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The cell biology of aging

    Published Online:https://doi.org/10.1091/mbc.E14-06-1084

    Abstract

    One of the original hypotheses of organismal longevity posits that aging is the natural result of entropy on the cells, tissues, and organs of the animal—a slow, inexorable slide into nonfunctionality caused by stochastic degradation of its parts. We now have evidence that aging is instead at least in part genetically regulated. Many mutations have been discovered to extend lifespan in organisms of all complexities, from yeast to mammals. The study of metazoan model organisms, such as Caenorhabditis elegans, has been instrumental in understanding the role of genetics in the cell biology of aging. Longevity mutants across the spectrum of model organisms demonstrate that rates of aging are regulated through genetic control of cellular processes. The regulation and subsequent breakdown of cellular processes represent a programmatic decision by the cell to either continue or abandon maintenance procedures with age. Our understanding of cell biological processes involved in regulating aging have been particularly informed by longevity mutants and treatments, such as reduced insulin/IGF-1 signaling and dietary restriction, which are critical in determining the distinction between causes of and responses to aging and have revealed a set of downstream targets that participate in a range of cell biological activities. Here we briefly review some of these important cellular processes.

    INTRODUCTION

    To achieve lifespan extension in humans, we must understand which cellular programs are responsible for aging and how their dysregulation directs senescence and decline. In many degenerative diseases associated with aging, the specific, proximal etiologies of the disease, such as protein aggregation, stem from dysregulation of processes responsible for regulation of healthy aging, such as autophagy and proteostasis. Addressing the role of such cellular processes not only with age but also in the context of Alzheimer’s disease and Parkinson’s disease will provide valuable insight into the fundamental biology of aging, as well as directly aid in increasing the quality of life of a population aging at high risk for these diseases.

    Here we review a number of crucial processes responsible for regulating cellular health in aging and the link between many of those diseases and aging. Cellular health is controlled at various points in the cell, starting in the nucleus through chromosome structure/organization, transcriptional regulation, and nuclear export/import, ranging outward to protein translation and quality control, autophagic recycling of organelles, maintenance of cytoskeletal structure, and finally maintenance of the extracellular matrix and extracellular signaling (Figure 1). Each regulatory system receives information from every other system, resulting in an intricate interplay of regulation controlling the aging of the cell.

    FIGURE 1:

    FIGURE 1: Major features of cellular aging. As the cell ages, translational defects and entropy progressively increase the amount of cellular damage, and clearance and quality control mechanisms grow less effective. (a) In a young cell, most organelles are very healthy, and when proteins are translated and misfolded or acquire damage in the cytosol, they are cleared either by ERAD (in the ER) or autophagy (in the cytosol). When organelles become too damaged, they are degraded to component parts by macroautophagy. (b) In an older cell, accumulated damage leads to a less healthy cell. ROS build up from damaged mitochondria and contribute to a greater fraction of the proteome consisting of damaged proteins and protein aggregates.

    CHROMOSOME AND TELOMERE REGULATION

    Telomeres cap each chromosome with a repetitive sequence, protecting chromosomes from damage caused by shortening (due to end-replication problems on the lagging strand and oxidative damage; Richter and von Zglinicki, 2007) at each replicative cycle (Richter and von Zglinicki, 2007). Telomere length, which is inversely correlated with lifespan (Gomes et al., 2011), and rate of accumulation of short telomeres are predictors of lifespan in zebra finch and mice (Heidinger et al., 2012; Vera et al., 2012), and the longest-lived organisms have long telomeres (Heidinger et al., 2012). Long telomeres are linked to increased stress resistance in Caenorhabditis elegans (Park et al., 2010), and increased stress in humans leads to increased telomere shortening (Shalev et al., 2013), suggesting that regulation of telomere length is predictive of longevity and influenced by longevity-related factors. Mammalian cell cultures enter senescence after 40–60 divisions (Hayflick, 1965), known as the Hayflick limit or replicative senescence (Hayflick and Moorhead, 1961). Shortening of the telomeres at each replication (Olovnikov, 1996; Shay and Wright, 2000) leads to cellular senescence (Harley et al., 1992). This telomere shortening has been implicated in many age-related phenotypes, such as decline in innate immunity (Effros and Pawelec, 1997; Effros et al., 2005), and even correlates with protein diseases, such as Alzheimer’s disease (Panossian et al., 2003).

