Age-Related Lysosomal Dysfunctions: Comparison
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Aging is a process associated with the detriment of normal physiological functions, which leads to the manifestation of diverse diseases such as cardiovascular and neurodegenerative diseases, joint degenerative diseases, and metabolic diseases such as diabetes, among others. Lysosomes are heterogeneous organelles enclosed by a lipid bilayer and filled with hydrolytic enzymes. The lysosomes are traditionally described as the subcellular structures where the degradation of other organelles and macromolecules takes place, a fundamental process for maintaining cellular proteostasis. There are several degradation processes in which the lysosomes are involved. If the substrate reaching the lysosomes comes from the extracellular environment, the degradation process is called endocytosis. If the material to be digested comes from the cell itself, the process is classified as autophagy. The lysosomes are also involved in plasma membrane repair through a mechanism called lysosomal exocytosis.  During aging, damage in cellular organelles disbalances the cellular homeostatic processes. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function. Thus, lysosomal alkalinization, amino acid storage, iron disturbances and lipofuscin accummulation are characteristic features of the lysosome during aging. 

  • lysosome
  • aging
  • senescence
  • mTORC
  • lipofuscin
  • TFEB
  • inflammation

1. Lysosomes

1.1. Lysosomal Structure and Components

To understand the lysosomal participation in these processes, the composition and structure of the organelle must be understood. The lysosome is delimited by a bilipidic membrane that encloses an acid lumen, where the degradative reactions take place. This lumen contains approximately 60 hydrolases that are active at acidic pH and participate in multistep catabolic processes to orchestrate the degradation of organelles and macromolecules to monomers [1]. Lysosomes have a role in protein degradation, since they contain proteases such as cathepsins. However, they are also involved in the degradation of other macromolecules such as lipids, which are catabolized by lipases such as the lysosomal acid lipase LIPA [2]. Nucleases such as RNase T2 or DNase II participate in nucleic acid degradation [3], and enzymes such as the acid alpha-glucosidase are important for polysaccharide degradation [4]. Macromolecules catabolized into monomers inside the lysosomes can be reused in anaplerotic reactions, connecting lysosomal function with cellular metabolism. The lysosomal membrane is covered in its internal part with a large glycocalyx, a thick layer of polysaccharides that prevent lysosomal membrane self-digestion, avoiding acid content leakage into the cytosol [1]. The lysosomal membrane contains key proteins for the fusion of the lysosome with autophagosomes, endosomes, or with the plasma membrane as well as pumps and channels that are fundamental for the transport of ions and molecules and to maintain lysosomal acidification [5]. Lysosomal acidification is tightly controlled. These organelles are acidified mainly by the action of the v-ATPase, which hydrolyses ATP to pump protons into the lysosomal lumen. This process generates a transmembrane voltage that is dissipated by the action of ion channels [5]. The correct functioning of these ion channels is important not just to dissipate the electrogenic gradient, but also for v-ATPase to continue introducing protons against the gradient. Indeed, an increase in lysosomal pH can have detrimental consequences on the digestion carried out by lysosomal hydrolases, since these enzymes are active at low pH (pH 4–5).

