Sci. Aging Knowl. Environ., 1 October 2003
Vol. 2003, Issue 39, p. pe27
[DOI: 10.1126/sageke.2003.39.pe27]

PERSPECTIVES

Ceramide, Stress, and a "LAG" in Aging

Lina M. Obeid, and Yusuf A. Hannun

Lina M. Obeid is in the Ralph H. Johnson Veterans Affairs Medical Center, Department of Veteran Affairs, Charleston, SC 29401, USA; the Department of Medicine, Division of General Internal Medicine, University of South Carolina, Charleston, SC 29425, USA; and the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA. Yusuf A. Hannun is in the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA. E-mail: obeidl{at}musc.edu

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/39/pe27

Key Words: ceramide • LAG1 • stress • calorie restriction • insulin • IGF-1

Introduction

A recent exciting discovery revealed that the yeast longevity assurance gene LAG1 and its homolog LAC1 encode proteins involved in the de novo synthesis of the sphingolipid molecule ceramide (1, 2). Coupled with significant data on a crucial role for ceramide in regulating the yeast and mammalian stress responses (3) and mammalian cellular senescence (4), this discovery begs the following question: What role does ceramide play in mediating organismal aging and by what mechanisms? In turn, this raises the question of how the pathways of sphingolipid metabolism and signaling interact with other emerging mechanisms in the regulation of life span and cell senescence. This Perspective attempts to shed light on these questions by reviewing and synthesizing an accumulating body of literature related to aging in organisms ranging from yeast to Drosophila to mammals.

Lag1 and Ceramide Metabolism

The de novo synthesis of sphingolipids (Fig. 1) in eukaryotes commences with the pyridoxal-5'-phosphate-dependent condensation of serine and palmitate (provided by palmitoyl CoA) to form 3-keto-sphinganine through the action of serine palmitoyl transferase (SPT). SPT is composed of at least two subunits, Lcb1 and Lcb2. Mutations in human Lcb1 underlie hereditary autonomous neuropathy, a neurodegenerative disorder of the peripheral nervous system (5). 3-keto-sphinganine is then reduced to the sphingoid base dihydrosphingosine (DHS). In Saccharomyces cerevisiae, DHS is hydroxylated at the C4 position to form phytosphingosine, which serves as the immediate precursor for (phyto)ceramide synthesis by ceramide synthase (also known as sphingoid base N-acyl transferase). In mammals, dihydrosphingosine is the direct substrate for (dihydro)ceramide synthase, resulting in the formation of dihydroceramide, which is then desaturated by dihydroceramide reductase to form mammalian-type ceramides. Mutation of the recently discovered analogous desaturase in Drosophila results in the formation of degenerative spermatocytes (6). Mammalian sphingosine derives from ceramides by the action of ceramidases. Sphingosine can then serve as a direct substrate for the synthesis of sphingosine phosphate via sphingosine kinases, or it can be reacylated by the same ceramide synthases to form ceramide.



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Fig. 1. Sphingolipid metabolism in yeast and mammalian cells. Black represents common steps in the synthetic/catabolic pathway. Red represents steps unique to mammalian metabolism. Green represents steps unique to yeast metabolism.

 
The two recent studies referred to above show that the LAG1 and LAC1 genes are essential for the expression of ceramide synthase activity, suggesting that they either harbor the catalytic activity or play some other essential role in the ceramide synthase reaction. LAG1 previously had been identified as a regulator of yeast life span/longevity, such that deletion of LAG1 prolongs the life span of S. cerevisiae by 50% (7). LAC1 was identified as an S. cerevisiae homolog of LAG1. Deletion of LAC1 does not affect life span, but the double deletion mutant lag1{Delta}lac1{Delta} is inviable (8).

Do Mammalian LAG1 Homologs Regulate Ceramide Synthesis?

