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The Journal of Physiology logoLink to The Journal of Physiology
. 2017 Nov 21;595(24):7275–7309. doi: 10.1113/JP275072

The role of declining adaptive homeostasis in ageing

Laura C D Pomatto 1, Kelvin J A Davies 1,2,
PMCID: PMC5730851  PMID: 29028112

Abstract

Adaptive homeostasis is “the transient expansion or contraction of the homeostatic range for any given physiological parameter in response to exposure to sub‐toxic, non‐damaging, signalling molecules or events, or the removal or cessation of such molecules or events” (Davies, 2016). Adaptive homeostasis enables biological systems to make continuous short‐term adjustments for optimal functioning despite ever‐changing internal and external environments. Initiation of adaptation in response to an appropriate signal allows organisms to successfully cope with much greater, normally toxic, stresses. These short‐term responses are initiated following effective signals, including hypoxia, cold shock, heat shock, oxidative stress, exercise‐induced adaptation, caloric restriction, osmotic stress, mechanical stress, immune response, and even emotional stress. There is now substantial literature detailing a decline in adaptive homeostasis that, unfortunately, appears to manifest with ageing, especially in the last third of the lifespan. In this review, we present the hypothesis that one hallmark of the ageing process is a significant decline in adaptive homeostasis capacity. We discuss the mechanistic importance of diminished capacity for short‐term (reversible) adaptive responses (both biochemical and signal transduction/gene expression‐based) to changing internal and external conditions, for short‐term survival and for lifespan and healthspan. Studies of cultured mammalian cells, worms, flies, rodents, simians, apes, and even humans, all indicate declining adaptive homeostasis as a potential contributor to age‐dependent senescence, increased risk of disease, and even mortality. Emerging work points to Nrf2‐Keap1 signal transduction pathway inhibitors, including Bach1 and c‐Myc, both of whose tissue concentrations increase with age, as possible major causes for age‐dependent loss of adaptive homeostasis.

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Keywords: stress response, hypoxia, cold shock, heat shock, oxidative stress, exercise‐induced adaptation, caloric restriction, osmotic stress, mechanical stress, immune response, emotional stress, Nrf2‐Keap1, proteasome, Lon protease

Introduction

Adaptation, or ‘adaptive homeostasis’ is a highly conserved process, wherein cells, tissues, and whole organisms transiently activate various signalling pathways in response to short‐term mild internal or external perturbations, thereby effecting transient changes in gene expression and stress resistance. These dynamic short‐term responses demonstrate the continual homeostatic adjustments that organisms make in order to cope with ever‐changing environments. Importantly, such adjustments transiently increase stress resistance and can protect against more damaging insults that may occur over a period of several hours. As a descriptive example, consider the case of bacteria, protozoans and algae living in a pond and generating toxins to kill‐off (outcompete) their neighbors: a situation much like that experienced by our earliest ancestors. Since toxins generated by one creature have to diffuse through the aqueous medium to reach their intended ‘victims,’ a concentration gradient quickly develops and, at first, only a few molecules of the toxin actually reach their targets. Such a small amount of toxin is unlikely to actually be harmful but, if the target organism can utilize it as a ‘signal’ to generate increased resistance, the target is more likely to be able to survive when the bulk of the toxin actually arrives. Thus, being able to make use of very small amounts of agents as signalling molecules that would be harmful at much higher concentrations can have great survival benefits. If the adaptation in the homeostatic level of resistance can be transient, the energy cost is minimized and the organism can potentially react rapidly to multiple transitory fluctuations in environmental hazards: this is the basic concept of ‘adaptive homeostasis’ (Davies, 2016).

A more formal definition of adaptive homeostasis has recently been published in which the concept is delineated as follows: “adaptive homeostasis is the transient expansion or contraction of the homeostatic range for any given physiological parameter in response to exposure to sub‐toxic, non‐damaging, signalling molecules or events, or the removal or cessation of such molecules or events” (Davies, 2016). Thus emphasizing that there is not a static homeostatic set‐point, but rather continual fluctuation arising from internal or environmentally derived stresses, including oxidative stress, heat stress, exercise‐induced stress, caloric restriction/fasting, hypoxia, mechanical stress, osmotic stress, and behavioural stress, which can all impact transcriptional and translational changes, with the beneficial effect of increased protection from excessive damage (Fig. 1).

Figure 1. Activation and deactivation of the adaptive homeostasis pathway.

Figure 1

During periods of homeostasis, the physiological range enables cells, tissues, and organisms to cope with minor changes in redox status. However, external or internal perturbations, that exceed the homeostatic range, trigger the transient activation of adaptive responses. Adaptive homeostasis is activated following exposure to sub‐lethal, non‐damaging amounts of a signalling event – such as exposure to nanomolar levels of hydrogen peroxide (H2O2). Although toxic amounts of a stressor can also induce adaptive responses, it is actually not the damage but rather the initial signalling that is important; this distinguishes adaptive homeostasis from hormesis (Davies, 2016). Initial exposure to low amounts of signalling agent or conditions triggers transcriptional activation, within minutes. One of the most notable pathways for adaptive homeostasis is the nuclear recruitment and binding of Nrf2 to antioxidant response elements (AREs), also called electrophile response elements (EPREs), located in the upstream activation sites of key stress protective genes. Following transcription, translational activation occurs over a period of hours, resulting in the upregulation of stress responsive enzymes, including the 20S Proteasome and the mitochondrial Lon protease. In turn, elevation in the levels of such protective enzymes better prepare cells, tissues, or organisms, to cope with future, potentially more harmful, stresses. Lastly, as the adaptive response is transient, adaptive homeostasis will gradually contract back to the basal homeostatic range.

One of the key components of adaptive homeostasis is its utilization of transient or short‐term responses, enabling quick activation and inactivation. This type of response is clearly a trait enjoyed by young organisms, from worms, to flies, to mice and rats, to human cells in culture. Indeed, a plethora of in vitro cell culture studies have shown the rapid induction of various stress responsive and antioxidant defensive enzymes in response to mild, short‐term stress exposure (Davies et al. 1995; Grune et al. 1996; Shringarpure et al. 2001; Ngo & Davies, 2009; Ngo et al. 2011; Beegle et al. 2015; Rodríguez‐Cotto et al. 2015). The phenomenon is also conserved in young model organisms, including the nematode worm Caenorhabditis elegans (C. elegans), and the fruit‐fly Drosophila melanogaster (D. melanogaster). (Landis et al. 2004, 2012; Oliveira et al. 2009; Pickering et al. 2013a,b). More recently, adaptive increases in stress‐responsive enzymes in young male mice exposed to short‐term, non‐lethal vehicular derived nanoparticles (Zhang et al. 2012; Chepelev et al. 2013) has also been demonstrated. Together, these findings indicate that rapid and robust adaptive responses, activated upon mild cellular perturbation, are a widespread property of diverse young living organisms.

Mounting evidence suggests, however, that adaptive homeostasis actually declines with age. Indeed, the nuanced modulation of the adaptive homeostatic response, may demonstrate one of the crucial differences between the young and the old. Ageing is associated with the inability to activate and/or modulate several adaptive responses. Suggestions of an ‘ageing’ phenomenon may be found in cell culture experiments showing that early passage cells pretreated with low (sub‐toxic) levels of an oxidant, to stimulate the signalling cascade, were better able to withstand future more toxic oxidative insults. Late passage cells, however, showed either sluggish or no response and were prone to damage accumulation (Sitte et al. 2000a; Ngo et al. 2011). Recently, this finding has been found to hold true in actual ageing studies with worms (Raynes et al. 2016a), flies (Pomatto et al. 2016a), and mice (Breusing et al. 2009; Zhang et al. 2012). Furthermore, the lack of activation of the adaptive response is accompanied by a basal elevation in multiple stress‐protective and antioxidant enzymes (Zhang et al. 2012; Raynes et al. 2016a). Thus ageing is associated with a twofold detrimental impact to adaptive homeostasis. The first being that aged organisms lose their ability to rapidly modulate the adaptive homeostatic response and secondly, the compensatory basal increase in stress‐responsive enzymes further compresses the maximal range of responses thus diminishing the cellular ability to efficiently mitigate damage (Fig. 2). The aim of this review is to demonstrate that although various types of sub‐toxic stress can activate unique protective signalling pathways in the young, these same adaptive homeostatic pathways share a common fate of decline and extinction with age.

Figure 2. Loss of adaptive homeostasis with age.

Figure 2

Young organisms show a wide basal homeostatic range (dashed green), that upon transient activation, results in the robust increase (continuous green) of the adaptive homeostatic response. For convenience, only positive adaptive homeostatic responses (expanding the homeostatic range) are shown. With age, however, the inducibility of the response declines, becoming evident beginning in middle age (continuous brown). As cells, tissues, and organisms age towards senescence (continuous red) adaptive homeostasis can decline so much that it may no longer be effective at all. Additionally, aged organisms are further compromised by compression of the basal homeostatic range (dashed red), limiting the ability to cope with even day‐to‐day small variations that are no challenge to their young counterparts.

Why adaptive homeostasis rather than hormesis

As proposed by Southam and Erlich (Southam, 1943) the term ‘hormesis’ describes processes by which damaging but sub‐lethal effects caused by small doses of a toxin or poison produce inflated repair responses, making the organism stronger than it was previously. Thus, hormesis may be viewed as something of a biological corollary of the words of German philosopher Friedrich Wilhelm Nietzsche (1844–1900): “That which does not kill us makes us stronger.” Another important component of hormesis is the concept that homeostasis has been interrupted or disrupted, and that hormesis acts to return affected systems to function within normal homeostatic range as quickly as possible.

Readers will quickly see that there are areas where adaptive homeostasis and hormesis may appear to resemble one another, perhaps even to overlap. In fact, however, hormesis necessitates that a small amount of damage is the requirement for, and mechanistic avenue by which, repair or restoration of damage produces a stronger organism (Calabrese, 2003, 2004; Calabrese & Baldwin, 2003; Gems & Partridge, 2008; Mattson, 2008; Mattson & Calabrese, 2010; Rattan & Le Bourg, 2014). Similarly, hormesis depicts a system striving to return to the normal range of homeostasis whereas adaptive homeostasis is built on the observation that transient adaptation is actually the result of a temporary expansion (or contraction) of the homeostatic range. We now have numerous examples of situations in which the homeostatic range for multiple functions is transiently expanded or contracted, without any damaging initiating stimulus and, therefore, with no repair process, as was explained previously (Davies, 2016). In fact, the adaptive responses described in this review only operate during an expansion or contraction of the homeostatic range; once the system has returned to normal homeostasis all adaptive responses are actually lost and stress resistance returns to pre‐exposure levels.

The concept of hormesis has been strongly supported by the work of toxicologist, Edward J. Calabrese who has emphasized biphasic dose‐response curves and a rethink of the scientific foundations of risk assessment and environmental regulation processes (Calabrese, 2003, 2004; Calabrese & Baldwin, 2003; Mattson & Calabrese, 2010). Both the concept and implications of hormesis have certainly experienced serious criticisms (Kaiser, 2003; Axelrod et al. 2004; Blagosklonny, 2011), nevertheless, Calabrese's work has effected a major change in our understanding of biphasic dose‐responses, and the importance of hormetic reactions to damaging levels of various environmental and industrial toxins. Both the requirement for damage as the initiator of hormesis, and the ability of hormesis to re‐establish the normal range of homeostasis, are made clear in this quote from a paper by Calabrese (Calabrese, 2005),

The survival value of a modest overcompensation stimulatory response may be seen within the context of its overall damage repair function. Biological systems have the capacity to recognize damage and initiate repair processes. How clearly the range of damage is detected, quantified, and differentiated as well as how such information is related to resource allocation for repair processes are keys to understanding the hormetic response. Based on the hormetic dose response, at low levels of damage more resources are typically allocated than needed to strictly repair damage and re‐establish homeostasis.

Thus, it will be abundantly clear that hormesis and adaptive homeostasis describe somewhat complimentary, but distinct biological processes. We suggest that hormesis is an entirely appropriate and useful concept within the broad scope of toxicology. In contrast, however, adaptive homeostasis belongs to the realm of physiological processes by which living organisms deal with changing external and internal environmental conditions on a minute‐by‐minute basis.