1.2. Lysosomal Biogenetic Pathways and Metabolic Integration

Lysosomal biogenesis is important for lysosomal adaptation to different situations and to replace disrupted or dysfunctional lysosomes. Similarly, under nutrient deprivation conditions, when autophagy is induced, lysosomal biogenesis is activated since the number of lysosomes must increase. Additionally, when a cell replicates, lysosomes have to be produced to be dispersed between the daughter cells. Diverse mechanisms participating in lysosome biogenesis have been described [6]. The mammalian target of rapamycin (mTORC) is a protein kinase involved in the regulation of cell growth and metabolism. mTORC is the main component of mTORC1 and mTORC2, two protein complexes that are distinguished by their accessory proteins. Aside from mTORC, mTORC1 contains the regulatory-associated protein of mTOR (RAPTOR), and mTORC2 is characterized by the presence of the rapamycin-insensitive subunit companion of mTOR (RICTOR) [7]. One mechanism that regulates lysosomal biogenesis depends on mTORC1 (mammalian target of rapamycin complex 1) activity, which converges in the activation or inhibition of TFEB (Figure 1). mTORC1 can sense the metabolic state of the cell. In nutrient-rich conditions, active mTORC1 binds with TFEB, the master transcriptional factor in the regulation of lysosome biogenesis and function, at the lysosomal surface [8]. mTORC1 phosphorylates TFEB, causing its binding, sequestration, and consequent inactivation by the regulatory 14-3-3 proteins in the cytosol. When the cell requires nutrients, mTORC1 is inactivated and TFEB translocates to the nucleus where it promotes the transcription of its target genes, thus enhancing lysosome biogenesis and autophagy [6]. This set of genes, involved in lysosome biogenesis, is known as the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network. TFEB is the main regulator of this network, but other transcription factors from the MiT/TFE family to which TFEB belongs such as TFE3, MITF, and TFEC can also regulate the transcription of these genes [9]. TFEB also regulates the expression of v-ATPase subunits, so mTORC1 indirectly regulates v-ATPase activity and the acidification process [10]. The v-ATPase subunit association is also a tightly regulated process. Although this mechanism has been better studied in yeast, it is known that in mammals, the assembly of v-ATPase is promoted by amino acid starvation and by glucose starvation [11]. Furthermore, TFEB enhances the expression of genes related to lipid catabolism as a response to cell starvation [12]. TFEB also enhances the transcription of PGC1-α, which is the master regulator of mitochondrial biogenesis and participates in mitochondrial clearance [13].
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Figure 1. An overview of TFEB regulation through mTORC1 and calcineurin activity. Under nutrient rich conditions, mTORC1 phosphorylates TFEB, which is sequestered in the cytosol by 14-3-3 proteins. Under nutrient deficiency, mTORC1 is inactive, and calcineurin eliminates TFEB phosphates, allowing nuclear translocation, where TFEB induces the expression of genes related to autophagy, endocytosis, lysosome exocytosis, and lysosome biogenesis.
Another described mechanism that regulates lysosomal biogenesis depends on protein kinase C (PKC). Similar to what has been described for mTORC1, the activation of PKC leads to phosphorylation and the consequent inactivation of the GSK3β kinase, which, in turn, fails to phosphorylate TFEB [14]. Unphosphorylated active TFEB translocates to the nucleus, where it performs its function. Additionally, the activation of PKC promotes lysosomal biogenesis through a second mechanism, in which the activation of JNK2/p38 leads to the phosphorylation of ZKSCAN3, a DNA-binding protein that upon phosphorylation leaves the nucleus, where it was repressing the expression of lysosomal genes [14].

2. Processes in which the Lysosome Participates

2.1. Endocytosis

Endocytosis is a cellular process in which cellular membrane engulfing allows for the internalization of external material. There are several types of endocytosis: phagocytosis, macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and clathrin-and caveolin-independent endocytosis [15]. In each type of endocytosis, different membrane receptors participate in the engulfing process. After plasma membrane engulfment, an endosome is formed. The newly formed endosome matures to an early endosome that mediates receptor recycling to the membrane. The transition to late endosome is coordinated by small GTPases following a maturation pathway. This maturation allows for the progressive acidification of the endosome, which finally fuses with the lysosome, where it reaches the most acidic pH [16].

2.2. Autophagy

Autophagy is a cellular catabolic process that is lysosomal-dependent, in which the cell degrades its own material. It can be classified into three types: microautophagy, chaperone-mediated autophagy, and macroautophagy [17]. Macroautophagy is characterized by the formation of double-membrane vesicles, called autophagosomes, which sequester the substrates to be degraded. It is the most studied process, and it is the only way of eliminating whole organelles, so it is crucial for the removal of damaged organelles.

