Aging of multicellular and unicellular eukaryotic organisms is owing to dysregulation of many processes within cells; the extent of such dysregulation progresses with cellular and organismal age . The spatiotemporal organization of these numerous cellular processes and their functional states define the replicative and chronological age of a eukaryotic cell [2, 3]. All these cellular processes are governed by an evolutionarily conserved signaling network. The network integrates the insulin/insulin-like growth factor 1, AMP-activated protein kinase/target of rapamycin (AMPK/TOR) and cAMP/protein kinase A (cAMP/PKA) nutrient- and energy-sensing signaling pathways [1, 2]. By sensing the intracellular and organismal nutrient and energy status, this longevity signaling network coordinates information flow along its convergent, divergent and multiply branched pathways to regulate cellular aging, influence age-related pathologies and define organismal lifespan [1, 3].
A theoretical framework of network biology has been successfully applied to system biological and computational analyses of age-related changes in gene expression, protein–protein interactions and metabolomes; these analyses yielded several models of the so-called biomolecular networks of cellular aging [2, 4, 5]. Recent findings support the notion that such biomolecular networks may progress through a series of lifespan checkpoints, each being monitored by a checkpoint-specific nutrient- and energy-sensing signaling pathway or pathways [2, 4, 5].
Numerous processes that define the replicative and chronological age of a eukaryotic cell are confined to various cellular organelles and also take place in the cytosol [6, 7]. The organelles housing these processes communicate with each other by establishing zones of close apposition and being involved in the unidirectional or bidirectional flow of certain soluble metabolites, peptides, proteins, DNA fragments and lipids; the flow of metabolites and proteins also underlies the communication between some of these organelles and the cytosol [6-8]. Emergent evidence supports the view that such directed, coordinated and regulated organelle–organelle and organelle–cytosol communications are essential for the development of a pro- or antiaging cellular pattern [6-8]. To reflect the essential role of crosstalk between different types of organelles in regulating cellular aging, we coined the term “an endomembrane system that governs cellular aging” . Here, we outline numerous interorganellar communications that institute this endomembrane system. We discuss recent progress in understanding how various interorganellar communications within the system—along with crosstalk between this endomembrane system and the cytosol—influence the development of a pro- or antiaging cellular pattern. We summarize and integrate into a model the evidence that an intricate network of intercompartmental (i.e., organelle–organelle and organelle–cytosol) communications underlies cellular aging in evolutionarily distant organisms.
Organelles Generate, Distribute and Process the Flow of Information that Initiates the Development of a Pro- or Antiaging Cellular Pattern
The functional state of a cellular organelle depends on the rates and efficiencies of processes confined to it. Growing evidence supports the notion that in response to age-related intracellular stresses and environmental factors some organelles can alter their functional states to become platforms for generating, directing and processing the flow of information that set off a pro- or antiaging cellular pattern [6-11]. This critical information is generated by an organelle as certain soluble metabolites, lipids, proteins, peptides or DNA fragments. These primary molecular signals are then distributed to other cellular compartments capable of processing them into the secondary molecular signals that ultimately define the long-term viability of the cell [6-11]. In this section, we outline how several cellular organelles respond to age-related alterations in their functional states by generating certain primary molecular signals, how these primary signals are distributed to other compartments within the cell and how these other cellular compartments process them into some secondary molecular signals that are critical for cell viability.
Mitochondria compartmentalize numerous processes that regulate cellular aging [3, 7, 8, 12, 13]. Age-related and environment-dependent changes in the rates and efficiencies of these processes modulate the ability of mitochondria to generate and release various molecular signals. Outside mitochondria, these signals initiate cascades of events that alter the rates and efficiencies of pro- and/or antiaging processes in other cellular locations [3, 7, 8, 12, 13]. Such dynamic communications of mitochondria with other compartments within the cell are essential for establishing the rate of cellular aging.
