Journal Pre-proof Perturbation of bulk and selective macroautophagy, abnormal UPR activation and their interplay pave the way to immune dysfunction, cancerogenesis and neurodegeneration in ageing Mara Cirone PII: S1568-1637(19)30490-8 DOI: https://doi.org/10.1016/j.arr.2020.101026 Reference: ARR 101026 To appear in: Ageing Research Reviews Received Date: 18 December 2019 Revised Date: 28 January 2020 Accepted Date: 31 January 2020 Please cite this article as: Cirone M, Perturbation of bulk and selective macroautophagy, abnormal UPR activation and their interplay pave the way to immune dysfunction, cancerogenesis and neurodegeneration in ageing, Ageing Research Reviews (2020), doi: https://doi.org/10.1016/j.arr.2020.101026 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier. Perturbation of bulk and selective macroautophagy, abnormal UPR activation and their interplay pave the way to immune dysfunction, cancerogenesis and neurodegeneration in ageing. Mara Cirone Department of Experimental Medicine, La Sapienza University of Rome, Viale Regina Elena 324, 00185, Rome, Italy. ro of Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy. -p Highlights Macroautophagy, CMA and the other adaptive responses to ER stress become dysfunctional in ageing.  Cellular homeostasis is altered in ageing, leading to cell dysfunction, especially in neuronal cells.  Perturbation of cellular homeostasis predisposes to immune dysfunction, neurodegeneration and cancer. Abstract ur na lP re  A plethora of studies has indicated that ageing is characterized by an altered proteostasis, ROS accumulation and a status of mild/chronic inflammation, in which macroautophagy reduction and Jo abnormal UPR activation play a pivotal role. The dysregulation of these inter-connected processes favors immune dysfunction and predisposes to a variety of several apparently unrelated pathological conditions including cancer and neurodegeneration. Given the progressive ageing of the population, a better understanding of the mechanisms regulating autophagy, UPR and their interplay is needed in order to design new therapeutic strategies able to counteract the effects of 1 ageing and concomitantly restrain the onset/progression of age-related diseases that represent a private and public health problem. The interplay between macroautophagy and UPR regulates cellular homeostasis. Ageing is a natural process characterized by a progressive impairment of the mechanisms required for the maintenance of cellular homeostasis and accumulation of misfolded/aggregated proteins, of defective organelles and reactive oxygen species (ROS) (Klaips et al., 2018). The latters trigger inflammation, i.e. by activating NFkB (Wang et al., 2007), transcription factor that in turn further ro induces ROS production by stimulating NAPH oxidase (NOX) family proteins (Forrester et al., -p 2018). Besides inflammation, the increase of ROS may cause damage of biomolecules, particularly of DNA (Salehi et al., 2018), effect worsened by the reduced efficiency of the DNA damage repair re (DDR) system in aged cells (White and Vijg, 2016). ROS accumulation may be due to their ur na lP increased production, in which the accumulation of dysfunctional mitochondria plays a major role, and/or to the reduced efficiency of the antioxidant system that also characterizes ageing (Tan et al., 2018). Macroautophagy, particularly a selective form of it, the mitophagy, specialized in the clearance of damaged mitochondria, is of fundamental importance in counteracting ROS increase (Jin and Youle, 2012). Both bulk and selective macroautophagy as well as chaperone-mediated autophagy (CMA) become progressively dysfunctional with ageing (Cuervo and Wong, 2014; Jo Metaxakis et al., 2018; Vernucci et al., 2019). Macroautophagy is regulated by a group of Autophagy-related Genes (ATGs) that control the different steps of the process, from autophagosome formation to their fusion with the endo/lysosomal compartment and degradation into the lysosomes (Klionsky et al., 2016). Although the exact molecular mechanisms that underlie the autophagic defects in ageing remain to be fully elucidated, the downregulation of ATG genes such as ATG5 or ATG7, the dysregulated production of hormones that regulate autophagy, the hyperactivation of mammalian target of rapamycin (mTOR), nutrient sensor with a key role in 2 regulating growth and metabolism (Stallone et al., 2019), the reduced expression of Sirtuin1 (SIRT1) that controls protein acetylation, activates AMPK and reduces mTOR activation, have been reported to play a role (Martinez-Lopez et al., 2015). Interestingly, mTOR hyperactivation is central in the impairment of proteostasis, as it not only negatively regulates autophagy but also stimulates protein synthesis (Hindupur et al., 2015). The frequent detection of a high amount of autophagosomes in aged tissues suggests that the final steps of the autophagic process could be impaired (Uddin et al., 2018) and accordingly, studies by Cuervo et al have demonstrated that of defects of the final phases of autophagy occur in ageing (Kaushik and Cuervo, 2018). This is due to an abnormal lipid metabolism and consequently to an altered lipid composition of the ro autophagososme and lysosome membranes that cause an impairment of their fusion (Cuervo and -p Wong, 2014; Koga et al., 2010). Indeed, it has been reported that the level of fatty acid chain desaturation and elongation in many species of sphingolipids, the highly conserved components of re cell membranes, increases during ageing (Cutler et al., 2014) and that sphingolipids act as ur na lP physiological regulator of macroautophagy in relation to cellular and organismal growth, survival and ageing (Harvald et al., 2015). Moreover, as a consequence of the altered lipid composition of lysosome membrane, the stability of the lysosomal protein LAMP2A is reduced and thus CMA, that requires the interaction of LAMP2A with HSC70 to address to lysosomes for degradation the misfolded proteins having the KFERQ motif, results dysfunctional (Cuervo and Wong, 2014) (Fig.1). Basally activated in all cells to maintain cellular homeostasis, macroautophagy is up- Jo regulated in stressful conditions such as starvation, since the molecules degraded through this process may be recycled and re-used as source of cellular nutrients (Shang et al., 2011). At molecular level, in this conditions, macroautophagy is induced by the inhibition of mTOR and the activation of AMPK, kinase that exerts an inhibitory effect on mTOR and, differently from this, phosphorylates unc-51-like kinase (ULK) 1 at Ser 317 and Ser 777 residues, resulting in autophagy activation (Hindupur et al., 2015; Kim et al., 2011). Besides nutrient shortage, the autophagic process can be upregulated by other conditions of cellular stress that lead to the accumulation of 3 misfolded proteins into the Endoplasmic Reticulum (ER), perturbing ER homeostasis and causing ER stress (Rashid et al., 2015). ER represents a checkpoint in which biosynthesis, folding, assembly and modification of proteins occur. In addition to mTOR inhibition and AMPK activation, ER stress triggers the Unfolded Protein Response (UPR) which is orchestrated by three sensors, namely Inositol-requiring enzyme (IRE) 1 alpha, protein kinase RNA-like ER kinase (PERK) and activating transcription factor (ATF) 6 (Rashid et al., 2015). The activation of these molecules, occurring after GRP78 (BIP) dissociate from them, represents an attempt of the cell to cope with ER stress and of preserve cell survival although, when the UPR protective capacity is overwhelmed, cell may face up to cell death (Kim et al., 2006). The activation of PERK (Luhr et al., 2019) or IRE1 alpha ro (Margariti et al., 2013) sensors have been reported to promote autophagy, as this is one of the most -p important mechanisms that help cells to ride out of protein aggregates that have caused ER stress. However, the activation of Ire1 may also negatively regulate the autophagic flux (Lee et al., 2013; re Luhr et al., 2019), suggesting that its role may vary depending on the cellular contest and the type ur na lP of stress. Macroautophagy and UPR are strongly inter-connected processes (Rashid et al., 2015; Zheng et al., 2019), therefore this implies that, when autophagy is reduced, ER stress is exacerbated and the UPR abnormally activated, changing the balance between cell survival and cell death (Fig.2) (Ogata et al., 2006). A part from autophagy induction, UPR activation may promote adaption of cell to ER stress by halting protein translation and by up-regulating the expression of ER chaperones that increase the protein folding capacity of ER (Merksamer and Papa, 2010). Jo However, as for bulk and selective macroautophagy, these UPR adaptive responses to ER stress become dysfunctional in aged cells, particularly the chaperoning function (Estebanez et al., 2018), further skewing UPR towards cell death induction. This may occur through the up-regulation of UPR pro-apoptotic molecules such as the C/EBP homologous protein (CHOP) that causes an unbalance between the expression of anti-apoptotic and pro-apoptotic proteins of the Bcl-2 family (Ge et al., 2018) . The defect of the adaptive responses of cells to stress that promotes the accumulation of ROS, damaged organelles and misfolded aggregate-prone proteins in ageing, leads 4 to cell dysfunction and predisposes to a variety of different diseases (Fig.3). Such defects induce more severe damages in post-mitotic cells such as neurons, as they are not able to dilute toxic materials through cell division (Komatsu et al., 2006). Indeed, the accumulation of unwanted/toxic materials within neuronal cells paves the way to the onset of neurodegenerative diseases such as Parkinson’s and Alzheimer’s (Stavoe and Holzbaur, 2019), both characterized by a dysregulated proteostasis and, particularly, by the accumulation of α‐synuclein (αSyn) in PD and amyloid β (Aβ) in AD (Rubinsztein et al., 2011). Moreover, the reduction of mitophagy in neuronal cells strongly of contributes to ROS accumulation that causes inflammation and neurodegeneration, as demonstrated by the beneficial effects obtained by enhancing the mitophagic process in AD (Fang et al., 2019) ro and even more in PD, in which several proteins that regulate the mitophagic process can be mutated -p and/or dysfunctional (Liu et al., 2019). ROS and protein accumulation, fostered by macroautophagy reduction and dysregulated UPR activation in aged cells, may alter multiple cellular functions, as re two of the three UPR sensors, PERK and