JoJoramar As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans. Similarly, soluble levels of the ribosomal chaperone NAC also decline by day three of adulthood due to sequestration by protein aggregates [ 13 ]. Early changes in stress response pathways: Many studies of aging have focused on molecular changes across the lifetime of an organism with the reasonable assumption that a series of progressive events collectively contribute to the aging process. Proteostasisa portmanteau of the words protein and homeostasisis the concept that there are competing and integrated biological pathways within cells that control the biogenesisfolding, trafficking and degradation of proteins present within and outside the cell.

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Download as PowerPoint Slide Figure 2. The life cycle of a protein. After synthesis, proteins require correct folding and trafficking to the correct cellular location. Pathways that regulate aging can modulate many aspects of proteostasis, through transcription factors such as DAF and HSF-1, and effector molecules such as the kinase mTOR.

The implication is that a loss of function of the proteostasis machinery occurs with age, and recent studies have supported this hypothesis. The causes of age-associated decline in proteostasis capacity are still largely unclear, but there is mounting evidence that aging pathways can directly modulate elements of the proteostasis machinery to extend healthy lifespan Fig.

Given this connection between proteome maintenance and the aging process, understanding how pathways that can regulate aging affect the proteostasis machinery is necessary in gaining an understanding of how to increase healthy lifespan.

It is this intersection between pathways that modulate aging, and protein homeostasis, that will be discussed in the rest of this review. Control of translation rate is generally achieved at two stages of translation initiation—the recruitment of the 40S ribosomal subunit, and the loading of this subunit with the initiator tRNA Gebauer and Hentze Phosphorylation of 4EBP-1 dissociates it from the translation initiation complex, whereas phosphorylation of S6K activates this kinase, allowing it to phosphorylate translational targets that include ribosomal protein S6 and the elongation factor 2 kinase.

Both events promote translation, and conversely, reduction of mTOR activity by DR decreases translation initiation. Indeed, reducing translation rates alone is sufficient to extend lifespan.

In yeast, deletion or inhibition of ribosomal protein levels increases replicative lifespan Chiocchetti et al. In addition, in C. Additionally, reduction of the worm homologs of translation initiation factors eIF4E ife-2 , eIF-4G ifg-1 , eIF-2B iftb-1 , and a range of ribosomal proteins, increases lifespan, whereas ifg-1 is reduced in long-lived dauers Hansen et al.

Initiation factor knockdown may be dependent on DAF to increase lifespan, whereas ribosomal proteins and S6K are independent of DAF, suggesting a complicated relationship between IIS and the control of translation. In addition, lifespan extension by translational inhibition and DR or mTOR reduction are additive, suggesting that these signaling pathways also invoke other mechanisms to extend lifespan Hansen et al.

It seems that reduction in translation is an important mechanism in the extension of lifespan. What therefore underlies this mechanistic importance? One explanation might be that reduced protein synthesis reduces the load on the remainder of the proteostasis machinery, allowing more efficient protein folding and degradation, for example, and consequently reducing the load of misfolded and damaged proteins.

This is substantiated by the observation that reducing translation rates renders cells tolerant to elevated temperature, a stress that causes protein misfolding Hansen et al. Reducing translation also causes preferential translation of certain mRNAs. DR in flies allows preferential translation of mitochondrial genes, including components of complexes I and IV, dependent on 4EBP1 and therefore reduced translation.

This altered translational profile enhances mitochondrial activity and facilitates lifespan extension Zid et al. In yeast, deletion of 60S ribosomal subunits increases lifespan through the preferential translation of the GCN4 transcription factor, inducing a transcriptional profile necessary for full lifespan extension by DR Steffen et al.

And finally, recent work suggests that reduced IIS may increase intrinsic thermotolerance and lifespan through preferential translation of specific transcripts McColl et al. They require assistance, provided in the form of molecular chaperones, and this assisted protein folding is crucial to maintaining protein homeostasis Morimoto The binding of chaperones to nascent polypeptides both prevents folding into inappropriate forms, and facilitates the assembly of the correct structure.

This assembly involves the stabilization of folding-competent intermediate states, and can also involve active ATP-driven folding into the native form, accomplished by the HSP70 family of chaperones Buckau et al.

In the case of proteins that have formed unwanted and potentially toxic aggregates, some chaperones, such as HSP, are able to disassemble these aggregates into intermediate forms that can then be assisted in refolding to the native state.

