Lysosomes were discovered more than 60 years ago as highly acidic cellular organelles containing many enzymes responsible for breaking down macromolecules . Since then, their roles have been considerably expanded including with regard to optimal longevity. In this Page, Lysosomes will be introduced (Section A) and thereafter, analyzed in term of optimizing longevity and a healthy lifespan. (Section B)
TExT UNDER CONSTRUCTION
Lysosomes function in autophagy, the process that breaks down cellular components to allow cell survival and homeostasis in the face of starvation . These organelles also have emerged as a signaling hub for the enzyme mechanistic target of rapamycin (mTOR), a protein kinase involved in cellular and organismal growth responses to nutrient availability. We also now recognize links between aberrant lysosomal function and several diseases, including lysosomal storage diseases (e.g., Tay-Sachs disease) and neurodegenerative disorders (e.g., Parkinson’s disease), and also with aging. On page 83 of this issue, Folick et al. indicate how lysosomes play a role in the latter—by deploying a lipid molecule to the nucleus, whose impact on gene expression extends life span in an animal model (the nematode Caenorhabditis elegans). The study not only uncovers a lysosome-to-nucleus signaling pathway but also highlights the potential of lipids in mediating long-range physiological effects.
For recent findings concerning lysosome’s functions, consider its knowledge status which was ascertained just a few months ago in an Italian medical conference.
“Sixty years later, it is clear that the lysosome greatly exceeded the expectations of its discoverer. Recent findings on the role of the lysosome in endocytosis, exocytosis, autophagy, nutrient sensing, signaling and on the mechanisms underlying lysosome positioning changed our traditional view of the lysosome from a dead-end organelle to a control center of cell homeostasis. Over 50 different types of lysosomal storage diseases have been identified, each due to the deficiency or malfunction of a specific lysosomal protein. These disorders affect many organ systems, most notably brain, leading to chronic illness and death of affected individuals”. (Source)
Lysosomes are the main catabolic organelles of a cell and play a pivotal role in a plethora of cellular processes, including responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation. In line with this pleiotropic importance for cellular and organismal life and death, lysosomal dysfunction is associated with many age-related pathologies like Parkinson’s and Alzheimer’s disease, as well as with a decline in lifespan. Conversely, targeting lysosomal functional capacity is emerging as a means to promote longevity. Here, we analyze the current knowledge on the prominent influence of lysosomes on aging-related processes, in particular as active players in the mechanisms underlying known lifespan-extending interventions like, for example, spermidine or rapamycin administration. In conclusion, this review aims at critically examining the nature and pliability of the different layers, in which lysosomes are involved as a control hub for aging and longevity.
Lysosomes are found in all animal cell types (except erythrocytes) and represent the cell’s main catabolic organelles. The variety of substrates degraded in the lysosomes is wide, ranging from intracellular macromolecules and organelles to surface receptors and pathogens, among others. To exert their catabolic function, lysosomes contain an extensive set of hydrolases, including proteases, nucleases, lipases, sulfatases or phosphatases, whose pH optima are usually low (pH 4.5–5). Accordingly, their degradative capacity depends on a highly acidic milieu, which is maintained via the activity of a proton-pumping V-type ATPase that pumps protons from the cytoplasm into the lysosomal lumen. However, lysosomes are not mere sites for disposal and processing of cellular waste but also act as pivotal regulators of cell homeostasis at different levels. For instance, they are involved in the regulation of cellular responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation, among many others (Braun et al., 2015a,b; Boya, 2012; Settembre et al., 2013b). Thus, lysosomes play a determining role in processes that control cellular and organismal life and death.
Lysosomes, nutrient storage and lifespan control
In addition to the lysosome’s function in cellular degradation pathways, it has become clear in recent years that this organelle also plays a central role in cellular nutrient homeostasis. As discussed above, the lysosome acts as sorting and recycling depot for nutrients such as amino acids during the process of autophagy. In addition to this function, the lysosome also acts as a storage organelle for many different metabolites, most prominently amino acids and ions (Li and Kane, 2009). Storage of nutrients occurs through the action of specific metabolite transporters and pumps localized to the lysosome membrane. Consistent with a prominent role in nutrient storage, the lysosome has recently emerged as a central regulator of nutrient sensing and signaling pathways (Efeyan et al., 2012).
