Protein aggregation as a paradigm of aging

Biochimica et Biophysica Acta 1790 (2009) 980–996

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

Review

Protein aggregation as a paradigm of aging Ariel B. Lindner ⁎, Alice Demarez INSERM U571, Paris, F-75015, France Paris Descartes University, Paris, F-75015, France

a r t i c l e

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Article history: Received 2 February 2009 Received in revised form 8 June 2009 Accepted 9 June 2009 Available online 13 June 2009 Keywords: Chaperone Protein misfolding Protein aggregation Asymmetry Proteostasis Aging network

a b s t r a c t The process of physiological decline leading to death of the individual is driven by the deteriorating capacity to withstand extrinsic and intrinsic hazards, resulting in damage accumulation with age. The dynamic changes with time of the network governing the outcome of misfolded proteins, exemplifying as intrinsic hazards, is considered here as a paradigm of aging. The main features of the network, namely, the non-linear increase of damage and the presence of amplifying feedback loops within the system are presented through a survey of the different components of the network and related cellular processes in aging and disease. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Aging is a fundamental characteristic of all living organisms down to bacteria. Yet while we commonly apprehend aging intuitively, arguably its concise global scientific understanding is still elusive. Aging can be generally defined and understood in the dynamic context of diminished fitness of the individual, recapitulated in a decrease of reproduction rate and an eventual exponential increase in mortality with time at the population level. This can be accounted for by time-dependent deterioration of physiological parameters of the organism. While aging is an overall deterministic phenomenon that can be viewed as the surrender of the living system to thermodynamic equilibration with its environment, it is a process driven by stochastic hazards of extrinsic (e.g., accidents, predation, weather, pollution, infections…) and intrinsic (e.g., reactive oxygen species (ROS), offpathway toxic metabolites, replication, transcription and translation errors, misfolded proteins…) nature. Indeed, aging prevails even when minimizing the extrinsic contribution, as in controlled laboratory settings. Inherent to the hazards implicated in the physiology of aging is their potential capacity to self- and-cross amplify their own frequencies as well as the deleterious consequences of their ensued damages (Fig. 1). According to this view, the non-linear accumulation of different damages results in the aging of the ‘host’ organism. This stochastically-initiated non-linearity may account for the large variability in

⁎ Corresponding author. Laboratoire de Genetique Moleculaire Evolutive et Medicale, INSERM U571, Faculté de Médecine Univ. Paris Descartes, 156, Rue de Vaugirard, 75730 Paris cedex 15, France. Tel.: +33 1 4061 5348; fax: +33 1 4061 5322. E-mail address: [email protected] (A.B. Lindner). 0304-4165/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2009.06.005

aging phenotypes and life-span, independent of environmental and clonal differences. It follows that the internal environment (intracellular, tissue, organ, body) modulates the probability and extent of hazard and damage. In particular, this lays ground for evolution to devise molecular systems to keep hazards and damages at bay until at least reproduction is assured by avoidance (fidelity) and maintenance (repair). This however does not come without a cost — given limited resources, investment into minimizing damages is on account of growth and reproduction. Thus, understanding aging amounts to the quantitative study of the time evolution of the global network [1–3], consisting of hazards, damages, quality control and regulation systems (Fig. 1). This review focuses on a subset of this network that captures many of the essential features of the global network and governs one of the main molecular phenotypes associated with aging: the time-dependent accumulation of protein aggregates. We describe the network consisting of proteins and their intrinsic potential propensity to misfold, aggregate and damage, as well as the imperfect, aggravated with age, cellular strategies to avoid, repair and eliminate this damage within the context of the cellular and external environment. Though aging and longevity studies mainly focused on signaling out the contribution of individual physiological traits to the aging process (e.g., dietary restriction, oxidative stress, DNA damage, protein aggregation), these cannot be easily disentangled. Given the emergent complexity due to their non-linear co-dependence, an integrated framework should be sought for and the understanding of the interplay between protein aggregation and other aging/longevity traits is crucial. Indeed, recent work has shed light to the intricate synergy between protein homeostasis and the caloric restrictionrelated insulin/insulin-like growth factor-1 [4,5] and sirtuin [6]

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spatially neighboring side-chains and backbone interactions [15–17]. Thus, rather than an invariant resolution towards the folded ‘native’ state (through multiple possible pathways [18]), proteins may be trapped in alternative pathways, resolving into a non-functional ‘misfolded’ conformation, often resulting in insolubility. 1.2. Multiple paths from misfolding to aggregation

Fig. 1. Schematic depiction of cellular network governing aging. External and internal hazards lead to the accumulation of damage with time, resulting in fitness decrease and death. Key characteristics of the network include intra- and inter-connectivity of hazards and control mechanisms, potential positive feedback of hazards as well as cross-amplification and cross-inhibition between control mechanisms and internal hazards.

pathways in longevity and protein aggregation disease models as reviewed elsewhere [4,7]. 1.1. Multiple paths to folding and misfolding Proteins' function relies on their 3D structure, yet for a nascent polypeptide to achieve its correct fold, coded in its sequence [8], is often not trivial. A unified framework has converged in the past few years from a great body of works to close the gap between the initial view of describing protein folding as an inevitable context-independent path to its final least energy unique form and the computational paradox of the astronomically large number of possible conformers for a given polypeptide that can be scanned only within an astronomical timescale [9]. Early works focused on in vitro folding of small (up to 100 amino acids) globular proteins in dilute solutions, where a single rate-limiting transition state governs folding [10]. These works were key to present the folding problem in the context of transition state kinetics, leading to experimental and theoretical work addressing larger proteins with multiple partially folded intermediates and potential folding pathways [11]. Evolution has thus encoded in the genotype not only the final structure but also the pathways leading to it within what can be represented by a free energy landscape of rugged nature, delineated by ensembles of conformations around intermediate and ground states [12,13]. A major effort in the field is to characterize such landscapes experimentally and computationally [14]. This landscape is punctuated by transition states representing energy barriers that determine the life-time, e.g., the kinetic stability, of the flanked intermediates. The energy differences between the different conformational species is often rather small (5–10 kcal), suggesting that the unfolded polypeptide chain travels within this landscape, driven by energy minimization through stochastic sampling of different native and non-native intra-molecular interactions by structural fluctuations. Few, key interactions (mostly of hydrophobic nature) may govern the structure of the intermediate steps, followed in a cooperative manner by many small contributions of