On the other hand, at high concentrations of aggregative proteins, HSP, TRiC, and potentially other chaperones, can actively aggregate these toxic species into less toxic types of aggregates Behrends et al. Chaperones represent many of the transcriptional targets of the C. Heat shock proteins are in fact required for full lifespan extension in daf-2 mutants, and over-expression of HSP is sufficient to extend lifespan in both wild type and long-lived mutant worms Murphy et al.

Expression of small heat shock proteins is also sufficient to extend lifespan in Drosophila Morrow et al. This suggests that the ability to correctly fold proteins is important in maintaining youthful cells, and is a target of lifespan extension pathways.

Introduction of a new, folding-sensitive protein to cells can result in a subsequent destabilization and decreased folding of the rest of the proteome, suggesting that normal chaperone capacity can be easily exceeded by increases in demand Gidalevitz et al. Many stresses perturb protein folding, necessitating a dramatic up-regulation of chaperones and other proteostasis components if cells are to survive this challenge to their proteome.

The responses to different cellular stresses are coordinated by upstream transcription factors that respond to distinct stimuli, and several of these stress responses have been implicated in aging and the extension of longevity Morimoto In turn, over-expression of HSF-1 enhances the folding of aggregative proteins, and can extend lifespan, as can administration of a sublethal dose of heat shock in both C.

The heat shock response therefore seems to form an important component of lifespan extension pathways, and without the HSR, animals age at an accelerated rate. The ability to induce the HSR declines with age and this appears to be a relatively early event in the aging process, occurring shortly after the reproductive period in C.

The mechanisms underlying the loss of the response are unclear, but it seems likely that losing the ability to induce the HSR and therefore cope with increases in protein misfolding might underlie deterioration associated with aging.

Under conditions of normoxia, prolyl hydroxylases hydroxylate HIF1 at specific proline residues. In hypoxia HIF1 is not targeted for degradation and is able to activate a transcriptional program required for survival in low oxygen conditions.

Recent data suggests that HIF-1 plays a role in regulating longevity in C. The picture, however, is confusing. Although one report has suggested that increasing active HIF-1 by knockdown of its negative regulator VHL-1 increases lifespan, independent of other lifespan extension pathways, another report suggests the opposite—that null mutations in HIF-1 increase lifespan, in a manner not additive to the lifespan extension observed in S6K mutants, suggesting that it lies downstream of the TOR pathway Mehta et al.

The discrepancies might be explained by technical differences between the studies, including the different temperatures at which the lifespan assays were performed. In addition, a third study found that both HIF-1 over-expression, and hif-1 loss of function mutations, extend lifespan, through different pathways Zhang et al. Therefore, although the HIF-1 hypoxia pathway seems to influence lifespan, the nature of this influence and it is interaction with aging pathways is not understood, and may lie in a complex interaction between hypoxia, nutrient availability, and temperature.

The endoplasmic reticulum ER maintains a set of chaperones to guide the folding of secreted and membrane proteins. In addition, the ER has its own stress response, enabling the organelle to cope with increased flux, for example during development or in cell types with heavy secretory loads, or during stresses such as heat shock that increase protein misfolding Schroder and Kaufman It was recently shown that in C.

It seems likely, therefore, that the UPR might also play an important role in aging and lifespan extension. Indeed, recent findings suggest that in C. It will be interesting to explore further the roles that this stress response pathway plays in longevity.

Although it is currently unclear whether the protein trafficking machinery changes with age, there is evidence that components of this machinery are crucial to the lifespan extension induced by reductions in IIS activity. In a study of genes required for daf-2 mediated lifespan extension, a large number of the genes identified were involved in endolysosomal trafficking and vesicle membrane fusion, including subunits of the HOPS and ESCRT complexes Samuelson et al.

Knockdown of most of these genes alter vesicular trafficking. Genes acting in the fusion of vesicles with lysosomes appeared to function within the IIS pathway, whereas other genes functioned in parallel, but converging with the IIS system. Interestingly, inactivation of some of the genes affecting vesicle-lysosome fusion also prevented the up-regulation of a known DAF target, SOD-3, suggesting that these genes might influence IIS signaling itself.

Trafficking to the lysosome therefore seems important in maintaining a youthful proteome. This may reflect the importance of being able to degrade misfolded secreted or membrane proteins through endosomal uptake, maturation and fusion with the lysosome.

