16. Cowart LA, Obeid LM (2007) Yeast sphingolipids: recent developments in understanding biosynthesis, regulation, and function. Biochim Biophys Acta 1771: 421–431. 17. Breslow DK, Weissman JS (2010) Membranes in balance: mechanisms of sphingolipid homeostasis. Mol Cell 40: 267–279. 18. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, et al. (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426: 620. 19. Jia K, Chen D, Riddle DL (2004) The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131: 3897–3906. 20. Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, et al. (2007) Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 26: 663–674. 21. Liu K, Zhang X, Lester RL, Dickson RC (2005) The sphingoid long chain base phytosphingosine activates AGC-type protein kinases in Saccharomyces cerevisiae including Ypk1, Ypk2, and Sch9. J Biol Chem 280: 22679–22987. 22. Roelants FM, Torrance PD, Thorner J (2004) Differential roles of PDK1- and PDK2-phosphorylation sites in the yeast AGC kinases Ypk1, Pkc1 and Sch9. Microbiology 150: 3289–3304. 23. Jacinto E, Lorberg A (2008) TOR regulation of AGC kinases in yeast and mammals. Biochem J 410: 19–37. 24. Soulard A, Cremonesi A, Moes S, Schutz F, Jeno P, et al. (2010) The rapamycin- sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. Mol Biol Cell 21: 3475–3486. 25. Voordeckers K, Kimpe M, Haesendonckx S, Louwet W, Versele M, et al. (2011) Yeast 3-phosphoinositide-dependent protein kinase-1 (PDK1) orthologs Pkh1-3 differentially regulate phosphorylation of protein kinase A (PKA) and the protein kinase B (PKB)/S6K ortholog Sch9. J Biol Chem 286: 22017–22027. 26. Frohlich F, Moreira K, Aguilar PS, Hubner NC, Mann M, et al. (2009) A genome-wide screen for genes affecting eisosomes reveals Nce102 function in sphingolipid signaling. J Cell Biol 185: 1227–1242. 27. Roelants FM, Baltz AG, Trott AE, Fereres S, Thorner J (2010) A protein kinase network regulates the function of aminophospholipid flippases. Proc Natl Acad Sci U S A 107: 34–39. 28. Mnaimneh S, Davierwala AP, Haynes J, Moffat J, Peng WT, et al. (2004) Exploration of essential gene functions via titratable promoter alleles. Cell 118: 31–44. 29. Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, et al. (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18: 2491–2505. 30. Wei M, Fabrizio P, Hu J, Ge H, Cheng C, et al. (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4: e13. doi:10.1371/journal.pgen. 0040013. 31. Burtner CR, Murakami CJ, Kennedy BK, Kaeberlein M (2009) A molecular mechanism of chronological aging in yeast. Cell Cycle 8: 1256–1270. 32. Weinberger M, Feng L, Paul A, Smith DL, Jr., Hontz RD, et al. (2007) DNA replication stress is a determinant of chronological lifespan in budding yeast. PLoS One 2: e748. doi:10.1371/journal.pone.0000748. 33. Kaplan CD, Kaplan J (2009) Iron acquisition and transcriptional regulation. Chem Rev 109: 4536–4552. 34. Burtner CR, Murakami CJ, Olsen B, Kennedy BK, Kaeberlein M (2011) A genomic analysis of chronological longevity factors in budding yeast. Cell Cycle 10: 1385–1396. 35. Lippman SI, Broach JR (2009) Protein kinase A and TORC1 activate genes for ribosomal biogenesis by inactivating repressors encoded by Dot6 and its homolog Tod6. Proc Natl Acad Sci U S A 106: 19928–19933. 36. Huber A, French SL, Tekotte H, Yerlikaya S, Stahl M, et al. (2011) Sch9 regulates ribosome biogenesis via Stb3, Dot6 and Tod6 and the histone deacetylase complex RPD3L. EMBO J 30: 3052–3064. 37. Stribinskis V, Ramos KS (2007) Rpm2p, a protein subunit of mitochondrial RNase P, physically and genetically interacts with cytoplasmic processing bodies. Nucleic Acids Res 35: 1301–1311. 38. Lavoie H, Whiteway M (2008) Increased respiration in the sch9Delta mutant is required for increasing chronological life span but not replicative life span. Eukaryot Cell 7: 1127–1135. 39. Pan Y, Shadel GS (2009) Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochon- drial OXPHOS complex density. Aging (Albany NY) 1: 131–145. 40. Fabrizio P, Battistella L, Vardavas R, Gattazzo C, Liou LL, et al. (2004) Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae. J Cell Biol 166: 1055–1067. 41. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, et al. (2005) Sir2 blocks extreme life-span extension. Cell 123: 655–667. 42. Madia F, Gattazzo C, Wei M, Fabrizio P, Burhans WC, et al. (2008) Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system. J Cell Biol 180: 67–81. 43. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201–204. 44. Anderson RM, Weindruch R (2010) Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Metab 21: 134–141. 45. Mulholland J, Konopka J, Singer-Kruger B, Zerial M, Botstein D (1999) Visualization of receptor-mediated endocytosis in yeast. Mol Biol Cell 10: 799–817. Sphingolipids Control Lifespan 46. Toda T, Cameron S, Sass P, Wigler M (1988) SCH9, a gene of Saccharomyces cerevisiae that encodes a protein distinct from, but functionally and structurally related to, cAMP- dependent protein kinase catalytic subunits. Genes and Development 2: 517–527. 