title: Sphingolipids and lifespan regulation.
abstract: Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipids so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
authors: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, 741 S. Limestone, Lexington, KY 40536, USA.
authors: Xinhe
authors: X
authors: Huang
authors: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, 741 S. Limestone, Lexington, KY 40536, USA.
authors: Bradley R
authors: BR
authors: Withers
authors: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, 741 S. Limestone, Lexington, KY 40536, USA. Electronic address: bobd@uky.edu.
authors: Robert C
authors: RC
authors: Dickson
mesh_terms: D000818:Animals; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008954:Models, Biological; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: D013107:Sphingolipids
keywords: Aging; Autophagy; Ceramide; Myriocin; Sphingosing-1-phosphate
references: Age (Dordr). 2008 Mar;30(1):43-52
references: 19424872
references: PLoS Genet. 2011 May;7(5):e1002063
references: 21625621
references: Nature. 2010 Mar 25;464(7288):504-12
references: 20336132
references: Microbiology (Reading). 2004 Oct;150(Pt 10):3289-304
references: 15470109
references: Chem Rev. 2011 Oct 12;111(10):6387-422
references: 21942574
references: Handb Exp Pharmacol. 2013;(215):197-210
references: 23579457
references: Mech Ageing Dev. 2012 May;133(5):317-30
references: 22445853
references: Curr Opin Genet Dev. 2013 Feb;23(1):53-62
references: 23317514
references: Antioxid Redox Signal. 2011 Nov 1;15(9):2501-17
references: 21453197
references: J Biol Chem. 2005 Jun 17;280(24):22679-87
references: 15840588
references: Genes Dev. 1996 Feb 15;10(4):382-94
references: 8600023
references: Adv Cancer Res. 2013;117:37-58
references: 23290776
references: Cell. 2011 Sep 2;146(5):682-95
references: 21884931
references: Biochem J. 2012 Feb 1;441(3):789-802
references: 22248339
references: Cell Metab. 2008 Mar;7(3):200-3
references: 18316025
references: PLoS One. 2011;6(6):e20411
references: 21687659
references: Am J Pathol. 2012 Oct;181(4):1142-6
references: 22841821
references: J Biol Chem. 2001 Jun 8;276(23):20589-96
references: 11279185
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11364-9
references: 17592126
references: Biochim Biophys Acta. 2002 Jun 13;1583(1):13-25
references: 12069845
references: Biochim Biophys Acta. 2000 Sep 18;1469(2):63-77
references: 10998569
references: Comp Biochem Physiol B Biochem Mol Biol. 2012 Sep;163(1):26-36
references: 22613819
references: Nature. 2009 Jul 16;460(7253):392-5
references: 19587680
references: Adv Exp Med Biol. 2011;721:19-39
references: 21910080
references: Biochim Biophys Acta. 2003 Jun 10;1632(1-3):16-30
references: 12782147
references: Geriatr Gerontol Int. 2010 Jul;10 Suppl 1:S41-52
references: 20590841
references: Nat Rev Cancer. 2013 Jan;13(1):51-65
references: 23235911
references: J Biol Chem. 1997 Nov 21;272(47):29620-5
references: 9368028
references: Trends Cell Biol. 2012 Jan;22(1):50-60
references: 22001186
references: Subcell Biochem. 2008;49:469-86
references: 18751923
references: Am J Hum Biol. 2012 Mar-Apr;24(2):101-6
references: 22290875
references: Biochem Soc Trans. 2011 Apr;39(2):460-5
references: 21428920
references: Cell Mol Life Sci. 2008 Jun;65(12):1933-42
references: 18500447
references: Science. 2013 Mar 29;339(6127):1546-58
references: 23539594
references: Development. 2004 Aug;131(16):3897-906
references: 15253933
references: Clin Sci (Lond). 2010 Mar 30;118(12):727-36
references: 20102334
references: Mol Cell Biochem. 2010 Apr;337(1-2):153-8
references: 19856145
references: EMBO J. 2001 Jun 1;20(11):2655-65
references: 11387200
references: Mol Microbiol. 2011 Jul;81(2):515-27
references: 21707788
references: PLoS Genet. 2012;8(8):e1002834
references: 22912585
references: J Clin Invest. 2013 Mar;123(3):946-50
references: 23454756
references: Biochim Biophys Acta. 1999 Jun 10;1438(3):305-21
references: 10366774
references: Anticancer Agents Med Chem. 2011 Nov;11(9):782-93
references: 21707493
references: J Biol Chem. 2000 Dec 15;275(50):39793-8
references: 11006294
references: J Neurol Sci. 2009 Mar 15;278(1-2):5-15
references: 19147160
references: Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1119-29
references: 18203850
references: PLoS One. 2012;7(5):e37703
references: 22629445
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
references: 18216770
references: J Clin Invest. 2012 May;122(5):1786-90
references: 22466649
references: PLoS Genet. 2012 Feb;8(2):e1002493
references: 22319457
references: Nature. 2003 Dec 11;426(6967):620
references: 14668850
references: J Biol Chem. 2011 Aug 12;286(32):27855-62
references: 21693702
references: Mol Cell. 2007 Jun 8;26(5):663-74