The above-described ‘ideal’ landscape for a given isolated protein is further complexified when considering that in non-diluted solutions as in the context of the highly concentrated crowded intracellular milieu [19]. A competition there occurs between the folding-driving intra-protein and the inter-protein interactions with surrounding polypeptides' folding intermediates that may lead to oligomerization that may collapse into insoluble, aggregated forms; their thermodynamic stability is often higher than that of the native folded form [17]. Indeed, folded proteins when left long enough in solution may eventually aggregate, as many experimentalists often encountered in their aging test-tubes. Thus, the aggregation propensity of a protein relies intrinsically on its folding kinetics and lifetime of intermediates as well as on its concentration and environment. The concentration dependence of aggregation is exemplified by recent result demonstrating that aggregation propensity of a battery of human proteins, as modeled in silico and measured in vitro, is negatively correlated with their in vivo expression levels, suggesting an evolutionary tuning of protein stability with respect to their cellular concentration. A further implication is that the cellular protein quality control system (see below) has evolved to provide only a limited capacity to buffer decreasing solubility [20]. Indeed, over expression of α-synuclein as a result of the gene's loci genomic amplification is sufficient to lead to its aggregation and Parkinson's disease [21]. The environmental component is exemplified in vitro by sensitivity to pH, heat, pressure [22] and presence of co-solvents [15] that differentially shape the landscape kinetically and thermodynamically (e.g. the relative stabilities of the native, misfolded states). The interactions governing both correct folding and aggregation are of similar nature, namely, hydrophobicity and hydrogen-bonding as in secondary structure β-sheets of amyloids (see below). The evolutionary correlate is evident from structural analysis, suggesting a strong selection pressure on the protein sequence to stabilize their native folding pathway conformations in order to avoid misfolding kinetic traps. This is achieved through the presence of charged residues [23], dispersion and covering aggregation-prone β-sheet stretches within stable α-helices, flanking aggregation-prone fragments [24–27] by ‘gate-keeping’, flexible residues (e.g., glycine) [28] and conformation-breaking residues (e.g., proline) [17,29]. Whether kinetic intermediates are shared between the least-energy pathways leading to the native and the misfolded ground states or distinct from each other is currently unresolved and may be protein specific [30,31]. It is clear though that the energy landscape of individual protein (mis)folding is extended and modified by presence of other polypeptides to include the aggregation outcome [15–17]. 2. The amyloids Rather than a direct collapse, aggregation follows key intermediate steps that can be kinetically resolved [32,33], leading to aggregates that may be classed into two groups: amorphous [34] or rather ordered fibrillar amyloids of heterogeneous forms [35–39]. Scarce knowledge is available concerning the physiological outcome from amorphous aggregates from the aging perspective, though arguably they are formed and may accumulate in all cells. Most studies were focused on unicellular over-expression systems that often result in such inclusion bodies [40]. Though the effect of ‘amorphous’ aggregates on aging is not as spectacular as of amyloids, they were associated to aging in the E. coli bacteria [41] and yeast [42–44] (see below). In contrast, much

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more is known about amyloid aggregation (appearing in forms of plaques or tangles) as they are is associated with numerous diseases, many of which are age-related [23] (box 1, Fig. 2). The focus on age-related folding diseases is not only driven by the economic burden on developed societies and the optimistic projection of huge populations from developing countries to increase their lifespan and therefore be potentially afflicted by these diseases but also by the personal agony of facing diseased people around us. Given the inherent universality of protein folding and conservation of the involved machineries throughout the tree of life, many facets of amyloid diseases can be captured in animal models spanning from yeast [45] through nematodes [46] and fruit flies [47] to rodents [48] by mere expression of the human amyloid-aggregation prone proteins, including amyloid deposits, neuronal, muscle and lens degeneration as well as dementia and increased mortality. These models are key not only to better understanding of the disease at hand but to shed light on the genetic networks and physiological conditions governing protein homeostasis in vivo (Figs. 3, 4). The amyloid structure is characterized by ensembles of ordered polypeptides with β-sheets organized perpendicularly to the fibril axes [15,49]. The amyloid form is not only the misfortune of a limited disease-related proteins; it was proven in vitro to be a potential generic outcome for any protein, irrespective of its native structure, providing the right environmental condition (e.g., pH, heat, pressure and presence of co-solvents [15]). In disease related amyloids, mutations were isolated that increase both the aggregation propensity and toxicity as well as reduce the disease onset and organism's lifespan (polyglutamine (PolyQ) expansions as example, see Box 1). In addition, it is now appreciated that many proteins are naturally intrinsically disordered [50–52], suggesting a very shallow native landscape where such proteins need not unfold to be prone to aggregation. These include several of the disease-associated amyloids

(e.g., α-synuclein, Tau proteins, islet amyloid peptide and the Aβ amyloid [23,53]; Box 1). Importantly, a rugged folding landscape may explain as well how structural globular proteins can aggregate under native conditions. Protein conformations that are rather similar to the ground state native structure, yet energetically disfavored and therefore sparsely populated, may play an intermediate role by funneling native proteins to irreversible aggregations [15]. On the other hand, such conformations may encompass alternative substrate specificities [54] and activities (often referred to as ‘moonlighting’ or ‘promiscuous’) that could serve as jumping boards for the evolution of new functionalities [55]. 3. Soluble prefibrillar aggregates as intrinsic hazard linked to aging Much evidence suggests that accumulation of amyloid aggregation and deposits is age-related yet not necessarily disease-related [56]. In cell cultures, expression of aggregated-prone proteins leads to cell death, yet the presence of visualized insoluble aggregates (PolyQderived aggregates, present in Huntington disease [57], Parkinson disease related α-synuclein insoluble aggregates [58,59]) is poorly correlated with death. Rather, presence of aggregates seems to correlate with cellular survival [57,60,61] leading to the hypothesis that aggregation may be protective. In addition, inclusion bodies are prevalent in Huntington disease within the cortex whereas the most severe degeneration occurs in the striatum [62]. Furthermore, comparison of amyloid beta plaques in post mortem aged humans shows weak correlation between Alzheimer disease severity and plaque density [59]. Indeed, recent phase I trials of immunization of Alzheimer patients suggest that while treatment resulted in clearance of Aβ extracellular plaques, it did not prevent the disease progressive neurodegeneration [63]. While this may be due to treatment of

Fig. 2. Age-related misfolding diseases. Mean age at disease onset and extreme values for genetically-driven (red) and sporadic diseases (blue). References: Alzheimer [335], Parkinson [336,337], Spongiform encephalopathies [338], Frontotemporal dementia with Parkinsonism: [339], Huntingtin [340], Hereditary dentatorubral-pallidoluysian atrophy [341], Spinocerebellar ataxias [342], Familial British dementia [343], AL amyloidosis [344], Dementia with Lewy bodies [345].

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Fig. 3. Protein network in aging and aggregation. This protein interaction map was realized on the basis of automated semantic data-mining and graphic representation (Ali Baba freeware, Humboldt-Universität, Berlin), querying the 200 most recent research articles in PubMed database with “aging AND (aggregation OR misfolding)”. Isolated and generic (e.g., ‘kinase’) terms were manually deleted, relevant missing edges were added (b 5% of links), followed by isolating and color coding the emerged groups. The resulted network represents well current knowledge in the area. Given the exponential expansion of scientific literature, advancements in semantic data-mining are key to our scientific apprehension.

advanced disease [64], it may also indicate that the plaques are downstream of the cause of disease. This initial frustration had lead researchers to probe in detail the amyloid formation pathway, suggesting fibrillation follows distinct intermediate oligomeric states [23,32]. In particular, small soluble oligomeric spherical prefibrillar assemblies of 2–10 monomers were identified, their assembly into protofibrils may be the potential source of aggregate toxicity [65].

Such soluble oligomeric intermediates can be detected both in vitro [15], in vivo within model organisms [66] as well as in diseased patients [67]. Structural studies suggest that these intermediates are partially unstructured yet present some cross β-sheet motifs and show different assembly structures (as beads, string of beads or in annular form probably by folding of the string) and pathways [33,39,68–71]. These protofibrils serve as nucleation centers for the

Fig. 4. Contribution of model organisms to the understanding of age-related amyloid diseases. Different components of proteostasis associated to the diseases as emerged from Human subjects and derived cell-lines (pink), Mammalian (blue) and Other models (e.g., in vitro, yeast, vertebrates; green), ordered within each block by relative publication date (manual PubMed data-mining). A feedback emerges lending credence to pursue biomedical research with model systems: preliminary phenotype identification in patients followed by extensive research in model organisms, resulting in the identification of new factors. PTM — post-transcriptional modifications.