One other very important concept to consider is that adaptive homeostasis very often occurs under conditions that do also cause damage, but that the damage itself is not the cause of adaptive responses. In experiments involving graded exposure to increasing levels of hydrogen peroxide (H2O2) for example, we found that mammalian cells, worms, and flies all adapted to H2O2 by increasing expression of various protective enzymes. Importantly, however, adaptation occurred at the lowest H2O2 levels tested that caused no damage whatsoever, and it also occurred at much higher H2O2 levels that also did cause collateral damage (Grune et al. 2011; Pickering & Davies, 2012b; Pickering et al. 2012, 2013a,b; Pomatto et al. 2016a, 2017a,b; Raynes et al. 2016a). Similar results have been seen with many other stimuli, including heat exposure, cold exposure, exercise, hypoxia, caloric restriction, osmotic pressure, mechanical stress, immune responses, and emotional and psychological stresses. Thus, it is important to separate the causes and mechanisms of adaptive responses that provide the cell or organism with increased protection, from measures or examples of damage that may still occur; this is especially true if one wishes to study and understand the reasons for declining adaptive homeostasis in ageing.

The hypothesis: ageing involves a significant decline in adaptive homeostasis capacity

In the present work, we bring together a series of examples of physiological adaptive homeostasis that are initiated by signalling pathways rather than damage, and that are exemplified by reversible expansions or contractions of the homeostatic range that provide for transient adaptation, rather than a rapid return to the unstimulated homeostatic range. These examples include oxidative stress, heat shock, glucose stress, hypoxia, cold shock, exercise‐induced adaptations, caloric restriction, osmotic stress, mechanical stress, immune response, and emotional and psychological stress. Importantly, our own research, and analysis of the literature, indicates that all these examples of adaptive homeostasis exhibit significant declines with age. Indeed, ageing may be the quintessential consequence of the inability to modulate the transient adaptive response. In this model, ageing is seen as the result of continual (or even continuous) activation of adaptive pathways, due to chronic or excessively repetitive stimuli. This may be an underlying distinction between the young and old, wherein a young organism, with relatively limited exposure to adaptive stimuli, is capable of rapidly activating the transient protective responses of adaptive homeostasis. In contrast, an aged organism, which has faced a lifetime of chronic or excessively repetitive adaptive stimuli, relies upon constant activation stress responses, with little or no ability to modulate adaptive homeostasis. Therefore, chronic or excessively repetitive exposure to stress, over the lifespan appears to be detrimental to good health (Pickering et al. 2013b). Thus, in this review, we present the hypothesis that one hallmark of the ageing process is a significant decline in adaptive homeostasis capacity.

Adaptive homeostasis and oxidative stress

General aspects of adaptation induced by oxidant signals

For many years, reactive oxygen and nitrogen species were considered to be solely detrimental, due to their elevated concentrations in various diseases and in ageing (Harman, 1955). However, our perception of such reactive species, including many free radicals, has recently changed since low concentrations have been shown to act as crucial signalling molecules necessary for cellular homeostasis (Ray et al. 2012). Mitochondria are a primary source of cellular free radical generation due to the electron leakage (1–5%) that occurs during mitochondrial oxidative phosphorylation (Turrens, 1997). This results in the formation of superoxide (O2 •−) whose dismutation produces the non‐radical, mild oxidant and signalling molecule hydrogen peroxide (H2O2). Interaction of O2 •− and H2O2 can generate the strongly oxidizing hydroxyl radical (HO), and reaction of O2 •− with the nitric oxide radical (NO) utilized in vasodilatation generates the peroxynitrite moiety (ONOO), which is another strong oxidant. In turn, these molecules serve as critical links in the mitochondrial‐nuclear communication pathway. Various reactive oxygen and nitrogen species are also generated in response to xenobiotics, cytokines, and bacterial inflammation that in turn can activate additional metabolic pathways. Hence, oxidative damage only ensues when the generation of free radicals and reactive oxygen and nitrogen species exceeds the capacity of cellular defense mechanisms (Haigis & Yankner, 2010). If left unchecked, such high levels of oxidants can even lead to DNA, protein, and lipid damage (Schieber & Chandel, 2014).

To combat the accumulation of damaged constituents, cells rely upon various antioxidant enzymes, and damage removal/repair enzymes (proteases, lipases, and DNA repair enzymes) for cellular maintenance. Three crucial antioxidant enzymes necessary for the breakdown of O2 and H2O2 are superoxide dismutase (SOD), glutathione peroxidase, and catalase (in various different cellular compartments). The intracellular dismutation of O2 to H2O2 is mediated by two isoforms of SOD: the cytosolic copper‐zinc SOD (CuZnSOD) and the mitochondrial manganese SOD (MnSOD). Moreover, overexpression of SODs has been found to confer oxidative stress resistance in worms (Doonan et al. 2008), flies (Sun et al. 2002) and mice (Dumont et al. 2009). Next, hydrogen peroxide must be broken down because, although it is not highly reactive, it can quickly form the hydroxyl radical in the presence of ferrous iron (Fe2+). Hence, the crucial role of glutathione peroxidase and catalase in hydrogen peroxide's reduction to water (Mueller et al. 1997). Indeed, overexpression of both glutathione peroxidase and catalase have been shown to increase stress resistance (Mockett et al. 2003; Murakami et al. 2003).

Additional cellular defenses include various proteases that are necessary for proteostasis. The cytosolic 20S Proteasome (Pickering & Davies, 2012a; Raynes et al. 2016b) and the mitochondrial Lon protease (Ngo et al. 2013; Bezawork‐Geleta et al. 2015; Pomatto et al. 2016b), cellular levels of which have been shown to transiently increase in response to mild oxidant perturbations, are crucial in protein quality control. Studies in cell culture (Pickering & Davies, 2012b; Pickering et al. 2012), worms (Pickering et al. 2013a; Raynes et al. 2016a), and flies (Pickering et al. 2013a,b) have demonstrated the rapid and short‐term induction of 20S Proteasome expression and activity following exposure to a mild, non‐damaging, adaptive amount of an oxidant. In turn, increased Proteasome expression has been shown to ensure protection against oxidative injury should the cells, worms, or flies, subsequently be exposed to a much higher dose of oxidant that would normally be toxic. Furthermore, induction of the 20S Proteasome was found to protect against excess protein oxidation, evidenced by decreased carbonyl accumulation (Jung et al. 2006; Poppek & Grune, 2006). Similarly, in vitro studies have shown that the mitochondrial Lon protease is transiently induced in response to multiples signals; including heat shock, serum starvation, hydrogen peroxide pretreatment, and endoplasmic reticulum (ER) stress (Hori et al. 2002; Ngo & Davies, 2009; Ngo et al. 2011). More recently, studies in D. melanogaster have shown the female‐specific induction of the Lon protease and its unique sex‐dependent protein isoforms found in fruit flies and mouse tissues (Pomatto et al. 2016a).

Cell culture studies have also revealed interesting differences between acute, repeated, and chronic exposures to adaptive levels of oxidants (Pickering, 2013b). Whereas a single exposure to low, signalling levels of H2O2 induced a strong adaptive response in cultured mammalian cells, this adaptive homeostatic response was lost with chronic exposure. Furthermore, although repeated exposures to signalling levels of H2O2 induced strong adaptive responses if the time intervals between treatments were kept sufficiently long, repeated exposures at very short intervals resulted in an abrogation of adaptive homeostasis (Pickering, 2013b). With more detailed research, these findings may eventually have particular significance for the field of environmental toxicology, and for occupational health and safety standards.

A major driving force in the activation of the transient stress response relies upon the transcriptional regulator nuclear factor erythroid 2‐related factor 2 (Nrf2) that activates target stress responsive genes, including subunits of the 20S Proteasome (Pickering et al. 2012), heme‐oxygenase‐1 (Alam et al. 1999), glutathione S‐transferases (Hayes et al. 2000), and NAD(P)H: quinone oxidoreductase 1 (NQO1) (Nioi & Hayes, 2004) by binding to antioxidant response elements (AREs), also known as electrophile response elements (EpREs). Under basal homeostatic conditions, Nrf2 is sequestered in the cytosol by Kelch‐like ECH‐associated protein 1 (Keap1) enabling the polyubiquitination of Nrf2 by the E3 ubiquitin‐ligase complex Cul3‐Rbx1 (Kobayashi et al. 2004), and its subsequent degradation by the ATP‐dependent 26S Proteasome (Itoh et al. 2003). However, upon exposure to electrophiles or oxidants, cysteine residues on Keap1 are modified and the protein may be phosphorylated, freeing Nrf2 from the Keap1‐Cul‐3 complex, and enabling its translocation across the nuclear membrane and subsequent binding to target genes within the nucleus (Zhang & Hannink, 2003; Kansanen et al. 2013). This phenomenon is found to occur even with mild exposure to non‐damaging levels of various oxidants (Pickering et al. 2012). Hence, due to the global protective effect of Nrf2, it is not surprising that many cancer cells show mutations in Keap1, promoting Nrf2 nuclear accumulation with (presumed) increased protection from immune surveillance (Zhang et al. 2010). Nor is chronic overexpression of Nrf2 always beneficial, as in vivo studies showed Keap1 knockout strains to be embryonic lethal (Wakabayashi et al. 2003). Thus the correct balance between Nrf2 degradation and activation is essential for an appropriate adaptive response (Fig. 3).

Figure 3. Increased transcription of stress‐protective genes by the Keap1‐Nrf2 signal transduction pathway.

Figure 3

During normal periods of homeostasis (‘no stress’), Nrf2 is kept in the cytoplasm by Keap1 which prevents Nrf2 from moving into the nucleus and binding to antioxidant response elements (AREs or EpREs) of stress‐responsive genes. Nrf2 levels are kept low (despite high rates of synthesis) by first being poly‐ubiquitinylated and then targeted for degradation by the 26S Proteasome. In this process, the Cul3 ubiquitin ligase component of the Keap1‐Cul3 complex is responsible for poly‐ubiquitinylation of Nrf2. During periods of stress, the 26S Proteasome undergoes disassembly by Ecm29 and HSP70 (generating free 20S Proteasomes) and Nrf2 can no longer be degraded. Nrf2 then disassociates from Keap1 and undergoes phosphorylation, enabling it to translocate into the nucleus and bind to ARE/EpRE elements in the upstream regions of target (protective) genes. These processes are the steps that cause activation of the adaptive homeostatic response, leading to the upregulation of stress‐protective enzymes an overall, but transient, increase in stress resistance.

Impaired adaptation to oxidant signals in ageing

Early work in yeast and mammalian cell cultures, demonstrated the rapid activation of stress‐responsive enzymes upon a mild oxidative stimulus. Non‐damaging levels of hydrogen peroxide (micromolar amounts) were found to actually stimulate cell growth. Furthermore, cells pretreated with adaptive (signalling) levels of an oxidant, showed no detrimental effects on cellular growth when subsequently exposed to a (normally) damaging level of the same (or similar) agent (Davies et al. 1995; Wiese et al. 1995; Shringarpure et al. 2001; Ngo & Davies, 2009; Pickering et al. 2012). However, in high‐passage or senescent cells, the rapid induction of the adaptive machinery is sluggish, at best. Human lung fibroblasts show a senescent‐dependent decline in the ability to activate stress‐responsive enzymes, such as the mitochondrial Lon protease (Ngo et al. 2011). In turn, high‐passage cells show a parallel decline to in the capacity to degrade and remove oxidized proteins, whether they are pre‐treated or not, coupled with increased susceptibility to apoptosis (Sitte et al. 2000a,b,c,d; Grune et al. 2001; Shringarpure & Davies, 2002).

The induction (and age‐dependent loss) of the stress‐responsive machinery is also evident and conserved in higher organisms. Recent work in C. elegans highlights this age‐associated loss. Three‐day old (young) nematode worms, pretreated with an adaptive dose of an oxidant (such as hydrogen peroxide), show increased survivorship compared to those not pretreated and subjected to the same semi‐lethal amount. However, with age this response is lost, as 10‐day old (aged) worms, irrespective of pretreatment, show no change in survival following semi‐lethal exposure (Raynes et al. 2016a). In a similar manner, 3‐day old (young) D. melanogaster flies are capable of increased survival when exposed to high levels of oxidants, if they are first pre‐treated with a low signalling level of oxidant, albeit in a sex‐specific manner. Older flies (10 days), however, completely lose this ability to adapt (Pomatto et al. 2016a, 2017b). Moreover, this trend in age‐dependent dysregulation of the adaptive homeostatic response has now been shown to be conserved in mice: young mice adapt well to low signalling levels of oxidants, whereas old mice fail to adapt (Zhang et al. 2012). Taken together, the above results indicate that abrogation or loss of oxidation‐induced adaptive homeostasis appears to be a widespread phenomenon of biological ageing.

