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ER stress and hormetic regulation of the aging process
Ageing Research Reviews 9 (2010) 211–217
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Review
ER stress and hormetic regulation of the aging process Antero Salminen a,b,∗ , Kai Kaarniranta c,d a
Department of Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland c Department of Ophthalmology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland d Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland b
a r t i c l e
i n f o
Article history: Received 17 February 2010 Received in revised form 25 March 2010 Accepted 14 April 2010 Keywords: ER stress Hormesis Longevity Stress resistance UPR Review
a b s t r a c t An ability to mount a stress resistance under pressure is a major host defence mechanism and has been a fundamental force during evolution. However, the adaptation capacity clearly declines during aging and this loss of stress resistance accelerates the aging process exposing the organism to degenerative diseases. The effect of stress on organisms seems to be a dose-dependent response, i.e. mild stress induces a stress tolerance and extends the lifespan whereas excessive stress accentuates the aging process. This paradox is known as hormesis in aging research. It is essential to distinguish the intensity of cellular stress and thus mount an appropriate host defence. The endoplasmic reticulum (ER) contains three branches of stress transducers, i.e. IRE1, PERK, and ATF6 pathways, all of which recognize stress-related disturbances in the function of ER. These transducers trigger a complex signaling network which activates an unfolded protein response (UPR). Interestingly, ER stress transducers can distinguish the intensity of ER stress and induce a dose-dependent UPR, either adaptive response to stress or apoptotic cell death. The efficiency of the stress recognition system and UPR signaling declines during aging. We will discuss the role of ER stress in hormetic regulation of aging process and longevity. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction A capacity to adapt to hostile environmental conditions and intrinsic stress is a crucial characteristic of organisms during evolution. Studies on model organisms, in particular on Caenorhabditis elegans, have revealed that responses to stress and aging process share the same mechanisms and moreover, adaptation to stress can increase the life expectancy in conjunction with the healthy aging process (Johnson et al., 2002; Pardon, 2007; Rion and Kawecki, 2007). Interestingly, the effect of stress on organisms seems to be a dose-dependent process, i.e. mild stress induces a stress tolerance and expands the lifespan whereas excessive stress exacerbates the aging process. This phenomenon is called hormesis in aging research (Gems and Partridge, 2008; Mattson, 2008a; Rattan, 2008). During the course of evolution, it has been indispensable to recognize the cellular stress and trigger the adaptive host defence. The endoplasmic reticulum (ER) occupies a unique position as a cellular organelle responsible for the control of protein quality in order to distinguish attacks on protein fidelity. A variety of stressors, direct or indirect, induce ER stress which generates via different trans-
∗ Corresponding author at: Department of Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN70211 Kuopio, Finland. E-mail address: antero.salminen@uef.fi (A. Salminen). 1568-1637/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.arr.2010.04.003
ducer proteins a response, called unfolded protein response (UPR) (Schröder, 2005; Bernales et al., 2006) (Fig. 1). This signaling system from ER lumen to the nucleus is evolutionary conserved; only the number of functional sensors has increased during evolution (Mori, 2009). It seems that ER stress transducers can recognize the intensity of ER stress and induce a dose-dependent UPR, either evoking an adaptive defence or triggering apoptotic cell death (Szegezdi et al., 2006; Hetz, 2007) (Fig. 1). This characteristic fits well to the definition of hormesis (Mattson, 2008a). Interestingly, several observations clearly demonstrate that the efficiency of the ER stress-UPR system declines during aging (Naidoo, 2009a,b) and in that way can expose the organism to an entropic aging process. We will discuss the role of ER stress and UPR signaling in hormetic regulation of aging process and longevity.
2. Stress resistance: a hallmark of longevity During evolution, it has been essential that organisms develop the ability to adapt to harsh environmental conditions and intrinsic stress. This stress resistance capacity has evolved from a complex set of molecular self-defence mechanisms (e.g. Kensler et al., 2007; Landriscina et al., 2009). Reproductive diapauses of invertebrates and caloric restriction in many species have been the most widely studied and are today the best known stress resistance models (Tatar and Yin, 2001; Rion and Kawecki, 2007). Organisms are also
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Fig. 1. Regulation of the aging process by ER stress. Several pro-aging insults trigger ER stress and activate the UPR (green box) via IRE1, PERK and ATF6 transducers. UPR induces the expression of stress resistance components which can also extend the lifespan. However, prolonged and excessive ER stress can lead to the pathological consequences that accelerate the aging process (red arrows and red boxes).
able to develop an adaptive tolerance to a wide variety of stress insults, e.g. oxidative stress, heat shock, and hypoxia (Feder and Hofmann, 1999; Martindale and Holbrook, 2002; Ramirez et al., 2007). One of the age-related paradoxes is the observation that increased stress resistance can extend the lifespan of the organisms. This result has been verified in studies conducted on a variety of species and many stress conditions (Pardon, 2007; Vermeulen and Loeschcke, 2007; Masoro, 2009). Moreover, long-lived mouse models exhibit a clear cellular tolerance to many stress insults, e.g. UV light and ROS (reactive oxygen species) (Murakami, 2006). This demonstrates that the acquired stress resistance appears even at the cellular level and is not confined to the organismal function. Interestingly, the ability to withstand a distinct stress situation frequently also provides prevention against several other harmful insults or conditions suggesting that the same pathways can protect against different insults (e.g. Johnson et al., 2002). During unfavourable environmental conditions, C. elegans and several insects enter a diapause state which arrests development and triggers the appearance of a dauer larva phenotype with extended lifespan (Tatar and Yin, 2001). The formation of the dauer stage is induced by endocrinological regulation and alternate metabolism (Tatar and Yin, 2001; Baumeister et al., 2006). Studies on C. elegans long-lived mutants have revealed several DAF genes (DAuer Formation) which can clearly extend the lifespan of adult nematodes (Braeckman and Vanfleteren, 2007). The DAF-2 pathway is the most important, e.g. C. elegans with loss-of-function mutations in the genes of that pathway display a long-lived and stress resistant phenotype. Interestingly, the DAF-2 pathway is the ortholog to mammalian insulin/IGF-1 pathway which is known to regulate metabolic homeostasis and lifespan also in vertebrates (Karpac and Jasper, 2009). The DAF-2 pathway regulates the function of DAF-16 (ortholog to FoxO family) transcription factors which control the expression of several stress resistance genes (Barthel et al., 2005; Jensen et al., 2006). Progress in gene expression profiling techniques has helped to unravel the genetic background of different stress resistance mod-
els also in vertebrates. For instance, whole-genome transcriptional data has been established in caloric restriction model (Swindell, 2009) and hypoxia tolerance (Benita et al., 2009). Bioinformatic techniques have revealed distinct transcription factor pathways involved in the induction of stress resistance, e.g. HSF-1, HIF-1, p53, FoxOs, and SIRT1 (Jensen et al., 2006; Benita et al., 2009; Swindell, 2009). Several studies have highlighted the role of chaperones in the increase of stress resistance (Feder and Hofmann, 1999). Swindell (2009) observed that caloric restriction, a wellknown way to extend the lifespan also in mammals, induces the expression of genes which inhibit oxidative stress and inflammation. Interestingly, de Magalhaes et al. (2009) observed that aging increases the expression of genes of the immune response, lysosomal degradation and antiapoptotic defence. In general, many of these observations support the role of stress resistance in lifespan extension, although caloric restriction does not induce genomewide reversal of age-related gene expression (Swindell, 2009). 3. Hormesis: live longer with a mild stress Studies on the role of stress resistance in the regulation of lifespan have revealed a dose-dependency, i.e. a mild, low-dose stress increases the lifespan of organism but conversely, a higher intensity of stress or a prolonged exposure, overwhelming to the organism, can evoke detrimental effects and decrease the lifespan (Gems and Partridge, 2008; Mattson, 2008a; Rattan, 2008). This hormetic regulation has been observed both in vivo in organisms and in vitro in cell culture studies. The term hormesis comes from toxicology and refers to a kind of dose–response relationship with low-dose inducing stimulation and higher doses inhibition of the reaction (Calabrese, 2008a). Hormesis involves the adaptive responses of cells and organisms to mild and moderate stress including heat, irradiation, hypoxia, oxidative stress and caloric restriction (Fig. 1). Many chemicals can also induce hormetic stress resistance; these compounds are called hormetins (Mattson, 2008a; Rattan, 2008). For instance, several phytochemicals can induce adaptive
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Fig. 2. ER stress is a hormetic lifespan rheostat. From mild up to moderate ER stress induces stress resistance (green box) that can extend the lifespan but a prolonged and overwhelming stress accelerates the aging process (red box).
responses when they are used at subtoxic doses (Mattson and Cheng, 2006). It should be stressed that the phenomenon of hormesis has nothing to do with homeopathy (Calabrese, 2009). Hormetic regulation of the aging process provides interesting insights into the aging mechanism itself. It seems that aging is a physiological process that can be extended by increasing stress resistance (see Section 2). Stress tolerance is normally evoked by mild, optimal insults. However, the duration of stress is an important parameter since a sustained stress can be detrimental and cause pathological changes (Fig. 2). This may explain many of the inconsistent results in experiments with oxidative stress (Lapointe and Hekimi, 2010). Oxidative stress is a well-known proaging insult but in some contexts it can extend the lifespan (Van Raamsdonk and Hekimi, 2009; Lapointe and Hekimi, 2010). The effects of oxidative stress have been extensively studied and it is known that the responses are clearly dependent on many factors, e.g. the dose of ROS, type of ROS, tissue exposed and the age of organism (see Holbrook and Ikeyama, 2002; Martindale and Holbrook, 2002; Yoon et al., 2002). Different proteotoxic responses, such as protein unfolding, modification and aggregation, are typical changes encountered after hormetic insults, but, interestingly, similar changes progressively accumulate during aging. Thus one could argue that protein quality control and cleansing systems represent common threads between adaptive hormetic changes and lifespan extension. It is known that the chaperone protein expression and cellular levels are clearly increased during the appearance of stress resistance (Feder and Hofmann, 1999; Jäättelä, 1999). Heat shock proteins HSP27, HSP70 and HSP90 are common stress-responsive chaperones, the expressions of which are highly increased in a variety of stress conditions. In model organisms, HSPs have been reported to ameliorate age-related proteotoxicity and increase lifespan (Tower, 2008; Calderwood et al., 2009).