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formation of mature protofilaments that constitute the amyloid fibrils [15,72] in a dynamical manner where unit molecules dissociate and re-associate frequently [73]. Such nucleation process is reminiscent to crystallization nucleation [74] and follows similar kinetics, namely long lag followed by fast auto-catalytic increase of fibril size [23,75]. The discovery of protofibril-specific, sequence-independent antibodies that inhibit further aggregation and toxicity [76–78] suggest that these intermediates, sharing no apparent sequence, charge nor amino acid profile, share common detailed structure. Indeed, cellular toxicity can be induced by prefibrillar but not mature fibrils from diseaseunrelated polypeptides (e.g., bacterial HipF and SH3 domain fragments) in tissue culture and animal models [79,80]. Thus, while folding and to a large extent misfolding is largely sequencedetermined, the aggregation process and associated toxicity are partially blind to the detailed sequence [81]. Thus, misfolded proteins may induce the co-aggregation of other proteins, not only into ‘amorphous’ aggregated bodies but to some extent into structured fibrils in vitro (down to 30% homology within immunoglobulin domains [82]) as well as in vivo [83]. Indeed, numerous cases were recorded of seizing heterologous proteins within amyloid aggregates (e.g., Ataxin and Huntingtin [84] Synuclein and Tau, Synphilin-1 [85], Huntingtin and mTor [86]). Such amplification may result in cooccurrence of two distinct diseases as Alzheimer and ALS [87] or Parkinson [88,89]. The hypothesis that protofibril intermediates, rather than the mature fibrils, are the main toxic element leading to downstream cellular degeneration. is well-supported by numerous data as reviewed for Alzheimer's and Parkinson's diseases [90]. For instance, a series of papers demonstrated that dimer to tetrameric prefibrillar intermediates, isolated from human cerebral cortex and cerebrospinal fluid [91–93] as well synthetic Aβ protofibrils [94] (or Aβ diffusible ligands [95]) can recapture key disease manifestations in model animals. Furthermore, in silico predictions of protofibrillar aggregation propensities of Aβ42 synthetic mutants, meet their measured aggregation in vitro and correlate with their pathogenic effect when expressed in Drosophila, in terms of decreased locomotion and lifespan [96]. Similar indications concerning other cases (e.g. Parkinson's disease [97–99], Huntington's disease [60,100], type II diabetes [101], model amyloid — bacterial HypF [102]) resulted in the dogma shift of presenting kinetic intermediates of the fibril formation as key to understanding aggregation toxicity. Interestingly, as the formation of prefibrillar or protofibrillar intermediates may be reversible, they may be involved in other diseases where matured aggregation in forms of inclusion bodies, plaques or fibrils are not detected. 4. Age-related damage by protein aggregates Toxic aggregate intermediate hazards may lead to the propagation of damage in either a direct or indirect manner. The latter includes sequestering other proteins to the aggregate, eliminating key cellular functions (e.g., the cAMP response element binding (CREB)-binding protein (CBP) by polyQ [84]) or by inhibiting the cell's protein quality control network members (see below). In an early work, soluble aggregates of Aβ amyloids in a mouse mode correlated with neuroendocrine dysfunction, impairment of stress response and regulation of blood glucose levels [103], suggesting disruption of signaling pathways and cross-talk between multiple aging phenotypes. In another damaging venue, the association of polyQ Huntingtin fragments to mitochondria increases with age in knock-in mice, disrupting mitochondria transport and resulting in decreased ATP production [104] and increased oxidative stress (as shown with numerous amyloidoses in tissue culture [105]. Evidence to direct toxicity includes membrane integration and depolarization [106], damaging neuronal signaling and triggering apoptosis [107]. Importantly, permeabilizing mitochondria leads to burst of reactive oxidative species (ROS) [105] that can lead to damage amplification

by destabilizing proteins and increase their aggregation (see below). The permeabilization mechanism is still under debate; formation of channels was evoked [108,109] though often challenged [107]. Specific damage to neuronal cells in the different diseases includes induction of hippocampal synapse requiring NMDA-type glutamate receptor activity by Aβ dimer and trimer oligomers [66,67,92], depressing synaptic function and integrity [110], and inhibition of hippocampal long-term potentiation [111,112]. In yet another example of neuronal damage, Synuclein soluble accumulation correlates with gradual loss of dopamine caused by a decrease of its synthesis rate-limiting tyrosine hydroxylase levels. The dopamine loss is accelerated when Synuclein levels pass a threshold and aggregate due to induced damaged lysosomal activity [113]. 5. The protein quality control network Within the cellular physiological context, protein folding is rarely achieved autonomously. Not only does the nascent polypeptide chain arising from the ribosome needs to be held by auxiliary proteins [114] to reach its translation end, many proteins (20%–30% [115]) may never reach their folding state without assistance, resulting mostly in rapid degradation [116]. An adaptive network of universally conserved functions, commonly referred to as the protein quality control (PQC) [117], has evolved to maintain the cellular protein homeostasis [118] (or ‘proteostasis’ [119]), through maximizing cellular protein folding capacity (by the chaperone system), minimizing intrinsic and extrinsic protein assaults and degradation of misfolded proteins (by proteases, the ubiquitin–proteosome system (UPS), and lysosome) (Fig. 5). 6. Chaperones: controlling protein folding fidelity and repair Chaperones [120,121] evolved to assist in folding proteins and their maintenance in the native form. The chaperones do not serve as template or code for their substrates' structures but help to avoid or reverse unproductive, non-functional conformations [122]. They constitute a significant fraction of cellular proteins yet can also be induced by different proteotoxic stress conditions [123] of which heat-shock (for which they are named ‘heat shock proteins’ or ‘hsp’) serves as a paradigm [124]. The chaperone expression is controlled, both in prokaryotes and eukaryotes by specific transcription factors (TF) (RpoH [125] and HSF (heat shock factor) variants [126], respectively), whereby under native conditions the TF are held as monomers by chaperones away from their chromosomal targets, resulting in basal transcription level of their downstream targets. In the presence of misfolding stress, the heat-shock response (or unfolded protein response (UPR) in the ER), is induced by the rapid presence of unfolded proteins that titrate the chaperones, releasing the TF to trimerize, translocate to the nucleus and induce chaperones expression [127]. Chaperones overlap in their substrate profile and act together and in synergy within the chaperone network [128] and with other PQC systems as the proteosome and lysosomal degradation pathways (see below). Further cross-talk with other cellular networks (as the insulinlike signaling (ILS) and sirtuin pathways) provide further control within the context of the organism's well-being [4,7]. Importantly, there is difference in chaperone profile within cellular organelles and among cellular lineages, resulting in differences in handling misfolded protein stress. For example, extended PolyQ polypeptides form readily amyloid aggregates in eukaryotic cytoplasm yet fail to do so in mitochondria or the endoplasmic reticulum [129]. Furthermore, within the brain, chaperone expression differs between cell types [123]. 7. The HSP chaperones The different chaperones are divided into different families, classified both by size and partially differentiated yet concerted actions ([130–133]):

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Fig. 5. Protein folding and aggregation cellular network. Schematic depiction of the interactions between the protein components of the PQC and the folding/misfolding of cellular proteins. Hatched — rate modulation; Solid — direct concentration modulation.