Interestingly, simply more is not always better as evidenced by many studies showing that chronic overexpression of various antioxidant and stress‐responsive enzymes is not sufficient to extend lifespan (Pérez et al. 2009), and in some instances is even detrimental (Reis‐Rodrigues et al. 2012; Pomatto et al. 2016a). Nor is chronic overexpression able to restore adaptation (Raynes et al. 2016a). Indeed, ageing itself is associated with basal elevation in the levels (not necessarily the activities) of various stress responsive proteins, including the 20S Proteasome (Zhang et al. 2012; Raynes et al. 2016a). Importantly, inhibitors of Nrf2, such as Bach1 and c‐Myc have also been found to increase in ageing (Zhang et al. 2012; Raynes et al. 2016a), which may help to explain diminished Nrf2 signalling with age. Surprisingly, findings from long‐lived species showed lower basal levels of reactive oxygen species compared to short‐lived species. This may allow long‐lived animals to have lower basal levels of endogenous antioxidants and lower DNA and protein repair activity compared to short‐lived organisms (Barja, 2004; Pamplona & Costantini, 2011), although variation is seen within individual protein‐turnover systems (Pickering et al. 2015). Hence, longer‐lived organisms may be more efficient at limiting oxidative damage throughout the lifespan. More importantly, it is energetically less costly to lower endogenous oxidant levels than to elevate the expression of protective enzymes (Koga et al. 2011); or as Benjamin Franklin is quoted as saying, “an ounce of prevention is worth a pound of cure.”

As a result, long‐lived animals may have a greater basal reserve capacity (i.e. lower baseline amounts of stress‐responsive enzymes) than do short‐lived creatures. In turn, when the adaptive stress response is activated in older long‐lived organisms, they are better able to combat the stress compared to older animals from shorter‐lived species. Thus, in our efforts to restore the adaptive response, which clearly is normally lost with age (Pomatto et al. 2016a; Raynes et al. 2016a), one potentially sensible approach might initially be to focus our efforts on lowering the lifelong accumulation of damage, rather than simply forcing the chronic overexpression of stress responsive defenses. In this regard, it may also be important to note that, thus far, our attempts have demonstrated a ‘ceiling effect’ in the activation of the adaptive stress response (Fig. 1).

Adaptive homeostasis and heat shock

The heat shock response is an evolutionarily conserved mechanism, originally identified as a means to protect against the environmental consequences of heat stress, primarily protein misfolding (Mahat et al. 2016). The heat shock response was later identified to be activated by a variety of other stressors that also cause protein misfolding (Tower, 2011). Importantly, the heat shock response is initiated at temperatures below those that actually cause protein misfolding damage (although higher temperatures are also effective), thus qualifying as a true example of adaptive homeostasis. The response is mediated by the master transcription factor, heat shock factor 1 (HSF‐1) that, upon binding to heat shock response elements (HSEs), upregulates heat shock proteins (HSPs) (Parker & Topol, 1984). In turn, HSPs protect against protein aggregation by acting as chaperone proteins that bind to denatured or misfolded proteins and either help to restore correct folding or target proteins for degradation (Morimoto, 2008). The transient upregulation of HSPs offers the first line of defense against proteotoxicity, and they are quickly activated in response to only mild upward shifts in temperature (typically requiring only a few degrees above physiological temperature) that do not actually cause significant protein misfolding (Haslbeck & Vierling, 2015). Indeed, the transient, short‐term activation of HSPs, enable newly hatched D. melanogaster to withstand future, typically lethal temperatures, coupled with increased lifespan (Smith, 1958).

Moreover, the role of HSPs also supports the activation of additional adaptive stress responses, most notably in the freeing of the 20S Proteasome. Upon oxidative stress, the Ecm29 protein and HSP70 associate with the 19S caps of the 26S Proteasome, sequestering them away from the 20S ATP‐independent catalytic core (Wang et al. 2010; Grune et al. 2011). HSP70 remains bound to the 19S caps for 3–5 h, protecting them from proteolytic digestion, after which the 26S Proteasome is reassembled (Grune et al. 2011). The transient loss of intact 26S Proteasomes seems to account for the very rapid rise in Nrf2 levels, since Nrf2 is still synthesized but cannot be degraded during this period (Fig. 3). Additionally, HSP70 has been shown to interact with, and promote the degradation of, oxidized proteins by the 20S Proteasome (Reeg et al. 2016). Conversely, thermotolerance gained by increased HSP70 expression, is lost upon knock‐down of Nrf2, the transcriptional activator of proteasomal subunits (Bozaykut et al. 2016), indicating the tight interaction between these different stress responsive pathways in the cellular capability to prevent protein aggregation.

One of the leading hallmarks of ageing is loss of proteostasis (Ben‐Zvi et al. 2009; López‐Otín et al. 2013). To compensate, basal increases in various HSPs, including Hsp70, have been detected in tissues from elderly patients (Wheeler et al. 1995). Conversely, over‐expression of HSPs, or their transcriptional regulator, HSF‐1, have been found to promote stress resistance and longevity in both worms (Hsu et al. 2003; Prithika et al. 2016) and flies (Kurapati et al. 2000). Moreover, higher basal levels of multiple HSPs (including Hsp60 and Hsp70) were found to be characteristic of long‐lived organisms (Salway et al. 2011), while loss of the small mitochondrial heat shock protein (Hsp22) was found to be detrimental to lifespan (Morrow et al. 2004) Indeed, the expression of HSPs, primarily Hsp70, have been suggested as a potential biomarker of ageing, in D. melanogaster, due to the correlation between elevated Hsp70 and Hsp22 expression and lifespan (Yang & Tower, 2009). This finding is supported by the sudden spike in Hsp70 and Hsp60 expression approximately 10 h prior to fly death (Grover et al. 2009). Moreover, flies that show increased lifespan also show increased HSP expression (Kurapati et al. 2000). Interestingly, multiple mammalian cancer lines show elevated Hsp70 expression, with higher levels typically associated with poor prognosis and higher resistance to chemotherapy (Calderwood et al. 2006).

The basal expression of HSPs exhibits an age‐related increase; however, their inducibility strongly declines. Studies using rat lung and skin fibroblasts from 24‐month old animals, showed decreased induction of Hsp70 following heat treatment (Fargnoli et al. 1990). Similarly, aged skeletal muscle shows delayed induction of HSPs following exercise (Vasilaki et al. 2003b). Together, these findings indicate that the loss of adaptative homeostasis capacity with ageing leaves animals and cells unable to compensate for the deteriorating regulation of proteostasis, and hence the progression of the ageing phenotype. Apparently, even compensatory increases in basal levels of heat shock proteins are unable to compensate for this decline in adaptive homeostasis that occurs with ageing.

Adaptive homeostasis and glucose stress

Normal physiological processes generate cellular perturbations, including those arising from glucose deprivation. The endoplasmic reticulum (ER) stress response, also known as the unfolded protein response (UPR), serves to maintain the cellular proteome during periods of cellular duress (Hetz, 2012). To withstand such perturbations, the ER relies upon chaperone proteins, which are essential for proper protein folding. The 78 kDa glucose‐regulated protein (GRP78), also known as binding immunoglobulin protein (BiP) is a protein encoded by the HSPA5 gene in humans which, along with other GRPs such as GRP94, is induced by glucose starvation (Ting & Lee, 1988; Hendershot et al. 1994; Lee, 2014). The GRPs are also induced by heat stress (see above), hypoxia, calcium imbalance, and several other stressors that challenge proteostasis. GRPs have also been implicated in responses to metastasis.

GRP78 and GRP94 are the two most abundant ER chaperone proteins. Yet unlike GRP78, which is conserved from yeast to humans, GRP94 is unique to multicellular organisms, potentially due to its important role in the innate and adaptive immune response (Zhu & Lee, 2015). Additionally, GRP78 serves as a general ER chaperone protein, in contrast to GRP94, which selectively assists with the folding of proteins involved in immunity, growth signalling, and cell adhesion (Staron et al. 2010).

GRPs serve not only as ER‐chaperone proteins, but regulate the UPR response, with GRP78 acting as the gate‐keeper for UPR initiation. Under homeostatic conditions, GRP78 is bound to three ER‐bound signalling proteins, IRE‐1, PERK, and ATF6, retaining them in an inactive state. However, upon ER accumulation of misfolded proteins, GRP78 dissociates, enabling the activation of downstream signalling pathways. Following ER stress, three stages of UPR activation ensue. First, attenuation of global protein translation is mediated by the recently released serine‐threonine kinase, PERK (Brostrom & Brostrom, 1998; Ni et al. 2009). In parallel, ATF6 translocates and binds to ER stress responsive elements, including GRP78 and GRP94, leading to their increased expression (Okada et al. 2002). Lastly, the Proteasome works to augment protein degradation by ER associated degradation (ERAD) (Hiller et al. 1996). GRPs are not confined solely to the ER upon stress. Specifically, GRP78 and GRP94 contain a C‐terminal tetrapeptide sequence KDEL, enabling them to be released from the ER during stress. GRP78 can be excreted into the extracellular space (Delpino & Castelli, 2002) and, along with GRP94, can also be presented on the cell surface (Altmeyer et al. 1996). Additionally, GRP78 has been found to associate with the mitochondrial matrix (Sun et al. 2006), with evidence suggesting it interacts with the mitochondrial stress responsive Lon protease (Kao et al. 2015). Thus GRPs are probably not limited only to roles in the ER environment, but also appear to be necessary for other diverse cellular functions and signalling.

Malignant cells are highly stress adaptive. The unique tumour microenvironment alters glucose metabolism due to impaired blood flow and resultant hypoxia. These conditions are all known inducers of ER stress. Not surprisingly, various cancer cells show elevated GRP78 expression, as poor nutrient perfusion and resulting glucose starvation are known inducers of GRP78. In turn, elevated GRP78 expression can further augment tumour survivability and chemoresistance (Li & Lee, 2006; Virrey et al. 2008). In a study conducted with 219 prostate cancer patients, elevated GRP78 expression was associated with poor prognosis (Pootrakul et al. 2006). Moreover, high expression of GRP78 increases the risk for recurrence of a variety of cancers and is associated with lower patient survival (Daneshmand et al. 2007; Pyrko et al. 2007; Zhuang et al. 2009).

Glucose homeostasis, mediated by insulin signalling, plays a pivotal role in ER stress and GRP expression levels, and is extremely malleable to normal physiological perturbations. Upregulation of insulin, and corresponding activation of insulin‐like growth factor (IGF‐1) signalling, induces protein synthesis and cellular growth. For example, the rise in plasma insulin levels resulting from feeding cause GRP78 expression and expression of the UPR machinery in rat hepatic tissues (Pfaffenbach et al. 2010). In addition, activation of IGF‐1 can prevent apoptosis arising from prolonged ER stress. Mammalian cell culture studies have indicated that insulin exposure results in a rise in GRP78 expression levels and parallel activation of the UPR machinery (Novosyadlyy et al. 2008); conversely, caloric restriction causes a decrease in GRP78 expression (Pfaffenbach et al. 2012).

Nor is the impact of IGF‐1 signalling unidirectional. Changes in the levels of ER chaperone proteins can modulate insulin sensitivity and glucose homeostasis, as in the case of IGF‐1, with levels shown to be proportional to GRP94 activity (Barton et al. 2012). Moreover, metabolic disorders, such as type II diabetes, provide further evidence of the important role of GRPs in insulin sensitivity. As metabolic disorders trigger chronic ER stress (Eizirik et al. 2007), upregulation of GRPs may serve to counteract cellular damage. Indeed, overexpression of GRP78 reduced hepatic steatosis and improved insulin sensitivity in the diabetic‐prone ob/ob mouse strain (Kammoun et al. 2009). Administration of ER chaperones also decreased weight gain and restored insulin sensitivity in ob/ob mice (Özcan et al. 2006). The relationship between GRPs and metabolic disorders appears to be conserved in humans, as patients who underwent gastric bypass surgery showed a decline in ER stress within adipose tissue 1 year after the surgery, including decreased levels of adipose GRP78 expression (Gregor et al. 2009). Furthermore, GRP expression may prevent the development of metabolic disorders. Following a 30‐week high fat diet, GRP78 heterozygous mice, (with the standard C57/B6 genetic background) showed lower rates of insulin resistance and increased glucose homeostasis, irrespective of weight gain, compared to wild‐type controls (Ye et al. 2010). These results suggest important roles of GRPs, not only in preventing metabolic disorders, but also as critical components of the stress‐response arsenal.

