Aging as an Event of Proteostasis Collapse Rebecca C. Taylor and Andrew Dillin
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Abstract Aging cells accumulate damaged and misfolded proteins through a functional decline in their protein homeostasis (proteostasis) machinery, leading to reduced cellular viability and the development of protein misfolding diseases such as Alzheimer’s and Huntington’s. Metabolic signaling pathways that regulate the aging process, mediated by insulin/IGF-1 signaling, dietary restriction, and reduced mitochondrial function, can modulate the proteostasis machinery in many ways to maintain a youthful proteome for longer and prevent the onset of age-associated diseases. These mechanisms therefore represent potential therapeutic targets in the prevention and treatment of such pathologies.
Go to: PATHWAYS THAT INFLUENCE THE AGING PROCESS Aging was once regarded as a stochastic, progressive decline. However, the discovery of metabolic pathways able to modulate the aging process has challenged this view. Three main signaling pathways have been identified that can influence the rate of aging (Fig. 1) (Wolff and Dillin 2006). The first, dietary restriction (DR) has been shown to extend lifespan in multiple species (Mair and Dillin 2008). The reduction of dietary intake below unlimited or “ad libitum” levels causes an increase in lifespan, to an optimum point of consumption, typically around 60% of ad libitum food intake. However, although this extension of lifespan by DR has been observed for several decades, its mechanistic basis remains unclear. Evidence suggests that the amino-acid-sensing serine/threonine kinase mTOR, and the energy status-dependent kinase AMPK, are involved in DR signaling (Kapahi and Zid 2004; Kahn et al. 2005). In addition, recent studies in Caenorhabditis elegans have suggested that two transcription factors, PHA-4 and SKN-1, are essential for this process, and act specifically in lifespan extension by DR (Panowski et al. 2007; Bishop and Guarente 2007).
An external file that holds a picture, illustration, etc. Object name is cshperspect-PRT-004440_F1.jpg Figure 1. Pathways that regulate aging. The insulin-signaling pathway and dietary restriction pathway induce longevity through mechanisms that are at least partially understood. Reduced mitochondrial function also increases lifespan, but the signaling components are not clear.
Another pathway mediating lifespan extension, the insulin/IGF-1-like signaling pathway (IIS), has been remarkably well characterized in recent years. Reduced IIS activity extends lifespan in both invertebrate and vertebrate species (Bartke 2008). The role of the IIS system in aging was first identified in C. elegans, and it has been best characterized in that species (Panowski and Dillin, 2008). Following ligand binding, the C. elegans IIS receptor DAF-2 recruits the insulin receptor substrate homolog IST-1, and the PI3K AGE-1 (Wolkow and Ruvkun 2002; Morris et al. 1996). Production of PI3 through AGE-1 activity, opposed by the phosphatase DAF-18, activates AKT kinases, which phosphorylate the transcription factor DAF-16 (Hertweck et al. 2004; Paradis and Ruvkun 1998; Ogg and Ruvkun 1998; Henderson and Johnson 2001; Lee et al. 2001; Lin et al. 2001). Phosphorylation anchors DAF-16 in the cytosol through interaction with 14-3-3 proteins, whereas reduced IIS activity allows it to enter the nucleus, activating a diverse transcriptional profile that promotes extended lifespan (Lin et al. 1997; Ogg et al. 1997; Cahill et al. 2001). DAF-16 is also regulated by mechanisms other than localization, and requires cofactors such as SMK-1, HCF-1, and SIR-2 for extension of longevity (Wolff et al. 2006; Tissenbaum and Guarente 2001). At least one other transcription factor, the heat shock factor HSF-1, is also required for the IIS pathway to extend lifespan, although how the pathway regulates this transcription factor is unclear (Hsu et al. 2003). In addition, in turn, the IIS pathway also regulates localization of the SKN-1 transcription factor that is essential for the long lifespan of DR animals (Tullet et al. 2008).
The third pathway enabling extension of lifespan acts through reduction in the activity of the mitochondrial electron transport chain (ETC). This was first shown, again, in C. elegans, in which reduced expression of several mitochondrial genes including components of ETC complexes I, III, IV, and V by RNAi is sufficient to extend lifespan (Feng et al. 2001; Dillin et al. 2002b; Lee et al. 2003). The role of mitochondria in lifespan has since been shown in Drosophila and rodents (Liu et al. 2005; Copeland et al. 2009). However, the mechanisms and signaling pathways involved remain unknown.
Several lines of evidence suggest that these lifespan extension pathways are separate. For one, genetic epistasis experiments show that combining different lifespan extension pathways leads to additive increases in lifespan (Dillin et al. 2002b; Lakowski and Hekimi 1998). Additionally, temporal requirements for the pathways are different, reduction of IIS or DR has important lifespan extension effects in adulthood, whereas the mitochondrial pathway acts during development (Dillin et al. 2002a; Dillin et al. 2002b; Mair et al. 2003), and the core components act separately. DAF-16 is dispensable for DR-induced lifespan extension, whereas PHA-4 plays a role specifically in DR and not the IIS and ETC pathways (Lakowski and Hekimi 1998; Panowski et al. 2007).
Go to: THE IMPORTANCE OF PROTEOSTASIS IN AGING Although these lifespan extension pathways act independently, it is logical to hypothesize that their underlying downstream mechanisms might be the same. The phenotypes of long-lived animals overlap substantially, including increased stress resistance, altered metabolism, and delayed reproduction and development (Hekimi and Guarente 2003). One possibility is that a major downstream function of all these aging pathways is to change the way that the cellular proteome is maintained. Cellular proteins are challenged throughout life by a multitude of factors that cause protein misfolding and aggregation, including translational error, the presence of polymorphisms, and stresses that lead to covalent modifications such as oxidation. Misfolded proteins can have a range of negative consequences for the cell. Mutated and destabilized proteins with hydrophobic regions inappropriately exposed tend to aggregate with the hydrophobic regions of other proteins, and these protein aggregates can be directly cytotoxic, through disruption of membranes and interaction with cellular components (Chiti et al. 2003; Stefani and Dobson 2003). They may also create increased demands on the cell’s protein homeostasis (proteostasis) machinery, titrating away components of this network and consequently leading to further misfolding of other proteins. The consequences of even a low level of misfolded protein in the cell can be catastrophic—the expression of a metastable or misfolded protein in organismal models of proteotoxic stress has been shown to destabilize other, unrelated proteins in the proteome (Gidalevitz et al. 2006; Gidalevitz et al. 2009).
The importance of preventing protein misfolding has been shown in evolutionary terms in a model of molecular evolution, studying synonymous codon substitutions (Drummond and Wilke 2008). Translational inaccuracy is a major source of mutation, missense errors in translation are believed to occur once every 103–104 codons, suggesting that around 18% of translated proteins will contain an error, and some codons are translated more accurately than others. Mutation in turn leads to higher levels of protein misfolding and aggregation. The model found that the avoidance of translational error through the selection of the most accurately translated codons, driven by the negative consequences of misfolded mutant proteins, was sufficient to account for observed rates of codon evolution. Consistent with this hypothesis, the most conserved proteins are not those most essential for viability, but the ones expressed at the highest rate, and therefore the most damaging if mistranslated. Proteins expressed in long-lived postmitotic cells, in which the formation of misfolded proteins has the most potential to do harm, were also extremely slow evolving. The fact that the avoidance of protein misfolding seems to have been such a driving force in evolution indicates in turn the danger that protein misfolding presents to the cell.
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