The small hsp (sHSP) of molecular mass b43 kDa have the capacity to maintain the solubility of partially unfolded proteins through binding by protecting their exposed hydrophobic surface [134,135]. They can be found bound either to individual polypeptides as well as within formed misfolded oligomers and aggregates (hence named inclusion body proteins or Ibp in prokaryotes [136]). Evidence suggests that sHSP destabilizes the aggregates, facilitating their solubilisation and refolding (or degradation), mediated by Hsp70/40 and Hsp104 chaperones [137–139]. The sHSP are organized within large dynamic oligomeric structures, maintained through a conserved α-crystalline domain which function is not yet clarified. It was hypothesized that the oligomeric state is a ‘resting state’ providing sHSP stabilization (themselves prone to aggregation) and that this structure is dismantled with heat, providing active subunits, possibly as dimers [140]. Within the sHSP, the Hsp33 chaperones provide an example for the interplay between oxidative and misfolding stresses. It is only in the presence of the two stresses that the chaperone is activated [141]. The hsp60 chaperones are constructed from two stacked 7-mer rings, facilitating protein folding in an isolated cavity (referred to as the ‘Anfinsen cage’ [122]). Structural studies revealed that the inner surface of the Hsp60 (together with its cap protein Hsp10) cavity is hydrophobic in the substrate binding state and changes to a hydrophilic surface when the folded product is released through an allosteric conformational change mediated by ATP hydrolysis [142]. In eukaryotes such chaperones are present in the mitochondria, whereas a second, cytosolic class has no identified Hsp10 partner [143]. The Hsp70 chaperones [144,145] are cytosolic and, in eukaryotes, exist as well within organelles as the endoplasmic reticulum and mitochondria. Together with numerous co-factors (N40 in humans), Hsp70s take part in multiple tasks including folding of nascent polypeptides and their assembly, refolding of misfolded proteins, membrane translocation of proteins targeted for organelles and secretion as well as controlling the function and life-time of regulatory and signaling proteins. These multiple goals are achieved through ATP-driven cycles of substrate binding and release mediated by a battery of co-chaperones (e.g. Hsp40 family [146]) and factors effecting its nucleotide exchange rate (e.g., GrpE [147] and Bag-1 family proteins [148]). Co-factors also mediate the delivery of misfolded proteins after hsp70 unfolding to proteosome degradation (e.g. Bag-1 and ubiquitin ligase CHIP [149]; see below). Other factors

(e.g. Hop) may couple Hsp70 to the Hsp90 family and modulate their activity [150]. Rather than caging their substrate, the Hsp70 proteins interact mainly with short, around 7 amino-acid, hydrophobic regions that are statistically well-represented within proteins [143]. The ATP-dependent Hsp90 family [151], shares similar functions to Hsp70 to prevent non-specific aggregation of generic proteins. Hsp90 can mediate conformational changes of folded proteins, leading not only to their stabilization but also to their activation or degradation. Furthermore, together with it numerous co-factors, Hsp90 preferentially interacts more specifically with ‘client’ proteins, many of which in higher eukaryotes are involved in signal transduction (e.g. tyrosine kinases and hormone receptors), linking it in mammals to play a role in carcinogenesis [152]. However Hsp90 has many pleiotropic effects, as emerge through systematic screening approaches, including participation in cell cycle, meiosis, transport, secretion and chromatin remodeling, epigenetic gene regulation and viral replication [153– 155]. Moreover, Hsp90 (and to some extent Hsp70) is considered a genetic capacitor by buffering sequence variability through stabilization of native structure. Upon stress, or in absence of the capacitor, new phenotypes emerge that can, in high frequency, yield selective evolutionary advantages [156–158]. Finally, unlike the latter chaperone families, the Hsp104 proteins, members of the AAA+ (ATPase Associated with diverse Activities) family, are not abundant yet are highly induced upon external stress and confer strong resistance to it [159]. Furthermore, rather than prevention of misfolding, its main function may be disaggregation [160]. Hsp104 is sought to bind disaggregated oligomers and in synergy with Hsp70/Hsp40 and, at least in some cases sHSP, restore native structure and function or direct the disaggregated proteins to degradation [137,138]. Curiously, hsp104 was lost in recent evolution and it remains to be seen whether other proteins confer this unique function in metazoans. The Hsp104 mechanism has not been completely deciphered yet it involves ATP-dependent passage of the polypeptide through a pore within the Hsp104 twotiered ring-shape hexamer [161]. Earlier results showing bacterial (ClpB) and yeast Hsp104 mediated disaggregation has been recently coupled to observations suggesting that Hsp104 can mediate the disaggregation of amyloids by preferentially acting on aggregation intermediates in vitro (Aβ Amyloid prefibrillar oligomers, protofibrils [162]) as well as in vivo in rat model of Parkinson disease [163].

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8. Chaperone network age-linked phenotypes Numerous studies recorded a general decrease in stress responsiveness of the chaperone system as well as diminished activity of members of the chaperone system with age [164]. Studies of aged hepatocytes and fibroblasts suggest that the HSF1 transcription activity but not its protein levels decrease with age [164–166]. In addition, decreased heat-shock responsiveness in brain tissue with age was observed (rabbits [167] rats [168]). Importantly, a direct effect of HSF1 levels on longevity was shown in nematodes where decreased expression resulted in faster mortality whereas its over-expression yielded a significant increase in longevity [169], acting synergistically with the daf-16 longevity pathway, and accompanied by delay in polyQ aggregation onset [5]. The mechanism governing the decrease in HSF1 activity with age is still unknown though clues may arise from recent findings on novel factors that control its activity [168,170]. Measurement of relative specific chaperone activity in elders as compared to young individuals suggest a decrease of Hsp70 chaperone activity in retina (human and rhesus monkeys, [171]) and in myocardial tissue after exercise [172] and, along with Hsp90, in hepatocytes of rats [173,174]. Decreased Hsp70 activity was also observed in lymphoblasts of aged humans but not of centenarian subjects [175]. Other examples include the amyloid aggregation and concomitant decrease of activity of the sHSP α-crystallin in aged cataractous eye lens [176–178] and of αB-crystallin in mouse Alzheimer model [179]. The decreased chaperone activity may be assigned to their overload by increasing levels of misfolded proteins with age [3] — an amplifying loop where initial causality cannot be easily discerned. While it was shown by fluorescent microscopy that Hsp70-YFP fusion is not sequestered by CFP-tagged polyQ aggregates in tissue culture model system [180] though it does interact with diffusible polyQ polypeptides, it may be that chaperones are kinetically sequestered away from their native substrates. Further reasoning includes inhibitory post-translational modifications as oxidation, glycation (see below), rendering the chaperones ‘sick’ with time [164]. Chaperone activity decrease may have pronounced effects on cellular networks' robustness and impair the organism's adaptation capacity [3]. A correlate suggests that over-expression of chaperones will diminish the accumulation and toxicity of protein aggregates and may increase longevity. Indeed, numerous studies in neurodegenerative disease models of yeast [181,182], worms [183], fruit flies [184] and mice [185] demonstrate suppression of disease upon increasing chaperone levels [186]. The direct association of chaperones to aging is discerned from experimental systems permitting the tuning of their expression levels either by mild stress or over-expression. As example, ubiquitous or targeted expression of HSP22 in motor neurons mitochondria, increases the lifespan and the resistance to oxidative stress and heat shock in D.melanogaster [187]; inversely decreased lifespan is observed in absence of this sHSP [188]. However, increase in hsp70 copy number, though having a protective effect against heat stress did not effect significantly the fruit fly's lifespan [189] Earlier results of over-expression of Hsp70 in D.melanogaster derived cellular cultures [190] and animals [191] suggest a deleterious effect and decreased lifespan, possibly as a result of accumulation of Hsp70 as insoluble aggregates. These results and the fact that chaperones govern the function and lifetime numerous physiologically essential proteins suggest that chaperone homeostasis is critical to the organism's well being. Yet, tuning the stress response by “hormesis” — mild punctual [192,193] or repeated heat shock [194,195] appears to be beneficial both in providing stress tolerance and increased longevity in many experimental systems including nematodes, fruit flies, mice and human-derived cell-lines [196]. Similar hormesis was recorded using other stresses as dietary restriction [197], in support of the interplay between proteostasis and lifespan controlling networks [198]. Indeed, potentially, hormesis inducing drugs, as well as such