Ire1 alpha regulate the phosphorylation and the activity of ur na lP a variety of substrates: Glycogen synthase kinase (GSK) 3 beta (Nijholt et al., 2013), Signal Trasducer and activator (STAT) 3 (Meares et al., 2014), nuclear factor erythroid 2-related factor (NRF) 2 (Cullinan et al., 2003) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) (Garg et al., 2012), just to mention some of them. Of note, GSK3 beta activation may contribute to onset of AD by inducing the phosphorylation of Tau (Wang et al., 1998) protein that, following such post-transcriptional modification becomes prone to form neurofibrillary tangles Jo (NFTs), another hallmark of AD. A part from maintaining cellular homeostasis, particularly in neuronal cells, macroautophagy is required for other functions essential for multicellular organism survival, i.e. it plays an essential role in both innate and acquired immune response (Germic et al., 2019; Granato et al., 2015; Kuballa et al., 2012) and, by contributing to the elimination of apoptotic cells by phagocytes, helps to prevent chronic inflammation (Szondy et al., 2014). The important role of macroautophagy in immunity is clearly demonstrated by the finding that viruses need to manipulate this process in the immune system cells, in order to escape from immune recognition 5 and assure their own survival in the infected hosts (Gilardini Montani et al., 2019; Santarelli et al., 2016). UPR may also regulate the functions of immune cells (Komura et al., 2013a), although how it affects immune response remains to be completely elucidated. Indeed, it has been reported that IRE1-XPB1axis may positively regulate homeostasis and antigen presentation by CD8+ conventional DCs (Osorio F Nature Immunol 2014) or, conversely, that XBP1 activation may dampen the anti-tumor immune response of DCs (Cubillo-Ruiz JR Cell 2015). Finally, particularly important is to dissect the role of the autophagic processes in regulating the different phases of of cancerogenesis. While it is still controversial how macroautophagy may influence cancer survival in ro the course of anticancer chemotherapies (Cirone et al., 2019), its activation may helpful in counteracting the first steps of cancerogenesis (Chen and White, 2011; Granato et al., 2019), -p particularly because its selective form, the mitophagy, strongly contributes to the disposal of damaged mitochondria (Panda et al., 2015) the main source of ROS (Marinkovic et al., 2018). The re activation of UPR plays also a role in cancerogenesis, although it seems to vary depending on the ur na lP oncogenes that drive the process and on the cellular contexts in which they operate (Hart et al., 2012; Vanacker et al., 2017). Furthermore, it is important to remember that macroautophagy is involved in the control of the immunogenicity of tumor cell death, by promoting the release of ATP (Wang et al., 2013), DAMP that contributes to the activation of DCs, process essential for tumor eradication (Cirone et al., 2012). Moreover, macroautophagy induces the degradation of HDAC, proteins known to up-regulate checkpoint inhibitors such as PD-L1 (Shen et al., 2019). As for Jo neurodegenerative diseases, in correlation with the progressive reduction of the autophagic process with ageing, the incidence of cancer increases (Aunan et al., 2017) and concomitantly the immune surveillance against cancer decreases, further favoring its survival/progression. Finally ER stress/UPR activation may influence cell survival of established cancers (Avril et al., 2017) and the immune response against them, as it promotes the plasmamembrane exposure of calreticulin (Obeid et al., 2007), DAMP required for the phagocytosis of apoptotic tumor cells by DCs. Moreover, as recent studies have suggested, ER stress in tumor cells may lead to the release of not completely 6 identified factors that transfer the stress to immune cells, impairing their function (Cubillos-Ruiz et al., 2017; Cubillos-Ruiz et al., 2015; Rodvold et al., 2017). The dyregulation of macroautophagy and UPR promotes immune dysfunction. Macroautophagy is essential for a proper class II MHC antigen presentation of peptides originating from extracellular antigens. They are delivered to the late endosomal/lysosomal compartment and of degraded by the lysosomal proteases before being associated with class II MHC molecules (Valecka et al., 2018), after the invariant chain has been removed by the same proteases. Moreover, ro macroautophagy contributes to the presentation of antigens of intracellular origin that can be -p engulfed into autophagosomes and delivered to the lysosomes to be associated with class II MHC, in addition to their association with class I MHC molecules that classically takes place in the re endoplasmic reticulum (ER) (Crotzer and Blum, 2009). The autophagic process is important to ur na lP mitigate inflammation, not only because it contributes to the degradation of apoptotic bodies by phagocytic cells (Levine and Kroemer, 2008), but also because it helps to eliminate ROS-producing dysfunctional mitochondria (Jin, 2005) and prevents the formation of NLRP3-inflammosome (Nakahira et al., 2011; Zhou et al., 2011a). Finally, last but not least, macroautophagy is known to be required for proper differentiation of monocytes into macrophages and DCs (Zhang et al., 2012), the sole cells able to initiate and regulate an immune response towards a new antigen (Banchereau Jo et al., 2000). Given the pivotal role of autophagy in immunity, microbes, especially viruses that persist in the infected host, have put in place several strategies to interfere with the different steps of autophagy, particularly in infected myeloid immune cells such as monocytes/macrophages and dendritic cells. Examples are oncogenic herpesviruses such as EBV and KSHV (Gilardini Montani et al., 2019; Santarelli et al., 2015; Santarelli et al., 2016), not oncogenic herpesviruses such as HHV-6B (Romeo et al., 2019b) or viruses completely unrelated to herpesviruses such as the RNA virus HCV (Granato et al., 2014a). However, particularly important for microorganism survival is 7 the dysregulation of xenophagy, another selective form of macroautophagy that directly addresses intracellular pathogens to lysosomes for degradation (Deretic and Levine, 2018; Munz, 2016). Interestingly, during viral replication, autophagy impairment more frequently occurs at the final phases, as the first steps may exploited by viruses to facilitate their intracellular transport and promote viral replication (Granato et al., 2014b; Granato et al., 2015). Bulk and selective macroutophagy reduction has a strong impact on UPR activation in infected immune cells. Several reports have suggested that UPR activation may dampen the function of immune cells such as of myeloid cells, as for example the ER stressor tunicamycin has been shown to be able to impair the differentiation of THP1 monocytoid cells into macrophages (Komura et al., 2013b) or PERK and ro IRE1alpha activation and CHOP up-regulation have been observed in M2 alternatively -p differentiated macrophages (Oh et al., 2012), cells that promote instead of fighting cancer. Moreover, the accumulation of spliced XBP1 (XBP1s), generated by the endoribonucleasic activity re of IRE1 alpha, previously reported to be required for DC function (Iwakoshi et al., 2007; Osorio et ur na lP al., 2014) has been more recently associated to the dysfunction of DCs exposed to the oxidative stress of the tumor environment (Cubillos-Ruiz et al., 2015). Of note, besides by dysregulating autophagy, viruses may directly activate UPR in infected immune cells, due to the increase of protein synthesis and accumulation into the ER lumen and by increasing ROS production. UPR activation by viruses may contribute to the reduction of immune response, as we have recently shown in the case of HHV-6B-infected differentiating monocytes (Romeo et al., 2019b). Finally, it Jo is important to consider that the activation of PERK and IRE1 alpha may phosphorylate STAT3, pathway involved in dysfunction of immune cells exposed to cytokines such IL-6 or IL-10 or infected by viruses (Santarelli et al., 2014), particularly DCs (Kitamura et al., 2017). As the efficiency of immune response decreases in elderly (Sadighi Akha, 2018), the reduction of selective and bulk macroautophagy as well as the dysregulated UPR activation may strongly contribute to such effect (Cuervo and Macian, 2014). Immune dysfunction in ageing has been reported to involve several cell types and affect not only myeloid cells (Stranks et al., 2015) but also for example T 8 lymphocytes (Macian, 2019). Finally, it must be considered the interplay between dysregulated macroautophagy and UPR activation that promote chronic inflammation may prevent the ontogeny and function of a variety of cells of the immune system (Garcia-Gonzalez et al., 2018). The dyregulation of macroautophagy and UPR favors cancerogenesis. Bulk and selective macroautophagy are generally considered processes that counteract cancer onset, as their dysregulation may promote chronic inflammation, leading to an altered the secretion of pro- of inflammatory cytokines that in turn further dysregulate autophagy (Ge et al., 2018). Chronic inflammation indeed, differently from acute inflammation, induces tissue damage and remodeling, ro favoring cancer (Korniluk et al., 2017). Macroautophagy, particularly mitophagy, also contributes -p to the lysosomal degradation of toxic materials including damaged mitochondria that are the main source of ROS that cause DNA instability and mutations, predisposing to cancer (Xu and Hu, re 2019). The increase of ROS promotes ER stress, facilitating the accumulation in the ER of ur na lP misfolded proteins that exacerbates the oxidative stress, in a feed-back positive loop (Eletto et al., 2014). However, through the activation of PERK, UPR may also stimulate the anti-oxidant response, leading to the phosphorylation and activation of NRF2 (Cullinan et al., 2003), transcription factor that regulates both ROS production (Kovac et al., 2015) and ROS scavenging through the transcription of a variety of anti-oxidant enzymes (Vomund et al., 2017). It is important to remark that NRF2 activity is also controlled by autophagy through p62, a protein mainly Jo degraded through a complete autophagic flux. Indeed, p62 may target Keap1 for degradation, stabilizing NRF2 (Katsuragi et al., 2016). Interestingly, NRF2 in turn induces the transcription p62, highlighting the existence of a feed-back positive loop between these two molecules (Dayalan Naidu et al., 2017; Granato et al., 2018). However, the role of p62 in cancer is very complex, as this molecule may interact with transcription factors that promote inflammation and cell proliferation such as NFkB, may activate caspase 8 and interact with DDR machinery, as it has been reported that p62 promotes the degradation of key DDR molecules via proteasome (Hewitt et al., 2016). 