47. Zhang A, Shen Y, Gao W, Dong J (2011) Role of Sch9 in regulating Ras-cAMP signal pathway in Saccharomyces cerevisiae. FEBS Lett 585: 3026–3032. 48. Barbosa AD, Osorio H, Sims KJ, Almeida T, Alves M, et al. (2011) Role for Sit4p-dependent mitochondrial dysfunction in mediating the shortened chronological lifespan and oxidative stress sensitivity of Isc1p-deficient cells. Mol Microbiol 81: 515–527. 49. Aerts AM, Francois IE, Bammens L, Cammue BP, Smets B, et al. (2006) Level of M(IP)2C sphingolipid affects plant defensin sensitivity, oxidative stress resistance and chronological life-span in yeast. FEBS Lett 580: 1903–1907. 50. D’Mello NP, Childress AM, Franklin DS, Kale SP, Pinswasdi C, et al. (1994) Cloning and characterization of LAG1, a longevity-assurance gene in yeast. J Biol Chem 269: 15451–15459. 51. Schorling S, Vallee B, Barz WP, Riezman H, Oesterhelt D (2001) Lag1p and Lac1p Are Essential for the Acyl-CoA-dependent Ceramide Synthase Reaction in Saccharomyces cerevisae. Mol Biol Cell 12: 3417–3427. 52. Guillas I, Kirchman PA, Chuard R, Pfefferli M, Jiang JC, et al. (2001) C26- CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. Embo J 20: 2655–2665. 53. Dickson RC, Nagiec EE, Skrzypek M, Tillman P, Wells GB, et al. (1997) Sphingolipids are potential heat stress signals in Saccharomyces. Journal of Biological Chemistry 272: 30196–30200. 54. Zanolari B, Friant S, Funato K, Sutterlin C, Stevenson BJ, et al. (2000) Sphingoid base synthesis requirement for endocytosis in Saccharomyces cerevisiae. EMBO J 19: 2824–2833. 55. Jenkins GM, Hannun YA (2001) Role for de novo sphingoid base biosynthesis in the heat-induced transient cell cycle arrest of Saccharomyces cerevisiae. J Biol Chem 276: 8574–8581. 56. Meier KD, Deloche O, Kajiwara K, Funato K, Riezman H (2006) Sphingoid Base Is Required for Translation Initiation during Heat Stress in Saccharomyces cerevisiae. Mol Biol Cell 17: 1164–1175. 57. Skrzypek MS, Nagiec MM, Lester RL, Dickson RC (1998) Inhibition of amino acid transport by sphingoid long chain bases in Saccharomyces cerevisiae. J Biol Chem 273: 2829–2834. 58. Chung N, Mao C, Heitman J, Hannun YA, Obeid LM (2001) Phytosphingosine as a specific inhibitor of growth and nutrient import in Saccharomyces cerevisiae. J Biol Chem 276: 35614–35621. 59. Wang J, Jiang JC, Jazwinski SM (2010) Gene regulatory changes in yeast during life extension by nutrient limitation. Exp Gerontol 45: 621–631. 60. Nikolova-Karakashian M, Karakashian A, Rutkute K (2008) Role of neutral sphingomyelinases in aging and inflammation. Subcell Biochem 49: 469–486. 61. Sacket SJ, Chung HY, Okajima F, Im DS (2009) Increase in sphingolipid catabolic enzyme activity during aging. Acta Pharmacol Sin 30: 1454–1461. 62. Jana A, Hogan EL, Pahan K (2009) Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci 278: 5–15. 63. Guenther GG, Edinger AL (2009) A new take on ceramide: starving cells by cutting off the nutrient supply. Cell Cycle 8: 1122–1126. 64. Ohno-Iwashita Y, Shimada Y, Hayashi M, Inomata M (2010) Plasma membrane microdomains in aging and disease. Geriatr Gerontol Int 10 Suppl 1: S41–52. 65. Hernandez-Corbacho MJ, Jenkins RW, Clarke CJ, Hannun YA, Obeid LM, et al. (2011) Accumulation of Long-Chain Glycosphingolipids during Aging Is Prevented by Caloric Restriction. PLoS One 6: e20411. doi:10.1371/journal.pone. 0020411. 66. Yang Q, Gong ZJ, Zhou Y, Yuan JQ, Cheng J, et al. (2010) Role of Drosophila alkaline ceramidase (Dacer) in Drosophila development and longevity. Cell Mol Life Sci. 67. Sikorski RS, Hieter P (1989) A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics 122: 19–27. 68. Buede R, Rinker-Schaffer C, Pinto WJ, Lester RL, Dickson RC (1991) Cloning and characterization of LCB1, a Saccharomyces gene required for biosynthesis of the long-chain base component of sphingolipids. Journal of Bacteriology 173: 4325–4332. 69. Nagiec MM, Baltisberger JA, Wells GB, Lester RL, Dickson RC (1994) The LCB2 gene of Saccharomyces and the related LCB1 gene encode subunits of serine palmitoyltransferase, the initial enzyme in sphingolipid synthesis. Proceedings of the National Academy of Sciences USA 91: 7899–7902. 70. Chen C, Kolodner RD (1999) Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants. Nat Genet 23: 81–85. 71. Lester RL, Dickson RC (2001) High-performance liquid chromatography analysis of molecular species of sphingolipid-related long chain bases and long chain base phosphates in Saccharomyces cerevisiae after derivatization with 6- aminoquinolyl-N-hydroxysuccinimidyl carbamate. Anal Biochem 298: 283–292. 72. Dickson RC, Nagiec EE, Wells GB, Nagiec MM, Lester RL (1997) Synthesis of mannose-(inositol-P)2-ceramide, the major sphingolipid in Saccharomyces cerevisiae, requires the IPT1(YDR072c) gene. Journal of Biological Chemistry 272: 29620–29625. PLoS Genetics | www.plosgenetics.org 15 February 2012 | Volume 8 | Issue 2 | e1002493