4. ER stress: paradigm of hormetic regulation The ER tubular network contains a unique protein quality control system which has three arms of stress transducers, i.e. IRE1, PERK, and ATF6 pathways (Schröder, 2005; Bernales et al., 2006). These sensors recognize the unfolding or misfolding of proteins during their maturation process in the ER. The ER compartment has also several other important cellular functions, e.g. the maintenance of calcium and redox homeostasis and membrane lipid synthesis and recycling. Several stress-related insults disturb the microenvironment of ER and subsequently stimulate the stress transducers which generate a defence reaction called the unfolded protein response (UPR) (Fig. 1). Common inducers of ER stress include oxidative stress, hypoxia, viral infection and toxic chemicals (Bernales et al., 2006; Fels and Koumenis, 2006; Ron and Walter, 2007; Malhotra and Kaufman, 2007; Doroudgar et al., 2009) but hormonal stress can also trigger ER stress (Mao et al., 2005). Transcription factors ATF4, ATF6 and XBP1 are the main signaling molecules of UPR but many other factors, e.g. CHOP (also called GADD153), JNK, NF-B and NRF-2, can be involved in UPR (Bernales et al., 2006; Cullinan and Diehl, 2006; Ron and Walter, 2007). Several studies demonstrate that a low-level of ER stress is protective, consisting of a stress resistance phase, and involving an increase in the expression of molecular chaperones, in both ER and cytosol, and Ca2+ -binding proteins along with antiapoptotic and antioxidative proteins (Figs. 1 and 2). The UPR is normally a beneficial adaptation mechanism and it improves stress resistance but in the case of cancer, increased hypoxic tolerance promotes tumor growth (Bi et al., 2005). Moreover, ER stress can activate autophagic cleansing of accumulating material in ER in order to prevent the detrimental collapse of the ER function (Hoyer-Hansen and Jäättelä, 2007).
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ER stress has been described as either a “double-edged sword” or a “Janus-faced system” (Malhotra and Kaufman, 2007; Kitamura, 2008). If present at a low or moderate intensity, ER stress initially stimulates an adaptive UPR to promote cellular survival whereas in the case of persistent, chronic stress, UPR can trigger apoptotic cell death program (Kim et al., 2008; Schröder, 2008) (Figs. 1 and 2). This can be viewed as beneficial since apoptosis can kill the damaged cell but rescue the neighbouring cells from suffering necrotic cell death. ER stress can induce apoptotic cell death via several pathways, e.g. (i) the activation of CHOP transcription factor through PERK and ATF6 pathways, (ii) the IRE1␣-TRAF2-ASK1 signaling, and (iii) the Ca2+ outflow from ER and translocation to mitochondria (Oyadomari and Mori, 2004; Szegezdi et al., 2006; Hetz, 2007; Kim et al., 2008; Salminen et al., 2009) (Figs. 1 and 2). The key regulator of apoptosis, also that of ER stress-mediated apoptosis, is the balance between the anti- and proapoptotic BCL2 family of proteins (Szegezdi et al., 2006; Hetz, 2007). The CHOP transcription factor can inhibit the expression of the antiapoptotic BCL2 proteins but simultaneously, increase the expression of proapoptotic GADD34 and TRB3 (Szegezdi et al., 2006). Moreover, the IRE1␣-TRAF2mediated activation of JNK can phosphorylate and consequently inhibit the BCL2 proteins. The suppression of BCL2 function disturbs the balance between BCL2 proteins and proapoptotic BAX, BAK, and BH3-only proteins leading to the release of Ca2+ from the ER and apoptogenic proteins from mitochondria (Szegezdi et al., 2006; Hetz, 2007). Apoptotic cell death is executed via the activation of different caspase cascades (Zhivotovsky, 2003). The role of ER-located caspases, CASP4 and CASP12, in the induction of apoptosis is still under debate, but it has been proposed that they are involved in the induction of inflammation (Zhang and Kaufman, 2008; Salminen et al., 2009). Recently, several studies have demonstrated that prolonged ER stress can stimulate inflammatory responses, e.g. via IRE1␣-TRAF2-NF-B and ATF6-CREBH pathways (Zhang and Kaufman, 2008; Salminen et al., 2009) (Fig. 1). Interestingly, gene expression profiles have revealed that the genes linked to inflammation and immune responses identify a common signature of aging (de Magalhaes et al., 2009). In conclusion, the UPR induced by ER stress involves two different phases, i.e. an adaptive, survival phase and an apoptotic, degenerative phase. This dose-dependent sequence of responses to ER stress is closely compatible with the definition of hormesis (Mattson, 2008a) (Fig. 2).
5. ER stress and the aging process The aging process contains in abundance of characteristics indicating that ER stress could be activated, e.g. increased oxidative stress and accumulation of harmful protein modifications, misfolding and aggregation of proteins, disturbances in Ca2+ homeostasis and impairment in global protein synthesis (Finkel and Holbrook, 2000; Gems and Partridge, 2008; Tavernarakis, 2008; Puzianowska-Kuznicka and Kuznicki, 2009). In addition, the protein cleansing system becomes impaired during aging due to the decline in autophagic and proteasomal degradation (Vernace et al., 2007; Salminen and Kaarniranta, 2009). All these age-related changes imply that the efficient function of protein quality system is compromised during aging. Several studies have demonstrated that the expression levels of molecular chaperones and folding enzymes in the ER clearly reduce during aging (see Naidoo, 2009a,b); examples are (i) declines in the protein levels of ER resident chaperones, BiP/GRP78, GRP94 and calnexin, (ii) reduction in the enzyme activity of PDI, a key enzyme in disulfide bond formation (Nuss et al., 2008), and (iii) carbonylation of several ER proteins (Rabek et al., 2003).
A plethora of morphometric studies have described age-related, generally tissue-specific, changes in the ER–Golgi system. Most of these studies have observed a decline in ER volume, especially in smooth-surfaced endoplasmic or sarcoplasmic reticulum (e.g. Sachs et al., 1977; Schumucker et al., 1977; Schmucker, 1990). In addition, prominent changes occur during aging in the proteomic profiles of endoplasmic reticulum and Golgi complex in rat liver (Drabos et al., 2005). It seems that the sensitivity of the UPR system has declined during aging in different rat tissues, e.g. the phosphorylation level of eIF2␣ kinase and the expression of ATF4 and XBP1 are clearly reduced during aging (Paz Gavilan et al., 2006; Hussain and Ramaiah, 2007). This could be caused by the decrease in the expression of PERK and IRE1␣ which are the major transducers of ER stress (Paz Gavilan et al., 2006). Instead, the expression level of CHOP, the major apoptotic inducer, is increased in aged cells (Paz Gavilan et al., 2006; Hussain and Ramaiah, 2007). In support of this observation, Li and Holbrook (2004) demonstrated that the induction of ER stress by thapsigargin and tunicamycin evoked a significantly higher elevation in CHOP expression in hepatocytes isolated from old rats compared to the situation in young animals. They also observed that this age-related difference in CHOP expression was caused by the more effective signaling via the PERK/eIF2␣ pathway in aged cells (Li and Holbrook, 2004). These observations indicate that aged cells are more vulnerable to apoptosis induced by ER stress. Naidoo et al. (2008) have demonstrated that old mice display a decreased basal level of BiP/GRP78 expression in cerebral cortex whereas the expressions of proapoptotic CHOP and caspase-12 are markedly increased with aging. Interestingly, sleep deprivation, an inducer of ER stress in brain, triggered a prominent increase in the expression of CHOP and caspase-12, a response not observed in young mice (Naidoo et al., 2008). These studies (Li and Holbrook, 2004; Naidoo et al., 2008) suggest that young animals possess an efficient UPR system which prevents overwhelming ER stress and the induction of proapoptotic signaling via PERK/eIF2␣ and IRE1␣ pathways. This efficient ER-mediated stress resistance response declines with aging, causing problems in protein quality control and more pathological changes via dysfunctions in Ca2+ homeostasis and increased proapoptotic signaling.
6. ER stress: a hormetic lifespan rheostat? The mechanisms of the dose-responsive hormetic regulation in the aging process still await clarification, although transcriptionblocking DNA damage has been implicated (Schumacher, 2009). DNA damage increases during aging and DNA repair mechanisms are activated which can obviously enhance stress resistance and provide hormetic benefits in lifespan prolongation. However, this seems to be an exception since several other hormetic inducers are not related to DNA damage, such as hypoxic preconditioning, exercise, oxidative stress, dietary energy restriction or several phytochemical treatments (Gems and Partridge, 2008; Mattson, 2008a; Rattan, 2008). Indeed, the UPR linked to ER stress has several elements which bear resemblances to hormetic regulation, e.g. (i) ER transducers can recognize a large variety of stress inducers, directly or indirectly, and trigger UPR, (ii) the response is dose-dependent, low-dose induces stress resistance but a higher dose evokes degenerative effects, (iii) ER stress and the UPRlinked regulation are present in several diseases (Kim et al., 2008; Kitamura, 2008; Lin et al., 2008) and hormesis has been proposed to regulate disease resistance (Calabrese, 2008b; Mattson, 2008b). The aging process is linked to the decline in ER morphology and the expression levels of ER chaperones and transducers (see above).