A progressive decline in mitochondrial respiratory chain activity with the replicative age of a yeast cell causes an age-related gradual reduction of mitochondrial membrane potential (Δψm) . Such progressive deterioration of Δψm in replicatively aging yeast is the primary signal responsible for the activation of the mitochondrial retrograde (RTG) signaling pathway of cellular aging regulation [7, 12] (Fig. 1, path 1). The decline in Δψm activates the Rtg2 protein via a yet-to-be characterized mechanism. Rtg2 then stimulates nuclear import of the Rtg1–Rtg3 heterodimeric transcription factor, which in the nucleus triggers an antiaging transcriptional program [7, 12]. In addition, the nuclear pool of Rtg2 in replicatively aging yeast plays a vital antiaging role by enhancing genome stability and suppressing the deleterious accumulation of extrachromosomal rDNA circles [7, 12] (Fig. 1, path 1). A similar mitochondrial RTG pathway exists in mammalian cells, where functionally compromised mitochondria stimulate the nuclear factor kappa B (NFκB) protein attached to their surface  (Fig. 1, path 8). The ensuing association of NFκB with several other proteins yields heterodimeric transcription factors that are imported into the nucleus to orchestrate a global stress–response program affecting several age-related pathologies .
In addition to its stimulating effect on the antiaging RTG pathway, the progressive decline in Δψm with the replicative age of yeast cells also causes (via a yet-to-be established mechanism) a reduction of the TOR complex 1 (TORC1) protein kinase activity, thereby attenuating this master regulator of the key proaging signaling pathway [7, 12] (Fig. 1, path 2).
Lack of Afo1, a protein component of the large subunit of the mitochondrial ribosome, delays replicative aging of nonrespiring yeast cells in an independent of mitochondrial translation manner . Afo1 regulates replicative aging of yeast cells via the so-called back-signaling pathway; this pathway operates under conditions repressing the RTG pathway and is mediated by Sfp1, a transcription activator of genes encoding cytoplasmic ribosomal proteins  (Fig. 1, path 3). In addition, Afo1 indirectly suppresses the TORC1-governed proaging signaling pathway via a mechanism that remains to be defined  (Fig. 1, path 4).
The maintenance of protein homeostasis in mitochondria of mammalian cells and cells of the nematode Caenorhabditis elegans plays an important role in regulating cellular aging; mitochondrial proteostasis in these cells is sustained with the help of several antiaging unfolded protein response (UPRmt) pathways of mitochondria-to-nucleus communications [13, 15]. If unfolded or misfolded proteins accumulate within the intermembrane space (IMS) of mitochondria in mammalian cells, a yet-to-be identified molecular signal activates the UPRmt pathway . This antiaging pathway is mediated by the protein kinase AKT, which initiates a cascade of events stimulating transcription of nuclear genes coding for an IMS quality control protease and a transcription factor essential for mitochondrial biogenesis  (Fig. 1, path 5). Accumulation of unfolded or misfolded proteins within the matrix of mitochondria in mammalian cells triggers the antiaging UPRmt pathway mediated by the protein kinase JNK2 and the transcription factor CHOP; a similar UPRmt pathway in C. elegans cells operates via the transcription factor ATFS-1 [13, 15, 16] (Fig. 1, path 6). Another UPRmt pathway activated in C. elegans cells in response to a build-up of unfolded or misfolded proteins within the mitochondrial matrix involves the ubiquitin-like protein UBL-5 and the transcription factor DVE-1 [13, 15] (Fig. 1, path 7). The UPRmt pathways maintaining proteostasis within the matrix of mitochondria activate transcription of nuclear genes encoding several mitochondrial quality control proteases and chaperones [13, 15, 16]. Both antiaging UPRmt pathways operating in C. elegans cells are triggered by an HAF-1-driven efflux of peptides formed owing to a ClpP-dependent proteolysis of the unfolded and misfolded proteins excessively accumulated within the mitochondrial matrix .