that can upregulate the QPC are currently validated in animal and human trials [119]. 9. Peptidyl-Prolyl Isomerases (PPI) and Protein Disulfide Isomerase (PDI) role in age-related protein aggregation On top of the HSP chaperones, two classes of enzymes exist to catalyze key rate-limiting steps that ensure proteins' proper folding and stability: prolyl isomerization by the Peptidyl-Prolyl Isomerases (PPI) and cystine formation by Protein Disulfide Isomerase (PDI). Prolyl residues in proteins may exist with either trans or cis peptide bond conformations of similar energetic stability. Specific prolyl residues within native protein structures adopt a specific isomer and as the intrinsic isomerization rate is slow, enzymes (PPI) were evolved for its amplification. Moreover, specific PPI can interact with already folded proteins, leading to possible control of their conformation and therefore function [199]. For the Pin1 PPI, specific Ser/Thr-pro phosphorylation pattern is recognized on the substrate. As the activity of Ser/Thr kinases is highly dependent on the prolyl isomer, Pin1 plays a direct role in controlling large spectra of activities, including stress responses, cellular development and growth regulation, immune response, neuronal differentiation and survival [199]. Its antiaggregation activity is exemplified in its protective role in Alzheimer [200,201]. Indeed, Pin1 knock-out mice develop Alzheimer-like cognitive, motor and aggregation pathological symptoms [202]. Disulfide bonds, covalently linking cysteine thiol side-chains within proteins through their oxidation, play a major role in the latter's folding and stabilization [203]. Such oxidative folding takes place in confined organelles (e.g., the endoplasmic reticulum (ER), bacterial periplasm), protected from the cytoplasmic reducing environment. It is catalyzed by the PDI enzymes that ensure correct cysteine coupling and phasing of their formation with the folding process [204]. PDI, together with the hsp class chaperones are induced upon unfolding stress as part of the UPR [205]. Perturbation of the redox potential in the ER as well as negative modulation of the UPR results therefore in accumulation of misfolded, aggregated proteins. As example, PDI plays a role in attenuation of neuronal cell death triggered by misfolded proteins and its inhibition by nitrosylation (see below) results in higher neurotoxicity, as observed in sporadic Parkinson and Alzheimer diseased brains [206]. 10. Proteolytic clearance of misfolded proteins Despite the elaborative work of the chaperone system, many proteins never reach their native stable form and are degraded [116]. Cellular protein catabolic systems evolved not only to carefully tune the life-time of cellular proteins, exerting control on all essential cellular functions (e.g., transcription, cell cycle and apoptosis, antigen processing [207,208]) but also to ensure the proteostasis quality by elimination of non-functional, potentially toxic proteins [209]. Two major pathways, the ubiquitin–proteosome system and autophagy– lysosome systems that govern protein degradation in eukaryotes are described below. A third system of proteolysis, the calpain Ca2+activated cystein proteases is implicated in aging, with reports of increased activity [210–212] as well as decreased activity [213] with age, suggesting that deregulation of calpains is deleterious to maintenance of proteostasis and that the effects may be context, tissue dependent. 11. The ubiquitin–proteosome system (UPS) The (UPS) provides the cell with selective degradation of proteins, governing their lifetime and disposing of damaged proteins. Indeed, aggregation is enhanced when the UPS is impaired or inhibited [209,214]. The UPS is not limited to cytosolic proteins, but may handle compartmentalized proteins as ER-misfolded proteins through the

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ability to export such proteins back to cytosol (ER associated degradation (ERAD) [215]). The 26S proteosome is made of 50 protein subunits arranged to form a core, barrel-shaped 20S particle, encompassing a hollow channel where proteolysis takes place. Different subunit compositions of the proteosome exist, modulating specific functions. In the human proteosome, two active sites with distinct substrate specificities (e.g., chymotrypsin-, trypsin-like, activities) reside within the channel to digest unfolded proteins into small, 9–12mer peptides. The associated 19S particle facilitates, through extensive ATPase activity, the substrate recognition and ‘holding’ and translocation of the unfolded proteins into the 20S core [216]. An intricate control system drives proteins selectively to proteosome degradation by ATP-driven covalent attachment of multiple ubiquitin (a small 9 kDa peptide) units, mediated by numerous ubiquitin-activating (E1) and -carrier proteins (E2) as well as -ligases (E3) [217]. Energy consuming proteolysis, though not evident from a thermodynamic viewpoint, occurs universally also in absence of UPS within prokaryotes and mitochondria, their proteases' activity and structure often resembles that of chaperones (e.g., the Lon, ClpP, FtsH and HslUV proteases [218]), suggesting a common ancestor and a selective pressure to efficiently control and degrade aberrant proteins. Essentially, the function of different UPS factors is directly linked to proteotoxicity and lifespan (as shown for the 19S subunit homologue [219] and E3 ligase [220] in nematode studies). A strong link exists between the chaperone and the UPS systems [221]. The UPS relies on the ability to maintain misfolded proteins in a soluble form to facilitate their degradation and thus depends at least in part on the chaperone machinery. As example, CHIP functions both as an Hsp70 co-factor and as ubiquitin-ligase, demonstrating the tight interaction between the folding and degradation pathways [149]. Indeed, CHIP knock-out mice exhibit accumulation of toxic oligomeric aggregates and decreased longevity [222]. The orchestrated build-up of the proteosome machinery is chaperone-dependent [223], revealing another level of networking within the PQC. A close link exists as well between the UPS and the lysosomal degradation system (see below). The crucial role of the UPS in aging is reflected by the identification of specific neurodegenerative-prone mutations [224]. In addition, many studies correlated decreased proteosomal activity with age and related diseases [225–229]. Examples include cultured cells (senescence [230]), eye lens (cataract [231]), muscle (sporadic inclusionbody myositis [232]), epidermis (‘photoaging’ [233]), heart tissue (aging, [234], arteriosclerosis [235]) spinal cord [236] and the brain (neurodegenerative diseases [237]). This age-related proteosomal activity reduction with frequent concurrent accumulation of ubiquinylated and SUMOilated proteins may be due to accumulation of posttranslational damaged targeted proteins lending them difficult to digest (see below). Furthermore, proteosome reactivity towards some polypeptides as the Huntington-related long polyQ stretches may be impaired [238,239], leading to their age-related accumulation as toxic aggregates [240] due to entrapment of essential ERAD proteins by the Huntingtin polyQ aggregation [241]. Indeed, proteosomes' activity decline may be mainly due to their sequestration by the accumulated burden of misfolded protein compounds [242] as was observed in many age-related diseases (e.g., Alzheimer's [243] and Parkinson's [244] diseases). A complementary hypothesis of a ‘misfolding trap’ was recently put forward, suggesting that, transient binding of amyloid oligomers to folding intermediates of ‘normal’ newly synthesized proteins may lead to their ubiquitinylation and degradation, disrupting cellular proteostasis by loss of control of protein's life time [245]. 12. The autophagy–lysosome system As discussed above, misfolded proteins can collapse into an insoluble form and co-aggregate, either due to faster kinetics or failure of the chaperone system. Another line of defense is provided by

