Current Genetics

, Volume 64, Issue 4, pp 761–767 | Cite as

Emerging roles for sphingolipids in cellular aging

  • Pushpendra SinghEmail author
  • Rong Li


Aging is a gradual loss of physiological functions as organisms’ progress in age. Although aging in multicellular organisms is complex, some fundamental mechanisms and pathways may be shared from the single cellular yeast to human. Budding yeast Saccharomyces cerevisiae has been established model system for aging studies. A yeast cell divides asymmetrically to produce two cells that differ in size and age. The one that is smaller coming from bud is a newborn cell that with a full replicative potential head irrespective of the replicative age of its mother—the larger cell from which the bud grows out before division. The age asymmetry between daughter and mother is thought to be dependent on asymmetric segregation of certain factors such as protein aggregates, extrachromosomal DNA (ERCs) and dysfunctional organelles during successive cell divisions of the yeast replicative lifespan (RLS). It is also thought that certain plasma membrane proteins, in particular multidrug-resistant (MDR) proteins, asymmetrically partition between the mother and the bud based on the age of the polypeptides. Functional decline associated with the molecular aging of those proteins contributes to the fitness decline at advance age. In our recent study, we showed that sphingolipids facilitate the age-dependent segregation of MDRs between daughter and mother cell. In this review, we highlight and discuss the potential mechanisms by which sphingolipids regulate the aging process in yeast and cells of vertebrate animals including human.


Sphingolipids Replicative aging Multidrug resistance proteins Asymmetric cell division 



This work was supported by the Grant R35 GM118172 from the National Institutes of Health to R. Li. The authors apologize to the researchers whose work could not be cited or not cited fully due to space limitation.

Compliance with ethical standards

Conflict of interest

Authors declare that they have no conflict of interest.