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Interestingly, it seems that the aging process affects selectively the UPR induced by ER stress, i.e. apoptotic CHOP and caspase12 responses are known to be enhanced during aging (Li and Holbrook, 2004; Naidoo et al., 2008). In other words, the adaptive UPR defence is declining and thus the detrimental effects of ER stress gather strength and tissues become susceptible to pathological changes induced by ER stress (Fig. 2). The capacity to induce the stress resistance phenotype is reduced and cells become more vulnerable to protein quality problems, mitochondrial deficiencies, dysfunctions in Ca2+ homeostasis and apoptotic cell death (Fig. 2). In hormetic terms, longevity is dependent on the capability of cells and tissues to adapt to ER stress, probably to stress in general, and it is this capacity that declines during aging. It is likely that the regulation of ER stress and the UPR is linked to the cellular signaling network which is known to control longevity. Viswanathan et al. (2005) demonstrated that the SIR-2.1, a C. elegans analogue of Sir-2 family of longevity factors, regulates the expression of ER stress genes. They observed that the SIR-2.1 protein is a repressor of the abu-11 gene which increases the expression of a subset of pqn/abu stress genes in the ER. These authors noted that the overexpression of abu-11 gene could extend the lifespan of the nematode in a dosage-dependent manner. They also demonstrated that resveratrol increased the lifespan by stimulating the expression of the pqn/abu family of ER stress proteins, which seems to be a subset of ER stress proteins and to function in parallel with the UPR pathway (Viswanathan et al., 2005). Interestingly, the sir-2.1 mutants inducing a huge, 15–20-fold, increase in abu-11 expression displayed a short lifespan. This confirms very nicely our hypothesis that the intensity of ER stress controls lifespan in a hormetic manner. AMP-activated kinase (AMPK) is a sensitive energy metabolic sensor which is linked to the lifespan extension in caloric restriction regimens. In C. elegans, AAK-2/AMPK is involved in the lifespan extension mediated by both FoxO/DAF-16 and SIR-2.1 factors (Curtis et al., 2006; Greer and Brunet, 2009). Resveratrol increases the lifespan of C. elegans via AAK-2/AMPK signaling (Greer and Brunet, 2009). The mechanism involved in the AAK-2/AMPKinduced increase in longevity is still unknown but interestingly, Terai et al. (2005) demonstrated that AMPK could confer protection against hypoxic injuries in cardiomyocytes by reducing ER stress. Activation of AMPK prevented the apoptotic responses by decreasing CHOP expression and caspase-12 activation in hypoxic cells. AMPK also reduced protein synthesis via the eEF2 inactivation (Terai et al., 2005). The effect of AMPK activation was not restricted to the hypoxia model but the UPR response was also inhibited in thapsigargin and tunicamycin-treated cells. Several phytochemicals are hormetins, i.e. at a low-dose they can provoke stress resistance but higher doses cause toxic effects (Mattson and Cheng, 2006; Son et al., 2008). Interestingly, a number of natural plant molecules, ingredients in several plantderived medicinal extracts, can induce ER stress, e.g. resveratrol, curcumin and berberine (Viswanathan et al., 2005; Pae et al., 2007; Lin et al., 2007; Liu et al., 2010). In contrast, some potent plant toxins, e.g. ricin, can inhibit the activation of UPR (Parikh et al., 2008). Plants contain evolutionary conserved mechanisms for ER stress signaling and UPR defence which can be used for host defence or for killing insects (Urade, 2009). Generally, these phytochemicals are beneficial for mammals, stimulating the UPR and improving stress resistance but excessive use can be toxic to susceptible tissues, e.g. beta cells in pancreas, causing the development of diabetes (Hettiarachchi et al., 2008). Phytochemicals can also induce hormetic responses via the other signaling pathways, e.g. CREB, NF-B and NRF2 (Mattson and Cheng, 2006).
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7. Concluding remarks ER stress and the UPR system can be considered to conform well to the definition of hormesis, i.e. mild stress induces stress resistance via IRE1, PERK and ATF6 pathways whereas overloading provokes several destructive effects, e.g. dysfunction in Ca2+ homeostasis, energy metabolic deficiencies, inhibition of protein synthesis, and finally trigger apoptotic cell death (Fig. 1). Several observations imply that the responsiveness of the UPR system declines during aging and in addition, it seems that the UPR signaling preferentially evokes the pathological pathways, e.g. induction of CHOP and JNK, instead of survival responses via GRP78/94 and HSPs. This age-related dysfunction in UPR outcome can be caused by (i) an insufficiency in the recognition of stress by transducers or (ii) deficiency in the extent of UPR signaling. Moreover, chronic ER stress might trigger negative feedback effects to shut down the destructive consequences of excessive UPR. It is the lack of a proper UPR that impairs the protein quality control leading to defects in the functions of synthesized proteins and ultimately can trigger their aggregation. Currently, there is much work being done on the manipulation of ER stress and UPR response in several diseases, e.g. cancer, diabetes and neurodegeneration (Kim et al., 2008; Lin et al., 2008; Healy et al., 2009). In particular, ER stress has many important roles, i.e. not only in diabetes and the metabolic syndrome (Gregor and Hotamisligil, 2007; Eizirik et al., 2008) but also in cancer (Healy et al., 2009). There are two approaches that can be used, either (i) inhibiting UPR so that cells cannot adapt to stressful conditions or (ii) overloading UPR so that cells can trigger the apoptotic cell death. These treatments are potentially ideal for cancer therapy and several small molecular candidate compounds are being investigated (Healy et al., 2009). However, it seems that a slight enhancement of the ER stress and a boosting of the intensity of UPR could be a valid strategy for delaying the aging process and enhancing the healthy aging. Acknowledgements This study was financially supported by grants from the Academy of Finland and the University of Eastern Finland, Kuopio, Finland. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript. References Barthel, A., Schmoll, D., Unterman, T.G., 2005. FoxO proteins in insulin action and metabolism. FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183–189. Baumeister, R., Schaffitzel, E., Hertweck, M., 2006. Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J. Endocrinol. 190, 191–202. Benita, Y., Kikuchi, H., Smith, A.D., Zhang, M.Q., Chung, D.C., Xavier, R.J., 2009. An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acid Res. 37, 4587–4602. Bernales, S., Papa, F.R., Walter, P., 2006. Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487–508. Bi, M., Naczki, C., Koritzinsky, M., Fels, D., Blais, J., Hu, N., Harding, H., Novoa, I., Varia, M., Raleigh, J., Scheuner, D., Kaufman, R.J., Bell, J., Ron, D., Wouters, B.G., Koumenis, C., 2005. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481. Braeckman, B., Vanfleteren, J.R., 2007. Genetic control of longevity in C. elegans. Exp. Gerontol. 42, 90–98. Calabrese, E.J., 2008a. Hormesis: why it is important to toxicology and toxicologists. Environ. Toxicol. Chem. 27, 1451–1474. Calabrese, E.J., 2008b. Hormesis and medicine. Br. J. Clin. Pharmacol. 66, 594–617. Calabrese, E.J., 2009. Getting the dose–response wrong: why hormesis became marginalized and the threshold model accepted. Arch. Toxicol. 83, 227–247. Calderwood, S.K., Murshid, A., Prince, T., 2009. The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review. Gerontology 55, 550–558. Cullinan, S.B., Diehl, J.A., 2006. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int. J. Biochem. Cell Biol. 38, 317–332.