Lysosomes and anti-aging interventions
The idea that aging may be coupled to a progressive dysfunction of lysosomes raises the reciprocal question: is it possible to improve healthspan/lifespan by promoting lysosomal function? In fact, genetic overexpression data in diverse model organisms suggests that this is the case. In S. cerevisiae, for instance, overexpression of Pep4, the homolog of lysosomal cathepsin D, extends lifespan during chronological aging. This function is independent of its proteolytic activity and resides in the propeptide of the protein, which exerts anti-necrotic properties (Carmona-Gutiérrez et al., 2011). In C. elegans, the lysosomal acid lipase A LIPL-4 is highly expressed under conditions associated to extended lifespan (Lapierre et al., 2011). In line, overexpression of LIPL-4 promotes longevity in worms via the generation of the fatty acid oleoylethanolamide (OEA), which shuttles to the nucleus triggering the transcriptional activation of target genes (Folick et al., 2015). Also, overexpression of the TFEB homolog in C. elegans (HLH-30) extends lifespan, possibly via induction of autophagy (Lapierre et al., 2013). Interestingly, HLH-30 seems to regulate lysosomal lipolysis together with another transcription factor, MXL-3. While HLH-30 is crucial for lipolytic activity upon starvation, MXL-3 controls nutrient-triggered repression of lipolysis. Accordingly, mxl-3 mutant animals are long-lived (O’Rourke and Ruvkun, 2013). In D. melanogaster, overexpression of N-ethyl-maleimide sensitive fusion protein (NSF1) prevents neurodegeneration in a model of age-related Parkinson’s disease, possibly by sustaining trafficking of lysosomal proteases and autophagy (Babcock et al., 2015). Collectively, these examples show the protective potential of increasing lysosomal performance under aging conditions.
Similarly, lysosomal function is connected to most of the proposed anti-aging interventions that can be considered reliable, i.e. such with healthspan and/or lifespan-extending effects that have been validated in several model organisms and have been confirmed by different laboratories (De Cabo et al., 2014). This connection mostly arises from the crucial role of lysosomes in autophagic processing. This is the case for caloric restriction (CR; the reduction in the intake of calories without malnutrition), fasting regimens, and most pharmacological interventions, including the use of spermidine, metformin, resveratrol and rapamycin (De Cabo et al., 2014). The longevity-promoting effects of these approaches are tightly associated to autophagy induction and thereof resulting control of aging-relevant processes like proteostasis and mitochondrial quality control. The mechanisms by which they impact autophagy are diverse, reaching from epigenetic control to sirtuin activation (De Cabo et al., 2014).
For example, spermidine, a naturally occurring polyamine that – with the remarkable exception of centenarians (Pucciarelli et al., 2012) – declines with ongoing age, triggers autophagy through control of nuclear and cytosolic acetylation. In yeast, for instance, spermidine treatment results in histone H3 hypoacetylation possibly via inhibition of acetyltransferases. Thereby, the promoter region of the autophagy-essential gene ATG7 is excluded, allowing its increased expression (Eisenberg et al., 2009). In mice, spermidine injections induce autophagy along with the inhibition of acetylation of cytosolic proteins such as ATG proteins (Morselli et al., 2011). Resveratrol, a polyphenolic compound found in grapes and red wine, for its part, affects a series of stress-related targets, among them the NAD+ dependent deacetylase SIRT1 (Baur and Sinclair, 2006; Lagouge et al., 2006). Intriguingly, SIRT1 is also stimulated by CR, which results in the deacetylation of autophagic proteins and their subsequent activation (Lee et al., 2008). Equally important, activation of autophagy is required for resveratrol-mediated longevity in C. elegans (Morselli et al., 2010).
Some anti-aging interventions also seem to converge in the direct or indirect repression of TOR signaling (Lamming et al., 2013). For instance, rapamycin is a direct mTORC1-inhibitor and thus a potent inducer of autophagy (Li et al., 2014), whereas CR reduces insulin signaling (and IGF-1 levels), which can inactivate protein kinase B (AKT/PKB) and its downstream target mTORC1 (De Cabo et al., 2014; Fontana et al., 2010). As a result, the ULK1 complex is activated via the adenosine monophosphate- activated protein kinase (AMPK), thus promoting autophagosome formation (Rubinsztein et al., 2011). In addition, acetyltransferase MEC-17 is activated, which stimulates the cellular microtubule transport machinery, a prerequisite for effective autophagy (Mackeh et al., 2014). The biguanide metformin, on the other hand, indirectly prevents TOR activity via inhibition of oxidative phosphorylation, which results in an increase of the AMP/ATP ratio and AMPK activation (Dowling et al., 2007). At the same time, metformin can also upregulate REDD1 (REgulated in Development and DNA damage responses 1) and inhibit the Ras-related GTP binding (Rag) GTPases, both of which promote TOR repression (Ben Sahra et al., 2011; Kalender et al., 2010).