2.3. Mitophagy and Mitochondrial Dysfunction

Lysosomes and mitochondria are tightly interdependent [18]. Several mechanisms have been proposed to explain how lysosomal function interferes with mitochondrial function during aging. Mitophagy has emerged as the main link between these organelles. Mitochondria are double-membrane-bound organelles that play a major role in cellular metabolism since aerobic respiration takes place in these organelles. The TCA cycle and fatty acid oxidation generate reducing agents that donate electrons to the mitochondrial electron transport chain for ATP production. Aside from their function in bioenergetics, mitochondria are organelles that influence cell fate since many enzymes that regulate apoptosis such as BCL-2 proteins or cytochrome c are found in these cellular compartments [19]. When the mitochondria are damaged and the mitochondrial membrane potential decreases, the respiratory chain does not work efficiently and ROS are produced. ROS generate oxidized proteins and lipids that further exacerbate mitochondrial dysfunction. These impaired mitochondria have to be removed, and the main mechanism to eliminate whole organelles is macroautophagy. The selective degradation of deficient mitochondria through macroautophagy is called mitophagy [19]. Thus, lysosomes are directly involved in the maintenance of mechanisms of mitochondria quality control.

2.4. Lysosomal Exocytosis

Lysosomes can fuse with the plasma membrane and secrete lysosomal content through exocytosis. This process was first believed to be reserved for specialized cells such as macrophages or melanocytes [20][21], but it has been observed that it occurs in all cells as a repair mechanism of the plasma membrane [22]. Most lysosomes are localized in the perinuclear area, but when the plasma membrane is damaged, lysosomes migrate to the cell periphery to fuse with the plasma membrane promoting the recovery of the membrane. The lysosomal fusion with the membrane is regulated by lysosomal calcium efflux through TRPML1. Precisely, lysosomal exocytosis is frequently studied by the presence of lysosomal proteins such as LAMP1 or TRPML1 in the plasma membrane [23]. Lysosomal exocytosis is a process that also allows to get rid of unprocessed materials and it has been described in the case of lysosomal enzymes. Cathepsin D has been found in extracellular media upon lysosomal alkalinization [24]. Other groups have reported that lysosomes that fuse with the plasma membrane can get rid of autophagosomes [25]. LC3 lipidation is important for lysosomal exocytosis, so its regulation must be closely linked to autophagy [25].

3. Lysosomal Age-Related Dysfunctions

Lysosomal function is very important for cellular homeostasis, not only because of the recycling functions it exerts on damaged molecules and dysfunctional organelles, but also because of the impact it has on metabolic pathways or on organelles such as the mitochondria. Most studies are not focused on lysosomal function, but instead cover fields in which the lysosome is involved such as autophagy or mTORC1 status. However, some studies have reported dysfunctions associated with the lysosome in the context of aging (Figure 2).
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Figure 2. An overview of the lysosomal dysfunctions associated with aging or senescence. v-ATPase dysfunctions and membrane disruption impair the lysosomal acidification process, which shows increased alkalinization. Protons escaping the lysosome provoke cytosolic acidification, which alters cellular metabolism, and the presence of cathepsin B has been linked to NLRP3 inflammasome activation. Impaired hydrolysis inside the lysosome results in protein aggregation and lipofuscin storage. Incorrect amino acid storage is linked to mitochondrial dysfunction, and mTORC1 activation in the lysosome surface correlates with the synthesis of SASP molecules and geroconversion.
Precisely, mutations in enzymes related to lysosomal function such as in hydrolases or in lysosome membrane channels lead to lysosomal storage diseases, which are usually characterized by the increased accumulation of protein aggregates, leading to symptoms that resemble neurodegenerative diseases [26][27].

43.1. v-ATPAse Dysfunction and Lysosomal Alkalinization

Although some alterations have been described in luminal enzymes, the lysosomal membrane also has its relevance when it comes to aging. The correct v-ATPase function and lumen acidification has been correlated with delayed aging in yeast [28][29]. Many mutations in the v-ATPase subunits have been associated with neurodegenerative disorders, and animal models carrying mutations in v-ATPase subunits show lysosomal acidification problems accompanied by accelerated aging [30]. Cells lacking v-ATPase subunits also display mitochondrial dysfunctions, highlighting the important relation between lysosomes and mitochondria [31][32].