216
A. Salminen, K. Kaarniranta / Ageing Research Reviews 9 (2010) 211–217
Curtis, R., O’Connor, G., DiStefano, P.S., 2006. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolic pathways. Aging Cell 5, 119–126. de Magalhaes, J.P., Curado, J., Church, G.M., 2009. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25, 875–881. Doroudgar, S., Thuerauf, D.J., Marcinko, M.C., Belmont, P.J., Glembotski, C.C., 2009. Ischemia activates the ATF6 branch of the endoplasmic reticulum stress response. J. Biol. Chem. 284, 29735–29745. Drabos, K.L., Tran, H.C., Kiri, A.N., Lan, W.K., McRorie, D.K., Horn, M.J., 2005. Comparison of Golgi apparatus and endoplasmic reticulum proteins from livers of juvenile and aged rats using a novel technique for separation and enrichment of organelles. J. Biomol. Tech. 16, 347–355. Eizirik, D.L., Cardozo, A.K., Cnop, M., 2008. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29, 42–61. Feder, M.E., Hofmann, G.E., 1999. Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu. Rev. Physiol. 61, 243–282. Fels, D.R., Koumenis, C., 2006. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol. Ther. 5, 723–728. Finkel, T., Holbrook, N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247. Gems, D., Partridge, L., 2008. Stress–response hormesis and aging: “That which does not kill us makes us stronger”. Cell Metab. 7, 200–203. Greer, E.L., Brunet, A., 2009. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8, 113–127. Gregor, M.F., Hotamisligil, 2007. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J. Lipid Res. 48, 1905–1914. Healy, S.J.M., Gorman, A.M., Mousavi-Shafaei, P., Gupta, S., Samali, A., 2009. Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur. J. Pharmacol. 625, 234–246. Hettiarachchi, K.D., Zimmet, P.Z., Myers, M.A., 2008. Dietary toxins, endoplasmic reticulum (ER) stress and diabetes. Curr. Diabetes Rev. 4, 146–156. Hetz, C.A., 2007. ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage. Antioxidants Redox Signal. 9, 2345–2355. Holbrook, N.J., Ikeyama, S., 2002. Age-related decline in cellular response to oxidative stress: links to growth factor signaling pathways with common defects. Biochem. Pharmacol. 64, 999–1005. Hoyer-Hansen, M., Jäättelä, M., 2007. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 14, 1576–1582. Hussain, S.G., Ramaiah, K.V.A., 2007. Reduced eIF2␣ phosphorylation and increased proapoptotic proteins in aging. Biochem. Biophys. Res. Commun. 355, 365–370. Jäättelä, M., 1999. Heat shock proteins as cellular lifeguards. Ann. Med. 31, 261–271. Jensen, V.L., Gallo, M., Riddle, D.L., 2006. Targets of DAF-16 involved in Caenorhabditis elegans adult longevity and dauer formation. Exp. Gerontol. 41, 922–927. Johnson, T.E., Henderson, S., Murakami, S., de Castro, E., de Castro, S.H., Cypser, J., Rikke, B., Tedesco, P., Link, C., 2002. Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J. Inherit. Metab. Dis. 25, 197–206. Karpac, J., Jasper, H., 2009. Insulin and JNK: optimizing metabolic homeostasis and lifespan. Trends Endocrinol. Metab. 20, 100–106. Kensler, T.W., Wakabayashi, N., Biswal, S., 2007. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47, 89–116. Kim, I., Xu, W., Reed, J.C., 2008. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 7, 1013–1030. Kitamura, M., 2008. Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces. Am. J. Physiol. Renal Physiol. 295, F323–334. Landriscina, M., Maddalena, F., Laudiero, G., Esposito, F., 2009. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid. Redox Signal. 11, 2701–2716. Lapointe, J., Hekimi, S., 2010. When a theory of aging ages badly. Cell. Mol. Life Sci. 67, 1–8. Li, J., Holbrook, N.J., 2004. Elevated gadd153/chop expression and enhanced c-Jun N-terminal protein kinase activation sensitizes aged cells to ER stress. Exp. Gerontol. 39, 735–744. Lin, J.H., Walter, P., Yen, T.S.B., 2008. Endoplasmic reticulum stress in disease pathogenesis. Annu. Rev. Pathol. Mech. Dis. 3, 399–425. Lin, J.P., Yang, J.S., Chang, N.W., Chiu, T.H., Su, C.C., Lu, K.W., Ho, Y.T., Yeh, C.C., Mei-Dueyang, Lin, H.J., Chung, J.G., 2007. GADD153 mediates berberine-induced apoptosis in human cervical cancer Ca ski cells. Anticancer Res. 27, 3379–3386. Liu, B.Q., Gao, Y.Y., Niu, X.F., Xie, J.S., Guan, Y., Wang, H.Q., 2010. Implication of unfolded protein response in resveratrol-induced inhibition of K562 cell proliferation. Biochem. Biophys. Res. Commun. 391, 778–782. Malhotra, J.D., Kaufman, R.J., 2007. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxidants Redox Signal. 9, 2277–2293. Mao, W., Iwai, C., Qin, F., Liang, C., 2005. Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC2 cells via oxidative stress. Am. J. Physiol. Heart Circ. Physiol. 288, H2381–H2389. Martindale, J.L., Holbrook, N.J., 2002. Cellular response to oxidative stress: signaling for suicide and survival. J. Cell. Physiol. 192, 1–15. Masoro, E.J., 2009. Caloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms. Biochim. Biophys. Acta 1790, 1040–1048.
Mattson, M.P., 2008a. Hormesis defined. Ageing Res. Rev. 7, 1–7. Mattson, M.P., 2008b. Hormesis and disease resistance: activation of cellular stress response pathways. Hum. Exp. Toxicol. 27, 155–162. Mattson, M.P., Cheng, A., 2006. Neurohormetic phytochemicals: low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci. 29, 632– 639. Mori, K., 2009. Signalling pathways in the unfolded protein response: development from yeast to mammals. J. Biochem. 146, 743–750. Murakami, S., 2006. Stress resistance in long-lived mouse models. Exp. Gerontol. 41, 1014–1019. Naidoo, N., Ferber, M., Master, M., Zhu, Y., Pack, A.I., 2008. Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J. Neurosci. 28, 6539–6548. Naidoo, N., 2009a. ER and ageing—protein folding and the ER stress response. Ageing Res. Rev. 8, 150–159. Naidoo, N., 2009b. The endoplasmic reticulum stress response and aging. Rev. Neurosci. 20, 23–37. Nuss, J.E., Choksi, K.B., DeFord, J.H., Papaconstantinou, J., 2008. Decreased enzyme activities of chaperones PDI and BiP in aged mouse livers. Biochem. Biophys. Res. Commun. 365, 355–361. Oyadomari, S., Mori, M., 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11, 381–389. Pae, H.O., Jeong, S.O., Jeong, G.S., Kim, K.M., Kim, H.S., Kim, S.A., Kim, Y.C., Kang, S.D., Kim, B.N., Chung, H.T., 2007. Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells. Biochem. Biophys. Res. Commun. 353, 1040–1045. Pardon, M.C., 2007. Stress and ageing interactions: a paradox in the context of shared etiological and physiopathological processes. Brain Res. Rev. 54, 251–273. Parikh, B.A., Tortora, A., Li, X.P., Turner, N.E., 2008. Ricin inhibits activation of the unfolded protein response by preventing splicing of the HAC1 mRNA. J. Biol. Chem. 283, 6145–6153. Paz Gavilan, M., Vela, J., Castano, A., Ramos, B., del Rio, J.C., Vitorica, J., Ruano, D., 2006. Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol. Aging 27, 973–982. Puzianowska-Kuznicka, M., Kuznicki, J., 2009. The ER and ageing II: calcium homeostasis. Ageing Res. Rev. 8, 160–172. Rabek, J.P., Boylston III, W.H., Papaconstantinou, J., 2003. Carbonylation of ER chaperone proteins in aged mouse liver. Biochem. Biophys. Res. Commun. 305, 566–572. Ramirez, J.M., Folkow, L.P., Blix, A.S., 2007. Hypoxia tolerance in mammals and birds: from the wilderness to the clinic. Annu. Rev. Physiol. 69, 113–143. Rattan, S.I.S., 2008. Hormesis in aging. Ageing Res. Rev. 7, 63–78. Rion, S., Kawecki, T.J., 2007. Evolutionary biology of starvation resistance: what we have learned from Drosophila. J. Evol. Biol. 20, 1655–1664. Ron, D., Walter, P., 2007. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529. Sachs, H.G., Colgan, J.A., Lazarus, M.L., 1977. Ultrastructure of the aging myocardium: a morphometric approach. Am. J. Anat. 150, 63–71. Salminen, A., Kaarniranta, K., 2009. Regulation of the aging process by autophagy. Trends Mol. Med. 15, 217–224. Salminen, A., Kauppinen, A., Suuronen, T., Kaarniranta, K., Ojala, J., 2009. ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J. Neuroinflamm. 6, 41. Schröder, M., 2005. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789. Schröder, M., 2008. Endoplasmic reticulum stress responses. Cell. Mol. Life Sci. 65, 862–894. Schumucker, D.L., Mooney, J.S., Jones, A.L., 1977. Age-related changes in the hepatic endoplasmic reticulum: a quantitative analysis. Science 197, 1005–1008. Schmucker, D.L., 1990. Hepatocyte fine structure during maturation and senescence. J. Electron Microsc. Tech. 14, 106–125. Schumacher, B., 2009. Transcription-blocking DNA damage in aging: a mechanism for hormesis. Bioessays 31, 1347–1356. Son, T.G., Camandola, S., Mattson, M.P., 2008. Hormetic dietary phytochemicals. Neuromol. Med. 10, 236–246. Swindell, W.R., 2009. Genes and gene expression modules associated with caloric restriction and ageing in the laboratory mouse. BMC Genomics 10, 585. Szegezdi, E., Logue, S.E., Gorman, A.M., Samali, A., 2006. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7, 880–885. Tatar, M., Yin, C.M., 2001. Slow aging during insect reproductive diapauses: why butterflies, grasshoppers and flies are like worms. Exp. Gerontol. 36, 723– 738. Tavernarakis, N., 2008. Ageing and the regulation of protein synthesis: a balancing act? Trends Cell Biol. 18, 228–235. Terai, K., Hiramoto, Y., Masaki, M., Sugiyama, S., Kuroda, T., Hori, M., Kawase, I., Hirota, H., 2005. AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol. Cell. Biol. 25, 9554–9575. Tower, J., 2008. Hsps and aging. Trends Endocrinol. Metab. 20, 216–222. Urade, R., 2009. The endoplasmic reticulum stress signaling pathways in plants. Biofactors 35, 326–331. Van Raamsdonk, J.M., Hekimi, S., 2009. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 5, e1000361. Vermeulen, C.J., Loeschcke, V., 2007. Longevity and the stress response in Drosophila. Exp. Gerontol. 42, 153–159.
A. Salminen, K. Kaarniranta / Ageing Research Reviews 9 (2010) 211–217 Vernace, V.A., Schmidt-Glenewinkel, Figueiredo-Pereira, M.E., 2007. Aging and regulated protein degradation: who has the upper hand? Aging Cell 6, 599– 606. Viswanathan, M., Kim, S.K., Berdichevsky, A., Guarente, L., 2005. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9, 605–615.
217
Yoon, S.O., Yun, C.H., Chung, A.S., 2002. Dose effect of oxidative stress on signal transduction in aging. Mech. Ageing Dev. 123, 1597–1604. Zhang, K., Kaufman, R.J., 2008. From endoplasmic-reticulum stress to the inflammatory response. Nature 454, 455–462. Zhivotovsky, B., 2003. Caspases: the enzymes of death. Essays Biochem. 39, 25– 40.