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lysosomal autophagy [246,247]. In parallel to its role in regulation of cell-death and in elimination of dysfunctional organelles (e.g., mitochondria, peroxisomes) and pathogens, autophagy contributes to proteostasis through multiple pathways [248,249]. Macroautophagy, coordinated by multiple autophagy-related gene (ATG), eliminates bulk accumulation of aggregates (aggrosomes; see below) through engulfment and fusion with the resulting vacuoles. Furthermore, through stress-triggered chaperone-mediated autophagy (CMA), specific individual proteins containing a consensus aminoacid motif are delivered to the lysosome for degradation [250]. Lysosomes have in addition the capacity of engulfing small cytosolic portions to uptake and degrade proteins (microautophagy [251]). Ubiquitinylation plays a role in autophagy where E1, E2 and E3-like proteins are part of the Atg proteins that mediate membrane expansion and engulfment, suggesting a close cross-talk between the UPS and lysosomal degradation pathways [249,252]. As in the above described proteostasis-maintaining systems, the lysosomal system exhibits a general decrease of reactivity with age [246]. As was shown recently, this diminution can be reversed transgenically in rodents by modulating the expression of the LAMP-2A CMA receptor [253]. Lysosomal autophagy failure results in aggregate accumulation linked to age diseases as manifested in the case of Parkinson's [254], Alzheimer's diseases [255], polyQ aggregates [256] and neurodegeneration in mice models [257,258]. A further link between UPS and autophagy has been made recently by demonstrating that Parkin (an E3 phosphorylation-modulated ubiquitin ligase of which loss-offunction mutations are causally related to Parkinson's disease) associates to damaged mitochondria and mediates their removal by lysosomal autophagy. Under disease (or perhaps aging) conditions, this may lead to accumulation of defected mitochondria, resulting in further amplification of damage by spread of reactive oxygen species (see below) [259]. 13. Intrinsic hazards Within the global scenario of proteostasis: protein folding and aggregation landscapes modulated by the quality control system as detailed above, lay the details of individual proteins, each with its specific folding/aggregation landscape shaped by its genotype (sequence) and environment. The former may be subjected to mutations that can result in destabilization of the native form and promote aggregation. Such aggregation-prone mutations are closely linked to age-related misfolding diseases (as examples [260–264]). Moreover, limited by their fidelity, transcriptional [265–267] and translational [268,269] error rates (10− 5–10− 6 and 10− 3–10− 4 per codon, respectively) suggest that up to 20% of the synthesized proteins may be mistranslated [270] and be prone to aggregation [271]. Even silent mutations (where nucleotide replacement does not change the codon amino acid coupling), may influence protein's folding, probably by affecting its balanced translation and folding rates [272,273]. Importantly, proteins' natural amino-acids, some of which are inherently unstable (e.g., aspartyl and arginyl residues) may undergo spontaneous isomerization [274], racemization (e.g., aspartyl; debatable role in Aβ amyloid aggregation [275,276] as well as seryl, threonyl, and tyrosyl residues) and aspargine and glutamine deamidation (e.g., triggering cataract-associated crystallin aggregation [277]). These modifications further amplify the effect of inherent, replication, transcription and translation mutations. Moreover in vivo, proteins encounter molecular, covalent assaults that change as well their surface topology and charge that influence their misfolding propensity. These effects are exacerbated by the fact that folding intermediates by nature expose more residues to the bulk and are thus more sensitive to modifications that in turn can canalize the modified polypeptide to misfolding pathways by stabilization of the aggregated ground state, the intermediates leading to it or by destabilizing the native ground state. Yet again, mutations at all levels that result in

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destabilizing the folded state or increase the life time of intermediates will increase the chances of further post-modification and therefore of misfolding [278], accumulation of toxic intermediates and ground state aggregate inclusions. Indeed, the sensitivity of folding intermediates to modification can be harnessed by researchers to study folding dynamics by use of highly reactive modifiers and mass spectroscopy ([279]). Post-translation modifications that increase misfolding propensity and aggregation accumulation with age (and related diseases) include oxidative adducts generated by reactive oxygen and nitrosyl species (ROS [280] and RNS [281]) that escape the cellular capacity to eradicate them as well as by metabolic, e.g. advanced glycation end (AGE) products, lipid aldehydes (advanced lipid peroxidation end (ALE) products, and cholesterol abducts as examples [282–284]) generated by ROS. AGE-related cross-linked proteins, further modified by free radicals may be the source of the 19th century described accumulation of age pigments (also referred to as lipofuscin or ceroid [228]). Given its abundance and facilitated detection by derivation and antibody detection, protein carbonylation by metal-mediated oxidation by hydroxy radicals (Fenton reaction [285]) is a hallmark of the interplay between oxidative damage, protein aggregation and damage accumulation with age as is widely documented in all studied species from bacteria [286] and yeast [42,44] to humans where carbonylation and aggregation was documented for the SOD1 major antioxidant enzyme, further amplifying the damage [287]. Only some of these modifications can be reversed by specialized enzymes, linking their function to age-related aggregation and disease, as methionine sulfoxide reductase (yeast aging [288], Parkinson's disease [289]) and iso-aspartate methyltransferase (Alzheimer's disease [274]). Indeed methionine, one of the most oxidation-sensitive amino-acid, is oxidized into both R- and Sstereoisomers of methionine sulfoxide (MetO). Methionine sulfoxide reductase A and B (MsrA/B) are reducing those sulfoxides and therefore serve as ROS scavengers. Numerous studies show an effect of the MsrA/B expression on age relative oxidative stress and longevity; an over expression of MsrA in flies leads to an increase in longevity [290] whereas knock-out mice show a decrease in longevity [291]. Moreover it was shown that MsrA is involved in protection of dopaminergic cells against Parkinson's disease insults [292]. Accumulation of damaged proteins increases the burden on the quality control system and lowers its capacity to maintain proteostasis in native and stressed conditions. As example, cross-linked AGE proteins resist proteosome degradation [226] and impair autophagy [293], leading to accumulation of corrupt mitochondria that can further ensue ROS-mediated aggregation and damage. Furthermore, QPC members themselves are prone to such modifications [43] (and perhaps even more sensitive to them due to their exposed activityspecific residues surfaces [118]). This in turn results in a vicious damage accumulation cascade and disease. As example, S-nitrosylation of PDI [206], Parkin (E3 ligase) and of Uch-L1(PARK5; Ubiquitin terminal hydrolase L1) are associated with Parkinson's disease [281]. In another intertwined example, in Alzheimer's disease, oxidative stress promotes kinase-mediated hyper-phosphorylation of the Tao protein and formation of tangled amyloids. Indeed, a kinase inhibitor prevents both Tao hyper-phosphorylation and motor impairment in mouse model [294]. In turn, Tao tangles result in increase of oxidative stress leading to an auto-catalytic process [295,296]. 14. Extrinsic hazards Environmental factors may as well promote aggregation and agerelated neurodegenerative disease [262]. Reports include the role of heavy metals as iron and zinc (either through their catalytic role in oxidation or directly in promoting misfolding [297]) and prenatal exposure to lead effecting disease onset age [298]. The possible associative role of inorganic mercury, present in dental cavity