The involvement of lysosomes in these interventions probably spans beyond their degradative potential. Through their luminal load of amino acids, lysosomes control mTORC1-docking on their surface, which is a prerequisite for its activity (Zoncu et al., 2011). Thus, this might be another layer of autophagic regulation for mTORC1-related interventions via the lysosomes. In the light of other, emerging lysosomal functions during senescence, new anti-aging interventions may come to the forefront. For instance, dietary supplementation of lysosomally generated OEA promotes longevity in worms (Folick et al., 2015) and may thus be a potential candidate for a dietary anti-aging approach.
A very effective behavioral strategy against aging is exercise, which does not extend lifespan (Mercken et al., 2012) but has multisystemic health benefits (Warburton et al., 2006). Exercise has been shown to induce autophagic flux in muscle (He et al., 2012; Tam and Siu, 2014). Interestingly, recent evidence suggests that exercise-induced autophagy requires the release of lysosomal Ca2+ through the lysosomal calcium channel mucolipin 1 and the subsequent activation of calcineurin, which in turn promotes nuclear translocation of TFEB (Medina et al., 2015). Altogether, it can be concluded that most anti-aging interventions converge in the lysosome at different levels, underlining lysosomal function as an essential and pliable molecular hub for health- and lifespan control.
Mounting evidence suggests that a cell’s lifespan is partly determined by lysosomal function (Fig. 1). This implies that processes in which lysosomes are generally involved, but which have not been clearly associated to aging yet, might also directly or indirectly modulate longevity. Lysosomal exocytosis, for example, in which lysosomes dock to the cell surface, fuse with the plasma membrane and release their content into the extracellular space, has an important role in membrane repair (Reddy et al., 2001) and may contribute to intracellular regeneration upon cellular senescence. At the same time, lysosomal exocytosis is involved in secretion processes that could interact with aging-related intercellular signals at the tissue and organismal level and/or help alleviate intracellular stress conditions, possibly in cooperation with selective secretion through exosomes (Baixauli et al., 2014; Lehmann et al., 2008). Interestingly, lysosomal exocytosis is modulated by Ca2+ and TFEB (Medina et al., 2011), both of which have regulatory functions during aging.
On the other hand, molecular processes known to impact aging may at least partly do so because they affect lysosomal function. Such processes may engage single components of the cellular network that are involved in lifespan control, including mitochondria, the nucleus, or peroxisomes (Fransen et al., 2013; Green et al., 2011; Terlecky et al., 2006). Intriguingly, lysosomes not only communicate with other organelles in the frame of their autophagic removal. For example, the peroxisome-lysosome interaction does not seem to be restricted to pexophagy. The membranes of both organelles can come in close apposition (without fusion), creating lysosomal-peroxisome membrane contacts (LPMC), which are essential for the cellular trafficking of cholesterol (Chu et al., 2015). Interestingly, cholesterol oxide derivatives (oxysterols) are involved in different aging-relevant processes like redox equilibrium and inflammation. In addition, they have been associated to major age-related pathologies like neurodegenerative and cardiovascular diseases (Poli et al., 2013; Zarrouk et al., 2014). Thus, organelles associated with the generation, transformation and transport of such molecules may strongly influence their impact on aging. The occurrence of membrane tethering sites (microdomains) like LPMCs allows an efficient interplay between organelles (Schrader et al., 2015). Thus, the establishment of microdomains between lysosomes and other organelles may allow signal exchanges that contribute to a dynamic and orchestrated control of aging. Though some remain speculative in their causality, these lysosome-aging connections exemplify the multilayered mechanisms through which lysosomal function may crucially contribute to aging control. Recognizing this potential opens doors not only to further understand the process of aging but also to improve the ravages of time via lysosomal avenues.