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Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr
Review
ER stress and hormetic regulation of the aging process Antero Salminen a,b,∗ , Kai Kaarniranta c,d a
Department of Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland c Department of Ophthalmology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland d Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland b
a r t i c l e
i n f o
Article history: Received 17 February 2010 Received in revised form 25 March 2010 Accepted 14 April 2010 Keywords: ER stress Hormesis Longevity Stress resistance UPR Review
a b s t r a c t An ability to mount a stress resistance under pressure is a major host defence mechanism and has been a fundamental force during evolution. However, the adaptation capacity clearly declines during aging and this loss of stress resistance accelerates the aging process exposing the organism to degenerative diseases. The effect of stress on organisms seems to be a dose-dependent response, i.e. mild stress induces a stress tolerance and extends the lifespan whereas excessive stress accentuates the aging process. This paradox is known as hormesis in aging research. It is essential to distinguish the intensity of cellular stress and thus mount an appropriate host defence. The endoplasmic reticulum (ER) contains three branches of stress transducers, i.e. IRE1, PERK, and ATF6 pathways, all of which recognize stress-related disturbances in the function of ER. These transducers trigger a complex signaling network which activates an unfolded protein response (UPR). Interestingly, ER stress transducers can distinguish the intensity of ER stress and induce a dose-dependent UPR, either adaptive response to stress or apoptotic cell death. The efficiency of the stress recognition system and UPR signaling declines during aging. We will discuss the role of ER stress in hormetic regulation of aging process and longevity. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction A capacity to adapt to hostile environmental conditions and intrinsic stress is a crucial characteristic of organisms during evolution. Studies on model organisms, in particular on Caenorhabditis elegans, have revealed that responses to stress and aging process share the same mechanisms and moreover, adaptation to stress can increase the life expectancy in conjunction with the healthy aging process (Johnson et al., 2002; Pardon, 2007; Rion and Kawecki, 2007). Interestingly, the effect of stress on organisms seems to be a dose-dependent process, i.e. mild stress induces a stress tolerance and expands the lifespan whereas excessive stress exacerbates the aging process. This phenomenon is called hormesis in aging research (Gems and Partridge, 2008; Mattson, 2008a; Rattan, 2008). During the course of evolution, it has been indispensable to recognize the cellular stress and trigger the adaptive host defence. The endoplasmic reticulum (ER) occupies a unique position as a cellular organelle responsible for the control of protein quality in order to distinguish attacks on protein fidelity. A variety of stressors, direct or indirect, induce ER stress which generates via different trans-
∗ Corresponding author at: Department of Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, FIN70211 Kuopio, Finland. E-mail address: antero.salminen@uef.fi (A. Salminen). 1568-1637/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.arr.2010.04.003
ducer proteins a response, called unfolded protein response (UPR) (Schröder, 2005; Bernales et al., 2006) (Fig. 1). This signaling system from ER lumen to the nucleus is evolutionary conserved; only the number of functional sensors has increased during evolution (Mori, 2009). It seems that ER stress transducers can recognize the intensity of ER stress and induce a dose-dependent UPR, either evoking an adaptive defence or triggering apoptotic cell death (Szegezdi et al., 2006; Hetz, 2007) (Fig. 1). This characteristic fits well to the definition of hormesis (Mattson, 2008a). Interestingly, several observations clearly demonstrate that the efficiency of the ER stress-UPR system declines during aging (Naidoo, 2009a,b) and in that way can expose the organism to an entropic aging process. We will discuss the role of ER stress and UPR signaling in hormetic regulation of aging process and longevity.
2. Stress resistance: a hallmark of longevity During evolution, it has been essential that organisms develop the ability to adapt to harsh environmental conditions and intrinsic stress. This stress resistance capacity has evolved from a complex set of molecular self-defence mechanisms (e.g. Kensler et al., 2007; Landriscina et al., 2009). Reproductive diapauses of invertebrates and caloric restriction in many species have been the most widely studied and are today the best known stress resistance models (Tatar and Yin, 2001; Rion and Kawecki, 2007). Organisms are also
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Fig. 1. Regulation of the aging process by ER stress. Several pro-aging insults trigger ER stress and activate the UPR (green box) via IRE1, PERK and ATF6 transducers. UPR induces the expression of stress resistance components which can also extend the lifespan. However, prolonged and excessive ER stress can lead to the pathological consequences that accelerate the aging process (red arrows and red boxes).
able to develop an adaptive tolerance to a wide variety of stress insults, e.g. oxidative stress, heat shock, and hypoxia (Feder and Hofmann, 1999; Martindale and Holbrook, 2002; Ramirez et al., 2007). One of the age-related paradoxes is the observation that increased stress resistance can extend the lifespan of the organisms. This result has been verified in studies conducted on a variety of species and many stress conditions (Pardon, 2007; Vermeulen and Loeschcke, 2007; Masoro, 2009). Moreover, long-lived mouse models exhibit a clear cellular tolerance to many stress insults, e.g. UV light and ROS (reactive oxygen species) (Murakami, 2006). This demonstrates that the acquired stress resistance appears even at the cellular level and is not confined to the organismal function. Interestingly, the ability to withstand a distinct stress situation frequently also provides prevention against several other harmful insults or conditions suggesting that the same pathways can protect against different insults (e.g. Johnson et al., 2002). During unfavourable environmental conditions, C. elegans and several insects enter a diapause state which arrests development and triggers the appearance of a dauer larva phenotype with extended lifespan (Tatar and Yin, 2001). The formation of the dauer stage is induced by endocrinological regulation and alternate metabolism (Tatar and Yin, 2001; Baumeister et al., 2006). Studies on C. elegans long-lived mutants have revealed several DAF genes (DAuer Formation) which can clearly extend the lifespan of adult nematodes (Braeckman and Vanfleteren, 2007). The DAF-2 pathway is the most important, e.g. C. elegans with loss-of-function mutations in the genes of that pathway display a long-lived and stress resistant phenotype. Interestingly, the DAF-2 pathway is the ortholog to mammalian insulin/IGF-1 pathway which is known to regulate metabolic homeostasis and lifespan also in vertebrates (Karpac and Jasper, 2009). The DAF-2 pathway regulates the function of DAF-16 (ortholog to FoxO family) transcription factors which control the expression of several stress resistance genes (Barthel et al., 2005; Jensen et al., 2006). Progress in gene expression profiling techniques has helped to unravel the genetic background of different stress resistance mod-
els also in vertebrates. For instance, whole-genome transcriptional data has been established in caloric restriction model (Swindell, 2009) and hypoxia tolerance (Benita et al., 2009). Bioinformatic techniques have revealed distinct transcription factor pathways involved in the induction of stress resistance, e.g. HSF-1, HIF-1, p53, FoxOs, and SIRT1 (Jensen et al., 2006; Benita et al., 2009; Swindell, 2009). Several studies have highlighted the role of chaperones in the increase of stress resistance (Feder and Hofmann, 1999). Swindell (2009) observed that caloric restriction, a wellknown way to extend the lifespan also in mammals, induces the expression of genes which inhibit oxidative stress and inflammation. Interestingly, de Magalhaes et al. (2009) observed that aging increases the expression of genes of the immune response, lysosomal degradation and antiapoptotic defence. In general, many of these observations support the role of stress resistance in lifespan extension, although caloric restriction does not induce genomewide reversal of age-related gene expression (Swindell, 2009). 3. Hormesis: live longer with a mild stress Studies on the role of stress resistance in the regulation of lifespan have revealed a dose-dependency, i.e. a mild, low-dose stress increases the lifespan of organism but conversely, a higher intensity of stress or a prolonged exposure, overwhelming to the organism, can evoke detrimental effects and decrease the lifespan (Gems and Partridge, 2008; Mattson, 2008a; Rattan, 2008). This hormetic regulation has been observed both in vivo in organisms and in vitro in cell culture studies. The term hormesis comes from toxicology and refers to a kind of dose–response relationship with low-dose inducing stimulation and higher doses inhibition of the reaction (Calabrese, 2008a). Hormesis involves the adaptive responses of cells and organisms to mild and moderate stress including heat, irradiation, hypoxia, oxidative stress and caloric restriction (Fig. 1). Many chemicals can also induce hormetic stress resistance; these compounds are called hormetins (Mattson, 2008a; Rattan, 2008). For instance, several phytochemicals can induce adaptive
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Fig. 2. ER stress is a hormetic lifespan rheostat. From mild up to moderate ER stress induces stress resistance (green box) that can extend the lifespan but a prolonged and overwhelming stress accelerates the aging process (red box).
responses when they are used at subtoxic doses (Mattson and Cheng, 2006). It should be stressed that the phenomenon of hormesis has nothing to do with homeopathy (Calabrese, 2009). Hormetic regulation of the aging process provides interesting insights into the aging mechanism itself. It seems that aging is a physiological process that can be extended by increasing stress resistance (see Section 2). Stress tolerance is normally evoked by mild, optimal insults. However, the duration of stress is an important parameter since a sustained stress can be detrimental and cause pathological changes (Fig. 2). This may explain many of the inconsistent results in experiments with oxidative stress (Lapointe and Hekimi, 2010). Oxidative stress is a well-known proaging insult but in some contexts it can extend the lifespan (Van Raamsdonk and Hekimi, 2009; Lapointe and Hekimi, 2010). The effects of oxidative stress have been extensively studied and it is known that the responses are clearly dependent on many factors, e.g. the dose of ROS, type of ROS, tissue exposed and the age of organism (see Holbrook and Ikeyama, 2002; Martindale and Holbrook, 2002; Yoon et al., 2002). Different proteotoxic responses, such as protein unfolding, modification and aggregation, are typical changes encountered after hormetic insults, but, interestingly, similar changes progressively accumulate during aging. Thus one could argue that protein quality control and cleansing systems represent common threads between adaptive hormetic changes and lifespan extension. It is known that the chaperone protein expression and cellular levels are clearly increased during the appearance of stress resistance (Feder and Hofmann, 1999; Jäättelä, 1999). Heat shock proteins HSP27, HSP70 and HSP90 are common stress-responsive chaperones, the expressions of which are highly increased in a variety of stress conditions. In model organisms, HSPs have been reported to ameliorate age-related proteotoxicity and increase lifespan (Tower, 2008; Calderwood et al., 2009).