With age, however, activation of the adaptive arm of the UPR declines. This is partly because of age‐related structural changes within the ER and the gradual loss of stress‐responsive enzymes, which together limit proper protein folding. Moreover, loss of ER‐chaperone induction may help explain the increased risk for age‐dependent metabolic disorders. Indeed, the decline in IGF levels, evident with advancing age, may actually result from a decline in chaperone activity (Argon & Gidalevitz, 2015). Additionally, multiple tissues exhibit an age‐associated decline in GRP78 and GRP94 protein expression (Brown & Naidoo, 2012). For example, hepatic tissue from 22‐month old mice showed a significant reduction in GRP78 expression, coupled with increased evidence of oxidative damage (Nuss et al. 2008b). Moreover, multiple tissues from 22‐month old rats showed significant decreases in GRP78 expression, including the hippocampus (Paz Gavilan et al. 2006), cortex and cerebellum (Hussain & Ramaiah, 2007), and peripheral tissues (lung, liver, kidney, heart, and spleen) (Hussain & Ramaiah, 2007). Furthermore, with age, both GRP78 and GRP94 become increasingly susceptible to oxidation, further diminishing their functional capacity (Nuss et al. 2008a). As well, loss in GRP induction may promote age‐related neurodegenerative diseases, including Parkinson's and Alzheimer's disease. Although UPR activation in the early stages of these pathologies may initially serve a neuroprotective role against ER stress, sustained activation may trigger an apoptotic response leading to disease acceleration rather than mitigation. On the other hand, currently available evidence of ER‐chaperone induction is conflicting. One study found that neurons from Alzheimer's disease patients showed increased GRP78 expression (Hoozemans et al. 2005), while a later study showed no change (Lee et al. 2010), highlighting the need for further exploration. Overall, it would appear that the age‐associated loss of the acute and rapid modulation of ER‐chaperone proteins may accelerate the ageing process.

Adaptive homeostasis and hypoxia

During cellular normoxia (typically 5% intracellular O2 in many mammalian tissues), the conversion of glucose into pyruvate and subsequent ATP generation via the mitochondrial oxidative phosphorylation pathway is the predominant source of cellular energy. Approximately 90% of oxygen is utilized as the final electron acceptor in the mitochondrial electron transport chain (ETC) in this highly energy‐rich pathway (Semenza, 2007). In turn, only a small percentage (1–5%) of electron leakage (and subsequent O2 and H2O2 formation) occurs (Rich, 2003). However, during hypoxia, oxygen becomes the limiting factor in the ETC function, resulting in the ATP/AMP ratio falling and the production of mitochondrial‐derived O2 and H2O2 increasing (Hardie & Ashford, 2014).

Fortunately, adaptation to hypoxia enables cells to adapt by implementing the AMP‐activated protein kinase (AMPK) pathway (Mungai et al. 2011), which under short duress, can partially compensate for cellular energy demands. However prolonged hypoxia requires transcriptional remodelling, mediated by hypoxia inducible factor 1 (HIF‐1), a heterodimeric transcription factor comprising HIF‐1α and HIF‐1β, that binds to hypoxia response elements (Semenza et al. 1996), resulting in transcriptional reprogramming of a wide‐array of genes, most notably those involved in metabolism and the stress response (Blokhina et al. 2014). Moreover, the dimerized protein complex of HIF‐1 is crucial in the cellular shift from oxidative phosphorylation to glycolysis, as demonstrated by the concurrent increase of the glucose import proteins GLUT‐1 and GLUT‐4 (Clerici & Matthay, 2000), and the upregulation of its transcriptional target, pyruvate dehydrogenase kinase (PDK), which blocks the conversion of pyruvate to acetyl CoA (the first substrate of the mitochondrial TCA cycle) by pyruvate dehydrogenase. In turn, the accumulation of pyruvate increases lactate formation, via lactate dehydrogenase, ensuring NAD+ regeneration for continued glycolysis. To further facilitate the cellular transition to glycolysis, HIF‐1 promotes the transition from cytochrome c oxidase 4‐1 (Cox4‐1) to Cox4‐2, by directly promoting its expression and the upregulation of the mitochondrial Lon protease (Fukuda et al. 2007; Ngo et al. 2013; Bota & Davies, 2016), which actively degrades Cox4‐2 (Watabe et al. 1993), ensuring optimal ATP generation, while limiting reactive oxygen species formation under hypoxia. Clearly, none of the events described above are a response to damage and, instead, they may all be classified as part of a massive metabolic adaptive homeostatic response to low oxygen.

The ability to adapt to low‐O2 environments, is probably best exemplified by the hyper‐adapted cancer cell. The rapid growth of cancerous tumours, results in them quickly outgrowing both their oxygen and nutrient supply (Suda et al. 2011). Hence, many cancer cells (including those highly resistant to current pharmacological interventions) can quickly conscript oxygen‐sensing pathways to enable adaptation to hypoxic environments (as evidenced by increased rates of glycolysis), largely due to HIF‐1α stabilization (Semenza, 2013). This adaptive ability underlies the protection many malignant cells exhibit against a wide variety of cytotoxic drugs and radiotherapy (Hockel et al. 1993; Brizel et al. 1996). Certain forms of cancer show mutations in von Hippel‐Lindau (VHL) protein, a key cytosolic protein, which under normoxia conditions, ensures the ubiquitin‐Proteasome degradation of HIF‐1α. Yet, these mutations prevent the homeostatic degradation of HIF‐1α, and instead enable its nuclear accumulation. Increased HIF‐1α levels have been linked to poor patient prognosis, specifically in head, neck and breast cancers (Semenza, 2010a).

Interestingly, low oxygen exposure has been associated with increased lifespan. In vitro studies using human fibroblasts and vascular smooth muscle cells, exposed to chronic hypoxia, found a decreased rate of replicative senescence (Minamino et al. 2001). Moreover, removal of VHL in C. elegans showed lifespan extension and protection against proteotoxicity (Mehta et al. 2009). However, normal ageing shows an age‐dependent decrease in HIF‐1 DNA‐binding ability in lung, liver, kidney, and brain tissue from 24‐month old mice, following systemic hypoxia exposure (Frenkel‐Denkberg et al. 1999). This finding has also been corroborated by decreased HIF‐1α expression. Moreover, microarray analysis comparing fibroblasts from young adults (less than 25 population doublings) versus old (between 65 and 70 population doublings) found that genes involved in angiogenesis and oxidative stress were severely impaired, along with HIF‐target genes, including vascular endothelial growth factor (VEGF) (Rivard et al. 2000) and GLUT‐1 (Xia et al. 1997).

Due to the intricate connection between mitochondria and oxygen reliance, hypoxia therapies have been proposed as alternative therapeutic approaches to several diseases. Indeed, multiple chronic diseases (including type II diabetes, sarcopenia, and neurodegeneration), as well as ageing itself, are characterized by decreased mitochondrial oxidative phosphorylation and by mitochondrial dysfunction. To test this hypothesis, researchers relied upon a pediatric mitochondrial‐specific disease, Leigh syndrome, within a mouse model. Acute hypoxia (6 h at 8.5% O2), caused HIF‐1α stabilization. Furthermore, chronic hypoxia (11% O2) was capable of alleviating the disease phenotype, coupled with 50% improved mortality (120 days versus 60 days) (Jain et al. 2016). Together, these results indicate that hypoxia adaptation may play a role in not only slowing disease onset and/or disease progression, but may also provide a new potential avenue to extend the healthspan.

Intermittent, prolonged exposure to hypoxia is characteristic of aged tissues (Ogunshola & Antoniou, 2009; Semenza, 2010b; Zhang et al. 2011), as is evident following cyclical hypoxia, which is known to activate a wide‐array of cellular signalling pathways (O2 sensing, metabolism, oxidative stress, and immune function) (Douglas & Haddad, 2008). Continual dysregulation can have dire consequences for cellular function and integrity, with the cumulative impact leading to dampened ability to withstand future stress. A common form of intermittent hypoxia is sleep apnoea, which has been linked to an individual's risk for accelerated forms of dementia (Pan & Kastin, 2014) and the development of insulin resistance (Ip et al. 2002), which is further exacerbated by advancing age (Bixler et al. 1998). Moreover, individuals diagnosed with sleep apnoea are at elevated risk of stroke (Luo et al. 2014; Marshall et al. 2014), myocardial infarction (Lanfranchi & Somers, 2003), and sudden death (Shamsuzzaman et al. 2015).

At the cellular level, prolonged periods of low oxygen, result in the activation of HIF‐1α and a concurrent rise in generation of reactive oxygen/nitrogen species. This results from the cyclical hypoxia/normoxia phases, that increase the rate of O2 •− , H2O2, and HO formation (Semenza, 2000), predominantly from complex III of the mitochondrial electron transport chain (Guzy et al. 2005). In turn, excess free radicals accelerate lipid peroxidation (Chen et al. 2005; Li et al. 2007b), leading to tissue damage. Furthermore, the excess oxidants can activate the inflammatory response that leads not only to activation and/or perpetuation of atherosclerosis, but also to a cumulative rise in serum lipid levels (Li et al. 2007a) coupled with an increase in blood glucose (Kent et al. 2015). Together, these factors contribute to a downward cycle of vasculature health.

Heart disease is a prime example of the inability to modulate the hypoxic response. Currently, heart disease is one of the leading causes of death in the western world (Roger et al. 2012). During periods of reduced tissue perfusion (such as gradual arterial plaque accumulation), leads to a hypoxic environment and the subsequent chronic elevation in HIF‐1α. In turn, this promotes angiogenesis in an attempt to increase blood flow. Indeed, patients who show increased vasculature remodelling are likely to have lower cardiac tissue damage and smaller infarct size (Habib et al. 1991; Seiler et al. 2013). Single nucleotide polymorphisms of HIF‐1α may predispose individuals for greater vasculature remodelling, with one variant appearing at a fivefold higher rate in these patients (Resar et al. 2005). However, with age, this adaptive response declines, leaving tissue vulnerable to damage (Bosch‐Marce et al. 2007). In a similar manner, pressure overload heart failure triggers chronic activation of HIF‐1α. Hypertension leads to a systemic increase in arterial resistance, causing left ventricular hypertrophy in order to maintain ejection fraction. Eventually, however, the increased workload caused by hypertrophy leads to reduced ejection rate and the clinical presentation of heart failure (Levy et al. 1990). Slowing this progression is the chronic activation of HIF‐1α and its promotion of vasculature remodelling. Conversely, knockout of HIF‐1α in mouse cardiomyocytes resulted in a more rapid decline of cardiac ejection fraction and increased end‐systolic ventricular diameter, due to decreased capillary bed, resulting in cardiomyocyte hypoxia (Sano et al. 2007). Concurrently, chronic activation of HIF‐1α triggers metabolic reprogramming, shifting away from oxidation of fatty acids towards the glycolytic pathway for ATP production. However, this approach leads to an inadequate ATP supply for proper cardiac function (Taegtmeyer et al. 2004). Together, these different disease states highlight the consequences of inability to properly regulate HIF‐1α expression: in early stage disease HIF‐1α serves a protective role, whereas during disease progression it may promote pathogenesis.

Adaptive homeostasis and cold shock

Adaptation to variations in environmental temperature is one of the most common stresses with which organisms must cope, yet it is one of the least understood adaptive responses, especially in mammals. Moreover, the present‐day relevance of understanding the impact of cold shock is evident in methodologies used for cell‐culture and tissue preservation (Al‐Fageeh et al. 2006). Current research indicates that upon even mild cold exposure, most mammalian cells exhibit similar responses, including decreased metabolism, reduced glutathione and glutamine consumption, inhibition of ATP expenditure, decreased protein synthesis, and growth arrest (Van Breukelen & Martin, 2002). Moreover, cold shock causes two forms of stress: the direct result of decreased temperature and the indirect elevation in dissolved oxygen concentration (hyperoxia) (Chuppa et al. 1997).