    The sirtuins SIR3 and SIR4 are associated with lifespan and nuclear organization in Saccharomyces cerevisiae (Kaeberlein et al., 1999), regulating nucleolus fragmentation in aging yeast (Lewinska et al., 2014) and leading to a relocation of the telomeres to the nucleolus in old cells (Lo et al., 2006) and progressive dysregulation of the cell. Nuclear shape degrades, and heterochromatin becomes dissociated from the periphery in aged worms (Haithcock et al., 2005) but these processes are slowed in long-lived insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) mutants (Haithcock et al., 2005).

    TRANSCRIPTIONAL REGULATION

    Transcriptional regulation is key in coordinating the activation of many genes to extend lifespan. Most cellular processes that affect longevity are regulated at the transcriptional level through highly conserved signaling pathways (Kenyon, 2010a) including the IIS (Kenyon et al., 1993; Ogg et al., 1997; Lin et al., 2001; Lee et al., 2003; McElwee et al., 2003; Murphy et al., 2003) and target of rapamycin (TOR) pathways (Jia et al., 2004; Kaeberlein and Shamieh, 2010), which regulate gene expression in response to stress and nutrient availability stimuli (Jia et al., 2004). Regulation by the IIS pathway in C. elegans involves primarily the PQM-1 and DAF-16/FOXO transcription factors, which localize to the nucleus in a mutually exclusive manner (Tepper et al., 2013) and promote either growth/development or stress response/longevity, respectively (Kenyon et al., 1993; Lin et al., 1997, 2001; Ogg et al., 1997; Lee et al., 2003; McElwee et al., 2003; Murphy et al., 2003; Tepper et al., 2013); their mutually exclusive nuclear localization breaks down with age (Tepper et al., 2013). The downstream targets of these pathways include genes implicated in regulation of cellular health (Murphy et al., 2003). The heat shock factor HSF-1 is responsible for regulation of cytoskeletal integrity (Baird et al., 2014), heat stress resistance (Hsu et al., 2003; Morley and Morimoto, 2004), and protein quality control (Morley and Morimoto, 2004), all of which contribute to its effect on C. elegans longevity (Hsu et al., 2003; Morley and Morimoto, 2004; Baird et al., 2014). The Nrf/SKN-1 transcription factor mediates longevity (Tullet et al., 2008; Robida-Stubbs et al., 2012), as well as regulation of extracellular collagen matrices (Ewald et al., 2015).

    NUCLEAR TRAFFICKING AND ORGANIZATION

    The eukaryotic nuclear pore complex (NPC), one of the most complex molecular devices, serves an essential role in exporting messages and proteins into and out of the nucleus and is critical to many aspects of cellular regulation and health (Nigg, 1997; D’Angelo and Hetzer, 2008; Toyama et al., 2013), including tumor suppression (Pinkston-Gosse and Kenyon, 2007). mRNA is shuttled to the cytoplasm through the NPC (Cole and Scarcelli, 2006), and nuclear trafficking decreases with cellular senescence, leading to hyporesponsiveness to cellular stresses (Kim et al., 2010). NPC proteins are long lived (Rout et al., 2000), rendering them susceptible to age-related damage. Progressive degradation of nucleoporins further contributes to aging through leaking of proteins and messages (D’Angelo et al., 2009).

    Organization inside the nucleus is also important for cellular health. Incorrect organization of lamins at the nuclear envelope (Muchir et al., 2000; Mounkes et al., 2003), which spatially organize the genome, cause laminopathies, including “premature-aging” diseases (Broers et al., 2006); for example, Hutchinson–Gilford progeria patients display extreme aging phenotypes while very young (Scaffidi and Misteli, 2005). Genome instability caused by laminopathies renders DNA sensitive to damaging agents, causing higher rates of breaks, relocations, and aneuploidies (Liu et al., 2005a). Proper regulation of nuclear lamins is essential for maintenance of tissues in healthy adults (Mounkes et al., 2003; Hutchison and Worman, 2004), and lamin damage results in increased sensitivity to reactive oxygen species (ROS; Pekovic et al., 2011), leading to oxidative damage (Pekovic et al., 2011). Laminopathy-driven altered nuclear architectures are also observed in patients with cardiomyopathies (Muchir et al., 2004; Nikolova-Krstevski et al., 2011) and in aged (Zuo et al., 2012) and damaged (Park et al., 2011) stem cells.