An age-related mitochondrial dysfunction and the resulting decline in Δψm in mammalian cells reduce mitochondrial uptake of Ca2+, thereby elevating the concentration of free Ca2+ in the cytosol . This rise in cytosolic Ca2+ stimulates calcineurin (a protein phosphatase) and several Ca2+-dependent protein kinases that, in response, activate nuclear import of a distinct set of transcription factors, including ATF2, CHOP, CREB, Egr1, NFAT and NFκB  (Fig. 1, path 8). In the nucleus, these transcription factors cause a remodeling of gene expression patterns to influence several age-related pathologies—such as aging of neuronal cells, age-related degeneration of neurons and brain aging .
Certain dietary and pharmacological interventions that slow down cellular and organismal aging have been shown to elevate the cytosolic NAD+/NADH ratio by activating mitochondrial fatty acid oxidation and stimulating a malate–aspartate shuttle in the mitochondrial membrane . The resulting increase in cytosolic NAD+ level activates the NAD+-dependent type III deacetylase SIRT1, which resides predominately in the nucleus  (Fig. 1, path 9). Active SIRT1 then deacetylates and thus activates transcription factors such as FOXO1, FOXO3a, NFκB, PGC-1α and PPAR-α; in response, these transcription factors stimulate expression of numerous genes that are required for delaying cellular aging and slowing down the age-related progression of metabolic disorders [3, 20, 21].
Intracellular reactive oxygen species (ROS) are generated mainly as by-products of mitochondrial respiration; in addition, the IMS protein p66shc is involved in mitochondrial ROS formation in mice cells by oxidizing cytochrome c . A body of evidence supports the view that ROS play a dual role in regulating cellular aging. If mitochondrially produced ROS are maintained at sublethal levels, these potent signaling molecules initiate an antiaging cellular program by activating protein kinases JNK (in C. elegans and fruit flies Drosophila melanogaster) and MST-1 (in C. elegans) [3, 23-25] (Fig. 1, path 10). Both JNK and MST-1 then phosphorylate and thus activate the forkhead transcription factor FOXO, known to turn on expression of many genes required for slowing down cellular aging [3, 23-25] (Fig. 1, path 10). If, as it has been first postulated by the mitochondrial free-radical theory of aging , mitochondria are unable to maintain ROS concentration below a toxic threshold, ROS promote cellular aging by oxidatively damaging proteins, lipids and nucleic acids in various cellular locations [22, 27] (Fig. 1, path 16).
After being synthesized within and exported from mitochondria, iron–sulfur clusters (ISCs) in the cytosol of yeast and mammalian cells are actively transferred to various apoproteins as essential inorganic cofactors required for their activity [28, 29]. Some of these ISC-containing proteins are then imported into the nucleus, where they play vital roles in slowing down cellular aging by sustaining genome integrity through their involvement in DNA replication, DNA repair and telomere maintenance [29, 30] (Fig. 1, path 12). In replicatively aging yeast, the cytosolic ISC also attenuate activity and/or nuclear import of Aft1, a transcription factor that activates expression of genes involved in iron uptake and distribution within cells [28, 30] (Fig. 1, path 11). The resulting drop in free intracellular iron significantly reduces the extent of oxidative damage to various cellular proteins, thereby mitigating a process that accelerates cellular aging . An age-related mitochondrial dysfunction and the ensuing decline in Δψm in replicatively aging yeast hamper ISC synthesis in and/or export from mitochondria and, thus, reduce genome stability and elevate oxidative protein damage .
Both, the rate of mitochondrial DNA (mtDNA) fragments migration to the nucleus and the frequency of mtDNA fragments insertion into nuclear DNA, rise with the chronological age of a yeast cell [31, 32]. These progressive mitochondria-originated processes with age make essential contributions to cellular aging regulation in chronologically aging yeast, likely by influencing nuclear DNA replication, recombination, repair and transcription and ultimately reducing nuclear genome stability in an age-related manner [31, 32] (Fig. 1, path 13).