4. ER stress: paradigm of hormetic regulation The ER tubular network contains a unique protein quality control system which has three arms of stress transducers, i.e. IRE1, PERK, and ATF6 pathways (Schröder, 2005; Bernales et al., 2006). These sensors recognize the unfolding or misfolding of proteins during their maturation process in the ER. The ER compartment has also several other important cellular functions, e.g. the maintenance of calcium and redox homeostasis and membrane lipid synthesis and recycling. Several stress-related insults disturb the microenvironment of ER and subsequently stimulate the stress transducers which generate a defence reaction called the unfolded protein response (UPR) (Fig. 1). Common inducers of ER stress include oxidative stress, hypoxia, viral infection and toxic chemicals (Bernales et al., 2006; Fels and Koumenis, 2006; Ron and Walter, 2007; Malhotra and Kaufman, 2007; Doroudgar et al., 2009) but hormonal stress can also trigger ER stress (Mao et al., 2005). Transcription factors ATF4, ATF6 and XBP1 are the main signaling molecules of UPR but many other factors, e.g. CHOP (also called GADD153), JNK, NF-B and NRF-2, can be involved in UPR (Bernales et al., 2006; Cullinan and Diehl, 2006; Ron and Walter, 2007). Several studies demonstrate that a low-level of ER stress is protective, consisting of a stress resistance phase, and involving an increase in the expression of molecular chaperones, in both ER and cytosol, and Ca2+ -binding proteins along with antiapoptotic and antioxidative proteins (Figs. 1 and 2). The UPR is normally a beneficial adaptation mechanism and it improves stress resistance but in the case of cancer, increased hypoxic tolerance promotes tumor growth (Bi et al., 2005). Moreover, ER stress can activate autophagic cleansing of accumulating material in ER in order to prevent the detrimental collapse of the ER function (Hoyer-Hansen and Jäättelä, 2007).
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ER stress has been described as either a “double-edged sword” or a “Janus-faced system” (Malhotra and Kaufman, 2007; Kitamura, 2008). If present at a low or moderate intensity, ER stress initially stimulates an adaptive UPR to promote cellular survival whereas in the case of persistent, chronic stress, UPR can trigger apoptotic cell death program (Kim et al., 2008; Schröder, 2008) (Figs. 1 and 2). This can be viewed as beneficial since apoptosis can kill the damaged cell but rescue the neighbouring cells from suffering necrotic cell death. ER stress can induce apoptotic cell death via several pathways, e.g. (i) the activation of CHOP transcription factor through PERK and ATF6 pathways, (ii) the IRE1␣-TRAF2-ASK1 signaling, and (iii) the Ca2+ outflow from ER and translocation to mitochondria (Oyadomari and Mori, 2004; Szegezdi et al., 2006; Hetz, 2007; Kim et al., 2008; Salminen et al., 2009) (Figs. 1 and 2). The key regulator of apoptosis, also that of ER stress-mediated apoptosis, is the balance between the anti- and proapoptotic BCL2 family of proteins (Szegezdi et al., 2006; Hetz, 2007). The CHOP transcription factor can inhibit the expression of the antiapoptotic BCL2 proteins but simultaneously, increase the expression of proapoptotic GADD34 and TRB3 (Szegezdi et al., 2006). Moreover, the IRE1␣-TRAF2mediated activation of JNK can phosphorylate and consequently inhibit the BCL2 proteins. The suppression of BCL2 function disturbs the balance between BCL2 proteins and proapoptotic BAX, BAK, and BH3-only proteins leading to the release of Ca2+ from the ER and apoptogenic proteins from mitochondria (Szegezdi et al., 2006; Hetz, 2007). Apoptotic cell death is executed via the activation of different caspase cascades (Zhivotovsky, 2003). The role of ER-located caspases, CASP4 and CASP12, in the induction of apoptosis is still under debate, but it has been proposed that they are involved in the induction of inflammation (Zhang and Kaufman, 2008; Salminen et al., 2009). Recently, several studies have demonstrated that prolonged ER stress can stimulate inflammatory responses, e.g. via IRE1␣-TRAF2-NF-B and ATF6-CREBH pathways (Zhang and Kaufman, 2008; Salminen et al., 2009) (Fig. 1). Interestingly, gene expression profiles have revealed that the genes linked to inflammation and immune responses identify a common signature of aging (de Magalhaes et al., 2009). In conclusion, the UPR induced by ER stress involves two different phases, i.e. an adaptive, survival phase and an apoptotic, degenerative phase. This dose-dependent sequence of responses to ER stress is closely compatible with the definition of hormesis (Mattson, 2008a) (Fig. 2).
5. ER stress and the aging process The aging process contains in abundance of characteristics indicating that ER stress could be activated, e.g. increased oxidative stress and accumulation of harmful protein modifications, misfolding and aggregation of proteins, disturbances in Ca2+ homeostasis and impairment in global protein synthesis (Finkel and Holbrook, 2000; Gems and Partridge, 2008; Tavernarakis, 2008; Puzianowska-Kuznicka and Kuznicki, 2009). In addition, the protein cleansing system becomes impaired during aging due to the decline in autophagic and proteasomal degradation (Vernace et al., 2007; Salminen and Kaarniranta, 2009). All these age-related changes imply that the efficient function of protein quality system is compromised during aging. Several studies have demonstrated that the expression levels of molecular chaperones and folding enzymes in the ER clearly reduce during aging (see Naidoo, 2009a,b); examples are (i) declines in the protein levels of ER resident chaperones, BiP/GRP78, GRP94 and calnexin, (ii) reduction in the enzyme activity of PDI, a key enzyme in disulfide bond formation (Nuss et al., 2008), and (iii) carbonylation of several ER proteins (Rabek et al., 2003).
A plethora of morphometric studies have described age-related, generally tissue-specific, changes in the ER–Golgi system. Most of these studies have observed a decline in ER volume, especially in smooth-surfaced endoplasmic or sarcoplasmic reticulum (e.g. Sachs et al., 1977; Schumucker et al., 1977; Schmucker, 1990). In addition, prominent changes occur during aging in the proteomic profiles of endoplasmic reticulum and Golgi complex in rat liver (Drabos et al., 2005). It seems that the sensitivity of the UPR system has declined during aging in different rat tissues, e.g. the phosphorylation level of eIF2␣ kinase and the expression of ATF4 and XBP1 are clearly reduced during aging (Paz Gavilan et al., 2006; Hussain and Ramaiah, 2007). This could be caused by the decrease in the expression of PERK and IRE1␣ which are the major transducers of ER stress (Paz Gavilan et al., 2006). Instead, the expression level of CHOP, the major apoptotic inducer, is increased in aged cells (Paz Gavilan et al., 2006; Hussain and Ramaiah, 2007). In support of this observation, Li and Holbrook (2004) demonstrated that the induction of ER stress by thapsigargin and tunicamycin evoked a significantly higher elevation in CHOP expression in hepatocytes isolated from old rats compared to the situation in young animals. They also observed that this age-related difference in CHOP expression was caused by the more effective signaling via the PERK/eIF2␣ pathway in aged cells (Li and Holbrook, 2004). These observations indicate that aged cells are more vulnerable to apoptosis induced by ER stress. Naidoo et al. (2008) have demonstrated that old mice display a decreased basal level of BiP/GRP78 expression in cerebral cortex whereas the expressions of proapoptotic CHOP and caspase-12 are markedly increased with aging. Interestingly, sleep deprivation, an inducer of ER stress in brain, triggered a prominent increase in the expression of CHOP and caspase-12, a response not observed in young mice (Naidoo et al., 2008). These studies (Li and Holbrook, 2004; Naidoo et al., 2008) suggest that young animals possess an efficient UPR system which prevents overwhelming ER stress and the induction of proapoptotic signaling via PERK/eIF2␣ and IRE1␣ pathways. This efficient ER-mediated stress resistance response declines with aging, causing problems in protein quality control and more pathological changes via dysfunctions in Ca2+ homeostasis and increased proapoptotic signaling.
6. ER stress: a hormetic lifespan rheostat? The mechanisms of the dose-responsive hormetic regulation in the aging process still await clarification, although transcriptionblocking DNA damage has been implicated (Schumacher, 2009). DNA damage increases during aging and DNA repair mechanisms are activated which can obviously enhance stress resistance and provide hormetic benefits in lifespan prolongation. However, this seems to be an exception since several other hormetic inducers are not related to DNA damage, such as hypoxic preconditioning, exercise, oxidative stress, dietary energy restriction or several phytochemical treatments (Gems and Partridge, 2008; Mattson, 2008a; Rattan, 2008). Indeed, the UPR linked to ER stress has several elements which bear resemblances to hormetic regulation, e.g. (i) ER transducers can recognize a large variety of stress inducers, directly or indirectly, and trigger UPR, (ii) the response is dose-dependent, low-dose induces stress resistance but a higher dose evokes degenerative effects, (iii) ER stress and the UPRlinked regulation are present in several diseases (Kim et al., 2008; Kitamura, 2008; Lin et al., 2008) and hormesis has been proposed to regulate disease resistance (Calabrese, 2008b; Mattson, 2008b). The aging process is linked to the decline in ER morphology and the expression levels of ER chaperones and transducers (see above).