references: 17560372
references: Science. 2009 Apr 17;324(5925):381-4
references: 19372430
references: Nat Cell Biol. 2012 Apr 15;14(5):542-7
references: 22504275
references: Science. 2001 Apr 13;292(5515):288-90
references: 11292860
references: PLoS One. 2012;7(9):e45890
references: 23049887
references: FEBS Lett. 2005 Mar 28;579(9):1973-7
references: 15792805
references: J Biol Chem. 1994 Jun 3;269(22):15451-9
references: 8195187
references: Atherosclerosis. 2013 May;228(1):98-109
references: 23466071
references: Nat Med. 2011 Feb;17(2):179-88
references: 21217695
references: J Biol Chem. 2004 Mar 19;279(12):11537-45
references: 14699160
references: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
references: 22436748
references: Mol Syst Biol. 2010 Nov 30;6:430
references: 21119626
references: Aging Cell. 2013 Oct;12(5):833-41
references: 23725375
references: Pharmacol Res. 2011 Jan;63(1):23-9
references: 20934512
references: Apoptosis. 2007 May;12(5):923-39
references: 17294080
references: J Lipid Res. 2013 Jan;54(1):5-19
references: 23152582
references: PLoS One. 2012;7(10):e47650
references: 23110086
references: FEBS Lett. 2006 Mar 20;580(7):1903-7
references: 16527275
references: Membranes (Basel). 2011 Dec 1;1(4):394-411
references: 22368779
references: Nature. 2010 May 27;465(7297):492-6
references: 20505730
references: J Biol Chem. 2012 Nov 16;287(47):39898-910
references: 23035115
references: PLoS One. 2013;8(3):e56564
references: 23483888
references: Subcell Biochem. 2008;49:413-40
references: 18751921
references: Subcell Biochem. 2012;57:123-43
references: 22094420
references: Aging Cell. 2012 Aug;11(4):675-82
references: 22587563
references: Biochem J. 1998 Nov 1;335 ( Pt 3):465-80
references: 9794783
references: Cell Metab. 2012 Jul 3;16(1):18-31
references: 22768836
references: Cell Mol Life Sci. 2012 Jul;69(13):2135-46
references: 22294100
references: FEMS Microbiol Rev. 2012 Mar;36(2):306-39
references: 21658086
references: Cell Mol Life Sci. 2010 May;67(9):1477-90
references: 20112046
references: Mol Cell. 2010 Oct 22;40(2):267-79
references: 20965421
references: Nature. 2012 Sep 27;489(7417):585-9
references: 22940862
references: Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(4):426-37
references: 20431265
references: Nat Chem Biol. 2012 Oct;8(10):831-8
references: 22922758
references: Science. 2009 Oct 2;326(5949):140-4
references: 19797661
references: Cell Cycle. 2009 Apr 15;8(8):1122-6
references: 19282666
references: Biochem Soc Trans. 2012 Jun 1;40(3):547-54
references: 22616865
references: Mech Ageing Dev. 2001 Jul 15;122(9):895-908
references: 11348657
references: J Biol Chem. 2010 Sep 24;285(39):30224-32
references: 20647309
references: Cell Metab. 2010 Jan;11(1):35-46
references: 20074526
references: FEBS Lett. 2012 Aug 31;586(18):2858-67
references: 22824640
references: Mol Syst Biol. 2010;6:349
references: 20160710
references: Diabetes. 2012 Jun;61(6):1315-22
references: 22618766
references: Autophagy. 2013 Feb 1;9(2):258-9
references: 23182807
references: Vitam Horm. 2013;91:271-84
references: 23374721
references: Genes Dev. 2006 Jan 15;20(2):174-84
references: 16418483
references: Prog Lipid Res. 2012 Oct;51(4):378-93
references: 22835784
references: Adv Exp Med Biol. 2010;688:217-31
references: 20919657
references: Biochim Biophys Acta. 2006 Dec;1758(12):1864-84
references: 17052686
references: Mol Biol Cell. 2008 Mar;19(3):865-76
references: 18162582
references: Biochim Biophys Acta. 2013 Nov;1833(11):2511-8
references: 23611790
references: Mol Cell. 2010 Oct 22;40(2):333-44
references: 20965426
references: Science. 2012 Aug 31;337(6098):1047-9
references: 22936764
references: Curr Biol. 2012 Sep 11;22(17):R741-52
references: 22975005
references: Cell Metab. 2012 May 2;15(5):585-94
references: 22560211
references: Acta Pharmacol Sin. 2009 Oct;30(10):1454-61
references: 19749786
references: Neurology. 2012 Aug 14;79(7):633-41
references: 22815558
references: J Alzheimers Dis. 2012;30 Suppl 2:S231-49
references: 22337830
references: Aging Cell. 2013 Aug;12(4):652-60
references: 23601176
references: Mol Biol Cell. 2001 Nov;12(11):3417-27
references: 11694577
references: Mol Cell. 2012 Mar 30;45(6):743-53
references: 22445487
references: Aging Cell. 2003 Apr;2(2):73-81
references: 12882320
references: F1000Prime Rep. 2013;5:5
references: 23513177
references: Cell Biochem Funct. 2009 Dec;27(8):547-51
references: 19842094
references: Aging Cell. 2010 Oct;9(5):698-708
references: 20569235
references: J Biol Chem. 1995 Dec 22;270(51):30701-8
references: 8530509
references: Exp Gerontol. 2004 Jul;39(7):999-1009
references: 15236759
references: J Proteome Res. 2013 Jun 7;12(6):2679-89
references: 23590626