (Fig. 4). of such pathways is the Keep1–Nrf2 system (Kensler et al., Of course, transient adaptation is also seen in condi- 2007; Ma, 2013; Pickering et al., 2012, 2013; Zhang, 2006; tions where cells or organisms are exposed to toxic levels Zhang et al., 2015). Nrf2 (nuclear factor erythroid 2-related of agents, or to damaging conditions, unless the toxicity or factor 2) is a basic leucine zipper protein, with a Cap “n” damage is so great that irreparable harm or even death Collar (CCC) structure. Nrf2 is normally found in the cyto- occurs (Wiese et al., 1995). Such conditions may actually plasm of mammalian cells, where it is bound to the Keep1 include genetic or metabolic responses to actual damage, (Kelch ECH associating protein1), an E3 ubiquitin ligase that i.e. hormesis. A few examples of such truly hormetic re- actually polyubiquitinylates Nrf2 and targets it for proteo- sponses are well-characterized in the literature, such as the lytic degradation by the 26S Proteasome. This process keeps induction of DNA repair capacities in response to frank DNA cellular Nrf2 levels low, and prevents Nrf2 translocation to damage (Bin-Bing et al., 2000). In most cases, however, tran- the nucleus where it would have signaling effects. In re- sient changes in protection or repair capacities can clearly sponse to a wide variety of electrophiles and oxidants, Nrf2 be seen as the outcome of signal transduction pathways that avoids proteolytic digestion, undergoes phosphorylation, and are activated by very low, even trace, levels of initiating translocates to the nucleus where it binds to Electrophile agents, or conditions: i.e. they are true examples of Adap- Response Elements (EPREs) which are also called Antioxi- tive Homeostasis. dant Response Elements (AREs) within target gene sequences. Binding of Nrf2 to a gene’s EPRE or ARE (along 6. Summary and conclusions with other proteins, such as MafG) causes increased ex- pression of that gene for a limited period: a transient Our understanding of transient adaptive changes in ho- increase in homeostatic levels. meostatic capacities has been irrevocably altered by the 6 K.J.A. 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