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Interestingly, it seems that the aging process affects selectively the UPR induced by ER stress, i.e. apoptotic CHOP and caspase12 responses are known to be enhanced during aging (Li and Holbrook, 2004; Naidoo et al., 2008). In other words, the adaptive UPR defence is declining and thus the detrimental effects of ER stress gather strength and tissues become susceptible to pathological changes induced by ER stress (Fig. 2). The capacity to induce the stress resistance phenotype is reduced and cells become more vulnerable to protein quality problems, mitochondrial deficiencies, dysfunctions in Ca2+ homeostasis and apoptotic cell death (Fig. 2). In hormetic terms, longevity is dependent on the capability of cells and tissues to adapt to ER stress, probably to stress in general, and it is this capacity that declines during aging. It is likely that the regulation of ER stress and the UPR is linked to the cellular signaling network which is known to control longevity. Viswanathan et al. (2005) demonstrated that the SIR-2.1, a C. elegans analogue of Sir-2 family of longevity factors, regulates the expression of ER stress genes. They observed that the SIR-2.1 protein is a repressor of the abu-11 gene which increases the expression of a subset of pqn/abu stress genes in the ER. These authors noted that the overexpression of abu-11 gene could extend the lifespan of the nematode in a dosage-dependent manner. They also demonstrated that resveratrol increased the lifespan by stimulating the expression of the pqn/abu family of ER stress proteins, which seems to be a subset of ER stress proteins and to function in parallel with the UPR pathway (Viswanathan et al., 2005). Interestingly, the sir-2.1 mutants inducing a huge, 15–20-fold, increase in abu-11 expression displayed a short lifespan. This confirms very nicely our hypothesis that the intensity of ER stress controls lifespan in a hormetic manner. AMP-activated kinase (AMPK) is a sensitive energy metabolic sensor which is linked to the lifespan extension in caloric restriction regimens. In C. elegans, AAK-2/AMPK is involved in the lifespan extension mediated by both FoxO/DAF-16 and SIR-2.1 factors (Curtis et al., 2006; Greer and Brunet, 2009). Resveratrol increases the lifespan of C. elegans via AAK-2/AMPK signaling (Greer and Brunet, 2009). The mechanism involved in the AAK-2/AMPKinduced increase in longevity is still unknown but interestingly, Terai et al. (2005) demonstrated that AMPK could confer protection against hypoxic injuries in cardiomyocytes by reducing ER stress. Activation of AMPK prevented the apoptotic responses by decreasing CHOP expression and caspase-12 activation in hypoxic cells. AMPK also reduced protein synthesis via the eEF2 inactivation (Terai et al., 2005). The effect of AMPK activation was not restricted to the hypoxia model but the UPR response was also inhibited in thapsigargin and tunicamycin-treated cells. Several phytochemicals are hormetins, i.e. at a low-dose they can provoke stress resistance but higher doses cause toxic effects (Mattson and Cheng, 2006; Son et al., 2008). Interestingly, a number of natural plant molecules, ingredients in several plantderived medicinal extracts, can induce ER stress, e.g. resveratrol, curcumin and berberine (Viswanathan et al., 2005; Pae et al., 2007; Lin et al., 2007; Liu et al., 2010). In contrast, some potent plant toxins, e.g. ricin, can inhibit the activation of UPR (Parikh et al., 2008). Plants contain evolutionary conserved mechanisms for ER stress signaling and UPR defence which can be used for host defence or for killing insects (Urade, 2009). Generally, these phytochemicals are beneficial for mammals, stimulating the UPR and improving stress resistance but excessive use can be toxic to susceptible tissues, e.g. beta cells in pancreas, causing the development of diabetes (Hettiarachchi et al., 2008). Phytochemicals can also induce hormetic responses via the other signaling pathways, e.g. CREB, NF-B and NRF2 (Mattson and Cheng, 2006).
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7. Concluding remarks ER stress and the UPR system can be considered to conform well to the definition of hormesis, i.e. mild stress induces stress resistance via IRE1, PERK and ATF6 pathways whereas overloading provokes several destructive effects, e.g. dysfunction in Ca2+ homeostasis, energy metabolic deficiencies, inhibition of protein synthesis, and finally trigger apoptotic cell death (Fig. 1). Several observations imply that the responsiveness of the UPR system declines during aging and in addition, it seems that the UPR signaling preferentially evokes the pathological pathways, e.g. induction of CHOP and JNK, instead of survival responses via GRP78/94 and HSPs. This age-related dysfunction in UPR outcome can be caused by (i) an insufficiency in the recognition of stress by transducers or (ii) deficiency in the extent of UPR signaling. Moreover, chronic ER stress might trigger negative feedback effects to shut down the destructive consequences of excessive UPR. It is the lack of a proper UPR that impairs the protein quality control leading to defects in the functions of synthesized proteins and ultimately can trigger their aggregation. Currently, there is much work being done on the manipulation of ER stress and UPR response in several diseases, e.g. cancer, diabetes and neurodegeneration (Kim et al., 2008; Lin et al., 2008; Healy et al., 2009). In particular, ER stress has many important roles, i.e. not only in diabetes and the metabolic syndrome (Gregor and Hotamisligil, 2007; Eizirik et al., 2008) but also in cancer (Healy et al., 2009). There are two approaches that can be used, either (i) inhibiting UPR so that cells cannot adapt to stressful conditions or (ii) overloading UPR so that cells can trigger the apoptotic cell death. These treatments are potentially ideal for cancer therapy and several small molecular candidate compounds are being investigated (Healy et al., 2009). However, it seems that a slight enhancement of the ER stress and a boosting of the intensity of UPR could be a valid strategy for delaying the aging process and enhancing the healthy aging. Acknowledgements This study was financially supported by grants from the Academy of Finland and the University of Eastern Finland, Kuopio, Finland. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript. References Barthel, A., Schmoll, D., Unterman, T.G., 2005. FoxO proteins in insulin action and metabolism. FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183–189. Baumeister, R., Schaffitzel, E., Hertweck, M., 2006. Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J. Endocrinol. 190, 191–202. Benita, Y., Kikuchi, H., Smith, A.D., Zhang, M.Q., Chung, D.C., Xavier, R.J., 2009. An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acid Res. 37, 4587–4602. Bernales, S., Papa, F.R., Walter, P., 2006. Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487–508. Bi, M., Naczki, C., Koritzinsky, M., Fels, D., Blais, J., Hu, N., Harding, H., Novoa, I., Varia, M., Raleigh, J., Scheuner, D., Kaufman, R.J., Bell, J., Ron, D., Wouters, B.G., Koumenis, C., 2005. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481. Braeckman, B., Vanfleteren, J.R., 2007. Genetic control of longevity in C. elegans. Exp. Gerontol. 42, 90–98. Calabrese, E.J., 2008a. Hormesis: why it is important to toxicology and toxicologists. Environ. Toxicol. Chem. 27, 1451–1474. Calabrese, E.J., 2008b. Hormesis and medicine. Br. J. Clin. Pharmacol. 66, 594–617. Calabrese, E.J., 2009. Getting the dose–response wrong: why hormesis became marginalized and the threshold model accepted. Arch. Toxicol. 83, 227–247. Calderwood, S.K., Murshid, A., Prince, T., 2009. The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review. Gerontology 55, 550–558. Cullinan, S.B., Diehl, J.A., 2006. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int. J. Biochem. Cell Biol. 38, 317–332.
