Aging is a complex process. Studies involving a single-celled organism called budding yeast are commonly used to investigate the factors that contribute to aging. When these yeast cells divide, a small daughter cell buds out from a large mother cell. A mother cell has a limited lifespan and produces a finite number of daughter cells and then dies (a phenomenon referred to ‘replicative aging’). However, when a daughter cell forms, the daughter's age is reset to zero, giving it the full potential to produce new offspring.

Previous research on budding yeast has shown that damaged or aggregated proteins accumulate in the mother cells but not the daughter cells, and that this accumulation of proteins contributes to shortening the lifespan of the mother cell. Furthermore, protein aggregation has also been associated with a number of age-related diseases in humans, including neurodegenerative disorders such as Alzheimer's and Parkinson's disease. However, it remains unclear how cells respond to protein aggregation that occurs during aging.

Many studies that have previously investigated this question have relied on exposing cells to stressful conditions, such as high temperatures, in order to trigger proteins to aggregate. But now, Saarikangas and Barral have studied how proteins aggregate under normal, unstressed conditions in budding yeast as they age. The experiments revealed that most unstressed yeast cells develop a single deposit of aggregated proteins already during early aging. This age-associated structure proved to be a different type of response than the protein aggregation that occurs during stress.

Furthermore, the deposit did not form as a consequence of the cell having obvious problems with folding its proteins, nor did the deposit hinder cells from coping with stressful conditions that trigger protein misfolding. Rather, this deposit supported the ability of the cell to degrade defective proteins. This suggests that the deposit represents an early adaptive response to aging, which might consequently provide aged cells some advantage over their younger counterparts.

Saarikangas and Barral also found that this protein deposit was always retained in the mother cell and not passed onto the daughters at cell division. Further experiments showed that an enzyme called heat shock protein 42 was responsible for collecting target proteins and bring them together to form the single deposit. Reducing the levels of this enzyme prevented the deposit from forming and extended the lifespan of the mother cells. Thus, these findings suggest that mother cells collect harmful protein aggregates into a single deposit and prevent them from entering the daughter cells. Further work is needed to understand how the deposit is preferentially retained within the mother cell.

Aging results in an increasing decline of the organism's fitness over time (Lopez-Otin et al., 2013). Remarkably, this process segregates asymmetrically during budding yeast division: the mother cell forms an aging lineage, whereas the daughters generated by these mothers rejuvenate to form eternal lineages, similar to the segregation of soma and germ lineages in metazoans. Such lineage separation requires that the inheritance of factors that promote aging, such as defective/deleterious organelles, proteins, and DNA, is asymmetric during cell division (Sinclair and Guarente, 1997; Aguilaniu et al., 2003; Erjavec et al., 2007; Henderson and Gottschling, 2008; Shcheprova et al., 2008; Liu et al., 2010; Zhou et al., 2011; Hughes and Gottschling, 2012; Higuchi et al., 2013; Clay et al., 2014; Denoth Lippuner et al., 2014; Henderson et al., 2014; Higuchi-Sanabria et al., 2014; Thayer et al., 2014; Katajisto et al., 2015). Therefore, how cells are able to recognize, sort, and coordinate the asymmetric segregation of aging factors and other fate determinants is an outstanding question in biology (Neumuller and Knoblich, 2009).

Protein aggregates and/or damaged proteins are a hallmark in the etiology of many human disorders associated with aging (Hartl et al., 2011; Wolff et al., 2014), and their presence correlates with aging of mitotically active yeast and drosophila stem cells (Aguilaniu et al., 2003; Erjavec et al., 2007; Bufalino et al., 2013; Coelho et al., 2013). Studies on budding yeast have shown a correlation between the accumulation of protein aggregates and replicative aging by demonstrating that Hsp104-mediated protein disaggregation is required for full replicative life span (Erjavec et al., 2007), and that over-expression of Mca1, which counteracts the formation of stress- and age-associated protein aggregates (Lee et al., 2010; Hill et al., 2014), extends the life span of yeast mother cells (Hill et al., 2014).