These results are also interesting in light of the importance of the autophagy pathway in lifespan extension, discussed below. To remove and recycle these terminally altered proteins, the cell has pathways that mediate protein degradation. Both pathways have been implicated in the aging process. There have been three main types of autophagy characterized thus far.

In chaperone-mediated autophagy, specific proteins are recognized by chaperones and delivered to the lysosome, where they bind to the lysosomal LAMP2A receptor and are translocated into the lysosome for degradation.

Microautophagy is a poorly characterized process, involving the engulfment of regions of the cytosol by the lysosomal membrane itself. Macroautophagy, the most studied form of autophagy, involves the formation of a novel membrane that encloses cytosol, damaged proteins, and sometimes organelles, to form an autophagic vesicle that then fuses with the lysosome. The best characterized of these processes in the context of aging is macroautophagy. It has been known for some time that in older cells, lysosome function and autophagy decrease Vittorini et al.

It is not entirely clear what underlies this decrease. Studies in fly neurons have shown a decline in levels of several autophagy proteins with age Simonsen et al. In addition, mammalian studies have indicated a decreased ability to clear autophagosomes, and to respond to hormonal autophagy cues, in older cells Terman ; Brunk and Terman ; Donati et al.

The interactions between macroautophagy and aging pathways have been largely elucidated in C. Macroautophagy is necessary for both lifespan extension and formation of the long-lived dauer life cycle stage in daf-2 IIS mutants, and large numbers of autophagosomes are observed in the cells of these animals Melendez et al. This autophagy is independent of the DAF transcription factor, however, and given that DAF is essential for lifespan extension in this model, this suggests that increased autophagy is not sufficient for lifespan extension Hansen et al.

Worms subjected to DR have higher rates of protein turnover, reduced levels of oxidatively damaged proteins, and larger numbers of autophagosomes. The inhibition of mTOR under low nutrient conditions also results in enhanced autophagy, and this autophagy is required for the longevity of animals with reduced mTOR activity Hansen et al. The role of macroautophagy in lifespan regulation is not specific to C.

Perhaps the most persuasive indication of the importance of macroautophagy in aging has been the increased longevity seen folowing application of autophagy-inducing drugs. The application of rapamycin, a natural inhibitor of mTOR, to mice at a relatively late age days significantly increased longevity Harrison et al.

In a study of many different potentially lifespan-extending agents, using large cohorts of mice, this was the only one with such a profound effect on lifespan. In addition, a separate study has shown that treatment with spermidine, a polyamine the cellular levels of which decrease during aging, increases longevity of yeast, worms, flies, and human immune cells, and this enhanced longevity is dependent on the induction of autophagy Eisenberg et al.

Finally, chaperone-mediated autophagy CMA has also proven to be important in the aging process. Rates of CMA decrease with age, because of decreased levels of the lysosomal LAMP-2A receptor through impaired transit to the lysosomal membrane, and reduced receptor activation Cuervo and Dice ; Kiffin et al.

Rescue of LAMP-2A levels in mouse livers at 10 months old, the age at which LAMP-2A levels begin to decline, maintains youthful liver function in these animals, with an increased ability to respond to stress-induced damage Zhang and Cuervo An interesting aspect of this study was that the function of other aspects of the quality control machinery, including macroautophagy and the ubiquitin-proteasome system, were also improved, suggesting that the repair of individual elements of the proteostasis machinery could have indirect effects in preserving other components.

The effects of aging on proteasome activity, however, are only just becoming clear. Conflicting reports have previously suggested that proteasome activity is increased, decreased, or constant with increasing age Carrard et al. These studies have been complicated by tissue-specific differences, and a comprehensive look at proteasome activity with age in different tissues has been lacking.

A new tool in C. Using a photoconvertible fluorescent moiety, Dendra 2, conjugated to a mutant form of ubiquitin, Hamer et al. This line of research seems likely to contribute substantially to understanding the effects of age on UPS activity. The ubiquitin-proteasome degradation pathway also interacts directly with aging signaling pathways through the targeting of their components for degradation by specific E3 ligases. Mutations in rle-1 result in lifespan extension, dependent on an increase in DAF protein levels.

In addition, another C. The effect of age-dependent changes in UPS activity on signaling within these pathways might therefore represent an interesting area for future research.


Aging as an event of proteostasis collapse



Aging as an Event of Proteostasis Collapse



Aging as an event of proteostasis collapse.


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