9 Therefore autophagy, by regulating p62 expression level, controls cancerogenesis at multiple levels. It should be also considered that DDR positively regulates autophagy, since one of its major components, ATM, induces the activation of AMPK, and finally that DNA damage may itself induce autophagy, by activating JNK that phosphorylates Bcl-2 (Wei et al., 2008) or by activating p53 that promotes the transcription of pro-autophagic genes such as Sestrin1 and 2 (Maiuri et al., 2009) and DRAM (Crighton et al., 2006). Thus, the understanding of the intricate inter-connection between ROS, ER stress/UPR, autophagy, p62 and DDR may help to better control the process of of cancerogenesis. However, how UPR per se influences cancerogenesis is another aspect not completely elucidated. Indeed, it has been reported that the activation of PERK/eIF2alpha-ATF4- ro CHOP axis promotes c-myc-driven cancergenesis (Hart et al., 2012) and, conversely, that CHOP -p deletion prevents Kras-induced transformation promoting cell death of premalignant cells exposed to prolonged oxidative stress (Vanacker et al., 2017). These different findings suggest that the role re of UPR activation in regulating cancerogenesis may be dependent on the oncogenes and on the cell ur na lP types. Differently from cancer onset, UPR activation has been clearly demonstrated to promote survival and chemo-resistance of established cancers (Avril et al., 2017; Bahar et al., 2019). For example, a pro-survival role in cancer has been demonstrated for the upregulation of the UPR chaperone GRP78 (BIP) (Dong et al., 2008) and XBP1s (Romero-Ramirez et al., 2004; Sheng et al., 2019), generated by IRE1alpha activation. It is important to note that the targeting of XBP1 could be useful not only to reduce the survival of tumor cells but also to restore the function of DCs Jo exposed to the tumor environment (Cubillos-Ruiz et al., 2015). Macroautophagy and UPR dysregulation predisposes to age-related neurodegeneration. Defects in bulk or selective macroautophagy induce a more rapid accumulation of aggregate-prone proteins and ROS in cells that cannot undergo cell division such as neurons, in comparison with other cell types (Komatsu et al., 2006). Their reduced capacity to dispose toxic materials leads to a rapidly progressive decline of function/survival of these cells, favoring the onset of 10 neurodegenerative diseases (Uddin et al., 2018). Macroautophagy dysregulation in neurodegenerative diseases such as Alzheimer’s (Uddin et al., 2018) and Parkinson’s disease (PD) (Pitcairn et al., 2019) is suggested by autophagosome accumulation in the brains of patients suffering of these diseases (Nilsson and Iwarsson, 2013), finding also suggesting an impairment of autophagy at the final steps. In the course of AD, autophagy reduction has been shown to play a role in the extracellular and intracellular accumulation of Aβ peptide fragments of the amyloid precursor protein (APP) as well as in the formation of the neurofibrillary tangles (NFTs), composed of of the microtubule-associated hyperphosphorylated protein tau, the two most important hallmarks of this disease (Romeo et al., 2019a). The amyloidogenic process is initiated by the cleavage of ro APP mediated by the β-secretase (Feng et al., 2017), also known as β-site APP cleaving enzyme 1 -p or BACE-1 (Vassar et al., 1999) whose expression level is regulated by autophagy as well (Feng et al., 2017). Macroautophagy regulates the metabolism of APP, Aβ (Zhou et al., 2011b) and tau re protein (Wang and Mandelkow, 2012), indicating that this process may control AD ur na lP onset/progression at multiple levels. Similarly to AD, in the course of PD, autophagy dysregulation is involved in the accumulation of the inclusions called Lewy bodies (LBs), formed by misfolded and post‐translationally modified α‐synuclein (αSyn) (Spillantini et al., 1997) and by ubiquitinated proteins, that play an important pathogenic role in such disease. An abnormal UPR activation has been also reported to contribute to the neurodegenerative process (Cai et al., 2016). This occurs in correlation with autophagy dysfunction but is also due, in the case of PD, to the accumulation of Jo αSyn that alters the protein transportation from ER to Golgi apparatus, binds to ATF6 or dysregulates calcium metabolism in neuronal cells (Martinez et al., 2019), triggering ER stress. In the case of AD, the accumulation of Aβ contributes to the induction of ER stress and to the activation of PERK, kinase that leads to the phosphorylation of GSK3beta that, in turn phosphorylates Tau protein at several residues, favoring the formation the NFTs (Wang et al., 1998). We have recently shown that both autophagy and UPR dysregulation by HHV-6 A infection of neuronal cells contributed to the increase of Tau protein phosphorylation and Aβ amyloid 11 secretion and that similar effects were exerted by the lysomonotropic agent cloroquine that inhibits autophagy at the final phases (Romeo et al BBA 2020). Of note, as in the case of cancer, autophagy reduction and UPR dysregulation contribute to the increase of ROS, molecules that in turn further dysregulate these processes and promote a low-grade chronic and sterile inflammation that strongly predisposes to neurodegeneration. Conclusions and perspectives of It is increasingly emerging that defects of selective and bulk macroautophagy autophagy, UPR activation and their interplay contribute to the altered proteostasis and to the mild/chronic ro inflammation that characterizes ageing and predisposes to several, apparently unrelated, -p pathological conditions, from immune dysfunction, to cancer and neurodegeneration. Several studies have demonstrated that bulk macroautophagy and mitophagy induction may help to reduce re the onset of several age-related diseases and ultimately extend life span in several model organisms ur na lP including mice, flies and nematodes (Morselli et al., 2010). Macroautophagy can be triggered by calory restriction diets, in which the reduction of 20-40% of the calories of the diet leads to the inhibition of mTOR and the activation of AMPK and SIRT1. Interestingly the latter also positively regulates mitophagy and mitochondrial biogenesis (Tang, 2016). Alternatively, instead of calory restriction, as an easier strategy to adopt, calory restriction mimetics, such as Metformin or Resveratrol could be used to stimulate autophagy. These drugs mimic, at molecular level, the Jo effects induced by calory restriction (Madeo et al., 2019) and similarly to it may exert antiinflammatory and antioxidant effects, thus counteracting the onset of age-related diseases, by several means. Finally autophagy may be triggered by increasing physical exercise, as it also targets mTOR and helps to restrain ageing, especially when combined with calory restriction or calory restriction mimetics. It appears that the restoration of selective and bulk macroautophagy as well as of the other adaptive responses to stress may hold the key to counteract the effects of ageing and reduce the incidence of apparently unrelated diseases that ageing brings with it. Therefore it is 12 worth to better explore the underlying molecular mechanisms that regulate these interconnected processes in order to manipulate them in the attempt to prevent or more successfully treat agerelated pathologies. Funding The research within the realm of this manuscript is funded by Istituto Pasteur Italia Fondazione of Cenci Bolognetti, by Fondi Ateneo 2018, by PRIN 2017 and AIRC IG 2019-23040. Conflict of interest -p ro The Author declares no conflict of interest. References re Aunan, J.R., Cho, W.C., Soreide, K., 2017. The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks. Aging Dis 8, 628-642. ur na lP Avril, T., Vauleon, E., Chevet, E., 2017. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis 6, e373. Bahar, E., Kim, J.Y., Yoon, H., 2019. Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling. Cancers (Basel) 11. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y.J., Pulendran, B., Palucka, K., 2000. Immunobiology of dendritic cells. Annu Rev Immunol 18, 767-811. Cai, Y., Arikkath, J., Yang, L., Guo, M.L., Periyasamy, P., Buch, S., 2016. Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. Autophagy 12, 225- Jo 244. Chen, H.Y., White, E., 2011. Role of autophagy in cancer prevention. Cancer Prev Res (Phila) 4, 973-983. Cirone, M., Di Renzo, L., Lotti, L.V., Conte, V., Trivedi, P., Santarelli, R., Gonnella, R., Frati, L., Faggioni, A., 2012. Activation of dendritic cells by tumor cell death. Oncoimmunology 1, 12181219. 13 Cirone, M., Gilardini Montani, M.S., Granato, M., Garufi, A., Faggioni, A., D'Orazi, G., 2019. Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences. J Exp Clin Cancer Res 38, 262. Crighton, D., Wilkinson, S., O'Prey, J., Syed, N., Smith, P., Harrison, P.R., Gasco, M., Garrone, O., Crook, T., Ryan, K.M., 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121-134. Crotzer, V.L., Blum, J.S., 2009. Autophagy and its role in MHC-mediated antigen presentation. J Immunol 182, 3335-3341. Cubillos-Ruiz, J.R., Bettigole, S.E., Glimcher, L.H., 2017. Tumorigenic and Immunosuppressive of Effects of Endoplasmic Reticulum Stress in Cancer. Cell 168, 692-706. Cubillos-Ruiz, J.R., Silberman, P.C., Rutkowski, M.R., Chopra, S., Perales-Puchalt, A., Song, M., Zhang, S., Bettigole, S.E., Gupta, D., Holcomb, K., Ellenson, L.H., Caputo, T., Lee, A.H., Conejo- Disrupting Dendritic Cell Homeostasis. Cell 161, 1527-1538. ro Garcia, J.R., Glimcher, L.H., 2015. ER Stress Sensor XBP1 Controls Anti-tumor Immunity by -p Cuervo, A.M., Macian, F., 2014. Autophagy and the immune function in aging. Curr Opin Immunol 29, 97-104. Res 24, 92-104. re Cuervo, A.M., Wong, E., 2014. Chaperone-mediated autophagy: roles in disease and aging. Cell ur na lP Cullinan, S.B., Zhang, D., Hannink, M., Arvisais, E., Kaufman, R.J., Diehl, J.A., 2003. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23, 7198-7209. Cutler, R.G., Thompson, K.W., Camandola, S., Mack, K.T., Mattson, M.P., 2014. Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans. Mech Ageing Dev 143144, 9-18. Dayalan Naidu, S., Dikovskaya, D., Gaurilcikaite, E., Knatko, E.V., Healy, Z.R., Mohan, H., Koh, G., Laurell, A., Ball, G., Olagnier, D., de la Vega, L., Ganley, I.G., Talalay, P., Dinkova-Kostova, A.T., 2017. Transcription factors NRF2 and HSF1 have opposing functions in autophagy. Sci Rep Jo 7, 11023. Deretic, V., Levine, B., 2018. Autophagy balances inflammation in innate immunity. Autophagy 14, 243-251. Dong, D., Ni, M., Li, J., Xiong, S., Ye, W., Virrey, J.J., Mao, C., Ye, R., Wang, M., Pen, L., Dubeau, L., Groshen, S., Hofman, F.M., Lee, A.S., 2008. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res 68, 498-505. 14 Eletto, D., Chevet, E., Argon, Y., Appenzeller-Herzog, C., 2014. Redox controls UPR to control redox. J Cell Sci 127, 3649-3658. Estebanez, B., de Paz, J.A., Cuevas, M.J., Gonzalez-Gallego, J., 2018. Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update. Front Physiol 9, 1744. Fang, E.F., Hou, Y., Palikaras, K., Adriaanse, B.A., Kerr, J.S., Yang, B., Lautrup, S., Hasan-Olive, M.M., Caponio, D., Dan, X., Rocktaschel, P., Croteau, D.L., Akbari, M., Greig, N.H., Fladby, T., Nilsen, H., Cader, M.Z., Mattson, M.P., Tavernarakis, N., Bohr, V.A., 2019. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci 22, 401-412. of Feng, T., Tammineni, P., Agrawal, C., Jeong, Y.Y., Cai, Q., 2017. Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation. J Biol Chem 292, 1679-1690. Forrester, S.J., Kikuchi, D.S., Hernandes, M.S., Xu, Q., Griendling, K.K., 2018. Reactive Oxygen ro Species in Metabolic and Inflammatory Signaling. Circ Res 122, 877-902. Garcia-Gonzalez, P., Cabral-Miranda, F., Hetz, C., Osorio, F., 2018. Interplay Between the -p Unfolded Protein Response and Immune Function in the Development of Neurodegenerative Diseases. Front Immunol 9, 2541. re Garg, A.D., Kaczmarek, A., Krysko, O., Vandenabeele, P., Krysko, D.V., Agostinis, P., 2012. ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol Med 18, 589- ur na lP 598. Ge, Y., Huang, M., Yao, Y.M., 2018. Autophagy and proinflammatory cytokines: Interactions and clinical implications. Cytokine Growth Factor Rev 43, 38-46. Germic, N., Frangez, Z., Yousefi, S., Simon, H.U., 2019. Regulation of the innate immune system by autophagy: monocytes, macrophages, dendritic cells and antigen presentation. Cell Death Differ 26, 715-727. Gilardini Montani, M.S., Santarelli, R., Granato, M., Gonnella, R., Torrisi, M.R., Faggioni, A., Cirone, M., 2019. EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte Jo survival and differentiation. Autophagy 15, 652-667. Granato, M., Gilardini Montani, M.S., Angiolillo, C., D'Orazi, G., Faggioni, A., Cirone, M., 2018. Cytotoxic Drugs Activate KSHV Lytic Cycle in Latently Infected PEL Cells by Inducing a Moderate ROS Increase Controlled by HSF1, NRF2 and p62/SQSTM1. Viruses 11. Granato, M., Gilardini Montani, M.S., Zompetta, C., Santarelli, R., Gonnella, R., Romeo, M.A., D'Orazi, G., Faggioni, A., Cirone, M., 2019. Quercetin Interrupts the Positive Feedback Loop Between STAT3 and IL-6, Promotes Autophagy, and Reduces ROS, Preventing EBV-Driven B Cell Immortalization. Biomolecules 9. 15 Granato, M., Lacconi, V., Peddis, M., Di Renzo, L., Valia, S., Rivanera, D., Antonelli, G., Frati, L., Faggioni, A., Cirone, M., 2014a. Hepatitis C virus present in the sera of infected patients interferes with the autophagic process of monocytes impairing their in-vitro differentiation into dendritic cells. Biochim Biophys Acta 1843, 1348-1355. Granato, M., Santarelli, R., Farina, A., Gonnella, R., Lotti, L.V., Faggioni, A., Cirone, M., 2014b. Epstein-barr virus blocks the autophagic flux and appropriates the autophagic machinery to enhance viral replication. J Virol 88, 12715-12726. Granato, M., Santarelli, R., Filardi, M., Gonnella, R., Farina, A., Torrisi, M.R., Faggioni, A., Cirone, M., 2015. The activation of KSHV lytic cycle blocks autophagy in PEL cells. Autophagy of 11, 1978-1986. Hart, L.S., Cunningham, J.T., Datta, T., Dey, S., Tameire, F., Lehman, S.L., Qiu, B., Zhang, H., Cerniglia, G., Bi, M., Li, Y., Gao, Y., Liu, H., Li, C., Maity, A., Thomas-Tikhonenko, A., Perl, ro A.E., Koong, A., Fuchs, S.Y., Diehl, J.A., Mills, I.G., Ruggero, D., Koumenis, C., 2012. ER stressmediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest 122, -p 4621-4634. metabolism. Apoptosis 20, 658-670. re Harvald, E.B., Olsen, A.S., Faergeman, N.J., 2015. Autophagy in the light of sphingolipid Hewitt, G., Carroll, B., Sarallah, R., Correia-Melo, C., Ogrodnik, M., Nelson, G., Otten, E.G., ur na lP Manni, D., Antrobus, R., Morgan, B.A., von Zglinicki, T., Jurk, D., Seluanov, A., Gorbunova, V., Johansen, T., Passos, J.F., Korolchuk, V.I., 2016. SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy 12, 1917-1930. Hindupur, S.K., Gonzalez, A., Hall, M.N., 2015. The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol 7, a019141. Iwakoshi, N.N., Pypaert, M., Glimcher, L.H., 2007. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J Exp Med 204, 2267-2275. Jin, S., 2005. p53, Autophagy and tumor suppression. Autophagy 1, 171-173. Jo Jin, S.M., Youle, R.J., 2012. PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 125, 795-799. Katsuragi, Y., Ichimura, Y., Komatsu, M., 2016. Regulation of the Keap1–Nrf2 pathway by p62/SQSTM1. Current Opinion in Toxicology 1, 54-61. Kaushik, S., Cuervo, A.M., 2018. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19, 365-381. Kim, J., Kundu, M., Viollet, B., Guan, K.L., 2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132-141. 16 Kim, R., Emi, M., Tanabe, K., Murakami, S., 2006. Role of the unfolded protein response in cell death. Apoptosis 11, 5-13. Kitamura, H., Ohno, Y., Toyoshima, Y., Ohtake, J., Homma, S., Kawamura, H., Takahashi, N., Taketomi, A., 2017. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci 108, 1947-1952. Klaips, C.L., Jayaraj, G.G., Hartl, F.U., 2018. Pathways of cellular proteostasis in aging and disease. J Cell Biol 217, 51-63. Klionsky, D.J., Abdelmohsen, K., Abe, A., Abedin, M.J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C.M., Adams, P.D., Adeli, K., Adhihetty, P.J., Adler, S.G., Agam, G., of Agarwal, R., Aghi, M.K., Agnello, M., Agostinis, P., Aguilar, P.V., Aguirre-Ghiso, J., Airoldi, E.M., Ait-Si-Ali, S., Akematsu, T., Akporiaye, E.T., Al-Rubeai, M., Albaiceta, G.M., Albanese, C., Albani, D., Albert, M.L., Aldudo, J., Algul, H., Alirezaei, M., Alloza, I., Almasan, A., Almonte- ro Beceril, M., Alnemri, E.S., Alonso, C., Altan-Bonnet, N., Altieri, D.C., Alvarez, S., Alvarez-Erviti, L., Alves, S., Amadoro, G., Amano, A., Amantini, C., Ambrosio, S., Amelio, I., Amer, A.O., -p Amessou, M., Amon, A., An, Z., Anania, F.A., Andersen, S.U., Andley, U.P., Andreadi, C.K., Andrieu-Abadie, N., Anel, A., Ann, D.K., Anoopkumar-Dukie, S., Antonioli, M., Aoki, H., re Apostolova, N., Aquila, S., Aquilano, K., Araki, K., Arama, E., Aranda, A., Araya, J., Arcaro, A., Arias, E., Arimoto, H., Ariosa, A.R., Armstrong, J.L., Arnould, T., Arsov, I., Asanuma, K., ur na lP Askanas, V., Asselin, E., Atarashi, R., Atherton, S.S., Atkin, J.D., Attardi, L.D., Auberger, P., Auburger, G., Aurelian, L., Autelli, R., Avagliano, L., Avantaggiati, M.L., Avrahami, L., Awale, S., Azad, N., Bachetti, T., Backer, J.M., Bae, D.H., Bae, J.S., Bae, O.N., Bae, S.H., Baehrecke, E.H., Baek, S.H., Baghdiguian, S., Bagniewska-Zadworna, A., Bai, H., Bai, J., Bai, X.Y., Bailly, Y., Balaji, K.N., Balduini, W., Ballabio, A., Balzan, R., Banerjee, R., Banhegyi, G., Bao, H., Barbeau, B., Barrachina, M.D., Barreiro, E., Bartel, B., Bartolome, A., Bassham, D.C., Bassi, M.T., Bast, R.C., Jr., Basu, A., Batista, M.T., Batoko, H., Battino, M., Bauckman, K., Baumgarner, B.L., Bayer, K.U., Beale, R., Beaulieu, J.F., Beck, G.R., Jr., Becker, C., Beckham, J.D., Bedard, P.A., Jo Bednarski, P.J., Begley, T.J., Behl, C., Behrends, C., Behrens, G.M., Behrns, K.E., Bejarano, E., Belaid, A., Belleudi, F., Benard, G., Berchem, G., Bergamaschi, D., Bergami, M., Berkhout, B., Berliocchi, L., Bernard, A., Bernard, M., Bernassola, F., Bertolotti, A., Bess, A.S., Besteiro, S., Bettuzzi, S., Bhalla, S., Bhattacharyya, S., Bhutia, S.K., Biagosch, C., Bianchi, M.W., BiardPiechaczyk, M., Billes, V., Bincoletto, C., Bingol, B., Bird, S.W., Bitoun, M., Bjedov, I., Blackstone, C., Blanc, L., Blanco, G.A., Blomhoff, H.K., Boada-Romero, E., Bockler, S., Boes, M., Boesze-Battaglia, K., Boise, L.H., Bolino, A., Boman, A., Bonaldo, P., Bordi, M., Bosch, J., Botana, L.M., Botti, J., Bou, G., Bouche, M., Bouchecareilh, M., Boucher, M.J., Boulton, M.E., 17 Bouret, S.G., Boya, P., Boyer-Guittaut, M., Bozhkov, P.V., Brady, N., Braga, V.M., Brancolini, C., Braus, G.H., Bravo-San Pedro, J.M., Brennan, L.A., Bresnick, E.H., Brest, P., Bridges, D., Bringer, M.A., Brini, M., Brito, G.C., Brodin, B., Brookes, P.S., Brown, E.J., Brown, K., Broxmeyer, H.E., Bruhat, A., Brum, P.C., Brumell, J.H., Brunetti-Pierri, N., Bryson-Richardson, R.J., Buch, S., Buchan, A.M., Budak, H., Bulavin, D.V., Bultman, S.J., Bultynck, G., Bumbasirevic, V., Burelle, Y., Burke, R.E., Burmeister, M., Butikofer, P., Caberlotto, L., Cadwell, K., Cahova, M., Cai, D., Cai, J., Cai, Q., Calatayud, S., Camougrand, N., Campanella, M., Campbell, G.R., Campbell, M., Campello, S., Candau, R., Caniggia, I., Cantoni, L., Cao, L., Caplan, A.B., Caraglia, M., Cardinali, C., Cardoso, S.M., Carew, J.S., Carleton, L.A., Carlin, C.R., Carloni, S., Carlsson, S.R., Carmona- of Gutierrez, D., Carneiro, L.A., Carnevali, O., Carra, S., Carrier, A., Carroll, B., Casas, C., Casas, J., Cassinelli, G., Castets, P., Castro-Obregon, S., Cavallini, G., Ceccherini, I., Cecconi, F., Cederbaum, A.I., Cena, V., Cenci, S., Cerella, C., Cervia, D., Cetrullo, S., Chaachouay, H., Chae, ro H.J., Chagin, A.S., Chai, C.Y., Chakrabarti, G., Chamilos, G., Chan, E.Y., Chan, M.T., Chandra, D., Chandra, P., Chang, C.P., Chang, R.C., Chang, T.Y., Chatham, J.C., Chatterjee, S., Chauhan, S., -p Che, Y., Cheetham, M.E., Cheluvappa, R., Chen, C.J., Chen, G., Chen, G.C., Chen, G., Chen, H., Chen, J.W., Chen, J.K., Chen, M., Chen, M., Chen, P., Chen, Q., Chen, Q., Chen, S.D., Chen, S., re Chen, S.S., Chen, W., Chen, W.J., Chen, W.Q., Chen, W., Chen, X., Chen, Y.H., Chen, Y.G., Chen, Y., Chen, Y., Chen, Y., Chen, Y.J., Chen, Y.Q., Chen, Y., Chen, Z., Chen, Z., Cheng, A., Cheng, ur na lP