Protein components comprising the so-called mitochondrial translation control (MTC) module are known to be involved in the processing, stabilization and translational activation of mtDNA-encoded mRNAs . Lack of any of the eight specific members of this protein module slows down replicative aging of yeast cells (i) independently of the effects of its absence on mitochondrial translation, respiration, ROS production and oxidative damage; and (ii) autonomously from the antiaging RTG and back-signaling pathways (Fig. 1, paths 1 and 3) . The absence of any of these MTC proteins beneficially influences the replicative lifespan of a yeast cell via two different pathways. One pathway delays cellular aging by suppressing the deleterious accumulation of extrachromosomal rDNA circles in the nucleus in a Pnc1- and Sir2-dependent manner ; Fig. 1, path 14); Pnc1 has been shown to deplete the level of nicotinamide, a strong noncompetitive inhibitor of the NAD+-dependent protein deacetylase Sir2 [1, 2]. Another pathway slows down cellular aging by reducing cAMP level and the PKA activity  (Fig. 1, path 15), thereby attenuating a global proaging PKA signaling network that inhibits vacuole-dependent autophagy, activates protein synthesis in the cytosol and suppresses a stress–response transcriptional program in the nucleus [1, 2]. The identity of the primary mitochondria-generated molecular signal that triggers these two pathways in response to the absence of a critical protein component of the MTC module remains to be established.
An age-related mitochondrial dysfunction and the resulting decline in intracellular ATP levels and rise in intracellular AMP levels increase the AMPK activity in organisms across phyla [3, 20] (Fig. 1, path 17). In C. elegans and mammals, AMPK, a central regulator of cellular energy homeostasis, can also be activated in response to certain longevity-extending dietary and pharmacological interventions [3, 20]. Activated AMPK delays cellular aging by (i) inhibiting the TORC1 protein kinase activity, thereby attenuating this master regulator of the key proaging signaling pathway ; (ii) turning on an antiaging process of lysosome-dependent autophagy ; (iii) promoting a SIRT1-dependent activating deacetylation of FOXO and PGC-1α transcription factors known to stimulate expression of numerous genes required for slowing down cellular aging and age-related metabolic disorders [3, 20, 21]; (iv) phosphorylating histone H2b to activate transcription of numerous stress–response genes essential for cell survival  and (v) inhibiting lipolysis of the neutral lipids triacylglycerols (TAGs) deposited in lipid droplets (LD) .
The m-AAA protease Afg3 with chaperone-like activity in the inner membrane of mitochondria is involved in degradation of unfolded and misfolded membrane proteins, assembly of electron-transport chain (ETC) complexes and proteolytic maturation of a mitochondrial ribosomal protein of the large subunit . Lack of Afg3 delays replicative aging of yeast cells, reduces the rate of protein synthesis in the cytosol and enhances resistance to the tunicamycin-induced unfolded protein stress in the endoplasmic reticulum (ER) . Thus, the Afg3-assisted protein degradation and/or multiprotein complex assembly in the inner membrane of mitochondria may accelerate replicative aging of yeast cells by generating some yet-to-be identified molecular signals that stimulate the proaging processes of protein synthesis in the cytosol and unfolded protein stress build-up in the ER  (Fig. 1, paths 18 and 19).
Lack of the outer mitochondrial membrane protein Uth1 slows down replicative aging of yeast cells and eliminates the micromitophagic mode of mitophagy, a mechanism of mitochondrial quality and quantity control responsible for the autophagic degradation within vacuoles of aged, dysfunctional, damaged or excessive mitochondria . In the absence of Uth1, another mode of mitophagy, called macromitophagy, remains functional . It has been recently suggested that macromitophagy could be a highly selective process responsible for autophagic degradation of only dysfunctional mitochondria accumulating in replicatively aging yeast cells, whereas a less selective process of micromitophagy could eliminate mitochondria en masse, regardless of their functional state . If such a hypothesis is correct, then lack of Uth1 (or perhaps a progressive decline in its level with the replicative age of a yeast cell) could delay cellular aging by reducing the extent of nonselective micromitophagic degradation of functional mitochondria, while preserving (or even increasing) the efficacy with which only dysfunctional mitochondria are eliminated in a selective process of macromitophagy (Fig. 1, path 20).