  1. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T (2003) Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science 299(5613):1751–1753. CrossRefPubMedGoogle Scholar
  2. An D, Na C, Bielawski J, Hannun YA, Kasper DL (2011) Membrane sphingolipids as essential molecular signals for bacteroides survival in the intestine. Proc Natl Acad Sci 108(Supplement 1):4666–4671. CrossRefGoogle Scholar
  3. Arner P, Bernard S, Salehpour M, Possnert G, Liebl J, Steier P et al (2011) Dynamics of human adipose lipid turnover in health and metabolic disease. Nature 478(7367).
  4. Balasubramanian MK, Bi E, Glotzer M (2004) Comparative analysis of cytokinesis in budding yeast, fission yeast and animal cells. Curr Biol 14(18):R806–R818. CrossRefPubMedGoogle Scholar
  5. Caudron F, Barral Y (2009) Septins and the lateral compartmentalization of eukaryotic membranes. Dev Cell 16(4):493–506. CrossRefGoogle Scholar
  6. Chen H, Chan AY, Stone DU, Mandal NA (2014) Beyond the cherry-red spot: ocular manifestations of sphingolipid-mediated neurodegenerative and inflammatory disorders. Surv Ophthalmol 59(1).
  7. Clay L, Caudron F, Denoth-Lippuner A, Boettcher B, Frei SB, Snapp EL, Barral Y (2014) A sphingolipid-dependent diffusion barrier confines ER stress to the yeast mother cell. Elife 3:e01883. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Collino S, Montoliu I, Martin F-PJ, Scherer M, Mari D, Salvioli S et al (2013) Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PloS One 8(3):e56564. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cutler RG, Thompson KW, Camandola S, Mack KT, Mattson MP (2014) Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans. Mech Ageing Dev 143–144:9–18. CrossRefPubMedGoogle Scholar
  10. Dawidowicz EA (1987) Dynamics of membrane lipid metabolism and turnover. Annu Rev Biochem 56:43–61. CrossRefGoogle Scholar
  11. Delaney JR, Ahmed U, Chou A, Sim S, Carr D, Murakami CJ et al (2013) Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging. Aging Cell 12(1):156–166. CrossRefPubMedGoogle Scholar
  12. Douglas LM, Konopka JB (2014) Fungal membrane organization: the eisosome concept. Annu Rev Microbiol 68:377–393. CrossRefPubMedGoogle Scholar
  13. Ejsing CS, Sampaio JL, Surendranath V, Duchoslav E, Ekroos K, Klemm RW et al (2009) Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry. Proc Natl Acad Sci USA 106(7):2136–2141. CrossRefPubMedGoogle Scholar
  14. Eldakak A, Rancati G, Rubinstein B, Paul P, Conaway V, Li R (2010) Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing. Nat Cell Biol 12(8):799–805. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Erjavec N, Larsson L, Grantham J, Nyström T (2007) Accelerated aging and failure to segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p. Genes Dev 21(19):2410–2421. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Ernst R, Klemm R, Schmitt L, Kuchler K (2005) Yeast ATP-binding cassette transporters: cellular cleaning pumps. Methods Enzymol 400:460–484.
  17. Gambin Y, Lopez-Esparza R, Reffay M, Sierecki E, Gov NS, Genest M et al (2006) Lateral mobility of proteins in liquid membranes revisited. Proc Natl Acad Sci USA 103(7):2098–2102. CrossRefGoogle Scholar
  18. Ganguly S, Singh P, Manoharlal R, Prasad R, Chattopadhyay A (2009) Differential dynamics of membrane proteins in yeast. Biochem Biophys Res Commun 387(4):661–665. CrossRefPubMedGoogle Scholar
  19. Gladfelter AS, Pringle JR, Lew DJ (2001) The septin cortex at the yeast mother-bud neck. Curr Opin Microbiol 4(6):681–689CrossRefPubMedGoogle Scholar
  20. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9(2):139–150. CrossRefPubMedGoogle Scholar
  21. Henderson KA, Gottschling DE (2008) A mother’s sacrifice: what is she keeping for herself? Curr Opin Cell Biol 20(6):723–728. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Huang X, Liu J, Dickson RC (2012) Down-regulating sphingolipid synthesis increases yeast lifespan. PLoS Genet 8(2):e1002493. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hughes AL, Gottschling DE (2012) An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492(7428):261–265. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hughes JR, Deeley JM, Blanksby SJ, Leisch F, Ellis SR, Truscott RJ, Mitchell TW (2012) Instability of the cellular lipidome with age. Age (Dordr) 34(4):935–947. CrossRefGoogle Scholar
  25. Hughes JR, Levchenko VA, Blanksby SJ, Mitchell TW, Williams A, Truscott RJW (2015) No turnover in lens lipids for the entire human lifespan. ELife 4.