From yeast to mammals, a specific set of cold shock proteins (CSPs) have been identified as a common adaptive response to cold exposure (Fujita, 1999; Homma et al. 2003), and these CSPs are induced even at temperatures that cause no observable damage so they are true examples of adaptive homeostasis. Mild hypothermia (25°C) was found to induce CSPs, most notably, the induction of cold‐inducible RNA‐binding protein (Cirp) and RNA binding motif 3 (Rbm3) in multiple mammalian cell lines (Gon et al. 1998; Neutelings et al. 2013), both of which have been characterized as RNA‐binding proteins necessary for translation of cold‐specific proteins (Dresios et al. 2005). Moreover, upon rewarming, the heat‐shock response is activated, indicating that return to normal physiological temperature (37°C) induces an additional burst of reactive oxygen species, most likely from the sudden activation of mitochondrial respiration (Liu et al. 1994). This is evident in D. melanogaster subjected to short‐term cold shock (60 min at 0°C) and then allowed to recover (8 h at 25°C), resulting in increased transcription of small heat shock proteins (Colinet et al. 2010). Additionally, cold exposure early in the life of D. Melanogaster increases stress resistance (including elevated heat tolerance) and results in lifespan extension in later life (Le Bourg, 2007). Together, these results indicate that adaptive signals continue, even after the return to normal physiological temperatures.

Adaptation to cold stress has been explored at the physiological level, most notably the usage of repeated exposure to cold temperatures as a means of cold acclimation in humans. ‘Cold acclimated’ subjects demonstrate an adaptive response to hypothermia: reduced body temperature at rest and delayed metabolic response when subjected to the cold, coupled with conserved body heat (20%) (Golden & Tipton, 1988; Janský et al. 1996). Together, these findings demonstrate a new physiological threshold for induction of cold thermogenesis occurring at a lower temperature set‐point. However, studies conducted in the short‐tailed field vole Microtus agrestis found that following short‐term exposure (1, 10, or 100 h) to acute cold (7 ± 3°C), protein turnover was suppressed and protein oxidation subsequently increased in all tissues (heart, liver, kidney, small intestine, and skeletal muscle), tested except for brown adipose tissue. Brown adipose tissue is critical in thermoregulation (Selman et al. 2002), indicating that a tissue‐specific preference may take precedence, and may be necessary for long‐term survival of cold exposure.

In a health context, mild cold exposure has been suggested as an alternative means of combating obesity. This is in large part because cold induces shivering (‘shivering thermogenesis’), an energy expending response for heat generation, and consequently, can raise the resting metabolic rate by fivefold, and is crucial in protecting against hypothermia (van der Lans et al. 2014). Additionally, non‐shivering thermogenesis (NST), which occurs in brown adipose tissue as a means to increase the core body temperature independently of muscle contractions, has been shown to increase in young to middle‐aged adults in response to mild cold (Harms & Seale, 2013). Moreover, repeated exposure to mild cold can trigger increased energy expenditure. One study found that a 2‐week period of repeated cold exposure resulted in decreased body fat content (Yoneshiro et al.). Thus regular cold exposure may increase an individuals’ fortitude which may be especially important in vulnerable populations. For example, epidemiological studies, have reported that sudden exposure to cold weather without pre‐conditioning is associated with increased mortality in patients with cardiovascular disease, pulmonary disease, or cancer (Gómez‐Acebo et al.).

Currently, the literature has little to say about the changes in cellular adaptations to cold stress that may occur with age. Early studies did indicate, however, that baseline body temperature decreases with advancing age (Primrose & Smith, 1982), coupled with reduced ability to maintain core body temperature (Fox et al. 1973). Moreover, upon exposure to hypothermia, vasoconstriction (a protective response against hypothermia) appears to exhibit an age‐dependent decline (Frank et al. 2000). This is partly because vasoconstriction relies upon effective tissue insulation, mediated by contractile skeletal muscles, which is dampened due to age‐associated muscle loss (sarcopenia). In turn, older adults are less able to thermoregulate, resulting in a 20% decline in basal heat production (Poehlman et al. 1993). Moreover, sudden exposure to dramatic changes in temperature can be harmful (even life‐threatening) to the elderly, who have much lower temperature tolerance, compared to young adults (van Marken Lichtenbelt et al. 2014).

Adaptive homeostasis and exercise training

Endurance exercise adaptation

Skeletal muscle is a highly malleable and adaptable tissue. It can respond to various types of exercise (short‐term acute bouts or long‐term endurance training), primarily through transient cellular remodelling. Endurance type training (long duration at low to moderate intensities) results in large increases in the mitochondrial content of muscles (especially slow‐twitch and fast‐twitch oxidative fibres) whereas sprint training and resistance training (high intensity and short duration) have little effect on muscle mitochondria, but greatly increase glycolytic capacity (especially in fast‐twitch fibres) and muscle hypertrophy (Davies et al. 1981, 1982a,b, 1984; Maguire et al. 1982; Merry & Ristow, 2016). A single bout of truly exhaustive endurance exercise generates greatly increased production of reactive oxygen and nitrogen species and activates synthesis of heat‐shock and other stress‐related proteins (Davies & Hochstein, 1982; Davies et al. 1982c; Salo et al. 1991). On the other hand, endurance exercise training (also called aerobic exercise training) for several weeks duration at much lower levels of exertion causes adaptations while avoiding excess free radical production, activation of shock/stress responses, or evidence of tissue damage (Salo et al. 1991). Thus, endurance exercise training causes adaptive homeostatic increases in muscle mitochondria and exercise endurance that last only as long as the training stimulus is maintained; if exercise training is discontinued, both the mitochondrial content of muscle and the enhanced exercise performance will gradually revert to pre‐training levels. Importantly, as part of a true adaptive homeostasis response, the training effect actually protects against potentially harmful metabolic byproducts, including reactive oxygen and nitrogen species, free radicals, acids, and aldehydes, which in high quantities can be damaging to cellular proteins, lipids, and DNA (Hemnani & Parihar, 1998; Bergamini et al. 2004). Clearly, regular aerobic exercise ensures an adaptive physiological change in both the basal set‐point and improved tolerance to future insults; however, it must be remembered that all such adaptive changes are transient and both animals and people undergo reversion, or de‐adaptation, if training is terminated.

During exercise mitochondrial metabolism (oxidative phosphorylation) is increased to meet the energy demands of contracting skeletal muscle, consequently, elevating cellular reactive oxygen and nitrogen species (Powers et al. 2010), mainly nitric oxide (formed from nitric oxide synthase) (Ghafourifar & Cadenas, 2005) and O2 •− (formed from ubisemiquinone, complex I and III) (Barja, 1999), which is dismutated into the mild oxidant H2O2. Due to their relatively long half‐lives, chemical stability and diffusion radius, both serve as crucial exercise‐induced mitochondrial signalling molecules, that stimulate cellular remodelling and indirectly help mediate an exercise‐induced adaptive response.

Together, these mitochondrial signals work to amplify cellular remodelling, including increased mitochondrial biogenesis (Davies et al. 1981, 1982a, 1984; Konopka et al. 2013). In turn, as over 95% of mitochondrial proteins are nuclear‐encoded, this requires transcriptional activation by various mediators, most notably through the upregulation of arguably the master regulator of mitochondrial biogenesis, PGC‐1α (Scarpulla, 2006). Indeed, overexpression of PGC‐1α obliterates age‐associated muscular decline in type I muscle fibres and increased endurance capacity (Lin et al. 2002). As well, the nuclear respiratory factor 1 (Nrf1), shown to increase in response to contractile stimulation, is necessary for the upregulation of various nuclear‐encoded mitochondrial genes, including the mitochondrial transcription factor A (TFAM), which is vital for mitochondrial translation of key ETC complexes (Kaufman et al. 2007).

At the physiological level, endurance training results in an adaptive response manifested by increased muscle glycogen stores, enhanced glycogen utilization via increased fatty acid oxidation, and increased mitochondrial biogenesis (Adhihetty et al. 2003), all of which contribute to improve resistance to fatigue. Moreover, muscular adaptability is highly dependent on mitochondrial plasticity. Hence, continual exercise can transiently elevate basal mitochondrial protein content by 50–100% within 6 weeks of commencing an exercise regime (Zierath & Hawley, 2004). Moreover, within 3–12 h after exercise, transient increases in the mRNA levels of key antioxidant responsive enzymes are already detectable, including catalase and superoxide dismutase (Bickel et al. 2005; Mahoney et al. 2005). Yet long‐term exercise‐mediated adaptation requires daily bouts to reap the beneficial effects (Li et al. 2006).

At higher levels of exertion, damage occurs in addition to adaptation and exercise‐induced stress causes perturbations to the mitochondrial proteome. The close proximity of mitochondrial proteins to reactive byproducts of the electron transport chain makes them easy targets for damage, activating the mitochondrial unfolded protein response (mtUPR) (Runkel et al. 2013). This is mediated through the mitochondrial export of small peptides: degradation products of non‐functioning mitochondrial matrix proteins formed by various mitochondrial proteases, most notably the Lon protease (Ngo et al. 2013). Elevation in mitochondrial metabolites (specifically a change in the AMP/ATP ratio) (Richter & Ruderman, 2009) and efflux of mitochondrial calcium (Luo et al. 1997) further contribute to the amplification of exercise‐induced mitochondrial signalling to the nucleus.

Concurrently, stress‐responsive and maintenance pathways are also transiently induced upon exercise. Specifically, activation of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFкB) signalling cascade, which is involved in regulating stress‐responsive enzymes (Kramer & Goodyear, 2007), promoting anti‐inflammatory signalling, and DNA repair and maintenance (Radák et al. 2002). In addition, upregulation of protein chaperones, namely heat‐shock proteins (González & Manso, 2004; Lancaster et al. 2004) and those regulating protein turnover, such as the Proteasome (Louis et al. 2007), all show increased transient expression and activity following exercise‐induced stress. Conversely, blockage of reactive oxygen species generation, eliminates exercise‐induced expression of antioxidant enzymes, including mitochondrial superoxide dismutase (SOD2) and the inducible form of nitric oxide synthase (iNOS) (Gomez‐Cabrera et al. 2005; Gomez‐Cabrera et al. 2015).

Adaptation to resistance training

In contrast with endurance training, resistance training requires muscles to work against an opposing force, providing a potent stimulus to induce muscle hypertrophy. In order to generate force, skeletal muscles rely upon the contractile actions of post‐mitotic, multinucleated myofibres which, following resistance training, adapt through increased fibre diameter, longitudinal growth, and predominance of fibre type (Davies et al. 1982c, 1984), along with increased protein synthesis (Davies & Hochstein, 1982). Unlike endurance training, which shows a higher ratio of ‘slow‐twitch’ or mitochondrial‐enriched Type I fibres (Salo et al. 1991), resistance training activates ‘fast‐twitch’ or glycolytic Type IIA and IIB fibres (Hemnani & Parihar, 1998; Bergamini et al. 2004), indicating differences in energy‐utilization and corresponding adaptive responses. Perhaps nowhere is the coincidence of adaptive homeostatic enhancements of tissue capabilities and clear evidence of actual tissue damage so clear as in resistance training of mammalian muscles. Again, however, there is little or no evidence to suggest that damage is responsible for adaptation, rather than the multiple signal transduction systems described below.

Activation of quiescent myogenic precursor cells, also known as satellite cells, is central to this muscular remodelling, and is found to be induced throughout the lifespan (Ghafourifar & Cadenas, 2005; Powers et al. 2010). This is mediated predominantly by mechanical stress that causes perturbations to skeletal muscle integrity. In turn, activating a plethora of cellular pathways in response to changes in mechanochemical signalling, including the Akt/mammalian target of rapamycin (mTOR) pathway (Davies et al. 1982c) and parallel increases in IGF‐1 levels (Barja, 1999). Indeed, evidence suggests that mechanical stress, alone, is capable of activating the mTOR pathway, mediated by the kinase‐tuberous sclerosis complex 2 (Erk‐TSC2) (Runkel et al. 2013). Concurrently, multiple isoforms of the insulin growth factor have been identified as crucial molecules in muscular adaptive responses to resistance training, which together are termed the mechano‐growth factor (MGF). Indeed, following mechanically induced muscular activation, MGF levels are reported to undergo rapid elevation (Richter & Ruderman, 2009). The localized production of MGF suggests it may work to promote muscular recovery, as it may serve to ‘kick‐start’ the hypertrophic response, thus facilitating rapid repair and growth (Luo et al. 1997). Additionally, findings suggest MGF acts to promote the fusion of satellite cells with existing muscle fibres, ensuring the optimal ratio between DNA and protein levels necessary for long‐term muscular growth (Scarpulla, 2006; Konopka et al. 2013).