How cells respond to protein aggregation that occurs specifically during aging has remained elusive since most studies investigating the cellular responses to protein aggregation have relied on over-expression of non-native, aggregation prone proteins, proteostasis inhibitors, or other stressors, such as heat (Kaganovich et al., 2008; Liu et al., 2010; Specht et al., 2011; Zhou et al., 2011; Malinovska et al., 2012; Spokoini et al., 2012; Winkler et al., 2012; Escusa-Toret et al., 2013; Zhou et al., 2014). These studies have uncovered specific modes of cytosolic compartmentalization that take place when cells encounter proteotoxic stress. For example, cells stressed with heat respond by forming multiple protein aggregates (referred to as peripheral aggregates, stress foci, Q-bodies, or CytoQ) at the surface of the ER (Specht et al., 2011; Spokoini et al., 2012; Escusa-Toret et al., 2013; Miller et al., 2015; Zhou et al., 2014; Wallace et al., 2015). These structures, hereafter referred as Q-bodies, contain acutely misfolded proteins that are sorted between the nuclear and cytoplasmic degradation/deposit sites by the Hook family proteins Btn2 and Cur1 (Malinovska et al., 2012), and coalesce together by the aid of small heat shock proteins; Hsp42 in budding yeast (Specht et al., 2011; Escusa-Toret et al., 2013), and Hsp16 in fission yeast (Coelho et al., 2014). Simultaneously, Q-bodies are being rapidly resolved by the protein disaggregase Hsp104 (Parsell et al., 1994; Specht et al., 2011; Zhou et al., 2011; Spokoini et al., 2012; Escusa-Toret et al., 2013), together with other heat shock responsive chaperones such as Hsp70 and Hsp82 (Escusa-Toret et al., 2013). The formation of Q-bodies seems to aid stress survival, as the deletion of HSP42 resulted in defective tolerance of prolonged heat stress (Escusa-Toret et al., 2013). The asymmetric inheritance of Q-bodies by the mother cells is promoted by the geometry of the bud neck (Zhou et al., 2011), tethering to mitochondria (Zhou et al., 2014), and by actin cable-mediated retrograde transport, which is dependent of Hsp104 and Sir2 (Liu et al., 2010; Song et al., 2014). Notably, Sir2 is also a key player in processes that underlie the asymmetric segregation of damaged mitochondria (Higuchi et al., 2013) and the accumulation of extrachromosomal DNA circles (Sinclair and Guarente, 1997; Kaeberlein et al., 1999) to the aging mother cell.

Prolonged Q-body-inducing stress (heat or over-expression of thermolabile proteins) combined with proteasome inhibition can lead to the formation of a dynamically exchanging deposit of ubiquitylated proteins named the juxtanuclear quality compartment, JUNQ (Kaganovich et al., 2008; Escusa-Toret et al., 2013). This structure is regulated by the Upb3 deubiqutinase (Oling et al., 2014), by proteosomal activity (Andersson et al., 2013) and by lipid droplets (Moldavski et al., 2015), and it was also shown to appear during replicative aging (Oling et al., 2014). The faithful inheritance of this structure by the mother cell is dependent on its association with the nucleus (Spokoini et al., 2012). More recently, it was shown that the ‘JUNQ’ might actually reside inside the nucleus, and it was thus renamed as intranuclear quality control compartment, INQ (Miller et al., 2015). The JUNQ/INQ assembly is dependent on Btn2-aggregase (Miller et al., 2015), a protein also found to be involved in prion curing (Kryndushkin et al., 2008, 2012). Apart from the JUNQ/INQ structure, terminally aggregating proteins, such as the amyloidogenic prions Rnq1 and Ure2, were shown to partition to an non-dynamic, vacuole-associated deposit called the insoluble protein deposit IPOD (Kaganovich et al., 2008; Tyedmers et al., 2010b), which has remained less well characterized.

Despite this wealth of data, it remains unclear how these exogenous/stress-induced aggregation models relate to protein aggregation that takes place during physiological ‘healthy’ aging. Particularly, it is unclear why/how protein aggregates arise during aging, how are they segregated during cell division and, importantly, what is their consequence to the protein quality control of the aging cell, as well as to the aging process itself. To illuminate these aspects, we probed the role of protein aggregation during unperturbed replicative aging. Our findings indicate that protein aggregation is a prevalent and highly coordinated event of early aging and is not solely associated with proteostasis deterioration. Instead, we provide evidence that age-associated protein aggregation may initially benefit the cytosolic protein quality control, but eventually becomes involved with age-associated loss of fitness.

Protein aggregation has been frequently associated with aging and aging-associated diseases. Here, by using the budding yeast as a model for replicative aging, we identify an Hsp42-promoted and Hsp104/Hsp70-counteracted pathway that deposits age-associated protein aggregates and thereby ensures their biased segregation to the aging mother-lineage upon cell division (see model in Figure 7D). This might represent a common mechanism to drive asymmetric segregation of aberrant proteins in dividing cells, as stressed fission yeast cells utilize a similar Hsp16-dependent mechanism for asymmetric partitioning of misfolded proteins (Coelho et al., 2014). Intriguingly, our data suggest that depositing age-associated protein aggregates to the mother cells might be a mixed blessing. On one hand, the age-associated deposit can promote spatial protein quality control (Figures 4, 5) and promote cell diversity as an asymmetrically dividing structure that may harbor protein conformation encoded epigenetic information, such as the prion fold of Sup35 (Figure 2). At the same time, the long-term consequences of this pathway appear negative for the aging lineage (Figure 8C). Why the deposit-forming pathway ultimately becomes associated with age-dependent loss of fitness remains to be determined. In this regard, it will be of great importance to elucidate how age-associated deposit relates to other aging pathways, such as those influencing the function of mitochondria (McMurray and Gottschling, 2003; McFaline-Figueroa et al., 2011), vacuoles (Hughes and Gottschling, 2012) and nuclear pores (Shcheprova et al., 2008; Denoth-Lippuner et al., 2014; Webster et al., 2014), and how the deposit localizes relative to these organelles and their components (Chong et al., 2015).