References Of Selective Material
Lysosome-related organelles as mediators of metal homeostasis
J. Biol. Chem., 289 (2014), pp. 28129-28136, 10.1074/jbc.R114.592618
The Ras/cAMP/protein kinase A pathway regulates glucose-dependent assembly of the vacuolar (H + )-ATPase in yeast
J. Biol. Chem., 283 (2008), pp. 36513-36521, 10.1074/jbc.M805232200
Lysosomal function and dysfunction: mechanism and disease
Antioxid. Redox Signal., 17 (2012), pp. 766-774, 10.1089/ars.2011.4405
Autophagy: a lysosomal degradation pathway with a central role in health and disease
Biochim. Biophys. Acta—Mol. Cell Res., 1793 (2009), pp. 664-673, 10.1016/j.bbamcr.2008.07.014
Epidemiology of lysosomal storage diseases: an overview
A. Mehta, M. Beck, G. Sunder-Plassmann (Eds.), Fabry Disease: Perspectives from 5 Years of FOS, Oxford PharmaGenesis, Oxford (2006)
Metformin, independent of AMPK, inhibits mTORC1 In a Rag GTPase-dependent Manner
Cell Metab., 11 (2010), pp. 390-401, 10.1016/j.cmet.2010.03.014
Autophagy and aging
Adv. Exp. Med. Biol., 847 (2015), pp. 73-87, 10.1007/978-1-4939-2404-2_3
The exact cellular effects of lipofuscin are largely hypothetical and still under discussion, but may e.g. involve the production of oxidants, possibly via iron-mediated catalysis of free radicals (Höhn et al., 2010),
Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, cell signaling, and energy metabolism.
The lysosomes also act as the waste disposal system of the cell by digesting unwanted materials in the cytoplasm, both from outside the cell and obsolete components inside the cell. Material from outside the cell is taken-up through endocytosis, while material from the inside of the cell is digested through autophagy. Their sizes can be very different—the biggest ones can be more than 10 times bigger than the smallest ones. They were discovered and named by Belgian biologist Christian de Duve, who eventually received the Nobel Prize in Physiology or Medicine in 1974.
Lysosomes are known to contain more than 60 different enzymes. Enzymes of the lysosomes are synthesised in the rough endoplasmic reticulum.
Synthesis of lysosomal enzymes is controlled by nuclear genes. Mutations in the genes for these enzymes are responsible for more than 30 different human genetic disorders, which are collectively known as lysosomal storage diseases. These diseases result from an accumulation of specific substrates, due to the inability to break them down. These genetic defects are related to several neurodegenerative disorders, cancer, cardiovascular diseases, and ageing-related diseases.[
2 Jump up
^ Settembre C, Fraldi A, Medina DL, Ballabio A (May 2013). “Signals from the lysosome: a control centre for cellular clearance and energy metabolism”. Nature Reviews Molecular Cell Biology. 14 (5): 283–96. doi:10.1038/nrm3565. PMC 4387238 . PMID 23609508.
3 Jump up
^ Lüllmznn-Rauch R (2005). “History and Morphology of Lysosome”. In Zaftig P. Lysosomes (Online-Ausg. 1 ed.). Georgetown, Tex.: Landes Bioscience/Eurekah.com. pp. 1–16. ISBN 978-0-387-28957-1.
5 Jump up
^ “Lysosomal Enzymes”. www.rndsystems.com. R&D Systems. Retrieved 4 October 2016.
6 Jump up
^ Saftig, Paul; Klumperman, Judith (2009). “Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function”. Nature Reviews Molecular Cell Biology. 10 (9): 623–635. doi:10.1038/nrm2745. PMID 19672277.
8^ Jump up to:
a b Platt FM, Boland B, van der Spoel AC (November 2012). “The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction”. The Journal of Cell Biology. 199 (5): 723–34. doi:10.1083/jcb.201208152. PMC 3514785 . PMID 23185029.
10 Jump up
^ Susana Castro-Obregon (2010). “The Discovery of Lysosomes and Autophagy”. Nature Education. 3 (9): 49.
12 Jump up
^ Novikoff AB, Beaufay H, De Duve C (July 1956). “Electron microscopy of lysosomerich fractions from rat liver”. The Journal of Biophysical and Biochemical Cytology. 2 (4 Suppl): 179–84. doi:10.1083/jcb.2.4.179. PMC 2229688 . PMID 13357540.