The search for mammalian homologs of yeast LAG1 yielded a predicted product of an open reading frame (ORF) termed UOG1 (8), for upstream of GDF1 (growth and differentiation factor 1). The two proteins Uog1 and Gdf1 are translated from an unusual bicistronic message, implying that transcription of the two ORFs is coregulated. Gdf1 is a member of the transforming growth factor-{beta} (TGF-{beta}) family of proteins and is specifically expressed in the nervous system (9). TGF-{beta} is a cytokine that inhibits proliferation of epithelial cells and induces apoptosis. UOG1 is also predominantly expressed in neuronal tissues (8), and Futerman and colleagues demonstrated that the UOG1 gene product regulates ceramide synthesis in mammalian cells (10). What is especially intriguing about the work of Futerman and colleagues is that Uog1 was shown to specifically regulate the synthesis of ceramides with C18 acyl side chains that are preferentially incorporated into neutral glycosphingolipids and not into sphingomyelin or gangliosides. The implications of this selectivity are unclear, but it is tempting to hypothesize that the various glycosphingolipids have distinct roles in neuronal differentiation and/or neurodegenerative diseases. The results also suggest that there are several ceramide synthases that regulate the formation of the various ceramide species (ceramides usually have a C18 sphingosine and N-linked acyl chains varying in length from C14 to C26). It is intriguing that the mammalian UOG1 gene (also termed LASS1) is able to normalize the life span of the S. cerevisiae lag1{Delta}lac1{Delta} strain 85% as effectively as does S. cerevisiae LAG1 (8), thus clearly implicating this ceramide synthase in yeast longevity.

The identification of yeast Lag1p and the mammalian Uog1/Lass1 protein led to an informatics approach that showed that these two genes belong to a substantial gene family (91 members to date) of endoplasmic reticulum (ER) membrane-associated proteins that share a conservation of five predicted transmembrane alpha helices. This conserved domain has been termed the TLC domain for TRAM-Lag1p-CLN8 (SMART accession number SM0724), which are the names of three proteins that are members of this family (11). In addition to Lag1p, Tram and Cln8 are particularly interesting proteins. The translocating chain-associated membrane (TRAM) protein is involved in regulating cytosolic exposure of nascent secretory proteins while translocating into the ER (12). Human TRAM, however, is unable to complement the growth defect of the yeast lag1{Delta}lac1{Delta} double mutant (8), suggesting that it may not exhibit ceramide synthase activity. Of note is the involvement of Lag1p and Lac1p in protein transport, albeit in a manner that differs from that of TRAM; the lag1{Delta}lac1{Delta} deletion strain is defective in ER-to-Golgi transport of glucosylphosphorylinositol (GPI)-anchored proteins (13), an event known to require sphingolipid synthesis in S. cerevisiae (14). The relation of this defective protein transport phenotype to yeast longevity has not yet been elucidated; however, the lag1{Delta}lac1{Delta} deletion strain has a defective cell wall, which could predispose this strain to chronic stress responses that affect life span.

CLN8 is mutated in the childhood disease progressive epilepsy with mental retardation (EPMR) (15), a disease that belongs to a heterogeneous group of progressive neurodegenerative disorders referred to as neuronal ceroid lipfuscinoses (NCLs). The mouse Cln8 gene was assigned to the same location as the chromosomal defect in a naturally occurring mouse model of NCL, namely the mnd mouse, which suffers from progressive motor neuron and retinal degeneration (16). The function of the CLN8 protein product is unknown, and a new study by Guillas et al. (17) demonstrated that the CLN8 gene is unable to restore the viability of the lag1{Delta}lac1{Delta} double mutant yeast strain. However, the Cln8 protein, as well as TRAM, could still be involved in ceramide synthesis but require either (i) a posttranslational modification that does not occur in yeast or (ii) specific substrates not found in yeast cells (for example, sphingosine, which is a substrate of the mammalian ceramide synthase species).

Several other members of this protein family share the TLC domain but, in addition, contain a homeobox transcription factor HOX domain that is N-terminal to the TLC region. Two such members were identified by Guillas et al. and named Clone 1 and Clone 4 (17). When these human cDNAs were expressed in yeast, ceramide synthase activity was induced. On the other hand, another LAG1 homolog, LASS2, which is a short version of Clone 1 that lacks the HOX domain, was unable to induce ceramide synthase activity in yeast. It is thus possible to speculate that the HOX domain of Clone 1 is cleaved at the ER membrane and translocates to the nucleus to regulate ceramide synthase activity. Such an occurrence has been previously described for other transcription factors, such as SREBP and ATF6, whereby their ER membrane-associated pro-proteins are activated by proteolysis in response to ER stress (18). It is also intriguing that ceramide synthase activity is potentially tied to a transcription factor that is regulated developmentally and in cancer (19): LASS2 was cloned independently as a full-length cDNA encoding a protein that (i) interacts with membrane-associated receptors and transporters involved in development and (ii) inhibits the formation of colonies by human hepatoma cells (20).