  26. Jazwinski SM (2002) Growing old: metabolic control and yeast aging. Annu Rev Microbiol 56:769–792. CrossRefGoogle Scholar
  27. Jin K, Simpkins JW, Ji X, Leis M, Stambler I (2014) The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging Dis 6(1):1–5. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kabeche R, Howard L, Moseley JB (2015) Eisosomes provide membrane reservoirs for rapid expansion of the yeast plasma membrane. J Cell Sci 128(22):4057–4062. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kaeberlein M, Burtner CR, Kennedy BK (2007) Recent developments in yeast aging. PLoS Genet 3(5):e84. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kasahara K, Sanai Y (2000) Functional roles of glycosphingolipids in signal transduction via lipid rafts. Glycoconj J 17(3–4):153–162CrossRefPubMedGoogle Scholar
  31. Kirkwood TB (2005) Understanding the odd science of aging. Cell 120(4):437–447. CrossRefPubMedGoogle Scholar
  32. Kirkwood TB (2008) Understanding ageing from an evolutionary perspective. J Intern Med 263(2):117–127. CrossRefPubMedGoogle Scholar
  33. Lee AG (2004) How lipids affect the activities of integral membrane proteins. Biochim Biophys Acta 1666(1–2):62–87. CrossRefPubMedGoogle Scholar
  34. Liu L, Rando TA (2011) Manifestations and mechanisms of stem cell aging. J Cell Biol 193(2):257–266. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Liu J, Zeng F-F, Liu Z-M, Zhang C-X, Ling W, Chen Y-M (2013a) Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis 12:159. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Liu J, Huang X, Withers BR, Blalock E, Liu K, Dickson RC (2013b) Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan. Aging Cell 12(5):833–841. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217. CrossRefGoogle Scholar
  38. Marsh D (2008) Energetics of hydrophobic matching in lipid–protein interactions. Biophys J 94(10):3996–4013. CrossRefGoogle Scholar
  39. Maxwell PH (2016) What might retrotransposons teach us about aging? Curr Genet 62(2):277–282. CrossRefPubMedGoogle Scholar
  40. McFaline-Figueroa JR, Vevea J, Swayne TC, Zhou C, Liu C, Leung G et al (2011) Mitochondrial quality control during inheritance is associated with lifespan and mother-daughter age asymmetry in budding yeast. Aging Cell 10(5):885–895. CrossRefGoogle Scholar
  41. Mitchison JM, Nurse P (1985) Growth in cell length in the fission yeast Schizosaccharomyces pombe. J Cell Sci 75:357–376PubMedGoogle Scholar
  42. Molano A, Huang Z, Marko MG, Azzi A, Wu D, Wang E et al (2012) Age-dependent changes in the sphingolipid composition of mouse CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction. PloS One 7(10):e47650. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Montoliu I, Scherer M, Beguelin F, DaSilva L, Mari D, Salvioli S et al (2014) Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity. Aging 6(1):9–25. CrossRefGoogle Scholar
  44. Moreira KE, Walther TC, Aguilar PS, Walter P (2009) Pil1 controls eisosome biogenesis. Mol Biol Cell 20(3):809–818. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Morrow MR, Singh D, Lu D, Grant CW (1995) Glycosphingolipid fatty acid arrangement in phospholipid bilayers: cholesterol effects. Biophys J 68(1):179–186. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Mostowy S, Cossart P (2012) Septins: the fourth component of the cytoskeleton. Nat Rev Mol Cell Biol 13(3):183–194. CrossRefGoogle Scholar
  47. Nakase M, Tani M, Morita T, Kitamoto HK, Kashiwazaki J, Nakamura T et al (2010) Mannosylinositol phosphorylceramide is a major sphingolipid component and is required for proper localization of plasma-membrane proteins in Schizosaccharomyces pombe. J Cell Sci 123(Pt 9):1578–1587. CrossRefPubMedGoogle Scholar
  48. Obara K, Kojima R, Kihara A (2013) Effects on vesicular transport pathways at the late endosome in cells with limited very long-chain fatty acids. J Lipid Res 54(3):831–842. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Ong K, Wloka C, Okada S, Svitkina T, Bi E (2014) Architecture and dynamic remodelling of the septin cytoskeleton during the cell cycle. Nat Commun 5.