Aup1p is a protein phosphatase within the IMS of yeast mitochondria . In chronologically aging yeast cells, Aup1 functions as a longevity assurance protein which (i) stimulates the antiaging process of selective macromitophagy  (Fig. 1, path 21) and (ii) promotes the dephosphorylation and nuclear import of Rtg3, a key transcriptional activator of the antiaging RTG signaling pathway  (Fig. 1, path 22).
Lysosomes and Vacuoles
The surface of lysosomes in mammalian cells (vacuoles in yeast cells) provides a platform for the activation of TORC1, a master regulator of the key signaling pathway accelerating cellular aging [10, 11]. Dietary regimens that reduce the intake of amino acids, the most critical intracellular signals for TORC1 activation, are known to delay aging in evolutionarily distant organisms . A rise in the level of amino acids in the cytosol of yeast cells causes an increase in protein kinase activity of TORC1 by stimulating the formation of a complex between permanently bound to the vacuolar surface inactive TORC1 and two Rag family GTPases . In mammalian cells, elevated levels of amino acids in the cytosol trigger the Rag GTPase-dependent recruitment of an enzymatically inactive TORC1 from the cytosol to the surface of lysosomes; TORC1 is activated at the lysosomal surface only after it binds to the small GTPase Rheb in its GTP-bound state acquired in response to active growth factor signaling [10, 43].
Once activated at the surface of lysosomes or vacuoles, TORC1 sets off a proaging program in the cell by phosphorylating several target proteins that then activate proaging processes or inhibit antiaging processes confined to various cellular compartments [10, 11, 43]. From the surface of lysosomes or vacuoles, active TORC1 phosphorylates the following proteins essential for cellular aging regulation: (i) the key translational regulators 4E-BP1 and S6K1 in mammalian cells, thereby stimulating the proaging process of protein synthesis in the cytosol (Fig. 2, path 23); (ii) the autophagy-initiating proteins ATG13 and ULK1 in mammalian cells (Atg13 in yeast cells), thus inhibiting autophagosome formation in the cytosol to suppress the antiaging process of autophagy (Fig. 2, path 24); (iii) the nutrient-sensory protein kinase Sch9 in yeast cells, therefore attenuating the antiaging processes of protein synthesis in mitochondria (Fig. 2, path 25) and transcription of numerous stress–response genes in the nucleus (Fig. 2, path 26); (iv) the phosphatidic acid phosphatase Lipin-1 in mammalian cells, consequently stimulating the proaging process of transcription of many genes involved in de novo lipid synthesis and adipogenesis (Fig. 2, path 27) and (v) the transcription factor TFEB in mammalian cells, thereby suppressing the antiaging process of transcription of several genes essential for lysosome biogenesis and autophagy (Fig. 2, path 28) [10, 11, 44].
It needs to be emphasized that in replicatively aging yeast cells cytosolic concentration of neutral amino acids (including glutamine, a potent TORC1 activator) is under the stringent control of age-related changes in vacuolar pH [45, 46]. In replicatively “young” cells, the high activity of the vacuolar H+-ATPase maintains high vacuole acidity by efficiently coupling ATP hydrolysis to proton import into the vacuole . The high concentration of protons in the vacuole of replicatively “young” cells drives the proton-dependent import of neutral amino acids from the cytosol into this organelle—thereby sustaining the concentration of neutral amino acids (including glutamine) in the cytosol at a low level . A progressive decline in vacuole acidity with the replicative age of a yeast cell attenuates the proton-dependent import of neutral amino acids into the vacuole and, thus, increases their concentrations in the cytosol . The gradual rise in the levels of neutral amino acids (including the potent TORC1 activator glutamine) in the cytosol of replicatively aging cells may initiate the development of a proaging cellular pattern by: (i) intensifying the proton-dependent uptake of amassed in the cytosol neutral amino acids by mitochondria, thereby significantly reducing Δψm to ultimately cause mitochondrial fragmentation  (Fig. 2, path 29); and/or (ii) activating TORC1 at the vacuolar surface in a glutamine-dependent fashion  (Fig. 2, path 30), thus promoting TORC1-dependent phosphorylation of several target proteins that in respond activate proaging processes or inhibit antiaging processes confined to various cellular compartments (Fig. 2, paths 23–28).