    PROTEIN TRANSLATION

    Protein translation is a critical control mechanism in longevity regulation; down-regulation of translation upon reduced nutrient availability (Evans et al., 2011) extends lifespan in many organisms (Syntichaki et al., 2007), including worms (Hansen et al., 2007) and flies (Partridge et al., 2011), via TOR signaling in dietary restriction (DR) regimes (Hansen et al., 2007; Katewa and Kapahi, 2011) and IIS/FOXO signaling (Hansen et al., 2007). Loss of the C. elegans eukaryotic initiation factor 4F (eIF-4F)/ife-2 extends lifespan (Hansen et al., 2007), as does loss of ribosomal-protein S6 kinase (S6K)/rsks-1 (Hansen et al., 2007). Loss of TOR signaling, eIF-4E/ife-2, or S6K/rsks-1 also increases heat stress resistance (Hansen et al., 2007).

    PROTEOSTASIS

    Maintenance of protein quality, or proteostasis, is critical for the health and longevity of the cell. Proteostasis ensures a supply of high-quality protein by culling misfolded and damaged proteins from the cellular pool and replacing them with newly formed proteins (Powers et al., 2009). Molecular chaperones direct amino acid chains to the correctly folded state (Hartl and Hayer-Hartl, 2002; Dobson, 2003; Kim et al., 2013), direct misfolded proteins to degradation pathways (Bukau et al., 2006; Hartl et al., 2011), and refold misfolded proteins (Wickner et al., 1999) before they enter the wider population of cellular proteins. Disruption of proteostasis alters the proteome (David et al., 2010; Walther et al., 2015), is hastened by stress (Ben-Zvi et al., 2009), and signals organismal aging in C. elegans (Ben-Zvi et al., 2009; David et al., 2010) but is forestalled by HSF-1 and DAF-16/FOXO activity (Ben-Zvi et al., 2009). IIS and FOXO are critical regulators of healthy aging across eukaryotes (Demontis and Perrimon, 2010; Haigis and Yankner, 2010), increasing resistance to oxygenation damage (Adachi et al., 1998), decreasing accumulation of carbonylated proteins (Adachi et al., 1998), and slowing proteome decline (Walther et al., 2015). Chaperones, including small heat shock proteins, as well as superoxide dismutase and catalase, are upregulated in long-lived daf-2 mutants by DAF-16/FOXO (Murphy et al., 2003) and HSF-1 (Hsu et al., 2003; Morley and Morimoto, 2004; Ben-Zvi et al., 2009). Increased proteostasis is necessary for the longevity of daf-2 mutants (Matilainen et al., 2013). Protein aggregation is decreased in human cells with reduced IIS (O’Neill et al., 2012), and reducing IGF-1 signaling in mice slows the onset of dysregulation of proteostasis, increasing healthy aging (Ben-Zvi et al., 2009).

    Many age-related diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, are associated with aggregated and misfolded proteins. Conformational defects allow the seeding of protein aggregates (Polymeropoulos et al., 1997), which can expand into macroscopic plaques (Jarrett et al., 1993), leading to tissue degeneration. Thus proper regulation of proteostasis is strongly correlated with healthy aging (Balch et al., 2008).

    UNFOLDED PROTEIN RESPONSE

    The unfolded protein response (UPR) monitors quality of unfolded amino acid chains primarily in the endoplasmic reticulum (ER), where much of translation occurs (Ron and Walter, 2007), and is linked with ER-associated protein quality regulation processes, particularly the ER-associated degradation (ERAD) pathway (Travers et al., 2000). UPR dysregulation is linked to several diseases (Walter and Ron, 2011), especially age-related protein conformational diseases such as Alzheimer’s and Parkinson’s (Yoshida, 2007). Low nutrient sensing through the TOR pathway (Vellai et al., 2003), rapamycin treatment (Harrison et al., 2009), and low insulin signaling regulate the UPR (Jia et al., 2004), whereas the protein/histone deacetylase SIR-2.1 acts in insulin signaling–dependent (Berdichevsky et al., 2006) and –independent manners to regulate the UPR (Viswanathan et al., 2005). In C. elegans IIS mutants, the ER stress response is up-regulated by XBP-1 and the DAF-16/FOXO (Henis-Korenblit et al., 2010), leading to better clearance of damaged proteins by UPR. ER stress in mouse fibroblasts also increases the UPR through Xbp-1 (Akha et al., 2011).