Protein deposit-containing cells efficiently coped with acute proteotoxic stress (Figure 4) and displayed improved degradation of cytosolic UPS substrate during early- to mid-life span (Figure 5). It is important to note, however, that our assays were conducted with relatively young cells that had recently acquired the protein deposit, and hence it is possible that UPS function starts to decline later during the aging process, as shown previously (Andersson et al., 2013). Curiously, the decline in proteostasis has been associated with protein aggregation pathologies such as Alzheimer's, Huntington's, and Parkinson's disease (Vilchez et al., 2014). The decreased degradation of cytosolic UPS substrates in a polyQ disease model was found to be due to the sequestration of the Hsp40 protein Sis1 (Park et al., 2013)—a protein that was not associated with the age-associated deposit (Figure 1C). It is thus plausible that the presence of the deposit might, for example, lead to increased levels of available (substrate unbound) Sis1, thereby allowing more efficient nuclear import and degradation of cytosolic UPS substrates. Altogether, these data suggest that there is a need to better differentiate between pathophysiological protein aggregation and ‘homeostatic’ protein aggregation that takes place during physiological aging, of which the latter might initially help to coordinate chaperones and UPS factors involved in protein quality control. Related to this, the age-associated protein deposit did not clearly fill out the set criterion for any of the previously characterized cytosolic deposits, including Q-bodies, JUNQ/INQ, or IPOD, but rather seems to exist in parallel with the JUNQ and IPOD structures (Figure 1, Figure 3)—although, for example, the chaperones regulating these deposits were often shared between these structures. This favors the notion that pathological aggregation processes (mimicked e.g., by VHL and Rnq1 over-expression) can hijack endogenous proteostasis regulatory mechanisms, possibly underlying their harmful effects in cells (Park et al., 2013). Altogether, these apparent differences between the stress-induced, pathological, and aging-associated protein aggregates (Figure 2, Figure 3) demonstrates that protein aggregates are not all equal in their composition or in the way they are being recognized and dealt by the cell and reinforces the importance to discriminate between different aggregation models.

In the future, it will be important to identify the cargo deposited to the age-associated protein deposits. In this aspect, it is interesting to note that many of the long-lived asymmetrically retained proteins that accumulate to mother cells as they age (Thayer et al., 2014) were among those localizing to the age-associated protein deposit (including Hsp104, Ssa1, Ssa2, and Hsp26). One example of an age-associated deposit resident protein was the prion-like Sup35. This storage rendered Sup35 to be inherited by the mother cells (unlike a prion, analogous to a mnemon (Caudron and Barral, 2013)) (Figure 2), which is consistent with the size-dependent transmission model of Sup35-aggregates (Derdowski et al., 2010). However, aging does not enhance Sup35-dependent [PSI+] prion generation (Shewmaker and Wickner, 2006). Together, these notions suggest that Sup35 cannot escape the age-associated deposit under normal growth conditions, perhaps owing to the rigid amyloid-like packing (Saibil et al., 2012), being consistent with the durable and non-dynamic nature of these deposits. However, this notion may come with a caveat: we found that the age-associated deposit could be, at least temporarily, disassembled by the heat shock response (Figure 4). This suggests the captivating possibility that changes in the environment might trigger the spread from the age-associated deposit. For cells facing fluctuating environments in the wild, the strategy to stochastically store prion-like proteins in aged cells might prove beneficial, as it could allow stress-dependent spread of the prion conformers from a subpopulation of aged-cells to their daughters, promoting faster adaptation to the changing environment (Newby and Lindquist, 2013).

Since asymmetric inheritance of damaged proteins and protein aggregates seems to be conserved in metazoan stem cells (Rujano et al., 2006; Bufalino et al., 2013) that are also subjected to both replicative decline and segregation of lineages, we hypothesize that similar pathways that selectively segregate protein-aggregate based fate determinants asymmetrically during cell division are likely to be conserved and may contribute to cellular lineage specification across species.

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Author details

1. Juha Saarikangas

   Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland

   Contribution

   JS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   juha.saarikangas@bc.biol.ethz.ch

   Competing interests

   The authors declare that no competing interests exist.

2. Yves Barral

   Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland

   Contribution

   YB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   yves.barral@bc.biol.ethz.ch

   Competing interests

   The authors declare that no competing interests exist.

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