We recently discussed findings supporting the notion that dynamic communications of peroxisomes with other compartments within the cell influence the development of a pro- or antiaging cellular pattern [6, 9]. Efficient peroxisomal import of the hydrogen peroxide-decomposing enzyme catalase (Cta1) in replicatively and chronologically “young” cells not only minimizes the oxidative macromolecular damage within peroxisomes but also enables these organelles to sustain the extraperoxisomal concentration of hydrogen peroxide at a certain nontoxic and prohormetic level [6, 9]. At such a level, this ROS can stimulate a redox signaling network known to elicit “stress–response hormesis” by activating transcription of numerous nuclear stress–response genes essential for cell survival, thereby slowing down cellular aging [3, 6, 9, 22, 25] (Fig. 3A, path 31). A progressive decline in the efficacy of peroxisomal import of hydrogen peroxide-metabolizing catalase with the replicative and chronological age of a eukaryotic cell not only gradually elevates the oxidative macromolecular damage within peroxisomes but also impairs the ability of these organelles to maintain the extraperoxisomal concentration of hydrogen peroxide below a nontoxic threshold [6, 9]. Following a release of hydrogen peroxide in toxic concentrations from peroxisomes to the cytosol in replicatively and chronologically “old” cells, this ROS accelerates cellular aging by oxidatively damaging proteins, lipids and nucleic acids in various cellular locations [3, 6, 9, 22] (Fig. 3B, path 32).
Replicatively and chronologically “young” cells are proficient in peroxisomal import of Fox1, Fox2 and Fox3, the core enzymes of fatty acid β-oxidation [6, 9]. Therefore, peroxisomes of these cells efficiently oxidize fatty acids to acetyl-CoA. The subsequent conversion of acetyl-CoA to citrate and acetyl-carnitine in anaplerotic reactions taking place within peroxisomes of “young” cells promotes the replenishment of tricarboxylic acid (TCA) cycle intermediates destined for mitochondria  (Fig. 3A, path 33). The resulting stimulation of the TCA cycle and ETC in mitochondria of these cells allows these organelles to maintain ROS at sublethal levels that turn on expression of many nuclear genes required for decelerating cellular aging (Fig. 1, path 10). A progressive decrease in the efficacy of peroxisomal import of Fox1, Fox2 and Fox3 with the replicative and chronological age of a eukaryotic cell slows down fatty acid oxidation and anaplerotic reactions in peroxisomes, thereby diminishing the TCA cycle and ETC in mitochondria of “old” cells  (Fig. 3B, path 34). This, in turn, leads to an age-related decline in Δψm and causes a fragmentation of mitochondria by promoting fission of a mitochondrial network . The resulting release of cytochrome c (and, perhaps, of other proapoptotic proteins) from fragmented mitochondria in “old” cells triggers an age-related form of apoptotic cell death  (Fig. 3B).
The age-related deterioration of peroxisomal import of Fox1, Fox2 and Fox3 seen in “old” cells ultimately suppresses peroxisomal oxidation of fatty acids that originate from TAG synthesized in the ER and then deposited within LDs [4, 47] (Fig. 3B). This initiates several negative feedback loops that reduce lipolysis of TAG in LD and their biosynthesis in the ER, thus causing the excessive accumulation of fatty acids and diacylglycerol both in the ER and in the LD [4, 47] (Fig. 3B, path 35). Such remodeling of lipid dynamics promotes cellular aging and accelerates the onset an age-related form of necrotic cell death [4, 44] (Fig. 3B).
Peroxisomal polyamine oxidase in “young” cells is involved in the synthesis of spermidine, a polyamine whose intracellular level substantially declines with the replicative and chronological age of a eukaryotic cell [48, 49] (Fig. 3A). Spermidine has been shown to delay cellular aging in evolutionarily distant organisms by stimulating an antiaging process of lysosome/vacuole-dependent autophagy  (Fig. 3A, path 36).