C.H., Cheng, H., Cheong, H., Cherry, S., Chesney, J., Cheung, C.H., Chevet, E., Chi, H.C., Chi, S.G., Chiacchiera, F., Chiang, H.L., Chiarelli, R., Chiariello, M., Chieppa, M., Chin, L.S., Chiong, M., Chiu, G.N., Cho, D.H., Cho, S.G., Cho, W.C., Cho, Y.Y., Cho, Y.S., Choi, A.M., Choi, E.J., Choi, E.K., Choi, J., Choi, M.E., Choi, S.I., Chou, T.F., Chouaib, S., Choubey, D., Choubey, V., Chow, K.C., Chowdhury, K., Chu, C.T., Chuang, T.H., Chun, T., Chung, H., Chung, T., Chung, Y.L., Chwae, Y.J., Cianfanelli, V., Ciarcia, R., Ciechomska, I.A., Ciriolo, M.R., Cirone, M., Claerhout, S., Clague, M.J., Claria, J., Clarke, P.G., Clarke, R., Clementi, E., Cleyrat, C., Cnop, M., Coccia, E.M., Cocco, T., Codogno, P., Coers, J., Cohen, E.E., Colecchia, D., Coletto, L., Coll, N.S., Jo Colucci-Guyon, E., Comincini, S., Condello, M., Cook, K.L., Coombs, G.H., Cooper, C.D., Cooper, J.M., Coppens, I., Corasaniti, M.T., Corazzari, M., Corbalan, R., Corcelle-Termeau, E., Cordero, M.D., Corral-Ramos, C., Corti, O., Cossarizza, A., Costelli, P., Costes, S., Cotman, S.L., Coto-Montes, A., Cottet, S., Couve, E., Covey, L.R., Cowart, L.A., Cox, J.S., Coxon, F.P., Coyne, C.B., Cragg, M.S., Craven, R.J., Crepaldi, T., Crespo, J.L., Criollo, A., Crippa, V., Cruz, M.T., Cuervo, A.M., Cuezva, J.M., Cui, T., Cutillas, P.R., Czaja, M.J., Czyzyk-Krzeska, M.F., Dagda, R.K., Dahmen, U., Dai, C., Dai, W., Dai, Y., Dalby, K.N., Dalla Valle, L., Dalmasso, G., D'Amelio, M., Damme, M., Darfeuille-Michaud, A., Dargemont, C., Darley-Usmar, V.M., Dasarathy, S., 18 Dasgupta, B., Dash, S., Dass, C.R., Davey, H.M., Davids, L.M., Davila, D., Davis, R.J., Dawson, T.M., Dawson, V.L., Daza, P., de Belleroche, J., de Figueiredo, P., de Figueiredo, R.C., de la Fuente, J., De Martino, L., De Matteis, A., De Meyer, G.R., De Milito, A., De Santi, M., de Souza, W., De Tata, V., De Zio, D., Debnath, J., Dechant, R., Decuypere, J.P., Deegan, S., Dehay, B., Del Bello, B., Del Re, D.P., Delage-Mourroux, R., Delbridge, L.M., Deldicque, L., Delorme-Axford, E., Deng, Y., Dengjel, J., Denizot, M., Dent, P., Der, C.J., Deretic, V., Derrien, B., Deutsch, E., Devarenne, T.P., Devenish, R.J., Di Bartolomeo, S., Di Daniele, N., Di Domenico, F., Di Nardo, A., Di Paola, S., Di Pietro, A., Di Renzo, L., DiAntonio, A., Diaz-Araya, G., Diaz-Laviada, I., DiazMeco, M.T., Diaz-Nido, J., Dickey, C.A., Dickson, R.C., Diederich, M., Digard, P., Dikic, I., of Dinesh-Kumar, S.P., Ding, C., Ding, W.X., Ding, Z., Dini, L., Distler, J.H., Diwan, A., DjavaheriMergny, M., Dmytruk, K., Dobson, R.C., Doetsch, V., Dokladny, K., Dokudovskaya, S., Donadelli, M., Dong, X.C., Dong, X., Dong, Z., Donohue, T.M., Jr., Doran, K.S., D'Orazi, G., Dorn, G.W., ro 2nd, Dosenko, V., Dridi, S., Drucker, L., Du, J., Du, L.L., Du, L., du Toit, A., Dua, P., Duan, L., Duann, P., Dubey, V.K., Duchen, M.R., Duchosal, M.A., Duez, H., Dugail, I., Dumit, V.I., Duncan, -p M.C., Dunlop, E.A., Dunn, W.A., Jr., Dupont, N., Dupuis, L., Duran, R.V., Durcan, T.M., DuvezinCaubet, S., Duvvuri, U., Eapen, V., Ebrahimi-Fakhari, D., Echard, A., Eckhart, L., Edelstein, C.L., re Edinger, A.L., Eichinger, L., Eisenberg, T., Eisenberg-Lerner, A., Eissa, N.T., El-Deiry, W.S., ElKhoury, V., Elazar, Z., Eldar-Finkelman, H., Elliott, C.J., Emanuele, E., Emmenegger, U., Engedal, ur na lP N., Engelbrecht, A.M., Engelender, S., Enserink, J.M., Erdmann, R., Erenpreisa, J., Eri, R., Eriksen, J.L., Erman, A., Escalante, R., Eskelinen, E.L., Espert, L., Esteban-Martinez, L., Evans, T.J., Fabri, M., Fabrias, G., Fabrizi, C., Facchiano, A., Faergeman, N.J., Faggioni, A., Fairlie, W.D., Fan, C., Fan, D., Fan, J., Fang, S., Fanto, M., Fanzani, A., Farkas, T., Faure, M., Favier, F.B., Fearnhead, H., Federici, M., Fei, E., Felizardo, T.C., Feng, H., Feng, Y., Feng, Y., Ferguson, T.A., Fernandez, A.F., Fernandez-Barrena, M.G., Fernandez-Checa, J.C., Fernandez-Lopez, A., Fernandez-Zapico, M.E., Feron, O., Ferraro, E., Ferreira-Halder, C.V., Fesus, L., Feuer, R., Fiesel, F.C., Filippi-Chiela, E.C., Filomeni, G., Fimia, G.M., Fingert, J.H., Finkbeiner, S., Finkel, T., Fiorito, F., Fisher, P.B., Jo Flajolet, M., Flamigni, F., Florey, O., Florio, S., Floto, R.A., Folini, M., Follo, C., Fon, E.A., Fornai, F., Fortunato, F., Fraldi, A., Franco, R., Francois, A., Francois, A., Frankel, L.B., Fraser, I.D., Frey, N., Freyssenet, D.G., Frezza, C., Friedman, S.L., Frigo, D.E., Fu, D., Fuentes, J.M., Fueyo, J., Fujitani, Y., Fujiwara, Y., Fujiya, M., Fukuda, M., Fulda, S., Fusco, C., Gabryel, B., Gaestel, M., Gailly, P., Gajewska, M., Galadari, S., Galili, G., Galindo, I., Galindo, M.F., Galliciotti, G., Galluzzi, L., Galluzzi, L., Galy, V., Gammoh, N., Gandy, S., Ganesan, A.K., Ganesan, S., Ganley, I.G., Gannage, M., Gao, F.B., Gao, F., Gao, J.X., Garcia Nannig, L., Garcia Vescovi, E., Garcia-Macia, M., Garcia-Ruiz, C., Garg, A.D., Garg, P.K., Gargini, R., Gassen, N.C., 19 Gatica, D., Gatti, E., Gavard, J., Gavathiotis, E., Ge, L., Ge, P., Ge, S., Gean, P.W., Gelmetti, V., Genazzani, A.A., Geng, J., Genschik, P., Gerner, L., Gestwicki, J.E., Gewirtz, D.A., Ghavami, S., Ghigo, E., Ghosh, D., Giammarioli, A.M., Giampieri, F., Giampietri, C., Giatromanolaki, A., Gibbings, D.J., Gibellini, L., Gibson, S.B., Ginet, V., Giordano, A., Giorgini, F., Giovannetti, E., Girardin, S.E., Gispert, S., Giuliano, S., Gladson, C.L., Glavic, A., Gleave, M., Godefroy, N., Gogal, R.M., Jr., Gokulan, K., Goldman, G.H., Goletti, D., Goligorsky, M.S., Gomes, A.V., Gomes, L.C., Gomez, H., Gomez-Manzano, C., Gomez-Sanchez, R., Goncalves, D.A., Goncu, E., Gong, Q., Gongora, C., Gonzalez, C.B., Gonzalez-Alegre, P., Gonzalez-Cabo, P., Gonzalez-Polo, R.A., Goping, I.S., Gorbea, C., Gorbunov, N.V., Goring, D.R., Gorman, A.M., Gorski, S.M., Goruppi, S., of Goto-Yamada, S., Gotor, C., Gottlieb, R.A., Gozes, I., Gozuacik, D., Graba, Y., Graef, M., Granato, G.E., Grant, G.D., Grant, S., Gravina, G.L., Green, D.R., Greenhough, A., Greenwood, M.T., Grimaldi, B., Gros, F., Grose, C., Groulx, J.F., Gruber, F., Grumati, P., Grune, T., Guan, J.L., Guan, ro K.L., Guerra, B., Guillen, C., Gulshan, K., Gunst, J., Guo, C., Guo, L., Guo, M., Guo, W., Guo, X.G., Gust, A.A., Gustafsson, A.B., Gutierrez, E., Gutierrez, M.G., Gwak, H.S., Haas, A., Haber, -p J.E., Hadano, S., Hagedorn, M., Hahn, D.R., Halayko, A.J., Hamacher-Brady, A., Hamada, K., Hamai, A., Hamann, A., Hamasaki, M., Hamer, I., Hamid, Q., Hammond, E.M., Han, F., Han, W., re Handa, J.T., Hanover, J.A., Hansen, M., Harada, M., Harhaji-Trajkovic, L., Harper, J.W., Harrath, A.H., Harris, A.L., Harris, J., Hasler, U., Hasselblatt, P., Hasui, K., Hawley, R.G., Hawley, T.S., ur na lP He, C., He, C.Y., He, F., He, G., He, R.R., He, X.H., He, Y.W., He, Y.Y., Heath, J.K., Hebert, M.J., Heinzen, R.A., Helgason, G.V., Hensel, M., Henske, E.P., Her, C., Herman, P.K., Hernandez, A., Hernandez, C., Hernandez-Tiedra, S., Hetz, C., Hiesinger, P.R., Higaki, K., Hilfiker, S., Hill, B.G., Hill, J.A., Hill, W.D., Hino, K., Hofius, D., Hofman, P., Hoglinger, G.U., Hohfeld, J., Holz, M.K., Hong, Y., Hood, D.A., Hoozemans, J.J., Hoppe, T., Hsu, C., Hsu, C.Y., Hsu, L.C., Hu, D., Hu, G., Hu, H.M., Hu, H., Hu, M.C., Hu, Y.C., Hu, Z.W., Hua, F., Hua, Y., Huang, C., Huang, H.L., Huang, K.H., Huang, K.Y., Huang, S., Huang, S., Huang, W.P., Huang, Y.R., Huang, Y., Huang, Y., Huber, T.B., Huebbe, P., Huh, W.K., Hulmi, J.J., Hur, G.M., Hurley, J.H., Husak, Z., Hussain, Jo S.N., Hussain, S., Hwang, J.J., Hwang, S., Hwang, T.I., Ichihara, A., Imai, Y., Imbriano, C., Inomata, M., Into, T., Iovane, V., Iovanna, J.L., Iozzo, R.V., Ip, N.Y., Irazoqui, J.E., Iribarren, P., Isaka, Y., Isakovic, A.J., Ischiropoulos, H., Isenberg, J.S., Ishaq, M., Ishida, H., Ishii, I., Ishmael, J.E., Isidoro, C., Isobe, K., Isono, E., Issazadeh-Navikas, S., Itahana, K., Itakura, E., Ivanov, A.I., Iyer, A.K., Izquierdo, J.M., Izumi, Y., Izzo, V., Jaattela, M., Jaber, N., Jackson, D.J., Jackson, W.T., Jacob, T.G., Jacques, T.S., Jagannath, C., Jain, A., Jana, N.R., Jang, B.K., Jani, A., Janji, B., Jannig, P.R., Jansson, P.J., Jean, S., Jendrach, M., Jeon, J.H., Jessen, N., Jeung, E.B., Jia, K., Jia, L., Jiang, H., Jiang, H., Jiang, L., Jiang, T., Jiang, X., Jiang, X., Jiang, X., Jiang, Y., Jiang, Y., Jimenez, A., 20 Jin, C., Jin, H., Jin, L., Jin, M., Jin, S., Jinwal, U.K., Jo, E.K., Johansen, T., Johnson, D.E., Johnson, G.V., Johnson, J.D., Jonasch, E., Jones, C., Joosten, L.A., Jordan, J., Joseph, A.M., Joseph, B., Joubert, A.M., Ju, D., Ju, J., Juan, H.F., Juenemann, K., Juhasz, G., Jung, H.S., Jung, J.U., Jung, Y.K., Jungbluth, H., Justice, M.J., Jutten, B., Kaakoush, N.O., Kaarniranta, K., Kaasik, A., Kabuta, T., Kaeffer, B., Kagedal, K., Kahana, A., Kajimura, S., Kakhlon, O., Kalia, M., Kalvakolanu, D.V., Kamada, Y., Kambas, K., Kaminskyy, V.O., Kampinga, H.H., Kandouz, M., Kang, C., Kang, R., Kang, T.C., Kanki, T., Kanneganti, T.D., Kanno, H., Kanthasamy, A.G., Kantorow, M., KaparakisLiaskos, M., Kapuy, O., Karantza, V., Karim, M.R., Karmakar, P., Kaser, A., Kaushik, S., Kawula, T., Kaynar, A.M., Ke, P.Y., Ke, Z.J., Kehrl, J.H., Keller, K.E., Kemper, J.K., Kenworthy, A.K., of Kepp, O., Kern, A., Kesari, S., Kessel, D., Ketteler, R., Kettelhut Ido, C., Khambu, B., Khan, M.M., Khandelwal, V.K., Khare, S., Kiang, J.G., Kiger, A.A., Kihara, A., Kim, A.L., Kim, C.H., Kim, D.R., Kim, D.H., Kim, E.K., Kim, H.Y., Kim, H.R., Kim, J.S., Kim, J.H., Kim, J.C., Kim, J.H., ro Kim, K.W., Kim, M.D., Kim, M.M., Kim, P.K., Kim, S.W., Kim, S.Y., Kim, Y.S., Kim, Y., Kimchi, A., Kimmelman, A.C., Kimura, T., King, J.S., Kirkegaard, K., Kirkin, V., Kirshenbaum, -p L.A., Kishi, S., Kitajima, Y., Kitamoto, K., Kitaoka, Y., Kitazato, K., Kley, R.A., Klimecki, W.T., Klinkenberg, M., Klucken, J., Knaevelsrud, H., Knecht, E., Knuppertz, L., Ko, J.L., Kobayashi, S., re Koch, J.C., Koechlin-Ramonatxo, C., Koenig, U., Koh, Y.H., Kohler, K., Kohlwein, S.D., Koike, M., Komatsu, M., Kominami, E., Kong, D., Kong, H.J., Konstantakou, E.G., Kopp, B.T., ur na lP Korcsmaros, T., Korhonen, L., Korolchuk, V.I., Koshkina, N.V., Kou, Y., Koukourakis, M.I., Koumenis, C., Kovacs, A.L., Kovacs, T., Kovacs, W.J., Koya, D., Kraft, C., Krainc, D., Kramer, H., Kravic-Stevovic, T., Krek, W., Kretz-Remy, C., Krick, R., Krishnamurthy, M., Kriston-Vizi, J., Kroemer, G., Kruer, M.C., Kruger, R., Ktistakis, N.T., Kuchitsu, K., Kuhn, C., Kumar, A.P., Kumar, A., Kumar, A., Kumar, D., Kumar, D., Kumar, R., Kumar, S., Kundu, M., Kung, H.J., Kuno, A., Kuo, S.H., Kuret, J., Kurz, T., Kwok, T., Kwon, T.K., Kwon, Y.T., Kyrmizi, I., La Spada, A.R., Lafont, F., Lahm, T., Lakkaraju, A., Lam, T., Lamark, T., Lancel, S., Landowski, T.H., Lane, D.J., Lane, J.D., Lanzi, C., Lapaquette, P., Lapierre, L.R., Laporte, J., Laukkarinen, J., Jo Laurie, G.W., Lavandero, S., Lavie, L., LaVoie, M.J., Law, B.Y., Law, H.K., Law, K.B., Layfield, R., Lazo, P.A., Le Cam, L., Le Roch, K.G., Le