    AUTOPHAGY

    In much the same way as proteostasis is maintained through degradation and resynthesis of proteins, organelles are consumed by the cell through autophagy (Klionsky and Emr, 2000). In macroautophagy, the damaged organelle is encased in a double membrane to form the autophagosome, which traffics to the lysosome, where the organelle is broken down (Cesen et al., 2012). In microautophagy, cytosol is taken up in bulk directly to the lysosome (Massey et al., 2006), and in chaperone-mediated autophagy (CMA), specific proteins are targeted for transport to the lysosome (Cuervo et al., 2005; Massey et al., 2006; Mizushima et al., 2008).

    Autophagy is required for longevity paradigms across many species (Gelino and Hansen, 2012), including DR (Jia and Levine, 2007; Hansen et al., 2008), and IIS mutants (Melendez et al., 2003), and inhibition of autophagy generates hallmarks of aging at an accelerated rate (Cuervo et al., 2005; Rubinsztein et al., 2011). Dependence on autophagy for longevity suggests that autophagic clearing of damaged proteins, protein aggregates, organelles, lipids, and other cargo is required to provide new raw material (Kenyon, 2010b) for a healthy cell.

    Autophagy plays a complex role in neurodegenerative disease as well (Nixon, 2013). In Parkinson’s disease brains, autophagy is down-regulated (Alvarez-Erviti et al., 2010) and CMA is dysregulated (Massey et al., 2006). However, autophagy is up-regulated in the brains of patients with Alzheimer’s disease (Lipinski et al., 2010) and ALS (Sasaki, 2011). Regulatory differences occur at different steps in the autophagy pathway, suggesting a complex role of autophagy in maintaining health.

    MITOCHONDRIAL FUNCTION, BIOGENESIS, AND MITOPHAGY

    Maintenance of mitochondrial function is critical for cellular and organismal health, due to both the critical nature of their primary role in energy generation for the cell (McBride et al., 2006) and toxic by-products and side and intermediate products of energy generation (Richter et al., 1988), generating free radicals that cause damage (Harman, 1972). Mitochondria have their own mechanisms for proteostasis and regulation of unfolded proteins (Haynes and Ron, 2010), through chaperones and ubiquitin-mediated degradation (Kriegenburg et al., 2012). Mitophagy (mitochondrial autophagy) and mitochondrial biogenesis are coordinated and extended with age in C. elegans daf-2 mutants (Pinkston-Gosse and Kenyon, 2007) through the activity of DCT-1, a DAF-16/FOXO target, and the Nrf2 homologue SKN-1 (Palikaras et al., 2015).

    Defects in the oxidative phosphorylation chain extend lifespan in C. elegans (Kayser et al., 2004) and mice (Lapointe and Hekimi, 2008). Mutants in mitochondrial function, such as the DMQ hydroxylase clk-1 in C. elegans (Ewbank et al., 1997), affect biological timing, including longevity, development, and reproduction (Branicky et al., 2000; Stepanyan et al., 2006), which is also true in mice (Liu et al., 2005b). Mutations in the C. elegans clk-1 gene lead to modest lifespan gains at the expense of small and unhealthy mutants (Stepanyan et al., 2006) in a manner independent of more robust lifespan gains from insulin signaling mutations (Stepanyan et al., 2006). The mechanism is hypothesized to be related to ROS (Harman, 1972) but is incompletely understood (Shibata et al., 2003). However, increased expression of certain electron transport chain (ETC) components increases lifespan in Drosophila (Zid et al., 2009). This extension seems to be linked to the relative expression of different ETC components and the buildup of oxidative intermediates in the mitochondria (Rea et al., 2007). By contrast, C. elegans IIS mutants display healthier organelles overall by well-regulated autophagy (Melendez et al., 2003; Rubinsztein et al., 2011), resulting in overall better health than clk-1 mutants.

    Mitochondria have been associated with diseases stemming from direct pathology (Boffoli et al., 1994), aging-related diseases (de Grey, 2004), and neurological diseases such as Alzheimer’s and Parkinson’s (Devi and Anandatheerthavarada, 2010). Defects in autophagy are linked to multiple myopathies such as Pompe and Danon diseases (Masiero et al., 2009), primarily due to the highly toxic nature of decaying mitochondria (Wu et al., 2009) enriched in mammalian muscle (Wenz et al., 2009; Wu et al., 2009). Beyond the consequences of disruption of energy production, mitochondrial decay puts the cell at risk of leaking ROS and mitochondria-specific enzymes into the cytosol, generating stress that may lead to apoptosis (Green et al., 2011).