Due to the high energy demands involved in resistance training, it is not surprising that reactive oxygen species play an important role in modulating the adaptive muscular response. Indeed, mitochondria found in ‘fast‐twitch’ fibres show heightened production of reactive oxygen species, in comparison to mitochondria from ‘slow‐twitch’ fibres, which are typical in aerobically trained muscle (Lin et al. 2002). In addition, the relatively prolonged periods of muscular tension that occur during resistance training mimic an ischaemic‐reperfusion environment (Kaufman et al. 2007; Kramer & Goodyear, 2007), which is well documented to create high levels of reactive oxygen species (Radák et al. 2002). Conversely, removal of the transcriptional hypoxia regulator HIF‐1α causes decreased glycolysis and increased muscular damage (González & Manso, 2004; Lancaster et al. 2004), suggesting that myocytes are uniquely adapted to the hypoxic environment that arises during resistance training. Increased oxidant production has also been associated with not only smooth muscle and cardiomyocyte growth (Louis et al. 2007), but also myofibre growth (Gomez‐Cabrera et al. 2015). As well, studies involving mice deficient in selenoproteins, a class of antioxidant enzymes, showed increased exercise‐mediated muscular growth (Gomez‐Cabrera et al. 2005), suggesting that reactive oxygen species may serve as a moderator of the adaptive muscular response. In a similar manner, external application of reactive oxygen species to myocytes was found to activate the MAPK pathway, a prerequisite for protein synthesis (Adhihetty et al. 2003). Conversely, removal of redox signalling was found to significantly blunt IGF‐1‐induced phosphorylation of the IGF‐1 myocyte receptor, limiting muscular growth (Zierath & Hawley, 2004).

A unique adaptive muscular response that occurs only with resistance training, is cellular swelling. Increased intracellular hydration, or ‘cell swelling’ is associated with increased protein synthesis and decreased proteolysis (Bickel et al. 2005), two indicators of myofibre growth. Moreover, resistance training is associated with perturbing the intra‐ and extracellular osmotic balance (Mahoney et al. 2005), due to the resulting rise in lactate because of myofibre reliance upon glycolysis (Li et al. 2006). Fast‐twitch fibres are especially adapted to osmotic changes, as they show higher expression of aquaporins (Li et al. 2006; Degens, 2010). Indeed, lack of aquaporin expression in fast‐twitch fibres leaves them vulnerable to mechanical and osmotic stress, as evident in muscular dystrophy (Sarkar & Fisher, 2006). Thus cell swelling may play a crucial role in myofibre remodelling in response to resistance training.

Exercise adaptation in aged skeletal muscles

Aged skeletal muscle shows a rise in the basal set‐point of stress‐responsive and antioxidant enzymes. Indeed, increased basal inflammation (Degens, 2010), further augmenting the production of reactive oxygen species (Sarkar & Fisher, 2006; Sriram et al. 2011), accompanied by increased rates of protein degradation (Goto et al. 2007; Altun et al. 2010), all ensue, and are all contributing factors for age‐dependent sarcopenia (Fielding et al. 2011). Additionally, an age‐dependent decline was identified in aged (28‐month) versus young (5‐month) rats upon examination of the Akt and Erk signalling pathways and PGC‐1α, Nrf1, and TFAM expression (Wenz et al. 2009), while conversely basal expression of the stress‐responsive proteins increased, including the Proteasome (Ziaaldini et al. 2015), Hsp70 (Vasilaki et al. 2002), SOD1 (Cobley et al. 2014), HSF‐1 (Vasilaki et al. 2006), and NFкB (Fry et al. 2016). Hence, due to continual basal stress, aged muscle is unable to further upregulate crucial stress responsive proteins, demonstrating a marked loss in age‐dependent adaptability when challenged with an acute exercise bout (Vasilaki et al. 2003a, 2006). However, continual exercise training, over the lifespan, does enable the inducibility of certain (but not all) stress‐responsive proteins, including catalase. Moreover, protein nitration is lower in old trained individuals compared to sedentary counterparts.

Fortunately, the adaptive benefits of exercise are still somewhat inducible with age, albeit not to the levels of young animals. Following 12 weeks of endurance training, aged rat muscle showed a transient increase in PGC‐1α and TFAM mRNA levels, accompanied by lower oxidative damage (decreased lipid peroxidation) and increased SOD and glutathione activity when compared to age‐matched sedentary animals. Mitochondria from trained animals also demonstrated higher oxidative stress resistance (Kang et al. 2013). Indeed, studies in older subjects (71 years) showed transient upregulation of mitochondrial biogenesis genes following an acute bout of exercise (75% V˙O2 max ) (Iversen et al. 2011). Unfortunately, they were unable to match the basal levels of younger individuals, indicating that the physiological set point and the maximal adaptive homeostatic response range may compress with age.

Aged muscle is also at a heightened risk of developing sarcopenia, or the gradual loss in muscle mass and strength, specifically characterized by a reduction in the number of type I and II fibres, accompanied by type II fibre atrophy (Verdijk et al. 2007). Satellite cells, which are crucial in muscular repair and growth, show an age‐associated decline in number and function (Roth et al. 2000; Kadi et al. 2004). Hence, to maintain muscular mass and power output, strength training is an effective intervention within the ageing population (Martel et al. 2006; Reid & Fielding, 2012). Indeed, one study found that strength training specifically caused increased growth within type II fibres (Verdijk et al. 2009), leading to improved walking time, and balance across the sexes (Holviala et al. 2014). However, though resistance training is beneficial in slowing the age‐related decline in muscle mass, it is unable to restore muscular strength levels to those of the young.

Adaptive homeostasis and caloric restriction

Chronic dietary caloric restriction is the most common non‐pharmacological intervention found to extend lifespan in yeast (Lin et al. 2004), fruit‐flies (Rogina et al. 2002), rats (Richie et al. 1994), mice (Weindruch & Walford, 1982), and rhesus monkeys (Colman et al. 2014), albeit with inconsistent results (Mattison et al. 2012). Although long‐term benefits of caloric restriction in humans have been difficult to prove (perhaps at least partly due to compliance issues), short durations of caloric restriction have shown some beneficial health outcomes, including decreased levels of serum‐insulin, inflammatory markers, oxidative damage (Heilbronn et al. 2006), and basal metabolic rate (Ruggiero et al. 2008). However, the majority of caloric restriction studies have utilized overweight individuals (Horne et al. 2015), with only recent advances in understanding caloric restriction in a non‐obese population (Varady et al. 2013). Moreover, caloric restriction is not limited to the young, as beneficial outcomes have been reported in older rats (Cartee et al. 1994) and older humans (Witte et al. 2009).

Of all the examples of adaptive homeostasis given in this review, perhaps none as clearly demonstrates its difference from hormesis as does caloric restriction. Quite obviously, restricting caloric intake by some 15–40% does not cause any damage (and therefore no damage repair processes), nor does it promote a rapid return to the normal range of homeostasis: in fact, quite the reverse. Many of the beneficial effects of caloric restriction appear to stem from stimulation of stress‐protective signal transduction pathways that foster the upregulation of multiple defense, maintenance, and repair systems (Masoro, 2006). The ability to mitigate cellular damage is crucial in the ageing process, as evidenced by long‐lived species (Lambert et al. 2007) and has been found to increase during caloric restriction (Sanchez‐Roman & Barja, 2013). Several calorically restricted animals and long‐lived species exhibit low levels of damage accumulation, especially deriving from complex I of the mitochondria, which is a major endogenous source of reactive oxygen species (Barja et al. 1994). Moreover, long‐lived species and those subjected to caloric restriction, typically produce lower amounts of free radicals than do shorter lived species or ad libitum fed animals, thereby decreasing the need to synthesize antioxidant enzymes and repair enzymes necessary for cellular maintenance. Thus, the need to maintain high basal levels of stress‐responsive enzymes may not be necessary during caloric restriction and, instead they may be transiently induced only when required.

One of the major difficulties of maintaining continual caloric restriction, especially in humans, is long‐term compliance (Scheen, 2008). Hence, alternative approaches including intermittent fasting (Mattson et al. 2016) and pharmacological mimetics (Madeo et al. 2014) are under investigation. Reductions in dietary intake of carbohydrates, fats, and certain proteins have shown beneficial outcomes, indicating that these dietary components probably make at least partial contributions to the caloric restriction lifespan effect. Removal of specific amino acids, however, most notably methionine, has been suggested as a cause of decreased mitochondrial production of reactive oxygen species and of mitochondrial DNA damage (Sanz et al. 2006). Unlike other adaptive responses, which seem to decline with age, various caloric restriction approaches (including late‐life caloric restriction (Weindruch et al. 2001) or intermittent fasting in middle‐age (Martin et al. 2006)) appear capable of activating key pathways necessary in cellular maintenance that could positively affect the healthspan or even longevity. Increasing research, therefore, is focused on understanding not only the level of caloric restriction that is beneficial in the short‐term, but also the impact of dietary components on both long‐term healthspan and lifespan

Adaptive homeostasis and sirtuins

Sirtuins are NAD+‐dependent deacetylases that readily respond to various types of nutritional (caloric restriction, fasting) and environmental (oxidative stress, DNA damage) changes. They do so by upregulating a vast array of transcriptional responses that enhance metabolic function and provide protection against oxidative stress (Haigis & Sinclair, 2010). Sirtuins can transcriptionally upregulate the synthesis of antioxidant enzymes, including SOD2 (Chen et al. 2011), and various metabolic regulators, including the forkhead box transcription factor (FOXO) (Brunet et al. 2004). Sirtuins can also promote the repair of DNA damage by deacetylation (and hence activation) of repair proteins (Luo et al. 2001). Sir2 was originally discovered to have a beneficial impact on the lifespan of baker's yeast Saccharomyces cerevisiae (Kaeberlein et al. 1999), and homologues of the yeast Sir2 have since been identified in worms (Tissenbaum & Guarente, 2001), fruit‐flies (Rogina & Helfand, 2004b), and mammals (Cohen et al. 2004). Specifically, seven sirtuin mammalian variants exist (Sirt1–7), with Sirt1 being the most well characterized (Dali‐Youcef et al. 2007). The importance of Sirt1 is evident from its role in nutritional responses, including the coordinated regulation of insulin secretion (Bordone et al. 2005), lipid mobilization (Picard et al. 2004), and glucose tolerance (Rodgers et al. 2005).

The ability of sirtuins to influence metabolic responses stems from their dependence on NAD+. Due to this reliance upon the cellular ratio of NAD+/NADH, sirtuins have been likened to a ‘cellular canary’ in that they monitor and communicate cellular energy status. Nowhere is this facility more evident than during caloric restriction (CR). Early genetic studies suggested the activation of sirtuins as crucial mediators of the CR response in yeast (Lin et al. 2004), worms (Lin et al. 2000), fruit flies (Rogina & Helfand, 2004a), and mice (F. Wang et al. 2007). Studies in yeast indicated that the increased NAD+/NADH ratio resulting from CR stress, favoured the activation of the yeast Sir2. Moreover, genetic deletion of the yeast Sir2 blocked the life‐extending CR‐mediated effects (Fabrizio et al. 2005), with similar outcomes initially discovered in worms (Wang et al. 2006) and flies (Rogina & Helfand, 2004b).

Yet, the importance of sirtuins as metabolic sensors, especially in response to CR, is still up for debate. For example, in the presence of extrachromosomal RNA circles (ERCs), deletion of the yeast Sir2 had no impact upon lifespan (Kaeberlein et al. 2004). Similarly, follow‐up studies in worms found no increase in lifespan (Lee et al. 2006). However, multiple CR studies in flies do show consistent sirtuin‐dependent life‐extending benefits (Frankel et al. 2011). The latter results may suggest that sirtuins may be a parallel system that is indirectly activated in response to CR, whereas increases in the NAD+/NADH ratio consistently trigger increased sirtuin activity. More work will be necessary to fully elucidate not only the mechanisms behind the CR‐mediated effect, but also the (apparently) highly nuanced role of sirtuins.