amalgam, in Alzheimer's disease is under controversy [299]. Pesticides (rotenone and paraquat [300]) and inhalation of illegal drugs contaminant (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [301] are associated with Parkinson's disease. Perhaps the most striking evidence for an environmental involvement in misfolding disease is exemplified by a recent study of an Iceland-specific hereditary amyloid angiopathy, caused by a single mutation in the cystatin C gene, leading to its amyloid deposition, intracerebral hemorrhage, dementia and differing levels of paralysis. Noteworthy, wild-type cystatin C is found within Aβ amyloid Alzheimer's plaques and its locus is associated to susceptibility to the disease's sporadic form. Tracing back the mutation-carriers' lineages to the 19th century suggests that this disease could have been considered as an agingrelated amyloid disease, with mean lifespan of 65 years. Albeit at present, the mean lifespan is reduced to 31 [302], unexplainable by accumulation of other mutations within two generations. This adds to the notion of age-related misfolding disease as “cultural diseases”, that prevail in modern, medically-developed societies where the population reaches abundantly the diseases' onset age [303]. 15. Localisation and sequestration of misfolded and aggregated proteins As was discussed earlier, while some oligomeric aggregation intermediates can be toxic, their retention to large, stable aggregates may be protective and may mediate their clearance (as in autophagy). Microscopy studies identified protein inclusions within eukaryotic cells as autophagy-related vacuoles [304], aggrosomes [34], ERassociated compartments [305] and as co-existence of porous and dense inclusions [306], to name a few. Yet, how they are formed, regulated and whether these different observations relate to similar compartments, to different kinetic steps in aggregate accumulation and processing or rather point to functional disparity has remained largely unclear. A recent study, addressing the localisation and outcome of different aggregate-prone proteins in yeast and mammalian cells, sheds new light to this matter [307]. Two compartments, distinct in their cellular localisation, content and function, were identified. The first, ‘juxtanuclear quality control’ (‘JUNQ’) compartment retains mostly cytosolic ubiquinylated misfolded proteins that are at least partially soluble (as concluded by the possibility of proteins to diffuse/exit away) and is characterized by strong presence of proteosomes. The second perivacular compartment, designated as ‘insoluble protein deposit’ (or IPOD), appears after prolonged expression of non-amyloid aggregated proteins or upon expression of amyloid-prone proteins (yeast prion Ure2 and polyQ expanded Huntingtin protein), consists of non-diffusible, mostly aggregated proteins. As in previous observations, the formation of these compartments is microtubules-dependent; their disruption by a specific drug results in multiple small foci throughout the cytosol. It is therefore tempting to assume that JUNQ compartment deals with reversible refolding and degradation by chaperones and proteosomes whereas the IPOD structure sequesters aggregated proteins in a protective manner, possibly further processed by membrane engulfment and lysosomal autophagy. Further studies should shed light on the link between these observations and previously described inclusions, on whether differential chaperone content, sorting machinery exist, on the activity of microtubules in their assembly, on what maintains the boundary of the compartments, and on their presence and in vivo significance to aggregate processing in health and disease. 16. Asymmetric division of aggregates and aging Most of the data linking protein aggregation to aging are derived from observations in post-mitotic, non-dividing cells as in neurons and mature multi-cellular organisms as the fruit-fly and nematode. In

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dividing cells, protein aggregates are diluted through cellular growth and division and thus their aging-related phenotype may depend on the balance between their accumulation and dilution. Furthermore, the accumulation of misfolded proteins into small number of inclusions, suggests that their asymmetric division within progeny will result at the rejuvenation of part of the progeny, devoid of aggregates, at the expense of aging of an aggregate-carrying fraction of the progeny. In this context, unicellular organisms are relevant experimental models to understand the role of protein aggregation in aging of dividing cells. Indeed, recent studies in yeast [42–44] and bacteria [41] demonstrated that protein inclusions are not only divided asymmetrically but do so in a deterministic fashion, where the mother cell retains the aggregates to give rise to aggregate-free, rejuvenated daughter cells. The asymmetrically dividing yeast, Saccharomyces cerevisiae, is the first unicellular organism where aging was observed as mother cells give rise to limited number of small daughter buds before senescing [308]. A well-documented molecular asymmetry underlying yeast aging is the accumulation of extrachromosomal rDNA circles in mother cells [309]. More recently, protein aggregates (identified immunocytochemically by targeting protein carbonylation and aggregate-associated Hsp104-gfp fusion), were shown to accumulate preferentially in mother cells though ROS levels were similar in progenitor and daughter cells [42,43]. An active mechanism was implied, dependent on the actin cytoskeleton and the lifespanassociated Sir2p (NAD (nicotinamide adenine dinucleotide)-dependent histone deacetylase)). Sir2p deletion resulted in elevated carbonylation levels (with preference to chaperones), disruption of asymmetry and decreased lifespan. These phenotypes could be reversed by over-expression of Hsp104, suggesting that chaperones play a role in aggregate assembly and asymmetric segregation that is in turn crucial to minimize aging [43]. Further work with the Schizosaccharomyces pombe yeast demonstrated that uneven accumulation of carbonylated aggregates, results in cells with high damage content associated with longer generation time and accelerated aging [44]. Interestingly, in the asymmetrically dividing bacteria, Caulobacter crescentus, the abundance of heat-shock proteins involved in disaggregation (e.g., Lon and DnaK) is biased towards the aging [310] stalked cell [311]. Aging has been observed in apparent symmetric division bacteria as Escherichia coli [312] and Bacillus subtilis [313]. In these bacteria, the two apparently identical offspring cells can be distinguished by the age (in divisions) of their poles. Recording individual growth rate of each individual cell within a microcolony in homogenous and controlled environment demonstrated that cells inheriting the old pole exhibit diminished growth rates, decreased offspring production, and increased incidence of death [312]. Importantly, asymmetric segregation of protein aggregates (detected in vivo through the association of fluorescent protein-tagged sHSP chaperone (IbpA [136])) was observed, resulting in their accumulation within the old pole volume of aged bacteria. The measurement of cellular fitness (e.g., their growth rate) and, in parallel, of aggregation levels lead to the conclusion that up to 40% of the aging phenotype can be attributed to the presence of protein aggregates [41]. A passive process may drive E. coli's misfolded protein accumulation into inclusions, suggesting that this primordial route of segregation was harnessed to evolve the active mechanism present in eukaryotes. Indeed, modeling approaches generally suggest that asymmetric segregation of damage is potentially beneficial and can thus be evolved [44,314–316]. An open question remains, whether the aggregate load per se is responsible to the associated aging or whether the asymmetric presence of such insoluble aggregates reflects a concurrent bias of soluble toxic aggregates or a linkage to yet another unknown phenotype. While bacterial aggregates (inclusion bodies) were often considered ‘amorphous’, recent results suggest that at least when over-expressing heterologous amyloid-prone peptides [317,318] or