    CYTOSKELETAL INTEGRITY

    The cytoskeleton is critical in maintaining cell shape and integrity, and its dysregulation is an indicator of cellular aging (Gourlay and Ayscough, 2005). In yeast, actin turnover increases with increased ROS (Gourlay et al., 2004) and disruption of the Ras pathway with age (Ho and Bretscher, 2001). ROS (Gourlay and Ayscough, 2005), ischemia (Genesca et al., 2006), ultraviolet treatment (Kulms et al., 2002), or introduction of a toxin (Korsnes et al., 2007) can lead to cytoskeletal stress, which activates apoptosis (Ashkenazi and Dixit, 1998). The SM22 actin filament cross-linking protein (Prinjha et al., 1994) has been identified as a biomarker of aging across a range of organisms, including yeast, Drosophila, and humans (Prinjha et al., 1994; Camoretti-Mercado et al., 1998). In worms, loss of pat-10/troponin leads to cytoskeletal collapse, whereas overexpression leads to enhanced cytoskeletal stability and stress resistance (Baird et al., 2014).

    Cytoskeletal disruptions can cause degenerative neural diseases characteristic of aging. The apolipoprotein E4 (apoE4) is a risk indicator for early-onset Alzheimer’s disease in humans (Sando et al., 2008). ApoE4 is proteolyzed in neurons, forming toxic fragments that interact with the actin cytoskeleton (Mahley et al., 2006), hastening cell aging and oxidative stress (Aksenov et al., 2001), and eventually triggering decline and apoptosis. Par-4, which is increased in neurons of Alzheimer’s patients (Guo et al., 1998), interacts with Dlk to form stress fibers and cause apoptosis (DiazMeco et al., 1996; Sells et al., 1997; Vetterkind et al., 2005). Hyperphosphorylation of the microtubule-associated tau protein leads to formation of neurofibrillary tangles (Braak and Braak, 1991), another hallmark of Alzheimer’s disease, and inhibits proper proteasome activity (Keller et al., 2000a, b), allowing tangles to grow unchecked (Keck et al., 2003).

    THE CELL MEMBRANE AND THE EXTRACELLULAR MATRIX

    Extracellular signals pass into and out of the cell through the membrane, providing critical context for the health of the cell. Cells acquire geometric aberrations, which are driven by degradation and stress on the cytoskeleton (Kulms et al., 2002; Vetterkind et al., 2005), as they age (Kulms et al., 2002; Vetterkind et al., 2005), which can change surface texture in aging erythrocytes (Girasole et al., 2010). Cell signaling molecule recycling in the cell membrane becomes dysregulated with age (Meissner et al., 2004), leading to disruption of longevity-promoting cell signaling pathways (Meissner et al., 2004; Samuelson et al., 2007).

    The extracellular matrix (ECM) is an important contributor to health and longevity and is also an indicator of the health inside the cell. Regulation of collagens, an ECM component, is shared from invertebrates to humans (Myllyharju and Kivirikko, 2004). Collagen expression in C. elegans declines with age (Tullet et al., 2008; Ewald et al., 2015), and regulation of specific collagens is required for daf-2–mediated lifespan extension (Ewald et al., 2015). Aging humans also experience glycosylation and other proteomic damage to the ECM proteins (Brownlee, 1995; Kristic et al., 2014), a process that is accelerated in type 2 diabetes patients (Evans et al., 2002; Giacco and Brownlee, 2010) due to buildup of oxidative damage products and ROS (Giacco and Brownlee, 2010).

    REPLICATIVE AGING, SENESCENCE, AND RENEWAL

    In addition to decline of health with time, cells also experience aging linked to the number of divisions they have undergone (replicative aging). S. cerevisiae reproduces by budding a new cell off of the mother cell and can undergo ∼26 such divisions before succumbing to detrimental effects of age (Kaeberlein, 2010), whereas the daughter is not limited by the number of previous divisions of the mother cell (Kaeberlein, 2010), due to renewal of its replicative potential. Replicative aging can be modified by disruption of TOR signaling (Kaeberlein et al., 2005), dietary restriction (Kaeberlein et al., 2005), and modifications to intercellular pH (Schleit et al., 2013). During replicative aging, oxidative damage products such as carbonylated proteins and accumulated cellular damage build up in the yeast mother cell (Reverter-Branchat et al., 2004; Unal et al., 2011; Cabiscol et al., 2014) and are retained by the mother cell through a Sir2-dependent mechanism, allowing the newborn daughter cell to be born without this hallmark of aging (Aguilaniu et al., 2003; Wood et al., 2004). (Although carbonylated protein clearance also occurs in C. elegans oocytes [ Goudeau and Aguilaniu, 2010], this process is not dependent on sir-2 [ Viswanathan et al., 2005; Berdichevsky et al., 2006].) Resetting of replicative potential has clear parallels in mammalian and invertebrate gametogenesis. Stem cells undergo asymmetric divisions that segregate new mitochondria to the daughter cell, affecting their ability to maintain “stemness” (Katajisto et al., 2015).