Stunff, H., Leardkamolkarn, V., Lecuit, M., Lee, B.H., Lee, C.H., Lee, E.F., Lee, G.M., Lee, H.J., Lee, H., Lee, J.K., Lee, J., Lee, J.H., Lee, J.H., Lee, M., Lee, M.S., Lee, P.J., Lee, S.W., Lee, S.J., Lee, S.J., Lee, S.Y., Lee, S.H., Lee, S.S., Lee, S.J., Lee, S., Lee, Y.R., Lee, Y.J., Lee, Y.H., Leeuwenburgh, C., Lefort, S., Legouis, R., Lei, J., Lei, Q.Y., Leib, D.A., Leibowitz, G., Lekli, I., Lemaire, S.D., Lemasters, J.J., Lemberg, M.K., Lemoine, A., Leng, S., Lenz, G., Lenzi, P., Lerman, L.O., Lettieri Barbato, D., Leu, J.I., Leung, H.Y., Levine, B., Lewis, P.A., Lezoualc'h, F., Li, C., Li, F., Li, F.J., Li, J., Li, K., Li, L., Li, M., Li, M., Li, Q., Li, 21 R., Li, S., Li, W., Li, W., Li, X., Li, Y., Lian, J., Liang, C., Liang, Q., Liao, Y., Liberal, J., Liberski, P.P., Lie, P., Lieberman, A.P., Lim, H.J., Lim, K.L., Lim, K., Lima, R.T., Lin, C.S., Lin, C.F., Lin, F., Lin, F., Lin, F.C., Lin, K., Lin, K.H., Lin, P.H., Lin, T., Lin, W.W., Lin, Y.S., Lin, Y., Linden, R., Lindholm, D., Lindqvist, L.M., Lingor, P., Linkermann, A., Liotta, L.A., Lipinski, M.M., Lira, V.A., Lisanti, M.P., Liton, P.B., Liu, B., Liu, C., Liu, C.F., Liu, F., Liu, H.J., Liu, J., Liu, J.J., Liu, J.L., Liu, K., Liu, L., Liu, L., Liu, Q., Liu, R.Y., Liu, S., Liu, S., Liu, W., Liu, X.D., Liu, X., Liu, X.H., Liu, X., Liu, X., Liu, X., Liu, Y., Liu, Y., Liu, Z., Liu, Z., Liuzzi, J.P., Lizard, G., Ljujic, M., Lodhi, I.J., Logue, S.E., Lokeshwar, B.L., Long, Y.C., Lonial, S., Loos, B., Lopez-Otin, C., LopezVicario, C., Lorente, M., Lorenzi, P.L., Lorincz, P., Los, M., Lotze, M.T., Lovat, P.E., Lu, B., Lu, of B., Lu, J., Lu, Q., Lu, S.M., Lu, S., Lu, Y., Luciano, F., Luckhart, S., Lucocq, J.M., Ludovico, P., Lugea, A., Lukacs, N.W., Lum, J.J., Lund, A.H., Luo, H., Luo, J., Luo, S., Luparello, C., Lyons, T., Ma, J., Ma, Y., Ma, Y., Ma, Z., Machado, J., Machado-Santelli, G.M., Macian, F., MacIntosh, G.C., ro MacKeigan, J.P., Macleod, K.F., MacMicking, J.D., MacMillan-Crow, L.A., Madeo, F., Madesh, M., Madrigal-Matute, J., Maeda, A., Maeda, T., Maegawa, G., Maellaro, E., Maes, H., Magarinos, -p M., Maiese, K., Maiti, T.K., Maiuri, L., Maiuri, M.C., Maki, C.G., Malli, R., Malorni, W., Maloyan, A., Mami-Chouaib, F., Man, N., Mancias, J.D., Mandelkow, E.M., Mandell, M.A., re Manfredi, A.A., Manie, S.N., Manzoni, C., Mao, K., Mao, Z., Mao, Z.W., Marambaud, P., Marconi, A.M., Marelja, Z., Marfe, G., Margeta, M., Margittai, E., Mari, M., Mariani, F.V., Marin, C., ur na lP Marinelli, S., Marino, G., Markovic, I., Marquez, R., Martelli, A.M., Martens, S., Martin, K.R., Martin, S.J., Martin, S., Martin-Acebes, M.A., Martin-Sanz, P., Martinand-Mari, C., Martinet, W., Martinez, J., Martinez-Lopez, N., Martinez-Outschoorn, U., Martinez-Velazquez, M., MartinezVicente, M., Martins, W.K., Mashima, H., Mastrianni, J.A., Matarese, G., Matarrese, P., Mateo, R., Matoba, S., Matsumoto, N., Matsushita, T., Matsuura, A., Matsuzawa, T., Mattson, M.P., Matus, S., Maugeri, N., Mauvezin, C., Mayer, A., Maysinger, D., Mazzolini, G.D., McBrayer, M.K., McCall, K., McCormick, C., McInerney, G.M., McIver, S.C., McKenna, S., McMahon, J.J., McNeish, I.A., Mechta-Grigoriou, F., Medema, J.P., Medina, D.L., Megyeri, K., Mehrpour, M., Mehta, J.L., Mei, Jo Y., Meier, U.C., Meijer, A.J., Melendez, A., Melino, G., Melino, S., de Melo, E.J., Mena, M.A., Meneghini, M.D., Menendez, J.A., Menezes, R., Meng, L., Meng, L.H., Meng, S., Menghini, R., Menko, A.S., Menna-Barreto, R.F., Menon, M.B., Meraz-Rios, M.A., Merla, G., Merlini, L., Merlot, A.M., Meryk, A., Meschini, S., Meyer, J.N., Mi, M.T., Miao, C.Y., Micale, L., Michaeli, S., Michiels, C., Migliaccio, A.R., Mihailidou, A.S., Mijaljica, D., Mikoshiba, K., Milan, E., MillerFleming, L., Mills, G.B., Mills, I.G., Minakaki, G., Minassian, B.A., Ming, X.F., Minibayeva, F., Minina, E.A., Mintern, J.D., Minucci, S., Miranda-Vizuete, A., Mitchell, C.H., Miyamoto, S., Miyazawa, K., Mizushima, N., Mnich, K., Mograbi, B., Mohseni, S., Moita, L.F., Molinari, M., 22 Molinari, M., Moller, A.B., Mollereau, B., Mollinedo, F., Mongillo, M., Monick, M.M., Montagnaro, S., Montell, C., Moore, D.J., Moore, M.N., Mora-Rodriguez, R., Moreira, P.I., Morel, E., Morelli, M.B., Moreno, S., Morgan, M.J., Moris, A., Moriyasu, Y., Morrison, J.L., Morrison, L.A., Morselli, E., Moscat, J., Moseley, P.L., Mostowy, S., Motori, E., Mottet, D., Mottram, J.C., Moussa, C.E., Mpakou, V.E., Mukhtar, H., Mulcahy Levy, J.M., Muller, S., Munoz-Moreno, R., Munoz-Pinedo, C., Munz, C., Murphy, M.E., Murray, J.T., Murthy, A., Mysorekar, I.U., Nabi, I.R., Nabissi, M., Nader, G.A., Nagahara, Y., Nagai, Y., Nagata, K., Nagelkerke, A., Nagy, P., Naidu, S.R., Nair, S., Nakano, H., Nakatogawa, H., Nanjundan, M., Napolitano, G., Naqvi, N.I., Nardacci, R., Narendra, D.P., Narita, M., Nascimbeni, A.C., Natarajan, R., Navegantes, L.C., Nawrocki, S.T., of Nazarko, T.Y., Nazarko, V.Y., Neill, T., Neri, L.M., Netea, M.G., Netea-Maier, R.T., Neves, B.M., Ney, P.A., Nezis, I.P., Nguyen, H.T., Nguyen, H.P., Nicot, A.S., Nilsen, H., Nilsson, P., Nishimura, M., Nishino, I., Niso-Santano, M., Niu, H., Nixon, R.A., Njar, V.C., Noda, T., Noegel, A.A., Nolte, ro E.M., Norberg, E., Norga, K.K., Noureini, S.K., Notomi, S., Notterpek, L., Nowikovsky, K., Nukina, N., Nurnberger, T., O'Donnell, V.B., O'Donovan, T., O'Dwyer, P.J., Oehme, I., Oeste, -p C.L., Ogawa, M., Ogretmen, B., Ogura, Y., Oh, Y.J., Ohmuraya, M., Ohshima, T., Ojha, R., Okamoto, K., Okazaki, T., Oliver, F.J., Ollinger, K., Olsson, S., Orban, D.P., Ordonez, P., Orhon, re I., Orosz, L., O'Rourke, E.J., Orozco, H., Ortega, A.L., Ortona, E., Osellame, L.D., Oshima, J., Oshima, S., Osiewacz, H.D., Otomo, T., Otsu, K., Ou, J.H., Outeiro, T.F., Ouyang, D.Y., Ouyang, ur na lP H., Overholtzer, M., Ozbun, M.A., Ozdinler, P.H., Ozpolat, B., Pacelli, C., Paganetti, P., Page, G., Pages, G., Pagnini, U., Pajak, B., Pak, S.C., Pakos-Zebrucka, K., Pakpour, N., Palkova, Z., Palladino, F., Pallauf, K., Pallet, N., Palmieri, M., Paludan, S.R., Palumbo, C., Palumbo, S., Pampliega, O., Pan, H., Pan, W., Panaretakis, T., Pandey, A., Pantazopoulou, A., Papackova, Z., Papademetrio, D.L., Papassideri, I., Papini, A., Parajuli, N., Pardo, J., Parekh, V.V., Parenti, G., Park, J.I., Park, J., Park, O.K., Parker, R., Parlato, R., Parys, J.B., Parzych, K.R., Pasquet, J.M., Pasquier, B., Pasumarthi, K.B., Patschan, D., Patterson, C., Pattingre, S., Pattison, S., Pause, A., Pavenstadt, H., Pavone, F., Pedrozo, Z., Pena, F.J., Penalva, M.A., Pende, M., Peng, J., Penna, F., Jo Penninger, J.M., Pensalfini, A., Pepe, S., Pereira, G.J., Pereira, P.C., Perez-de la Cruz, V., PerezPerez, M.E., Perez-Rodriguez, D., Perez-Sala, D., Perier, C., Perl, A., Perlmutter, D.H., Perrotta, I., Pervaiz, S., Pesonen, M., Pessin, J.E., Peters, G.J., Petersen, M., Petrache, I., Petrof, B.J., Petrovski, G., Phang, J.M., Piacentini, M., Pierdominici, M., Pierre, P., Pierrefite-Carle, V., Pietrocola, F., Pimentel-Muinos, F.X., Pinar, M., Pineda, B., Pinkas-Kramarski, R., Pinti, M., Pinton, P., Piperdi, B., Piret, J.M., Platanias, L.C., Platta, H.W., Plowey, E.D., Poggeler, S., Poirot, M., Polcic, P., Poletti, A., Poon, A.H., Popelka, H., Popova, B., Poprawa, I., Poulose, S.M., Poulton, J., Powers, S.K., Powers, T., Pozuelo-Rubio, M., Prak, K., Prange, R., Prescott, M., Priault, M., Prince, S., 23 Proia, R.L., Proikas-Cezanne, T., Prokisch, H., Promponas, V.J., Przyklenk, K., Puertollano, R., Pugazhenthi, S., Puglielli, L., Pujol, A., Puyal, J., Pyeon, D., Qi, X., Qian, W.B., Qin, Z.H., Qiu, Y., Qu, Z., Quadrilatero, J., Quinn, F., Raben, N., Rabinowich, H., Radogna, F., Ragusa, M.J., Rahmani, M., Raina, K., Ramanadham, S., Ramesh, R., Rami, A., Randall-Demllo, S., Randow, F., Rao, H., Rao, V.A., Rasmussen, B.B., Rasse, T.M., Ratovitski, E.A., Rautou, P.E., Ray, S.K., Razani, B., Reed, B.H., Reggiori, F., Rehm, M., Reichert, A.S., Rein, T., Reiner, D.J., Reits, E., Ren, J., Ren, X., Renna, M., Reusch, J.E., Revuelta, J.L., Reyes, L., Rezaie, A.R., Richards, R.I., Richardson, D.R., Richetta, C., Riehle, M.A., Rihn, B.H., Rikihisa, Y., Riley, B.E., Rimbach, G., Rippo, M.R., Ritis, K., Rizzi, F., Rizzo, E., Roach, P.J., Robbins, J., Roberge, M., Roca, G., of Roccheri, M.C., Rocha, S., Rodrigues, C.M., Rodriguez, C.I., de Cordoba, S.R., Rodriguez-Muela, N., Roelofs, J., Rogov, V.V., Rohn, T.T., Rohrer, B., Romanelli, D., Romani, L., Romano, P.S., Roncero, M.I., Rosa, J.L., Rosello, A., Rosen, K.V., Rosenstiel, P., Rost-Roszkowska, M., Roth, ro K.A., Roue, G., Rouis, M., Rouschop, K.M., Ruan, D.T., Ruano, D., Rubinsztein, D.C., Rucker, E.B., 3rd, Rudich, A., Rudolf, E., Rudolf, R., Ruegg, M.A., Ruiz-Roldan, C., Ruparelia, A.A., -p Rusmini, P., Russ, D.W., Russo, G.L., Russo, G., Russo, R., Rusten, T.E., Ryabovol, V., Ryan, K.M., Ryter, S.W., Sabatini, D.M., Sacher, M., Sachse, C., Sack, M.N., Sadoshima, J., Saftig, P., re Sagi-Eisenberg, R., Sahni, S., Saikumar, P., Saito, T., Saitoh, T., Sakakura, K., Sakoh-Nakatogawa, M., Sakuraba, Y., Salazar-Roa, M., Salomoni, P., Saluja, A.K., Salvaterra, P.M., Salvioli, R., ur na lP Samali, A., Sanchez, A.M., Sanchez-Alcazar, J.A., Sanchez-Prieto, R., Sandri, M., Sanjuan, M.A., Santaguida, S., Santambrogio, L., Santoni, G., Dos Santos, C.N., Saran, S., Sardiello, M., Sargent, G., Sarkar, P., Sarkar, S., Sarrias, M.R., Sarwal, M.M., Sasakawa, C., Sasaki, M., Sass, M., Sato, K., Sato, M., Satriano, J., Savaraj, N., Saveljeva, S., Schaefer, L., Schaible, U.E., Scharl, M., Schatzl, H.M., Schekman, R., Scheper, W., Schiavi, A., Schipper, H.M., Schmeisser, H., Schmidt, J., Schmitz, I., Schneider, B.E., Schneider, E.M., Schneider, J.L., Schon, E.A., Schonenberger, M.J., Schonthal, A.H., Schorderet, D.F., Schroder, B., Schuck, S., Schulze, R.J., Schwarten, M., Schwarz, T.L., Sciarretta, S., Scotto, K., Scovassi, A.I., Screaton, R.A., Screen, M., Seca, H., Sedej, S., Jo Segatori, L., Segev, N., Seglen, P.O., Segui-Simarro, J.M., Segura-Aguilar, J., Seki, E., Sell, C., Seiliez, I., Semenkovich, C.F., Semenza, G.L., Sen, U., Serra, A.L., Serrano-Puebla, A., Sesaki, H., Setoguchi, T., Settembre, C., Shacka, J.J., Shajahan-Haq, A.N., Shapiro, I.M., Sharma, S., She, H., Shen, C.K., Shen, C.C., Shen, H.M., Shen, S., Shen, W., Sheng, R., Sheng, X., Sheng, Z.H., Shepherd, T.G., Shi, J., Shi, Q., Shi, Q., Shi, Y., Shibutani, S., Shibuya, K., Shidoji, Y., Shieh, J.J., Shih, C.M., Shimada, Y., Shimizu, S., Shin, D.W., Shinohara, M.L., Shintani, M., Shintani, T., Shioi, T., Shirabe, K., Shiri-Sverdlov, R., Shirihai, O., Shore, G.C., Shu, C.W., Shukla, D., Sibirny, A.A., Sica, V., Sigurdson, C.J., Sigurdsson, E.M., Sijwali, P.S., Sikorska, B., Silveira, W.A., 