What Is Ceramide's Function in Organismal and Cellular Aging?

In addition to the LAG1 connection to organismal aging, there are several other strong associations of ceramide and its metabolizing enzymes with cellular and organismal aging.

A recent study on modulating ceramide concentrations in a Drosophila model of retinal degeneration corroborated the critical role of ceramide in apoptosis and neurodegenerative diseases and extended the function of this sphingolipid to include regulatory processes in Drosophila (21). In this study, modulation of ceramide concentrations by targeted expression of the Drosophila neutral ceramidase (an enzyme that catalyzes the reverse reaction of that of Lag1) led to the rescue of Drosophila retinal degeneration. The mechanism of this rescue may involve a decrease in the concentrations of ceramide and/or an increase in the concentrations of sphingosine or sphingosine phosphate, because the latter has been amply demonstrated to counter the pro-apoptotic effects of ceramide. Thus, ceramidase serves to drive the concentrations of these two bioactive lipids in an anti-apoptotic direction. Also, by changing the ratio of ceramide and sphingosine, ceramidase could lead to alterations in the clathrin-mediated endocytosis of rhodopsin, which is thought to be an underlying defect in this model of retinal degeneration. Of note here is that in S. cerevisiae, phytosphingosine (the precursor or breakdown product of ceramide) is required for endocytosis (22) and, in mammalian Cos cells, ceramide inhibits phagocytosis (23). Inhibition of de novo ceramide synthesis also led to similar rescue from photoreceptor degeneration, thus again implicating ceramide accumulation and possibly a member of the LAG/UOG1 ceramide synthase family in photoreceptor degeneration.

In mammalian cells, ceramide has been implicated in the development of the senescence program (see "More Than a Sum of Our Cells"). Endogenous intracellular ceramide concentrations were shown to be elevated as human fibroblasts entered senescence. And the addition of ceramide to cultured fibroblasts was shown to induce dephosphorylation (and therefore activation) of the retinoblastoma (Rb) tumor suppressor protein (see Sharpless Perspective), inhibit the cell cycle regulator Cdk2 (24), increase the concentrations of the Cdk inhibitors p21/Sdi and p27/Kip1 (25), induce cell cycle arrest (26), and induce the morphology of cellular senescence (4, 27). More recently, endogenous ceramide has been implicated in the inhibition of telomerase activity in human cell lines by inhibiting transcription of the human telomerase gene hTERT (28), thus providing a link between ceramide-mediated senescence and telomerase. One mechanism of this inhibition involves ubiquitin-mediated degradation of the oncoprotein c-Myc, an important regulator of hTERT transcription (29). All of these studies strongly corroborate an important role for ceramide in regulation of the cellular senescence pathway.

Oxidative Stress, Metabolic Control, and Ceramide

These emerging roles for ceramide in mammalian senescence and yeast life span raise the question of how sphingolipid/ceramide metabolism and/or ceramide action relate to other emerging regulators of these processes. Strong cases have been developed for the functions of oxidative stress and metabolic control (see Masoro Review and Johnson Review ) in regulating life span and aging. Thus, metabolic function or oxidative stress may regulate sphingolipid metabolism, and/or, reciprocally, bioactive sphingolipids could in turn regulate metabolic function and oxidative stress responses. An examination of the current literature immediately suggests specific connections between ceramide and these physiological pathways but also raises some paradoxes.