    As cells age, they communicate their internal status—DNA damage (Kuilman et al., 2010), oncogene activation (Kuilman et al., 2010), and proteomic dysregulation (Walther et al., 2015)—to their neighbors by the senescence-associated secretory phenotype (SASP; Coppe et al., 2010; Kuilman et al., 2010). SASP has been reported in flies, mice, and humans (Coppe et al., 2008; Neves et al., 2015), but particular SASP profiles vary based on cell type and context (Gu and Kitamura, 2012). SASP regulates tumor formation (Lehmann et al., 2008) and may play a role in regulating organismal aging (Childs et al., 2014), as well as in age-related pathologies (van Deursen, 2014; Demaria et al., 2015), including neurodegenerative aging diseases (Chinta et al., 2015).

    Dysregulation of replicative lifespan is characteristic of diseases of aging, particularly cancer (Reya et al., 2001). Stem cells maintain a balance between multipotency and tumorogenicity by careful internal regulation (Thomson et al., 1998; Pittenger et al., 1999) and by sensing external stimuli (Engler et al., 2006). In cells induced to recover their stem cell–like state through coordinated factor expression (Takahashi and Yamanaka, 2006; Takahashi et al., 2007), chromosomal abnormalities quickly arise (Mayshar et al., 2010), as in normally aging cells (Aubert and Lansdorp, 2008) and immortalized cell lines (Landry et al., 2013). This tendency toward tumor formation suggests that aging and senescence plays an important role in limiting the chance of runaway errors that compromise the overall health of the organism.

    CONCLUSION

    Cellular health is regulated by a number of cell biological processes. Conserved gene-regulatory pathways coordinate separate processes of cellular aging to maintain cellular health. Because cellular health is regulated across a wide range of scales from molecular to cellular and across every spatial division of the cell, the processes of regulating cellular health are linked: poor protein quality leads to defective organelles, defective organelles lead to increased ROS, and increased ROS leads to further low protein quality. Each of these is linked to regulation of aging on the cellular level, ultimately impinging on the control of aging of the whole organism.

    The deeply conserved nature of the IIS pathway, the TOR pathway, and dietary restriction–induced longevity across eukaryotes suggests that regulation of aging is fundamental to eukaryotic evolution. The links between longevity, nutrient availability, and reproduction suggest that longevity pathways evolved to link somatic health to delayed reproduction in periods of low nutrient availability (Luo and Murphy, 2011). The robust, healthy-longevity phenotypes of DR and reduced IIS are the result of the systemic, coordinated change of many cell biological processes that together extend longevity.

    Understanding the global regulatory processes that control the cell’s health will lead to a greater understanding of aging, which may allow us to better treat and prevent aging-related degenerative diseases such as Alzheimer’s and Parkinson’s, diseases of incorrect senescence or failure to senesce, such as cancer, and slow aging itself, improving quality of life with age.

    FOOTNOTES

    Abbreviations used:
    CMA

    chaperone-mediated autophagy

    DMQ

    demethoxyubiquinone

    DR

    dietary restriction

    ECM

    extracellular matrix

    ER

    endoplasmic reticulum

    ERAD

    ER-associated decay

    ETC

    electron transport chain

    IGF-1

    insulin-like growth factor 1

    IIS

    insulin/IGF-1 signaling

    NPC

    nuclear pore complex

    ROS

    reactive oxygen species

    SASP

    senescence-associated secretory phenotype

    TOR

    target of rapamycin

    UPR

    unfolded protein response

    ACKNOWLEDGMENTS

    We thank Malene Hansen and members of the Murphy lab for discussion. C.T.M. is the Director of the Glenn Center for Aging Research at Princeton, and R.D. is supported by National Institutes of Health Grant T32 GM 007388.

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