24 Silvente-Poirot, S., Silverman, G.A., Simak, J., Simmet, T., Simon, A.K., Simon, H.U., Simone, C., Simons, M., Simonsen, A., Singh, R., Singh, S.V., Singh, S.K., Sinha, D., Sinha, S., Sinicrope, F.A., Sirko, A., Sirohi, K., Sishi, B.J., Sittler, A., Siu, P.M., Sivridis, E., Skwarska, A., Slack, R., Slaninova, I., Slavov, N., Smaili, S.S., Smalley, K.S., Smith, D.R., Soenen, S.J., Soleimanpour, S.A., Solhaug, A., Somasundaram, K., Son, J.H., Sonawane, A., Song, C., Song, F., Song, H.K., Song, J.X., Song, W., Soo, K.Y., Sood, A.K., Soong, T.W., Soontornniyomkij, V., Sorice, M., Sotgia, F., Soto-Pantoja, D.R., Sotthibundhu, A., Sousa, M.J., Spaink, H.P., Span, P.N., Spang, A., Sparks, J.D., Speck, P.G., Spector, S.A., Spies, C.D., Springer, W., Clair, D.S., Stacchiotti, A., Staels, B., Stang, M.T., Starczynowski, D.T., Starokadomskyy, P., Steegborn, C., Steele, J.W., of Stefanis, L., Steffan, J., Stellrecht, C.M., Stenmark, H., Stepkowski, T.M., Stern, S.T., Stevens, C., Stockwell, B.R., Stoka, V., Storchova, Z., Stork, B., Stratoulias, V., Stravopodis, D.J., Strnad, P., Strohecker, A.M., Strom, A.L., Stromhaug, P., Stulik, J., Su, Y.X., Su, Z., Subauste, C.S., ro Subramaniam, S., Sue, C.M., Suh, S.W., Sui, X., Sukseree, S., Sulzer, D., Sun, F.L., Sun, J., Sun, J., Sun, S.Y., Sun, Y., Sun, Y., Sun, Y., Sundaramoorthy, V., Sung, J., Suzuki, H., Suzuki, K., Suzuki, -p N., Suzuki, T., Suzuki, Y.J., Swanson, M.S., Swanton, C., Sward, K., Swarup, G., Sweeney, S.T., Sylvester, P.W., Szatmari, Z., Szegezdi, E., Szlosarek, P.W., Taegtmeyer, H., Tafani, M., re Taillebourg, E., Tait, S.W., Takacs-Vellai, K., Takahashi, Y., Takats, S., Takemura, G., Takigawa, N., Talbot, N.J., Tamagno, E., Tamburini, J., Tan, C.P., Tan, L., Tan, M.L., Tan, M., Tan, Y.J., ur na lP Tanaka, K., Tanaka, M., Tang, D., Tang, D., Tang, G., Tanida, I., Tanji, K., Tannous, B.A., Tapia, J.A., Tasset-Cuevas, I., Tatar, M., Tavassoly, I., Tavernarakis, N., Taylor, A., Taylor, G.S., Taylor, G.A., Taylor, J.P., Taylor, M.J., Tchetina, E.V., Tee, A.R., Teixeira-Clerc, F., Telang, S., Tencomnao, T., Teng, B.B., Teng, R.J., Terro, F., Tettamanti, G., Theiss, A.L., Theron, A.E., Thomas, K.J., Thome, M.P., Thomes, P.G., Thorburn, A., Thorner, J., Thum, T., Thumm, M., Thurston, T.L., Tian, L., Till, A., Ting, J.P., Titorenko, V.I., Toker, L., Toldo, S., Tooze, S.A., Topisirovic, I., Torgersen, M.L., Torosantucci, L., Torriglia, A., Torrisi, M.R., Tournier, C., Towns, R., Trajkovic, V., Travassos, L.H., Triola, G., Tripathi, D.N., Trisciuoglio, D., Troncoso, R., Jo Trougakos, I.P., Truttmann, A.C., Tsai, K.J., Tschan, M.P., Tseng, Y.H., Tsukuba, T., Tsung, A., Tsvetkov, A.S., Tu, S., Tuan, H.Y., Tucci, M., Tumbarello, D.A., Turk, B., Turk, V., Turner, R.F., Tveita, A.A., Tyagi, S.C., Ubukata, M., Uchiyama, Y., Udelnow, A., Ueno, T., Umekawa, M., Umemiya-Shirafuji, R., Underwood, B.R., Ungermann, C., Ureshino, R.P., Ushioda, R., Uversky, V.N., Uzcategui, N.L., Vaccari, T., Vaccaro, M.I., Vachova, L., Vakifahmetoglu-Norberg, H., Valdor, R., Valente, E.M., Vallette, F., Valverde, A.M., Van den Berghe, G., Van Den Bosch, L., van den Brink, G.R., van der Goot, F.G., van der Klei, I.J., van der Laan, L.J., van Doorn, W.G., van Egmond, M., van Golen, K.L., Van Kaer, L., van Lookeren Campagne, M., Vandenabeele, P., 25 Vandenberghe, W., Vanhorebeek, I., Varela-Nieto, I., Vasconcelos, M.H., Vasko, R., Vavvas, D.G., Vega-Naredo, I., Velasco, G., Velentzas, A.D., Velentzas, P.D., Vellai, T., Vellenga, E., Vendelbo, M.H., Venkatachalam, K., Ventura, N., Ventura, S., Veras, P.S., Verdier, M., Vertessy, B.G., Viale, A., Vidal, M., Vieira, H.L., Vierstra, R.D., Vigneswaran, N., Vij, N., Vila, M., Villar, M., Villar, V.H., Villarroya, J., Vindis, C., Viola, G., Viscomi, M.T., Vitale, G., Vogl, D.T., Voitsekhovskaja, O.V., von Haefen, C., von Schwarzenberg, K., Voth, D.E., Vouret-Craviari, V., Vuori, K., Vyas, J.M., Waeber, C., Walker, C.L., Walker, M.J., Walter, J., Wan, L., Wan, X., Wang, B., Wang, C., Wang, C.Y., Wang, C., Wang, C., Wang, C., Wang, D., Wang, F., Wang, F., Wang, G., Wang, H.J., Wang, H., Wang, H.G., Wang, H., Wang, H.D., Wang, J., Wang, J., Wang, M., Wang, M.Q., Wang, of P.Y., Wang, P., Wang, R.C., Wang, S., Wang, T.F., Wang, X., Wang, X.J., Wang, X.W., Wang, X., Wang, X., Wang, Y., Wang, Y., Wang, Y., Wang, Y.J., Wang, Y., Wang, Y., Wang, Y.T., Wang, Y., Wang, Z.N., Wappner, P., Ward, C., Ward, D.M., Warnes, G., Watada, H., Watanabe, Y., ro Watase, K., Weaver, T.E., Weekes, C.D., Wei, J., Weide, T., Weihl, C.C., Weindl, G., Weis, S.N., Wen, L., Wen, X., Wen, Y., Westermann, B., Weyand, C.M., White, A.R., White, E., Whitton, J.L., -p Whitworth, A.J., Wiels, J., Wild, F., Wildenberg, M.E., Wileman, T., Wilkinson, D.S., Wilkinson, S., Willbold, D., Williams, C., Williams, K., Williamson, P.R., Winklhofer, K.F., Witkin, S.S., re Wohlgemuth, S.E., Wollert, T., Wolvetang, E.J., Wong, E., Wong, G.W., Wong, R.W., Wong, V.K., Woodcock, E.A., Wright, K.L., Wu, C., Wu, D., Wu, G.S., Wu, J., Wu, J., Wu, M., Wu, M., ur na lP Wu, S., Wu, W.K., Wu, Y., Wu, Z., Xavier, C.P., Xavier, R.J., Xia, G.X., Xia, T., Xia, W., Xia, Y., Xiao, H., Xiao, J., Xiao, S., Xiao, W., Xie, C.M., Xie, Z., Xie, Z., Xilouri, M., Xiong, Y., Xu, C., Xu, C., Xu, F., Xu, H., Xu, H., Xu, J., Xu, J., Xu, J., Xu, L., Xu, X., Xu, Y., Xu, Y., Xu, Z.X., Xu, Z., Xue, Y., Yamada, T., Yamamoto, A., Yamanaka, K., Yamashina, S., Yamashiro, S., Yan, B., Yan, B., Yan, X., Yan, Z., Yanagi, Y., Yang, D.S., Yang, J.M., Yang, L., Yang, M., Yang, P.M., Yang, P., Yang, Q., Yang, W., Yang, W.Y., Yang, X., Yang, Y., Yang, Y., Yang, Z., Yang, Z., Yao, M.C., Yao, P.J., Yao, X., Yao, Z., Yao, Z., Yasui, L.S., Ye, M., Yedvobnick, B., Yeganeh, B., Yeh, E.S., Yeyati, P.L., Yi, F., Yi, L., Yin, X.M., Yip, C.K., Yoo, Y.M., Yoo, Y.H., Yoon, S.Y., Jo Yoshida, K., Yoshimori, T., Young, K.H., Yu, H., Yu, J.J., Yu, J.T., Yu, J., Yu, L., Yu, W.H., Yu, X.F., Yu, Z., Yuan, J., Yuan, Z.M., Yue, B.Y., Yue, J., Yue, Z., Zacks, D.N., Zacksenhaus, E., Zaffaroni, N., Zaglia, T., Zakeri, Z., Zecchini, V., Zeng, J., Zeng, M., Zeng, Q., Zervos, A.S., Zhang, D.D., Zhang, F., Zhang, G., Zhang, G.C., Zhang, H., Zhang, H., Zhang, H., Zhang, H., Zhang, J., Zhang, J., Zhang, J., Zhang, J., Zhang, J.P., Zhang, L., Zhang, L., Zhang, L., Zhang, L., Zhang, M.Y., Zhang, X., Zhang, X.D., Zhang, Y., Zhang, Y., Zhang, Y., Zhang, Y., Zhang, Y., Zhao, M., Zhao, W.L., Zhao, X., Zhao, Y.G., Zhao, Y., Zhao, Y., Zhao, Y.X., Zhao, Z., Zhao, Z.J., Zheng, D., Zheng, X.L., Zheng, X., Zhivotovsky, B., Zhong, Q., Zhou, G.Z., Zhou, G., Zhou, H., 26 Zhou, S.F., Zhou, X.J., Zhu, H., Zhu, H., Zhu, W.G., Zhu, W., Zhu, X.F., Zhu, Y., Zhuang, S.M., Zhuang, X., Ziparo, E., Zois, C.E., Zoladek, T., Zong, W.X., Zorzano, A., Zughaier, S.M., 2016. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222. Koga, H., Kaushik, S., Cuervo, A.M., 2010. Altered lipid content inhibits autophagic vesicular fusion. FASEB J 24, 3052-3065. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., Tanaka, K., 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884. of Komura, T., Sakai, Y., Honda, M., Takamura, T., Wada, T., Kaneko, S., 2013a. ER stress induced impaired TLR signaling and macrophage differentiation of human monocytes. Cell Immunol 282, 44-52. ro Komura, Y., Nikkuni, A., Hirashima, N., Uetake, T., Miyamoto, A., 2013b. Responses of pulvinar neurons reflect a subject's confidence in visual categorization. Nat Neurosci 16, 749-755. -p Korniluk, A., Koper, O., Kemona, H., Dymicka-Piekarska, V., 2017. From inflammation to cancer. Ir J Med Sci 186, 57-62. re Kovac, S., Angelova, P.R., Holmstrom, K.M., Zhang, Y., Dinkova-Kostova, A.T., Abramov, A.Y., 2015. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys ur na lP Acta 1850, 794-801. Kuballa, P., Nolte, W.M., Castoreno, A.B., Xavier, R.J., 2012. Autophagy and the immune system. Annu Rev Immunol 30, 611-646. Lee, S.H., Harold, D., Nyholt, D.R., Consortium, A.N., International Endogene, C., Genetic, Environmental Risk for Alzheimer's disease, C., Goddard, M.E., Zondervan, K.T., Williams, J., Montgomery, G.W., Wray, N.R., Visscher, P.M., 2013. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum Mol Genet 22, 832-841. Jo Levine, B., Kroemer, G., 2008. Autophagy in the pathogenesis of disease. Cell 132, 27-42. Liu, J., Liu, W., Li, R., Yang, H., 2019. Mitophagy in Parkinson's Disease: From Pathogenesis to Treatment. Cells 8. Luhr, M., Torgersen, M.L., Szalai, P., Hashim, A., Brech, A., Staerk, J., Engedal, N., 2019. The kinase PERK and the transcription factor ATF4 play distinct and essential roles in autophagy resulting from tunicamycin-induced ER stress. J Biol Chem 294, 8197-8217. Macian, F., 2019. Autophagy in T Cell Function and Aging. Front Cell Dev Biol 7, 213. 27 Madeo, F., Carmona-Gutierrez, D., Hofer, S.J., Kroemer, G., 2019. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metab 29, 592-610. Maiuri, M.C., Malik, S.A., Morselli, E., Kepp, O., Criollo, A., Mouchel, P.L., Carnuccio, R., Kroemer, G., 2009. Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8, 15711576. Margariti, A., Li, H., Chen, T., Martin, D., Vizcay-Barrena, G., Alam, S., Karamariti, E., Xiao, Q., Zampetaki, A., Zhang, Z., Wang, W., Jiang, Z., Gao, C., Ma, B., Chen, Y.G., Cockerill, G., Hu, Y., Xu, Q., Zeng, L., 2013. XBP1 mRNA splicing triggers an autophagic response in endothelial cells of through BECLIN-1 transcriptional activation. J Biol Chem 288, 859-872. Marinkovic, M., Sprung, M., Buljubasic, M., Novak, I., 2018. Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy. Oxid Med Cell Longev 2018, 8023821. ro Martinez, A., Lopez, N., Gonzalez, C., Hetz, C., 2019. Targeting of the unfolded protein response (UPR) as therapy for Parkinson's disease. Biol Cell 111, 161-168. -p Martinez-Lopez, N., Athonvarangkul, D., Singh, R., 2015. Autophagy and aging. Adv Exp Med Biol 847, 73-87. re Meares, G.P., Liu, Y., Rajbhandari, R., Qin, H., Nozell, S.E., Mobley, J.A., Corbett, J.A., Benveniste, E.N., 2014. PERK-dependent activation of JAK1 and STAT3 contributes to ur na lP endoplasmic reticulum stress-induced inflammation. Mol Cell Biol 34, 3911-3925. Merksamer, P.I., Papa, F.R., 2010. The UPR and cell fate at a glance. J Cell Sci 123, 1003-1006. Metaxakis, A., Ploumi, C., Tavernarakis, N., 2018. Autophagy in Age-Associated Neurodegeneration. Cells 7. Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., Michaud, M., Madeo, F., Tavernarakis, N., Kroemer, G., 2010. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis 1, e10. Jo Munz, C., 2016. Autophagy proteins in antigen processing for presentation on MHC molecules. Immunol Rev 272, 17-27. Nakahira, K., Haspel, J.A., Rathinam, V.A., Lee, S.J., Dolinay, T., Lam, H.C., Englert, J.A., Rabinovitch, M., Cernadas, M., Kim, H.P., Fitzgerald, K.A., Ryter, S.W., Choi, A.M., 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12, 222-230. 28 Nijholt, D.A., Nolle, A., van Haastert, E.S., Edelijn, H., Toonen, R.F., Hoozemans, J.J., Scheper, W., 2013. Unfolded protein response activates glycogen synthase kinase-3 via selective lysosomal degradation. Neurobiol Aging 34, 1759-1771. Nilsson, M.H., Iwarsson, S., 2013. Home and health in people ageing with Parkinson's disease: study protocol for a prospective longitudinal cohort survey study. BMC Neurol 13, 142. Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G.M., Apetoh, L., Perfettini, J.L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., Metivier, D., Larochette, N., van Endert, P., Ciccosanti, F., Piacentini, M., Zitvogel, L., Kroemer, G., 2007. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13, 54-61. of Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tanii, I., Yoshinaga, K., Shiosaka, S., Hammarback, J.A., Urano, F., Imaizumi, K., 2006. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26, 9220- ro 9231. Oh, J., Riek, A.E., Weng, S., Petty, M., Kim, D., Colonna, M., Cella, M., Bernal-Mizrachi, C., -p 2012. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287, 11629-11641. re Osorio, F., Tavernier, S.J., Hoffmann, E., Saeys, Y., Martens, L., Vetters, J., Delrue, I., De Rycke, R., Parthoens, E., Pouliot, P., Iwawaki, T., Janssens, S., Lambrecht, B.N., 2014. The unfolded- ur na lP protein-response sensor IRE-1alpha regulates the function of CD8alpha+ dendritic cells. Nat Immunol 15, 248-257. Panda, P.K., Mukhopadhyay, S., Das, D.N., Sinha, N., Naik, P.P., Bhutia, S.K., 2015. Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics. Semin Cell Dev Biol 39, 43-55. Pitcairn, C., Wani, W.Y., Mazzulli, J.R., 2019. Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease. Neurobiol Dis 122, 72-82. Rashid, H.O., Yadav, R.K., Kim, H.R., Chae, H.J., 2015. ER stress: Autophagy induction, inhibition and selection. Autophagy 11, 1956-1977. Jo Rodvold, J.J., Chiu, K.T., Hiramatsu, N., Nussbacher, J.K., Galimberti, V., Mahadevan, N.R., Willert, K., Lin, J.H., Zanetti, M., 2017. Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. Sci Signal 10. Romeo, M.A., Faggioni, A., Cirone, M., 2019a. Could autophagy dysregulation link neurotropic viruses to Alzheimer's disease? Neural Regen Res 14, 1503-1506. Romeo, M.A., Gilardini Montani, M.S., Falcinelli, L., Gaeta, A., Nazzari, C., Faggioni, A., Cirone, M., 2019b. HHV-6B reduces autophagy and induces ER stress in primary monocytes impairing their survival and differentiation into dendritic cells. Virus Res 273, 197757. 29 Romero-Ramirez, L., Cao, H., Nelson, D., Hammond, E., Lee, A.H., Yoshida, H., Mori, K., Glimcher, L.H., Denko, N.C., Giaccia, A.J., Le, Q.T., Koong, A.C., 2004. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64, 5943-5947. Rubinsztein, D.C., Marino, G., Kroemer, G., 2011. Autophagy and aging. Cell 146, 682-695. Sadighi Akha, A.A., 2018. Aging and the immune system: An overview. J Immunol Methods 463, 21-26. Salehi, F., Behboudi, H., Kavoosi, G., Ardestani, S.K., 2018. Oxidative DNA damage induced by ROS-modulating agents with the ability to target DNA: A comparison of the biological characteristics of citrus pectin and apple pectin. Sci Rep 8, 13902. of Santarelli, R., Gonnella, R., Di Giovenale, G., Cuomo, L., Capobianchi, A., Granato, M., Gentile, G., Faggioni, A., Cirone, M., 2014. STAT3 activation by KSHV correlates with IL-10, IL-6 and IL23 release and an autophagic block in dendritic cells. Sci Rep 4, 4241. ro Santarelli, R., Granato, M., Faggioni, A., Cirone, M., 2015. Interference with the Autophagic Process as a Viral Strategy to Escape from the Immune Control: Lesson from Gamma -p Herpesviruses. J Immunol Res 2015, 546063. Santarelli, R., Granato, M., Pentassuglia, G., Lacconi, V., Gilardini Montani, M.S., Gonnella, R., re Tafani, M., Torrisi, M.R., Faggioni, A., Cirone, M., 2016. KSHV reduces autophagy in THP-1 cells and in differentiating monocytes by decreasing CAST/calpastatin and ATG5 expression. Autophagy ur na lP 12, 2311-2325. Shang, L., Chen, S., Du, F., Li, S., Zhao, L., Wang, X., 2011. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A 108, 4788-4793. Shen, X., Zhang, L., Li, J., Li, Y., Wang, Y., Xu, Z.X., 2019. Recent Findings in the Regulation of Programmed Death Ligand 1 Expression. Front Immunol 10, 1337. Sheng, X., Nenseth, H.Z., Qu, S., Kuzu, O.F., Frahnow, T., Simon, L., Greene, S., Zeng, Q., Fazli, L., Rennie, P.S., Mills, I.G., Danielsen, H., Theis, F., Patterson, J.B., Jin, Y., Saatcioglu, F., 2019. Jo IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat Commun 10, 323. Spillantini, M.G., Schmidt, M.L., Lee, V.M., Trojanowski, J.Q., Jakes, R., Goedert, M., 1997. Alpha-synuclein in Lewy bodies. Nature 388, 839-840. Stallone, G., Infante, B., Prisciandaro, C., Grandaliano, G., 2019. mTOR and Aging: An Old Fashioned Dress. Int J Mol Sci 20. Stavoe, A.K.H., Holzbaur, E.L.F., 2019. Autophagy in Neurons. Annu Rev Cell Dev Biol 35, 477500. 30 Stranks, A.J., Hansen, A.L., Panse, I., Mortensen, M., Ferguson, D.J., Puleston, D.J., Shenderov, K., Watson, A.S., Veldhoen, M., Phadwal, K., Cerundolo, V., Simon, A.K., 2015. Autophagy Controls Acquisition of Aging Features in Macrophages. J Innate Immun 7, 375-391. Szondy, Z., Garabuczi, E., Joos, G., Tsay, G.J., Sarang, Z., 2014. Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications. Front Immunol 5, 354. Tan, B.L., Norhaizan, M.E., Liew, W.P., Sulaiman Rahman, H., 2018. Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. Front Pharmacol 9, 1162. Tang, B.L., 2016. Sirt1 and the Mitochondria. Mol Cells 39, 87-95. Uddin, M.S., Stachowiak, A., Mamun, A.A., Tzvetkov, N.T., Takeda, S., Atanasov, A.G., of Bergantin, L.B., Abdel-Daim, M.M., Stankiewicz, A.M., 2018. Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications. Front Aging Neurosci 10, 04. Valecka, J., Almeida, C.R., Su, B., Pierre, P., Gatti, E., 2018. Autophagy and MHC-restricted ro antigen presentation. Mol Immunol 99, 163-170. Vanacker, H., Vetters, J., Moudombi, L., Caux, C., Janssens, S., Michallet, M.C., 2017. Emerging -p Role of the Unfolded Protein Response in Tumor Immunosurveillance. Trends Cancer 3, 491-505. Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, re S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M.A., Biere, A.L., Curran, E., Burgess, T., Louis, J.C., Collins, F., Treanor, J., Rogers, G., Citron, M., ur na lP 1999. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741. Vernucci, E., Tomino, C., Molinari, F., Limongi, D., Aventaggiato, M., Sansone, L., Tafani, M., Russo, M.A., 2019. Mitophagy and Oxidative Stress in Cancer and Aging: Focus on Sirtuins and Nanomaterials. Oxid Med Cell Longev 2019, 6387357. Vomund, S., Schafer, A., Parnham, M.J., Brune, B., von Knethen, A., 2017. Nrf2, the Master Regulator of Anti-Oxidative Responses. Int J Mol Sci 18. Wang, J.Z., Wu, Q., Smith, A., Grundke-Iqbal, I., Iqbal, K., 1998. Tau is phosphorylated by GSK-3 Jo at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett 436, 28-34. Wang, Y., Huang, X., Cang, H., Gao, F., Yamamoto, T., Osaki, T., Yi, J., 2007. The endogenous reactive oxygen species promote NF-kappaB activation by targeting on activation of NF-kappaBinducing kinase in oral squamous carcinoma cells. Free Radic Res 41, 963-971. Wang, Y., Mandelkow, E., 2012. Degradation of tau protein by autophagy and proteasomal pathways. Biochem Soc Trans 40, 644-652. 31 Wang, Y., Martins, I., Ma, Y., Kepp, O., Galluzzi, L., Kroemer, G., 2013. Autophagy-dependent ATP release from dying cells via lysosomal exocytosis. Autophagy 9, 1624-1625. Wei, Y., Pattingre, S., Sinha, S., Bassik, M., Levine, B., 2008. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30, 678-688. White, R.R., Vijg, J., 2016. Do DNA Double-Strand Breaks Drive Aging? Mol Cell 63, 729-738. Xu, H.M., Hu, F., 2019. The role of autophagy and mitophagy in cancers. Arch Physiol Biochem, 1-9. Zhang, S.J., Rampal, R., Manshouri, T., Patel, J., Mensah, N., Kayserian, A., Hricik, T., Heguy, A., Hedvat, C., Gonen, M., Kantarjian, H., Levine, R.L., Abdel-Wahab, O., Verstovsek, S., 2012. of Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood 119, 4480-4485. Zheng, W., Xie, W., Yin, D., Luo, R., Liu, M., Guo, F., 2019. ATG5 and ATG7 induced autophagy ro interplays with UPR via PERK signaling. Cell Commun Signal 17, 42. inflammasome activation. Nature 469, 221-225. -p Zhou, R., Yazdi, A.S., Menu, P., Tschopp, J., 2011a. A role for mitochondria in NLRP3 Zhou, Z.D., Chan, C.H., Ma, Q.H., Xu, X.H., Xiao, Z.C., Tan, E.K., 2011b. The roles of amyloid Jo ur na lP disease. Cell Adh Migr 5, 280-292. re precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer 32 Figure 1. Progress of macroautophagy and CMA in youth and ageing. The reduction of macroautophagy and CMA in ageing, to which contributes the altered lipid composition of the autophagosome and lysosome membranes (indicated by different colors), leads to the accumulation of autophagosomes, unfolded proteins, damaged mitochondria and ROS that induces ER stress. YOUTH AGING Inhibition of CMA and autophagosome/lysosome fusion KFERQ KFERQ Ly Ly Functional CMA and macroautophagy N Au m m ER STRESS ro KFERK proteins (degraded through CMA) LY: lysosomes Au: autophagosomes m: mitochondria N: nucleus of Au -p Figure 1 re Figure 2. Scheme illustrating the intricate interplay between ER stress/UPR, macroautophagy, apoptosis and cell survival. In red: the UPR molecules and their interplay; in blue: some of the cell survival. ur na lP molecules affected by UPR; in black: the outcome of UPR activation on autophagy, apoptosis or ER stress ROS IRE1alfa ATF6 PERK Jo APOPTOSIS NRF2 JNK Cell survival mTOR inhibition AMPK activation eIF2alfa XBP1s BIP ATF4 MACROAUTOPHAGY ROS MACROAUTOPHAGY APOPTOSIS CHOP ROS Figure 2 33 Figure 3. The impairment of adaptive responses in ageing promotes the accumulation of aggregation-prone proteins and ROS that induces ER stress and alters cellular homeostasis, predisposing to immune dysfunction, neurodegeration and cancer. ER stress ROS IRE1alfa ATF6 PERK Cell survival JNK mTOR inhibition AMPK activation eIF2alfa XBP1s ATF4 ro BIP of NRF2 APOPTOSIS MACROAUTOPHAGY ROS MACROAUTOPHAGY APOPTOSIS CHOP -p ROS Jo ur na lP re Figure 2 34