Sirutins have an important role as signallers of the cellular energy state, so it should be of no surprise that they are key players in the regulation of mitochondrial biogenesis. Specifically, Sirt1 regulates mitochondrial biogenesis via deacetylation of PGC‐1α, which, in turn, causes transcriptional upregulation of the mitochondrial transcription factor A (TFAM) (Wu et al. 1999). Indeed, knockdown of Sirt1 expression resulted in increased acetylation, and consequently inactivation of PGC‐1α, and a corresponding decline in the expression levels of genes involved in gluconeogenesis (Rodgers & Puigserver, 2007). Moreover, upon fasting, increased Sirt1 activity results in increased PGC‐1α deacetylation (Gerhart‐Hines et al. 2007), providing further evidence for the dynamic role of sirtuins to metabolic changes. Additionally, Sirt1 helps in the clearance of damaged mitochondria via mitophagy. Indeed, Sirt1‐deficient mice show abnormal protein accumulation and enlarged mitochondria (Lee et al. 2008). Though the pathway of Sirt1‐dependent regulated mitophagy is still unclear, early evidence suggests it may work by the deacetylation of the crucial autophagy regulators Atg5 and Atg7 (Lee et al. 2008). Together, these findings suggest that sirtuins may function not only in response to changes in metabolic load, but may also serve an important purpose in the overall mitochondrial ‘flux,’ ensuring the continual maintenance of healthy mitochondria.

Yet, ageing is marked with the adaptive decline in sirtuin function. Indeed, multiple studies have demonstrated an age‐dependent loss in sirtuin activity (Massudi et al. 2012; Chang & Guarente, 2013). One deleterious consequence of declining sirtuin activity is a reduction in mitochondrial biogenesis. However, the canonical pathway of Sirt1 deacetylation of PGC‐1α is surprisingly not initially disrupted with age. Rather, loss of Sirt1 activity leads to the stabilization of HIF‐1α, stimulating a pseudo‐hypoxic state. This in turn, blocks the transcriptional regulator c‐Myc, inhibiting its transcriptional activation of TFAM and other mitochondrial‐targeted proteins (Li et al. 2005; Christian & Shadel, 2014; Lin et al. 2016). TFAM regulates expression of multiple mitochondrial genes encoded on the mitochondrial genome. Age‐related losses in TFAM expression can, therefore, have dire consequences for mitochondrial respiration, as several key proteins of the mitochondrial electron transport chain are encoded by mitochondrial DNA

A major contributing factor to the age‐dependent loss of sirtuin activity is declining NAD+ levels, as noted in studies of worms (Mouchiroud et al. 2013) and of multiple mammalian tissues (Yoshino et al. 2011). Indeed, the over‐expression of Sirt1 in the pancreatic β‐cells of mice, initially caused increased glucose‐stimulated insulin secretion, but this effect was lost with age, as the mice were unable to surmount the age‐related decline in NAD+ levels (Ramsey et al. 2008). Fortunately, restoration of NAD+ is possible via supplementation of its precursors, including NA mononucleotide (NMN) (Imai, 2009) and nicotinamide riboside (NR) (Belenky et al. 2007). Supplementation with NMN was capable of restoring NAD+ levels and mitigated age‐ and diet‐induced type II diabetes in wild‐type mice (Yoshino et al. 2011). Moreover, NR supplementation was shown to prevent age‐related declines in worms and mice, specifically by increasing the available mitochondrial pool of NAD+ (Cantó et al. 2012; Mouchiroud et al. 2013). Thus, sirtuins may provide a good target for slowing certain aspects of the ageing process, though further work will be necessary to identify effective activators and, more importantly, determining at which stage of the lifespan they should be applied.

Adaptive homeostasis and osmotic stress

The highly conserved process of osmotic stress adaptation is crucial for cells and organisms to cope with varying solute concentrations. Our understanding of osmotic adaptation is derived largely from studies in the yeast Saccharomyces cerevisiae (S. cerevisiae) and the nematode worm Caenorhabditis elegans (C. elegans), both organisms that are highly sensitive to changes in environmental osmolarity. Early studies demonstrated an adaptive response following osmotic stress, as high salinity ([200 mm]) pretreatment enabled increased survival in C. elegans following exposure to a typically salinity‐lethal ([500 mm]) environment (Lamitina et al. 2004). Additionally, selection for stress‐tolerant yeast results in picking organisms with a high adaptive capacity for survival and fermentation in high glucose (40%) environments (Watanabe et al. 2010).

Water loss triggers a rapid cellular response, including cellular shrinkage, elevation of organic osmolytes, primarily glycerol (Hohmann, 2002; Lamitina et al. 2004), and activation of the stress response repair systems (França et al. 2007). Indeed, hypertonicity causes immediate transcriptional increase of genes involved in the heat shock response (Schüller et al. 1994) and glycerol accumulation, specifically upregulation of glycerol‐3‐phosphate dehydrogenase (GPDH) in yeast (Albertyn et al. 1994) and worms (Lamitina et al. 2006). Similarly, sorbitol‐induced hyperosmolarity causes lifespan extension in worms (Chandler‐Brown et al. 2015) and increases replicative (Kaeberlein et al. 2002) and chronological lifespan in yeast (Smith et al. 2007). Both of these effects appear to be dependent upon GPDH expression rather than the more commonly age‐associated pathways, such as sirtuin activity and the IGF‐1 pathway. Indeed, RNAi studies identified 122 genes that cause constitutive activation of GPDH, with many having dual roles in protein regulation and chaperone‐like functions. Importantly, 73% of these genes have been identified as slowing age‐dependent protein aggregation within C. elegans (Lamitina et al. 2006).

Suppression of glycolytic activity, as seen in osmotic stress is linked to delayed age‐associated dysfunction and lifespan extension (Ingram & Roth, 2015). In turn, decreased glycation slows the formation of toxic metabolites that can cause proteotoxicity (Uchiki et al. 2012). Furthermore, half the genes essential for osmotic tolerance encode proteins that detect, transport, and degrade damaged proteins, including those of the ubiquitin‐Proteasome system (Choe & Strange, 2008). It should also be noted that other stress coping strategies (most well characterized in yeast) play important roles in osmotic tolerance. These include cell‐cycle arrest and transcription/translation alteration governed by the high osmolarity glycerol (HOG) pathway, whose core is the Hog1 MAP kinase (MAPK) cascade. Importantly, the HOG pathway is also conserved in higher eukaryotes (Saito & Posas, 2012). The importance of the HOG pathway is illustrated by the mammalian stress‐responsive p38 MAPK that can rescue the osmosensitivity of hog1Δ mutations in response to hyperosmotic challenge (Han et al. 1994; Sheikh‐Hamad & Gustin, 2004). Additionally, the HOG pathway has been shown to be activated during other stress conditions, including heat shock (Winkler et al. 2002), cold stress (Hayashi & Maeda, 2006), hypoxia (Hickman et al. 2011), and low pH conditions (Kapteyn et al. 2001), indicating the cellular redundancy that exist as a means of rapidly coping with changing environmental conditions.

Additional studies further suggest some overlap in these age‐associated pathways. Upon inhibition of insulin signalling, through DAF‐2 or its downstream target, AGE‐1, C. elegans show increased hypertonic stress resistance in a DAF‐16‐dependent manner yet insulin signalling is not required for the adaptation to hypertonic stress. More importantly, of the genes impacted, the majority encode for heat shock proteins, and those involved in glycerol formation (Lamitina & Strange, 2005). Together, these results suggest that although these pathways can be separately activated based upon the specific stress encountered, significant overlap exists and can further protect the organism against multiple environmental insults.

The disease state is a prime example of loss of osmotic regulation. One of the causalities of type II diabetes is hyperglycaemia, which promotes a hyperosmotic environment. This is characterized by increased production of sorbitol (6‐fold) in diabetic‐induced cataracts mediated by increased shunting of glucose through the polyol pathway, coupled with decreased glutathione and GDPH activity (Lee & Chung, 1999). In turn, sorbitol accumulation alters membrane permeability resulting in cellular lesions (Lee & Chung, 1999; Hashim & Zarina, 2012). Indeed, earlier studies reported high activity of aldose reductase, a key enzyme of the polyl pathway, in the lens of transgenic mice (Lee et al. 1995). Together, high aldose reductase activity and excessive glucose work to deplete the cellular pool of NADPH, critical for the regeneration of reduced glutathione, which further downregulates the cellular antioxidant capacity (Olofsson et al. 2012). Thus, inability to cope with osmotic stress further augments the deteriorating effects of type II diabetes.

Adaptive homeostasis and mechanical stress

Mechanical loading is a constantly varying force with which cells must cope, and one that results in adaptive homeostatic responses manifest in tissue morphogenesis. Mechanical tension, whether internally generated by the cell's cytoskeleton or externally applied, has been found to be a necessary signal in the regulation of cellular growth (Paszek et al. 2005) and differentiation (Engler et al. 2006). These findings demonstrate that changes in the mechanical properties of the cell's environment are translated in gene reprogramming and molecular responses (Discher et al. 2005). However, mechanical stimuli can also be detrimental to cellular behaviour. A quintessential example is the chronic force experienced by the vascular endothelium. Depending on the type of force, it can act either to promote inflammation and atherosclerosis or prevent it (Chatzizisis et al. 2007). Hence the ageing of the vasculature is arguably a prime example of chronic mechanical stress throughout the lifespan.

Due to the oscillatory rhythms of the cardiac cycle, variable blood pressures and volumes are continually experienced through the vasculature. At the frontlines, and a key mechanochemical responder, is the arterial endothelium. Under shear stress or mechanical stretching the endothelium responds via activation of electrophysiological signals (change in ion conductance, inositol triphosphate generation, and intracellular free calcium) triggering altered gene expression and structural reorganization. Although the majority of blood flow is laminar (causing relatively limited mechanical stress upon the endothelium) branching and bifurcations cause high shear stress and pressure. In consequence, many of these areas are potential weak points and common areas of plaque buildup (Nordsletten et al. 2006).

The vascular endothelium also responds to mechanical stress through the production of reactive oxygen species. This is important, especially during the maturation process, when low concentrations of oxidants, including H2O2 and NO, act as signalling molecules necessary for the growth and adaptability of the endothelial lining, promoting long‐term stress resistance (Gendron et al. 2012). However, with age, vascular endothelial cells show higher basal reactive oxygen/nitrogen species generation and damage accumulation, coupled with decreased antioxidant defenses (Sugamura & Keaney, 2011). These problems are further augmented upon plaque formation. Moreover, high uncontrolled levels of reactive oxygen/nitrogen species, promote the formation of stress‐induced premature senescent cells, that are characterized as being pro‐inflammatory and pro‐atherosclerotic (Voghel et al. 2007), and accelerate the development of hypertension (Touyz & Schiffrin, 2004) and eventually, of atherosclerosis (Madamanchi et al. 2005).

Thus, throughout the lifetime, chronic stretching will cause ‘wear and tear’ on normally elastic arteries, leading to vasculature remodelling (medial thickening) and eventual vasculature stiffness (Bolton & Rajkumar, 2011). Aged vessels have increased collagen and elastin content (Åstrand et al. 2011), accompanied by excess proinflammatory signals (M. Wang et al. 2007), that trigger monocyte migration, and subsequent uptake of plasma lipoproteins (Fournet‐Bourguignon et al. 2000), perpetuating the inflammatory response. Moreover, chronically high blood pressure increases the haemodynamic load experienced by the heart. In an attempt to cope with the excess load, the myocardium adapts via thickening of its walls (cardiac hypertrophy) (Ruwhof & van der Laarse, 2000).

One of the major maladaptive consequences of chronic mechanical stress is the development of atherosclerosis: a major underlying cause for serious cardiovascular complications, including stroke, ischaemic heart failure, and myocardial infarctions (Wang & Bennett, 2012). Sedentary lifestyle, smoking, and chronic disease pathologies (including type II diabetes) can all exacerbate the mechanical burden on the vasculature.

Adaptive homeostasis and the immune response

The immune response is an evolutionarily developed response, enabling organisms to protect themselves against tissue stress and/or damage, or pathogenic attack. Simplistically, it consists of three acute phases: (1) detection of pathogen‐associated molecular patterns (PAMPs), (2) mediated by pattern‐recognition receptors (PRRs) (Kawai & Akira, 2010); (3) PRRs in turn release specific cytokines, which cause lymphocyte differentiation specific to the type of insult (Iwasaki & Medzhitov, 2015). Due to the necessity of removing a potentially life‐threatening pathogen, inflammatory responses can supersede homeostatic signalling. This is evident in infections resulting in elevated body temperature, changes in metabolic pathways (blocking gluconeogenesis, activating lipolysis), and increased vascular permeability to fluids and solutes (Medzhitov, 2008). In parallel, the release of pro‐inflammatory cytokines from activated macrophages (TNF‐α, IL‐6, IL‐1β) all work to promote transient insulin resistance, decreasing nutrient storage and affording an effective defense mechanism against bacterial and viral pathogens, whereas the majority of immune responsive cells rely upon glycolysis to function (Odegaard & Chawla, 2013).