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globular proteins [319], amyloids are formed. It remains to be seen whether under unstressed ‘native’ conditions, bacterial aggregates, over-represented in senescent (non cultivable) bacterial cells [320] are of amyloid nature, yet the above results support the importance of studying aging and protein aggregation in bacteria. Evidence to asymmetry in damaged proteins segregation was established in higher eukaryotic dividing cells when expressing expanded Huntingtin in human embryonic kidney or hamster celllines cell lines. In addition, the polarized asymmetric inheritance of aggrosomes in Drosophila melanogaster neuronal precursor cells as well as in epithelial crypts of ataxia type 3 patients was reported. In the latter, no polyQ aggregates where found in putative stem cells although numbers of aggregates was strikingly high in the tissue, suggesting that stem cells are protected against aggregation. This result is compatible with the hypothesis that aggregate proteins are asymmetrically segregated in order to protect stem cells from damages proteins [321]. Interestingly, in mitotic division, thought to result in two identical cells, proteins targeted for degradation are preferentially inherited by one of the resulting somatic cells [322]. These accumulating results suggest that asymmetry may play a major role in proteostasis, in correspondence to its manifestations in many other cellular processes [323]. 17. Converging abstraction, modeling and quantification The main features of the proteostasis network documented in this review (Fig. 5), namely the non-linear increase of misfolded protein hazard probability, the presence of amplification loops within the system (as the capacity of misfolded proteins to self-amplify, inhibit the control systems and induce damage) can be further abstracted as a representative paradigm of the aging process (Fig. 6). In this framework, perceiving aging is synonymous to the understanding of the dynamic changes through time of such basic network, leading from a life supporting system to increased hazard, damage accumulation and death. Given the high variability in expression levels of the PQC members and stochastic nature of the aging process several predictions were made within the network framework. For instance, it was hypothesized that variability in chaperone expression can lead to bistability, underlying the non-linear transition to fast damage accumulation state [324]. In another venue, it was suggested that the pleiotropic nature of chaperone low affinity connectivity

Fig. 6. Aging as time-dependent change of global network dynamics.

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(common feature of proteins associated with senescence [325]), may play a critical role whereby their susceptibility to hazard and diminished activity with aging increases cellular ‘noise’ and deteriorates the coupling within the network, leading to increased damage and system's disintegration (“weak link theory of aging” [3]). Computational modeling of both abstract and specific network dynamics [324,326] in context of cellular dynamics (as asymmetric inheritance of damage upon division) may yield predictions that could then be tested experimentally. Indeed, the acquired qualitative molecular knowledge of the proteostasis network components and interactions forms the necessary basis to pursue the understanding of aging. To this end, the in vivo quantification of the network interactions kinetics and their change in time remains is critical and defines the major challenge that lies ahead. This amounts to parameterize the arrows (as those in Fig. 5) and deciphering the rules governing their change with time (Fig. 6). Recent advances in quantitative platforms as microscopy, microfluidics and proteomics can now support such “in vivo Biochemistry” approach. Studies of short-lived organisms amenable to fast genetic manipulations, can now couple controlled perturbations within defined environment with quantitative measures of network members' concentration and activities through time. Whether protein misfolding will emerge as a major causative factor of aging remains to be seen yet through such studies, key contributors to aging can be discerned [327]. The ground is set for merging predictive modeling and quantitative experimentation, suggesting near future breakthroughs in our understanding of aging.

Box-1. Age-related misfolding diseases Perhaps the most pronounced role of protein aggregations in aging is manifested by their association to cellular degeneracy in many age-related diseases [23] (Fig. 2). Key examples, mostly afflicting the central nervous systems, but also muscular tissues and eyes' lens are briefly described below. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with around seventeen million patients worldwide [328]. The disease symptoms include memory loss and/or dementia. Physiologically, AD is characterized by extracellular amyloid plaques deposition of the proteolitically derived short (40 and 42 amino acid forms) amyloid-beta (Aβ) protein in neurites and cerebral blood vessels. The 42-long isomer has a much higher aggregation propensity and its presence is correlated to disease. The other physiological marker of AD is presence of intracellular hallmark neurofibrillary tangles in neuron and glial cells. These inclusions are composed of hyperphosphorylated tau proteins (a microtubule-associated protein), assembled in paired helical filaments, twisted ribbons or straight filament. Sporadic PD represents 95% of the cases, but mutations leading to development of the disease are described and lead to a decrease in the mean age at onset of 77 years in familial AD and 82 years in sporadic cases [260,329]. Parkinson's disease (PD) is the second most common neurodegenerative disease. PD is the general name given to diseases having the same symptoms; loss of motor control associated with tremors, muscle rigidity, bradykinesia (slowness in movement), cognitive impairment and dementia. These syndromes are correlated with the presence of amyloid Lewy bodies and Lewy neurites. The major protein forming these abnormal amyloid fibrils is α-synuclein, a highly conserved protein expressed mainly in nervous tissues and

particularly in presynaptic terminals. Its function is still uncertain but it may play a role in synaptic dynamics and particularly in regulation of dopamine transmission and vesicular recycling [90]. Many mutations as α-synuclein duplication or triplication or in the parkin gene coding for an E3 ubiquitin ligase, have been identified to lead to hereditary PD with autosomal dominant or recessive inheritance [261]. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder affecting the brain. HD is characterized by movement disorder, chorea, and behavioral changes. This disease is caused by the extension of the polyQ domain at the N-Terminal of the Huntingtin protein (Htt), leading to its amyloid stable aggregation. The numbers of CAG repeat range from 11 to 35 in healthy people and from 30 to N70 repeats in patients [330]. The onset age of the disease is strongly correlated with the number of repeats but most onsets take place between the ages of 30 and 40 years [331]. HD represents one of the known polyQ diseases; others include spinobulbar muscular atrophy and spinocerebellar ataxia. Creutzfeldt–Jakob disease (CDJ) is a rare and fatal neurodegenerative disease causing degeneration in the brain and spinal cord, leading to psychiatric disorders like depression, schizophrenia and dementia. CJD is a prion protein disease characterized by a transmissible spongiform encephalopathy caused by an accumulation and amyloid aggregation of abnormal isoforms of prion protein (PrP), a membrane glycosylphosphatidylinositol-anchored glycoprotein. Sporadic cases of CDJ represent the majority of occurrences, joint by familial (mutation in the prion protein gene), and transmissible (cannibalism, ingestion of contaminated animal, or medical errors) cases [332]. Aged lens: cataract and presbyopia. Decrease in sight ability is one of the common characteristics of aging. Presbyopia affects almost all humans by the age of 50. An increase in the stiffness of aging lenses has been observed and correlated with a decrease in free soluble α-crystallin. α-crystallin is the most abundant protein in the lens, around 40% of the protein content, and belongs to the family of the small heat-shock chaperones [333]. A cataract is a decrease in transparency of the cornea due to formation of stable amyloid fibrils by the crystalline [231]. Cataracts can be caused by mutations, environmental factors, as exposure to UV, or in relation to other diseases (e.g., diabetes and hypertension). Sporadic inclusion-body myositis (s-IMB) the most abundant muscle disease associated with aging. S-IMB is an inflammatory myopathy. This disease is characterized by a T-cell inflammatory infiltration, cytotoxic necrosis and the presence of congophilic inclusions containing among others, Aβ and phosphorylated tau as well as other proteins [334].

Acknowledgements We wish to thank the former and present members of our group and in particular G. Paul, M. Ni, E.J. Stewart, M. Radman, and F. Taddei for numerous and enriching discussions that provided the framework to this review. Our work on aging is funded by grants from the French National Research Agency (ANR), HFSP and the Axa Foundation. References [1] T.B. Kirkwood, A. Kowald, Network theory of aging, Exp. Gerontol. 32 (1997) 395–399.

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