In macrophages, lysosomal exocytosis, which is an important functional mechanism, is propitiated by lysosomal alkalinization [23]. It would be interesting to know whether lysosomal exocytosis is also affected when lysosomal disruption and alkalinization occurs on senescent cells.
Importantly, the inhibition of lysosomal acidification by bafilomycin promotes iron deficiency, which results in impaired mitochondrial function and increased inflammation, linking correct lysosomal acidification to the functional mitochondrial state. Iron supplementation rescues these effects in cultured neurons and in a mouse model of impaired lysosomal acidification induced by the knockout of acid α-glucosidase, an essential enzyme for glycogen catabolism [32]. This evidences that lysosomal dysfunction led to imbalances in the compartmentalization of metabolites and ions, which have repercussions on other cellular functions.

43.2. Lysosomal Amino Acid Storage and Ion Homeostasis

Lysosomal dysfunctions lead to the accumulation of metabolites, and lysosomal storage diseases are an example of how the incorrect function of one lysosomal enzyme leads to storage problems, which conclude in signs and symptoms at the systemic level [33].

Lysosomes receive iron through the endocytic pathway. The lysosomal enzyme STEAP3, whose activity depends on correct lysosomal acidification, is essential for iron reduction into Fe2+, the form that is incorporated in iron-containing proteins. Moreover, lysosomes participate in the turnover of ferritin, the protein that stores iron inside the cell, and of mitochondria, organelles that contain great quantities of iron. Therefore, iron homeostasis is tightly regulated by the lysosome, and iron disturbances promote the accumulation of ROS as Fe2+ can react with hydrogen peroxide, inducing the formation of highly reactive species through the Fenton reaction [34]. Moreover, iron is indispensable for processes such as oxygen transport or collagen biosynthesis, and it is part of many mitochondrial complexes, as iron–sulfur clusters are essential for oxidation–reduction reactions [35][36]. For this reason, the dysregulation of iron homeostasis contributes to cardiovascular [37] and neurodegenerative diseases [38][39][40], among others.
Since disturbances in iron homeostasis lead to ROS formation, it is not surprising that iron imbalance contributes to the aging process. In fact, old people suffer from problems of absorbing iron at the systemic level, while an increase in iron at the cellular level has been observed in this same population. Indeed, senescent cells have a 10-fold increase in iron compared to young cells [41]. This iron accumulation during senescence is associated with impaired ferritin degradation in the lysosome and increased expression of cell cycle inhibitors [42]. Furthermore, lysosome involvement in iron homeostasis is linked to a type of cell death called ferroptosis. Ferroptosis, which has been linked to aging [43], is promoted by ROS generation, associated with iron disturbances in the lysosome.

43.3. Lipofuscin

During aging, autophagy and subsequent lysosomal degradation of lipofuscin is impaired, which promotes further aggregation of these granules. Additionally, not only do impaired lysosomes contribute to lipofuscin accumulation during senescence, but the lack of cell division impedes the distribution of these aggregates between the daughter cells, as would occur in proliferative cells. Moreover, the increase in ROS production and lipofuscin accumulation promotes mitochondrial dysfunction, which further exacerbates lysosomal impairment in a positive feedback mechanism [44]. Additionally, lipofuscin accumulation enhances the activity of caspase-3 and promotes lysosomal membrane disruption, having been linked to NLRP3 inflammasome activation and necroptosis induction [45][46].