216
A. Salminen, K. Kaarniranta / Ageing Research Reviews 9 (2010) 211–217
Curtis, R., O’Connor, G., DiStefano, P.S., 2006. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolic pathways. Aging Cell 5, 119–126. de Magalhaes, J.P., Curado, J., Church, G.M., 2009. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25, 875–881. Doroudgar, S., Thuerauf, D.J., Marcinko, M.C., Belmont, P.J., Glembotski, C.C., 2009. Ischemia activates the ATF6 branch of the endoplasmic reticulum stress response. J. Biol. Chem. 284, 29735–29745. Drabos, K.L., Tran, H.C., Kiri, A.N., Lan, W.K., McRorie, D.K., Horn, M.J., 2005. Comparison of Golgi apparatus and endoplasmic reticulum proteins from livers of juvenile and aged rats using a novel technique for separation and enrichment of organelles. J. Biomol. Tech. 16, 347–355. Eizirik, D.L., Cardozo, A.K., Cnop, M., 2008. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr. Rev. 29, 42–61. Feder, M.E., Hofmann, G.E., 1999. Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu. Rev. Physiol. 61, 243–282. Fels, D.R., Koumenis, C., 2006. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol. Ther. 5, 723–728. Finkel, T., Holbrook, N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247. Gems, D., Partridge, L., 2008. Stress–response hormesis and aging: “That which does not kill us makes us stronger”. Cell Metab. 7, 200–203. Greer, E.L., Brunet, A., 2009. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8, 113–127. Gregor, M.F., Hotamisligil, 2007. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J. Lipid Res. 48, 1905–1914. Healy, S.J.M., Gorman, A.M., Mousavi-Shafaei, P., Gupta, S., Samali, A., 2009. Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur. J. Pharmacol. 625, 234–246. Hettiarachchi, K.D., Zimmet, P.Z., Myers, M.A., 2008. Dietary toxins, endoplasmic reticulum (ER) stress and diabetes. Curr. Diabetes Rev. 4, 146–156. Hetz, C.A., 2007. ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage. Antioxidants Redox Signal. 9, 2345–2355. Holbrook, N.J., Ikeyama, S., 2002. Age-related decline in cellular response to oxidative stress: links to growth factor signaling pathways with common defects. Biochem. Pharmacol. 64, 999–1005. Hoyer-Hansen, M., Jäättelä, M., 2007. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 14, 1576–1582. Hussain, S.G., Ramaiah, K.V.A., 2007. Reduced eIF2␣ phosphorylation and increased proapoptotic proteins in aging. Biochem. Biophys. Res. Commun. 355, 365–370. Jäättelä, M., 1999. Heat shock proteins as cellular lifeguards. Ann. Med. 31, 261–271. Jensen, V.L., Gallo, M., Riddle, D.L., 2006. Targets of DAF-16 involved in Caenorhabditis elegans adult longevity and dauer formation. Exp. Gerontol. 41, 922–927. Johnson, T.E., Henderson, S., Murakami, S., de Castro, E., de Castro, S.H., Cypser, J., Rikke, B., Tedesco, P., Link, C., 2002. Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J. Inherit. Metab. Dis. 25, 197–206. Karpac, J., Jasper, H., 2009. Insulin and JNK: optimizing metabolic homeostasis and lifespan. Trends Endocrinol. Metab. 20, 100–106. Kensler, T.W., Wakabayashi, N., Biswal, S., 2007. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47, 89–116. Kim, I., Xu, W., Reed, J.C., 2008. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 7, 1013–1030. Kitamura, M., 2008. Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces. Am. J. Physiol. Renal Physiol. 295, F323–334. Landriscina, M., Maddalena, F., Laudiero, G., Esposito, F., 2009. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid. Redox Signal. 11, 2701–2716. Lapointe, J., Hekimi, S., 2010. When a theory of aging ages badly. Cell. Mol. Life Sci. 67, 1–8. Li, J., Holbrook, N.J., 2004. Elevated gadd153/chop expression and enhanced c-Jun N-terminal protein kinase activation sensitizes aged cells to ER stress. Exp. Gerontol. 39, 735–744. Lin, J.H., Walter, P., Yen, T.S.B., 2008. Endoplasmic reticulum stress in disease pathogenesis. Annu. Rev. Pathol. Mech. Dis. 3, 399–425. Lin, J.P., Yang, J.S., Chang, N.W., Chiu, T.H., Su, C.C., Lu, K.W., Ho, Y.T., Yeh, C.C., Mei-Dueyang, Lin, H.J., Chung, J.G., 2007. GADD153 mediates berberine-induced apoptosis in human cervical cancer Ca ski cells. Anticancer Res. 27, 3379–3386. Liu, B.Q., Gao, Y.Y., Niu, X.F., Xie, J.S., Guan, Y., Wang, H.Q., 2010. Implication of unfolded protein response in resveratrol-induced inhibition of K562 cell proliferation. Biochem. Biophys. Res. Commun. 391, 778–782. Malhotra, J.D., Kaufman, R.J., 2007. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxidants Redox Signal. 9, 2277–2293. Mao, W., Iwai, C., Qin, F., Liang, C., 2005. Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC2 cells via oxidative stress. Am. J. Physiol. Heart Circ. Physiol. 288, H2381–H2389. Martindale, J.L., Holbrook, N.J., 2002. Cellular response to oxidative stress: signaling for suicide and survival. J. Cell. Physiol. 192, 1–15. Masoro, E.J., 2009. Caloric restriction-induced life extension of rats and mice: a critique of proposed mechanisms. Biochim. Biophys. Acta 1790, 1040–1048.
Mattson, M.P., 2008a. Hormesis defined. Ageing Res. Rev. 7, 1–7. Mattson, M.P., 2008b. Hormesis and disease resistance: activation of cellular stress response pathways. Hum. Exp. Toxicol. 27, 155–162. Mattson, M.P., Cheng, A., 2006. Neurohormetic phytochemicals: low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci. 29, 632– 639. Mori, K., 2009. Signalling pathways in the unfolded protein response: development from yeast to mammals. J. Biochem. 146, 743–750. Murakami, S., 2006. Stress resistance in long-lived mouse models. Exp. Gerontol. 41, 1014–1019. Naidoo, N., Ferber, M., Master, M., Zhu, Y., Pack, A.I., 2008. Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J. Neurosci. 28, 6539–6548. Naidoo, N., 2009a. ER and ageing—protein folding and the ER stress response. Ageing Res. Rev. 8, 150–159. Naidoo, N., 2009b. The endoplasmic reticulum stress response and aging. Rev. Neurosci. 20, 23–37. Nuss, J.E., Choksi, K.B., DeFord, J.H., Papaconstantinou, J., 2008. Decreased enzyme activities of chaperones PDI and BiP in aged mouse livers. Biochem. Biophys. Res. Commun. 365, 355–361. Oyadomari, S., Mori, M., 2004. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11, 381–389. Pae, H.O., Jeong, S.O., Jeong, G.S., Kim, K.M., Kim, H.S., Kim, S.A., Kim, Y.C., Kang, S.D., Kim, B.N., Chung, H.T., 2007. Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells. Biochem. Biophys. Res. Commun. 353, 1040–1045. Pardon, M.C., 2007. Stress and ageing interactions: a paradox in the context of shared etiological and physiopathological processes. Brain Res. Rev. 54, 251–273. Parikh, B.A., Tortora, A., Li, X.P., Turner, N.E., 2008. Ricin inhibits activation of the unfolded protein response by preventing splicing of the HAC1 mRNA. J. Biol. Chem. 283, 6145–6153. Paz Gavilan, M., Vela, J., Castano, A., Ramos, B., del Rio, J.C., Vitorica, J., Ruano, D., 2006. Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol. Aging 27, 973–982. Puzianowska-Kuznicka, M., Kuznicki, J., 2009. The ER and ageing II: calcium homeostasis. Ageing Res. Rev. 8, 160–172. Rabek, J.P., Boylston III, W.H., Papaconstantinou, J., 2003. Carbonylation of ER chaperone proteins in aged mouse liver. Biochem. Biophys. Res. Commun. 305, 566–572. Ramirez, J.M., Folkow, L.P., Blix, A.S., 2007. Hypoxia tolerance in mammals and birds: from the wilderness to the clinic. Annu. Rev. Physiol. 69, 113–143. Rattan, S.I.S., 2008. Hormesis in aging. Ageing Res. Rev. 7, 63–78. Rion, S., Kawecki, T.J., 2007. Evolutionary biology of starvation resistance: what we have learned from Drosophila. J. Evol. Biol. 20, 1655–1664. Ron, D., Walter, P., 2007. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529. Sachs, H.G., Colgan, J.A., Lazarus, M.L., 1977. Ultrastructure of the aging myocardium: a morphometric approach. Am. J. Anat. 150, 63–71. Salminen, A., Kaarniranta, K., 2009. Regulation of the aging process by autophagy. Trends Mol. Med. 15, 217–224. Salminen, A., Kauppinen, A., Suuronen, T., Kaarniranta, K., Ojala, J., 2009. ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J. Neuroinflamm. 6, 41. Schröder, M., 2005. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789. Schröder, M., 2008. Endoplasmic reticulum stress responses. Cell. Mol. Life Sci. 65, 862–894. Schumucker, D.L., Mooney, J.S., Jones, A.L., 1977. Age-related changes in the hepatic endoplasmic reticulum: a quantitative analysis. Science 197, 1005–1008. Schmucker, D.L., 1990. Hepatocyte fine structure during maturation and senescence. J. Electron Microsc. Tech. 14, 106–125. Schumacher, B., 2009. Transcription-blocking DNA damage in aging: a mechanism for hormesis. Bioessays 31, 1347–1356. Son, T.G., Camandola, S., Mattson, M.P., 2008. Hormetic dietary phytochemicals. Neuromol. Med. 10, 236–246. Swindell, W.R., 2009. Genes and gene expression modules associated with caloric restriction and ageing in the laboratory mouse. BMC Genomics 10, 585. Szegezdi, E., Logue, S.E., Gorman, A.M., Samali, A., 2006. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7, 880–885. Tatar, M., Yin, C.M., 2001. Slow aging during insect reproductive diapauses: why butterflies, grasshoppers and flies are like worms. Exp. Gerontol. 36, 723– 738. Tavernarakis, N., 2008. Ageing and the regulation of protein synthesis: a balancing act? Trends Cell Biol. 18, 228–235. Terai, K., Hiramoto, Y., Masaki, M., Sugiyama, S., Kuroda, T., Hori, M., Kawase, I., Hirota, H., 2005. AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol. Cell. Biol. 25, 9554–9575. Tower, J., 2008. Hsps and aging. Trends Endocrinol. Metab. 20, 216–222. Urade, R., 2009. The endoplasmic reticulum stress signaling pathways in plants. Biofactors 35, 326–331. Van Raamsdonk, J.M., Hekimi, S., 2009. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 5, e1000361. Vermeulen, C.J., Loeschcke, V., 2007. Longevity and the stress response in Drosophila. Exp. Gerontol. 42, 153–159.
A. Salminen, K. Kaarniranta / Ageing Research Reviews 9 (2010) 211–217 Vernace, V.A., Schmidt-Glenewinkel, Figueiredo-Pereira, M.E., 2007. Aging and regulated protein degradation: who has the upper hand? Aging Cell 6, 599– 606. Viswanathan, M., Kim, S.K., Berdichevsky, A., Guarente, L., 2005. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9, 605–615.
217
Yoon, S.O., Yun, C.H., Chung, A.S., 2002. Dose effect of oxidative stress on signal transduction in aging. Mech. Ageing Dev. 123, 1597–1604. Zhang, K., Kaufman, R.J., 2008. From endoplasmic-reticulum stress to the inflammatory response. Nature 454, 455–462. Zhivotovsky, B., 2003. Caspases: the enzymes of death. Essays Biochem. 39, 25– 40.