In addition to its essential roles in yeast peroxisomal protein import, ER-derived preperoxisomal vesicle fusion, and cell differentiation , the predominantly peroxisomal protein Pex6 is also involved in sequestering dysfunctional mitochondria in replicatively “old” mother cells and/or segregating only functional mitochondria to their replicatively “young” budding progeny . The ability of Pex6 to regulate replicative aging of yeast cells by ensuring the age-related asymmetrical segregation of functional mitochondria between mother and daughter cells is likely owing to its involvement in mitochondrial import of Atp2, a β-subunit of the F1 sector of mitochondrial F0, F1-ATP synthase . It has been suggested that a mechanism underlying the essential contribution of peroxisome-associated pool of Pex6 to mitochondrial import of Atp2p and to the maintenance of age asymmetry between the mother and the daughter cells with respect to segregation of functional mitochondria may involve a recently discovered mitochondria-to-peroxisome vesicular traffic  (Fig. 3A, path 37).
A Model of an Intricate Network of Intercompartmental Communications Underlying Cellular Aging
A body of evidence summarized here and elsewhere [6, 9] suggests a depicted schematically in Fig. 4 model for an intricate network of intercompartmental (i.e., organelle–organelle and organelle–cytosol) communications that underly cellular aging in evolutionarily distant organisms. The presented model in Fig. 4 summarizes Figs. 1-3, and each path in Fig. 4 is numbered as in Fig. 1, 2 or 3. In our model, the network integrates unidirectional communications between (i) mitochondria and the nucleus (Fig. 4, paths 1, 3, 5–14 and 22); (ii) peroxisomes and the nucleus (Fig. 4, path 31); (iii) lysosomes/vacuoles and the nucleus (Fig. 4, paths 27 and 28); (iv) mitochondria and lysosomes/vacuoles (Fig. 4, paths 2, 4, 20 and 21); (v) peroxisomes and mitochondria (Fig. 4, paths 33, 34 and 37); (vi) mitochondria and the ER (Fig. 4, path 19); (vii) mitochondria and the plasma membrane (Fig. 4, path 15); (viii) the cytosol and the nucleus (Fig. 4, path 26) and (ix) peroxisomes and the cytosol (Fig. 4, path 32). Mitochondria and the cytosol (Fig. 4, paths 16–18, 25 and 29) as well as lysosomes/vacuoles and the cytosol (Fig. 4, paths 23, 24, 27, 28, 30 and 36) are also involved in bidirectional communications within the network underlying cellular aging. As outlined in the previous section, these unidirectional and bidirectional communications between different cellular compartments integrated into the network operate as a flow of certain soluble metabolites, peptides, proteins and DNA fragments. Moreover, the ER, LD and peroxisomes establish zones of close apposition. Within the network underlying cellular aging, these three organelles communicate via unidirectional flow of several lipid species; this lipid flow is under the stringent control of several negative feedback loops [4, 44, 47] (Fig. 4, path 35).
The central tenet of the model shown in Fig. 4 is that the numerous directed, coordinated and regulated organelle–organelle and organelle–cytosol communications integrated into the network are essential for the development of a pro- or antiaging cellular pattern. Thus, this network of intercompartmental communications plays a critical role in regulating cellular aging by programming the long-term viability of a eukaryotic cell.
Conclusions and Future Perspectives
Emergent evidence supports the view that numerous directed, coordinated and regulated organelle–organelle and organelle–cytosol communications within a eukaryotic cell are integrated into an intricate network critical for regulating cellular aging. The challenge remains to define molecular mechanisms underlying the various pathways of intercompartmental communications constituting this network. Future work will aim at understanding how age-related intracellular stresses and environmental factors influence the spatiotemporal dynamics of the entire network and how the network defines the long-term viability of a eukaryotic cell. This knowledge may reveal novel targets for antiaging dietary and pharmacological interventions that can slow down cellular and organismal aging by modulating information flow along the pathways of multidirectional intercompartmental communications within the network.
V.I.T. research is supported by grants from the NSERC of Canada and Concordia University Chair Fund. V.I.T. is a Concordia University Research Chair in Genomics, Cell Biology and Aging.