43.4. Inflammation and Cell Death

Senescent cells show increased mitochondrial mass, and these mitochondria are often dysfunctional. Typically, the mitochondria of senescent cells display low membrane potential, lower mitochondrial ATP production, and increased ROS production [19]. The decreased levels of mitophagy observed in many senescent cells supports a possible mechanism that explains the increase in dysfunctional mitochondria. Lysosomal dysfunction impedes the correct degradation of mitochondria, exacerbating mitochondrial ROS production which, in turn, increases lysosomal damage in a feedback fashion. Both mitochondria and lysosomes have been correlated to SASP production. In fact, mtDNA depletion seems to induce MiDAS with a characteristic SASP pattern that lacks the IL-1 inflammatory arm [5], while lysosomal disruption seems to induce IL-1 activation, enhancing NLRP3 inflammasome function [47]. Lysosomal membrane permeabilization is not only involved in the activation of pro-inflammatory pathways, but it has been suggested to be involved in the mechanisms of cell death, and recently, it has also been associated with pathophysiological conditions [48]. Indeed, some scholars have proposed that lysosomal membrane permeabilization in association with lysosomal quality control mechanisms can determine cell fate, since lysosomal components that are released into the cytosol can trigger the activation of diverse cellular pathways [49]. Several studies have suggested that lysosomal damage is related to apoptosis, necroptosis, and ferroptosis. Apoptosis, the main type of programmed cell death, which is characterized by cytochrome c release from mitochondria, can be fostered by the release of lysosomal cathepsins, which can degrade Bcl-2 [50][51], one of the proteins involved in mitochondrial membrane stability during apoptosis. Similarly, cathepsin D release has been associated to the activation of RIPK1 during necroptosis [52][53], a type of cell death though to be non-programmed, but now known to be regulated by receptor-interacting protein kinases (RIPK). Ferroptosis is a regulated cell death type in which intracellular iron incites the formation of ROS. Lysosomes are closely related to ferroptosis, since these organelles constitute one of the main iron storage places. Lysosomal membrane disruption seems to foster the activation of this cell death pathway [54].

54. mTORC and Senescence

mTORC1 seems to be activated during aging and in some senescent cells [55][56]. This activation is evidenced by the phosphorylation of mTORC1 downstream targets. It has been reported that in replicative senescent fibroblasts, p70S6K undergoes phosphorylation by the activity of mTORC1 [57]. Moreover, it has been found that constitutive mTORC1 activation induces premature senescence in fibroblasts carrying tuberous sclerosis complex (TCS) mutations [58]. S6 kinases, phosphorylated and activated by mTORC1, are observed in aged muscle [59] and in the brains of Alzheimer’s disease patients [60]. mTORC1 seems to be fundamental for the processing and activation of some SASP factors such as IL-6, IL-8, or IL-1A, which are, in turn, fundamental players in the inflammation induction that accompanies aging (Figure 2). Rapamycin treatment, which inhibits mTORC1, diminishes the pro-inflammatory phenotype of senescent cells through a reduction in the IL-1A and IL-6 levels [61]. Senescence induction seems to increase mTORC1 activity, which could be related to SASP induction through the TOR-Autophagy Spatial Coupling Compartment (TASCC). It has been suggested that mTORC1 localizes at this TASCC compartment in the Trans-Golgi and favors the synthesis of IL-6 and IL-8 cytokines [62]. Precisely, lysosomes originate from the Trans-Golgi network and mTORC1 activation occurs on the lysosomal membrane. Further studies are necessary to elucidate the relevance of the role of the mTORC1-lysosome on inflammation induction, but several scholars have pointed out the role of lysosomes on inflammasome activation [33][46]. The mTOR pathway can positively or negatively regulate p53, being cell type and stress dependent [63]. In fact, mTORC1 and mTORC2 were reported to participate in the stabilization of cell cycle inhibitors (Figure 3). In MEFS, mTORC1 activation promotes the association of p53 mRNA with ribosomes, leading to p53 translation [64]. The overexpression of the microRNA miR-107 increases MTORC1 activity through PTEN inhibition, resulting in the activation of p16 [65]. Precisely, the loss of PTEN enhances p53 translation, triggered by mTORC1 [66]. Moreover, it has been reported that in PTEN-depleted cells, mTORC1 and mTORC2 bind and phosphorylate p53 at Ser15 [67]. This exhibits the participation of mTORC1 in senescent state regulation.
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Figure 3. An overview of mTORC1 and mTORC2 on senescence control by the regulation of the p53/p21 and p16/pRb pathways. p21 is stabilized through mTORC1 dependent 4EBP phosphorylation, and through mTORC1 via S6K1 dependent mTORC2 inhibition, which has repercussions on p53 stabilization. p16 is activated downstream of mTORC1 by S6K1 phosphorylation, inhibiting the CDK–Cyclin complexes and impeding pRb phosphorylation. This results in the sequestration of E2F and the prevention of cell cycle progression, eventually leading to senescence.