  50. Phillips R, Ursell T, Wiggins P, Sens P (2009) Emerging roles for lipids in shaping membrane-protein function. Nature 459(7245):379–385. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Polymenis M, Kennedy BK (2012) Chronological and replicative lifespan in yeast. Cell Cycle 11(19):3531. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Poulos A, Johnson DW, Beckman K, White IG, Easton C (1987) Occurrence of unusual molecular species of sphingomyelin containing 28–34-carbon polyenoic fatty acids in ram spermatozoa. Biochem J 248(3):961–964CrossRefPubMedPubMedCentralGoogle Scholar
  53. Radner FPW, Streith IE, Schoiswohl G, Schweiger M, Kumari M, Eichmann TO et al (2010) Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58). J Biol Chem 285(10):7300–7311. CrossRefGoogle Scholar
  54. Ramadurai S, Duurkens R, Krasnikov VV, Poolman B (2010a) Lateral diffusion of membrane proteins: consequences of hydrophobic mismatch and lipid composition. Biophys J 99(5):1482–1489. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ramadurai S, Holt A, Schäfer LV, Krasnikov VV, Rijkers DTS, Marrink SJ et al (2010b) Influence of hydrophobic mismatch and amino acid composition on the lateral diffusion of transmembrane peptides. Biophys J 99(5):1447–1454. CrossRefGoogle Scholar
  56. Rao RP, Yuan C, Allegood JC, Rawat SS, Edwards MB, Wang X et al (2007) Ceramide transfer protein function is essential for normal oxidative stress response and lifespan. Proc Natl Acad Sci USA 104(27):11364–11369. CrossRefGoogle Scholar
  57. Reeve A, Simcox E, Turnbull D (2014) Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev 14(100):19–30. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Saarikangas J, Barral Y (2016) Protein aggregation as a mechanism of adaptive cellular responses. Curr Genet 62(4):711–724. CrossRefPubMedGoogle Scholar
  59. Sandhoff R (2010) Very long chain sphingolipids: tissue expression, function and synthesis. FEBS Lett 584(9):1907–1913. CrossRefGoogle Scholar
  60. Sassa T, Kihara A (2014) Metabolism of very long-chain fatty acids: genes and pathophysiology. Biomol Ther 22(2):83–92. CrossRefGoogle Scholar
  61. Schultz MB, Sinclair DA (2016) When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development (Cambridge England) 143(1):3–14. CrossRefGoogle Scholar
  62. Shmookler Reis RJ (2012) Coming to terms with complexity: limits to a reductionist view of aging. Front Genet 3:149. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387(6633), 569–572. CrossRefPubMedGoogle Scholar
  64. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles—a cause of aging in yeast. Cell 91(7):1033–1042CrossRefPubMedGoogle Scholar
  65. Singh P, Ramachandran SK, Zhu J, Kim BC, Biswas D, Ha T et al (2017) Sphingolipids facilitate age asymmetry of membrane proteins in dividing yeast cells. Mol Biol Cell. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sipiczki M (2000) Where does fission yeast sit on the tree of life? Genome Biol 1(2).
  67. Sonnino S, Prinetti A, Nakayama H, Yangida M, Ogawa H, Iwabuchi K (2009) Role of very long fatty acid-containing glycosphingolipids in membrane organization and cell signaling: the model of lactosylceramide in neutrophils. Glycoconj J 26(6):615–621. CrossRefPubMedGoogle Scholar
  68. Spira F, Mueller NS, Beck G, von Olshausen P, Beig J, Wedlich-Soldner R (2012) Patchwork organization of the yeast plasma membrane into numerous coexisting domains. Nat Cell Biol 14(6):640–648. CrossRefPubMedGoogle Scholar
  69. Thayer NH, Leverich CK, Fitzgibbon MP, Nelson ZW, Henderson KA, Gafken PR et al (2014) Identification of long-lived proteins retained in cells undergoing repeated asymmetric divisions. Proc Natl Acad Sci USA 111(39):14019–14026. CrossRefPubMedGoogle Scholar
  70. Wasko BM, Kaeberlein M (2014) Yeast replicative aging: a paradigm for defining conserved longevity interventions. FEMS Yeast Res 14(1):148–159. CrossRefPubMedGoogle Scholar
  71. Yi JK, Xu R, Jeong E, Mileva I, Truman J-P, Lin C-L et al (2016) Aging-related elevation of sphingoid bases shortens yeast chronological life span by compromising mitochondrial function. Oncotarget 7(16):21124–21144. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Laboratory of Adjuvant and Antigen Research, US Military HIV Research ProgramWalter Reed Army Institute of ResearchSilver SpringUSA
  2. 2.US Military HIV Research ProgramHenry M. Jackson Foundation for the Advancement of Military MedicineBethesdaUSA
  3. 3.Department of Cell Biology, Center for Cell DynamicsJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Department of Chemical and Biomolecular Engineering, Whiting School of EngineeringJohns Hopkins UniversityBaltimoreUSA

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