Unfortunately, one of the down‐sides of the acute immune‐response is the off‐target oxidative damage that may result from macrophages and monocytes as they remove invading pathogens (Holmstrom & Finkel, 2014). This is likely countered by the activation of the stress response, primarily mediated by the transcriptional regulator Nrf2 (Kim et al. 2010), which is activated during pathogenic infections including malaria (Jeney et al. 2014) and sepsis (Thimmulappa et al. 2006). Coupled with Nrf2 activation, infection also triggers a growth arrest, resulting in activation of the forkhead box transcription factor (FoxO), as evident in fruit flies (Dionne et al. 2006; Eijkelenboom & Burgering, 2013). However, the acute activation of the inflammatory response is transient and short‐term, which enables (hopefully) the successful elimination of the invading pathogen accompanied by limited damage accrual for the ‘host.’

Conversely, the inflammatory response has also been shown to be activated by oxidative stress (Lavrovsky et al. 2000). Moreover, key transcription factors involved in the inflammatory response are also shown to be upregulated, including nuclear factor kappa B (NFкB) (Gloire et al. 2006) activator protein‐1 (AP‐1) (Kim et al. 2002), and multiple peroxisome proliferator‐activated receptors (Zolezzi et al. 2013). Indeed, in vitro studies have shown that activation of NFкB by H2O2 triggers increased DNA binding (Schreck et al. 1991). Thus with age, as basal oxidative stress increases, so too does the inflammatory response (Labunskyy & Gladyshev, 2013).

The synergistic relationship between oxidative stress and the inflammatory response may contribute to the elevated low‐grade inflammation that is indicative of many chronic diseases (Franceschi & Campisi, 2014) and is also a characteristic of ageing (Chung et al. 2006). A strong example is the development of type II diabetes, largely a consequence of excess adipose accumulation (Malik et al. 2010). Normally, white adipose tissue is the body's primary energy storage and regulator of systemic metabolism through the secretion of adipokines and the pro‐inflammatory chemokines TNF‐α and IL‐6 (Scherer, 2006). Concurrently, healthy lean animals typically show very limited amounts of inflammatory cells within adipose tissue (10–15%) (Lumeng et al. 2007). However, upon excess adipose accumulation macrophage content increases to 45–60% (Weisberg et al. 2003). This, in turn, signals for localized inflammation which, if not corrected, can promote systemic insulin resistance (Xu et al. 2003). Serum levels of C‐reactive protein (CRP) also increase with additional fat deposits (Lemieux et al. 2001) along with opposite decreases in adiponectin and the anti‐inflammatory cytokine IL‐10 (Matsuzawa, 2010). Hence, increased visceral fat deposits (Yoneshiro et al. 2011) and decreased muscle mass (Janssen et al. 2000), also seen in ageing, promote systemic inflammation. Thus, the immune response appears to be chronically activated during ageing and associated diseases, and is no longer able to be transiently induced nor turned off.

Adaptive homeostasis and emotional and psychological stress

Emotional stress occurs when environmental demands exceed an individual's capacity to cope (Chrousos et al. 2013). In humans, financial problems, job stress, marital tension, and care giving have all been attributed to the hyper‐activation of the emotional stress response, mediated by the hypothalamic‐pituitary‐adrenocortical axis (HPA), causing elevated glucocorticoid levels.

Short‐term activation of the HPA improves cognition, increases respiratory rate, and inhibits resting functions (Charmandari et al. 2005), enabling animals and people to cope with the actual or perceived environmental stress. However, chronic HPA activation, indicative of emotional stress, can result in detrimental behavioural and physiological changes, all of which, if sustained over the long term, have been linked to adverse health outcomes (Habib et al. 2001). Thus transient and reversible adaptations to mild (non‐damaging) emotional and psychological stimuli are clear examples of adaptive homeostasis that improves the ability to deal with the realities of life. In contrast, chronic high levels of emotional stress are clearly detrimental.

The hypothalamus, which is crucial in memory (Wolf, 2003) and the functions of the autonomic nervous system (Grossman, 1975), is highly sensitive to prolonged increases in glucorticoid levels (Colla et al. 2007). Approximately 30% of aged rats show basal elevation in glucocorticoids accompanied by memory impairments and decreased hippocampal volume (Issa et al. 1990). This is a phenotype that can be recapitulated by glucocorticoid administration in middle‐aged rats, and that is also seen in the presentation of an Alzheimer's disease (AD)‐like pathology in primates (Landfield et al. 1978; Kulstad et al. 2005); this AD‐like pathology in primates can actually be slowed if glucocorticoid levels are decreased (Landfield et al. 1981). Actually, ageing itself, can trigger higher cortisol and glucorticoid levels even in healthy older adults. This has been considered to be a physiological change linked to decreases in hippocampal volume and memory, but it can be hyper‐elevated in individuals with AD (Rasmuson et al. 2001; Sotiropoulos & Sousa, 2015). Additionally, the prefrontal cortex, which is crucial in executive decision‐making, is sensitive to basal increases in glucorticoid levels that can decrease neuronal survival and/or function (McKlveen et al. 2013).

Nor are changes in cognition the only consequence of emotional stress. Chronic emotional stress, in early life and through adulthood is associated with 40–60% excess risk for cardiovascular disease (CVD), the leading cause of morbidity and mortality in the US (Steptoe & Kivimäki, 2013). Long‐term stress was also linked to increased risk for depression (McEwen, 2005), decreased immune function (Kiecolt‐Glaser & Glaser, 2002; Rohleder, 2014), metabolic syndrome (Kelly & Ismail, 2015; Joseph & Golden, 2016), and certain cancers (Cohen et al. 2007; McDonough et al. 2014), and premature mortality (Mroczek et al. 2015).

Chronic excessive stress is thought to exacerbate, or even cause, a number of age‐related diseases. We have previously provided evidence that the Regulator of Calcineurin 1 (RCAN1) gene products, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon (Ermak et al. 2011). The RCAN1‐4 protein isoform was originally discovered to enhance adaptation to oxidative stress, whereas increased expression of the RCAN1‐1L and RCAN1‐1S isoforms is associated with Down syndrome and Alzheimer's disease (Davies et al. 2007). Surprisingly, under‐expression of RCAN1‐1 has been suggested to promote the appearance or increase the severity of Huntington's disease symptoms (Ermak et al. 2009). In rodents, psychosocial/emotional stress causes RCAN1 induction, probably via increased levels of glucocorticoids (Ermak et al. 2011). We have shown that overexpression of the RCAN1‐1L protein in transgenic mice causes accumulation of hyper‐phosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease (Davies et al. 2007; Ermak et al. 2009). Therefore, we propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent psychosocial/emotional stress may cause chronic RCAN1 overexpression which (in turn) may promote or exacerbate various diseases, including tauopathies such as Alzheimer's disease. The mechanism by which psychosocial/emotional stress can lead to these diseases probably involves inhibition of calcineurin and induction of GSK‐3β by RCAN1 proteins. Inhibition of calcineurin and induction of GSK‐3β may both contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration.

The timing of severe emotional stress is highly indicative of later‐life morbidity and mortality risk. Individuals who experience early life trauma were found to have a 1.5 times greater incidence of cardiovascular disease, autoimmune disease, and premature mortality (Anda et al. 2009). For example, Israelis who experienced the traumas of WWII and later immigrated to Israel, had a greater risk for cancer compared to their same‐aged counterparts who moved to Israel prior to WWII (Keinan‐Boker et al. 2009). As well, natural disasters, major industrial accidents, and terrorist attacks have all been linked to increased rates of myocardial infarction or sudden cardiac death (Leor et al. 1996; Steptoe & Brydon, 2009). Taken together, these studies indicate that the negative effects of emotional stress are dependent upon duration, level, and timing, all of which can provide the tipping point(s) towards disease progression in later life. In turn, chronic emotional stress impacts biological health by compressing adaptive cellular stress responses.

Conclusions

Adaptive homeostasis is a crucial phenomenon that has now been found to be conserved across a wide array of species. It consists of the continual transient reprogramming of the homeostatic range, for all biological functions, which enables short‐term adaptation to varying internal and external conditions via regulation of protective enzymes that are essential in ensuring maintaining cellular/organismal fitness and health. Importantly, the concept of adaptive homeostasis redefines the homeostatic range as a continuously adapting (expanding and contracting) parameter rather than a static span as has traditionally been accepted (Selye, 1975).

Adaptive homeostasis enables young organisms to quickly activate a plethora of protective responses, depending on the type of signal received. Moreover, in young organisms, with typically relatively low exposure to free radical generation and oxidative damage, the basal levels of expression of various stress‐responsive enzymes is typically quite low. In contrast, aged organisms that have had to cope with a lifetime of both internal and externally derived sources of oxidative damage exhibit higher basal levels of protective enzymes. Unfortunately, the maximal levels of activation of protective systems appears not to change. Thus, the functional range of adaptive homeostasis in older organisms is significantly compressed. Aged organisms must therefore cope with higher levels of chronic low‐grade stress and lack‐lustre induction of compressed adaptive stress responses (Fig. 4). Therefore, we suggest that a potentially new avenue for assessing the ageing process would be to monitor the loss of adaptive homeostasis. Whether the decline in adaptive homeostasis with age can be minimized or even reversed remains to be seen, but this certainly appears (to us) to be an extremely important avenue for future research.

Figure 4. Age‐dependent loss of adaptive homeostasis appears to be a common biological phenomenon, as it is evident in multiple organisms.

Figure 4

Detailed studies in cultured mammalian cells, nematode worms (C. elegans), fruit flies (D. melanogaster), mice, and limited studies in humans show a consistent age‐dependent decline in the inducibility of the stress‐responsive circuitry; in other words, the capacity for adaptive homeostasis is lost with age. Studies from our lab and others have uniformly shown that young organisms can rapidly activate Nrf2 and increase the expression of multiple stress‐responsive enzymes, including the 20S Proteasome and the mitochondrial Lon protease (as well as their various regulators). With age, however, despite a significant increase in the basal steady‐state levels of these protective enzymes, no additional stress‐protective adaptive response is seen. Interestingly, the basal levels of protective enzymes, such as Proteasome and Lon, in older organisms approximate the inducible levels of these same enzymes in young organisms. These findings potentially demonstrate an upper limit or ‘ceiling‐effect’ for the inducibility of stress‐protective systems, and may also indicate that older organisms are in something of a state of constant or chronic stress.

Additional information

Competing interests

The authors attest that there are no competing interests.

Author contributions

Both authors contributed equally to the writing and revision of this article. Both wrote portions of each section, and both revised each other's work. Both authors approve the final, revised version of the manuscript submitted to The Journal of Physiology.

Funding

L.C.‐D.P. was supported by grant no. DGE‐1418060 of the USA National Science Foundation. K.J.A.D. was supported by grant no. ES003598 from the National Institute of Environmental Health Sciences of the US National Institutes of Health, and by grant no. AG 052374 from the National Institute on Aging of the US National Institutes of Health.

Biographies

Laura C. D. Pomatto gained BS degrees in both Biomedical Engineering and Gerontology, an MS degree in Biomedical Engineering, and a PhD degree in the biology of ageing from the University of Southern California (USC). She is currently a postdoctoral fellow in Kelvin Davies’ laboratory.

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Kelvin J. A. Davies, PhD, DSc, FRSC, FRCP is the James E. Birren Chair and Dean of Faculty at USC's Leonard Davis School of Gerontology, and Professor of Molecular and Computational Biology in USC's College of Letters, Arts, and Sciences. Educated at London and Liverpool Universities, the University of Wisconsin, Harvard, and the University of California at Berkeley, he was previously a faculty member at Harvard University, Harvard Medical School, and Albany Medical College. Pomatto and Davies are actively studying adaptive responses, particularly the inducibility of Proteasome and Lon by oxidants, and the decline of adaptive homeostasis with age in a wide range of organisms.

This is an Editor's Choice article from the 15 December 2017 issue.

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