65. Lysosomal Opportunities for Intervention in Aging

Strategies that increase autophagic activity have been proposed as a mechanism to eliminate senescent cells. In particular, the suppression of mTORC1 extends the lifespan of many animal models, and inhibitors of this pathway such as rapamycin or torin1 have been developed [68]. Other molecules such as metformin have been shown to increase autophagy and ameliorate inflammation [69].
It is suggested that the treatment of senescent cells with mTORC1 inhibitors ameliorates the senescence phenotype in many cases [70][71]. It has been pointed out that although senescent cells undergo a permanent loss of proliferative potential because their cell cycle is arrested, their cellular growth pathways remain active. For instance, among the several pathways deregulated during senescence, the presence of ROS has been linked to cell cycle block, along with an active mTORC1 [56]. Rapamycin, a mTORC1 inhibitor, could prevent the permanent loss of proliferation when cells are arrested by p21 or p16 function. The proliferation of cells arrested by p21 or p16 upregulation in the presence of rapamycin resumed the proliferation capacity once rapamycin was removed, suggesting that mTORC1 activation is important for the achievement of senescence [70].
Importantly, mTORC1 inhibition prevents geroconversion, defined as the transition from quiescence to senescence, supporting the importance of mTORC1 activity to achieve senescence [71]. During cellular starvation, contact inhibition or hypoxia, cells do not undergo senescence, and it is hypothesized that mTORC1 inhibition prevents the conversion into a senescent state. Precisely, the stimulation of mTORC1 during contact inhibition favors the geroconversion [71].
Since TFEB was reported as the master regulator of lysosome biogenesis, many efforts have been made to identify activators that promote lysosomal function and autophagy, since the correct function of lysosomes is the key to promoting longevity. Many compounds able to activate and upregulate TFEB affect TFEB downstream of the inhibition of mTORC1, but one compound called C1 has been identified as a direct activator of TFEB. Accordingly, C1 binds TFEB and promotes its nuclear translocation [72]. In some neurodegenerative disease models, increased TFEB function through genetic intervention induces the activation of autophagy and a re-establishment of proteostasis, ameliorating the protein accumulation characteristic of these diseases. In Huntington’s disease, studies with in vitro models have shown that TFEB activation reduces HTT protein aggregation and decreases disease-related symptoms in mice [73]. In Parkinson’s disease, TFEB activation also ameliorates α-synuclein toxicity through the stimulation of autophagy [74]. Alzheimer’s disease is also related to impairment of proteostasis, and an accumulation of autophagosomes in the brains of Alzheimer’s patients has been observed. TFEB activation could also have beneficial effects in this disease, since a reduction in tau pathology and neurodegeneration in a mouse model has been observed upon increased TFEB activity [75][76]. Other strategies do not focus on remodeling senescent metabolism, but on killing senescent cells. This is the case of senolytics, drugs that aspire to specifically remove senescent cells by targeting a mechanism that is normally upregulated in a specific senescent phenotype. However, as in the case of cancer treatments, it is difficult to address a treatment to a specific type of cell and avoid off-target effects. In recent years, an elegant proposal has been made, where the increased SA-β gal activity from the senescent lysosome was used to activate a senolytic compound [77]. The senolytic prodrug enters the cell and is sequestered in the lysosome, where SA-β gal can catalyze the cleavage of the prodrug, therefore selectively eliminating senescent cells.

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