Oxidative stress, a key process in the formation of reactive oxygen species, has clearly been implicated in cellular and organismal aging (30). The ceramide pathway is regulated by oxidative stress, whereby cellular glutathione (GSH) concentrations regulate the hydrolysis of sphingomyelin to generate ceramide (31). It has been proposed that when GSH concentrations drop, sphingomyelin hydrolysis proceeds, leading to the generation of excessive amounts of ceramide. Recently, ceramide generation was linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS) (see also Andersen Perspective), and this relation was shown to be mediated by oxidative stress (21, 32). Specifically, ceramide concentrations were found to be significantly elevated in spinal cord tissue from ALS patients with mutations in Cu/Zn superoxide dismutase (Cu/Zn SOD) and transgenic mice that harbor the same mutation. Of interest in this study is the finding that inhibition of sphingolipid synthesis rescues neuronal cell death, indicating a possible dysregulation in an enzyme of de novo sphingolipid synthesis. One possibility is that an enzyme from the LAG family of proteins is altered in ALS. Taken together, these results suggest that oxidative stress affects ceramide formation, and they implicate ceramide in mediating some of the effects of oxidative stress on senescence and apoptosis. Moreover, and mechanistically, oxidative stress regulates the tumor suppressor p53 (33), which itself is a known regulator of senescence (see Sharpless Perspective). Studies have shown that induction of p53 causes an elevation in ceramide concentrations (34) through an as-yet-unidentified mechanism.

In addition, studies in yeast have shown that sphingolipids function in the response of cells to various stresses, such as heat, osmotic stress, and nutrient deprivation (35). Evidence for this hypothesis comes from studies that (i) demonstrate an acute increase in the de novo synthesis of sphingolipids in response to heat stress (36), and (ii) show that inhibition of this increase (either pharmacologically or using a temperature-sensitive mutant of Lcb1p, the first and rate-limiting enzyme in de novo sphingolipid synthesis) prevents several specific responses of yeast cells to heat and other stresses, including the induction of cell cycle arrest. Also in S. cerevisiae, important connections are emerging between sphingolipids and metabolic regulation. Heat stress and starvation were both shown to induce ubiquitination and degradation of nutrient permeases, proteins that transport nutrients such as essential amino acids, and this response requires acute activation of de novo synthesis of sphingolipids (37, 38). The sphingolipid phytosphingosine was shown to enhance ubiquitination and degradation of Fur4p, the nutrient permease for uracil, suggesting that phytosphingosine may regulate the availability of other permeases as well (39, 40). Nutrient deprivation and other stressors have been implicated in prolonging life span in S. cerevisiae (41) (see Kaeberlein Perspective). Therefore, it follows that this extension of life span in yeast by stress could be mediated in part by de novo synthesis of the sphingolipid phytosphingosine. Deletion of LAG1 consequently would enhance phytosphingosine accumulation, ubiquitination and degradation of nutrient permeases, and nutrient deprivation, and thus lead to a state of prolonged stress and a longer life span. Given the available tools to dissect sphingolipid pathways in yeast, such hypotheses are now amenable to direct testing.

Studies in mammalian cells have also shown links between ceramide and metabolic control. Most notably, ceramide has been shown to induce dephosphorylation of the serine/threonine kinase Akt (42), which is a critical component of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. Studies in C. elegans, Drosophila, and mice have clearly implicated insulin-like receptors and their downstream components in the regulation of life span (see also Sonntag Perspective) (43). Ceramide also appears to play an important role in mediating the effects of saturated fatty acids on insulin production (through induction of cell death in pancreatic beta cells) and by inducing a state of insulin resistance (44).

Conclusion

The mechanisms by which ceramide can lead to cellular or organismal aging are diverse and involve signaling by ceramide itself in some cases and by its precursor/breakdown product sphingosine in other cases. Studies in yeast and other model organisms such as Drosophila are beginning to discern connections between sphingolipid metabolism, stress responses, and metabolic control (Fig. 2). Further studies are expected to clarify these connections and their mechanisms, producing potentially significant insights into the regulation of life span.



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Fig. 2. Schematic diagram of known modulators of the sphingolipids (phyto)ceramide and (phyto)sphingosine and of known downstream targets of these molecules.

 


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Citation: L. M. Obeid, Y. A. Hannun, Ceramide, Stress, and a "LAG" in Aging. Sci. SAGE KE 2003 (39), pe27 (2003).




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