TOR signaling never gets old: aging, longevity and TORC1 activity.
The target of rapamycin (TOR) signal transduction network monitors intra- and extracellular conditions that favor cell growth. Research during the last decade has revealed a modular structure of the TOR signaling network. Each signaling module senses a particular set of signals from the cellular milieu and exerts regulatory control towards TOR activity. The TOR pathway responds to growth factor signals, nutrient availability, and cellular stresses like hypoxia and energy stress. The signaling modules and their molecular components constituting the TOR network are remarkably conserved in both sequence and function across species. In yeast, roundworms, flies, and mice, the TOR pathway has been shown to regulate lifespan. Correspondingly, genetic, dietary or pharmacological manipulation of individual signaling modules as well as TOR activity itself extends lifespan in these model organisms. We discuss the potential impact of manipulating TOR activity for human health and lifespan.
Evans
Daniel S
DS
Department of Medicine, University of California, San Francisco, United States.
Kapahi
Pankaj
P
Hsueh
Wen-Chi
WC
Kockel
Lutz
L
D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C500984:CRTC1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; C500749:target of rapamycin protein, S cerevisiae
Mech Ageing Dev. 1998 May 1;102(1):45-53
9663791
PLoS Biol. 2007 Oct 2;5(10):e261
17914901
Nat Rev Genet. 2007 Sep;8(9):711-23
17680008
Nature. 2007 Nov 29;450(7170):712-6
18046409
J Gerontol A Biol Sci Med Sci. 2006 May;61(5):444-60
16720740
Mol Cell Biol. 2002 Mar;22(6):1656-63
11865045
Lancet. 2009 Oct 3;374(9696):1196-208
19801098
Science. 2005 Nov 18;310(5751):1193-6
16293764
Biochem Soc Trans. 2007 Nov;35(Pt 5):1187-90
17956308
Nature. 1999 May 20;399(6733):271-5
10353251
Curr Biol. 2004 May 25;14(10):885-90
15186745
Genes Dev. 2004 Dec 1;18(23):2893-904
15545625
Cell. 2009 Oct 2;139(1):149-60
19804760
Nature. 2009 Feb 5;457(7230):726-30
19079239
Nat Rev Mol Cell Biol. 2004 Oct;5(10):827-35
15459663
Genes Dev. 2000 Aug 1;14(15):1872-85
10921902
Physiology (Bethesda). 2006 Oct;21:362-9
16990457
Cell Metab. 2007 Apr;5(4):265-77
17403371
Sci Signal. 2009 Nov 24;2(98):ra75
19934433
Cell. 2006 Sep 8;126(5):955-68
16959574
Mol Cell. 2003 Aug;12(2):271-80
14536067
Nature. 2007 Feb 15;445(7129):785-8
17301792
J Cell Biol. 2004 Nov 8;167(3):399-403
15533996
PLoS Genet. 2007 Apr 6;3(4):e56
17411345
PLoS Genet. 2009 May;5(5):e1000486
19461873
Nat Cell Biol. 2008 Aug;10(8):935-45
18604198
Science. 2006 Oct 20;314(5798):467-71
17053147
Cell Cycle. 2009 Feb 15;8(4):567-72
19197153
EMBO J. 1995 Nov 15;14(22):5701-9
8521827
J Biol Chem. 2000 Aug 18;275(33):25733-41
10823831
Eur J Biochem. 1993 Apr 15;213(2):689-99
8386634
Cell Cycle. 2008 Sep 1;7(17):2769-73
18728386
Trends Cell Biol. 2004 Feb;14(2):78-85
15102439
Nature. 2009 Jul 16;460(7253):392-5
19587680
Nature. 2007 Feb 22;445(7130):922-6
17277769
Mol Cell. 2008 Apr 25;30(2):214-26
18439900
Nat Cell Biol. 2007 Mar;9(3):316-23
17277771
Genes Chromosomes Cancer. 2003 Dec;38(4):376-81
14566858
Genes Dev. 2000 Nov 1;14(21):2689-94
11069885
Autophagy. 2007 Nov-Dec;3(6):597-9
17912023
Mol Cell. 2008 May 23;30(4):393-402
18498744
Curr Biol. 2007 Oct 9;17(19):1646-56
17900900
Genetics. 2003 Jan;163(1):35-46
12586694
Aging Cell. 2007 Aug;6(4):525-33
17521386
Development. 2004 Aug;131(16):3897-906
15253933
Science. 2009 May 29;324(5931):1196-8
19372390
PLoS Biol. 2009 Feb 10;7(2):e38
19209957
Nature. 2009 Jul 30;460(7255):587-91
19641587
Nat Cell Biol. 2002 Sep;4(9):658-65
12172554
Curr Biol. 2005 Jan 11;15(1):24-30
15649360
PLoS Genet. 2009 May;5(5):e1000467
19424415
FEBS Lett. 2008 Sep 3;582(20):3005-10
18692051
Curr Biol. 2004 Sep 7;14(17):1540-9
15341740
Cell. 2005 Feb 25;120(4):449-60
15734678
Oncogene. 1999 Sep 9;18(36):5108-14
10490847
Mol Cell Biol. 2004 Apr;24(8):3112-24
15060135
Genome Res. 2008 Apr;18(4):564-70
18340043
Aging Cell. 2007 Feb;6(1):95-110
17266679
Biochem J. 2008 Jun 1;412(2):211-21
18387000
Cancer Cell. 2004 Jul;6(1):91-9
15261145
FASEB J. 2006 Mar;20(3):466-75
16507764
Nature. 2003 Jan 9;421(6919):182-7
12483226
Cell Metab. 2007 Jun;5(6):476-87
17550782
Dev Cell. 2005 Aug;9(2):271-81
16054033
J Biol Chem. 1998 Jun 5;273(23):14484-94
9603962
Nature. 2003 Dec 11;426(6967):620
14668850
Cell. 2008 Apr 18;133(2):292-302
18423200
Gastroenterology. 2009 Aug;137(2):482-8
19375425
Cancer Cell. 2007 Jul;12(1):9-22
17613433
Science. 2009 May 22;324(5930):1029-33
19460998
Genes Dev. 2004 Jul 1;18(13):1533-8
15231735
Nat Rev Cancer. 2008 May;8(5):387-98
18432252
Cell. 2001 Oct 5;107(1):43-54
11595184
Science. 2008 Jun 13;320(5882):1496-501
18497260
Trends Mol Med. 2009 May;15(5):217-24
19380253
Nature. 1959 Jun 20;183(4677):1751-2
13666896
EMBO J. 2006 Jun 21;25(12):2781-91
16763566
Science. 2001 Apr 6;292(5514):107-10
11292875
BMJ. 2005 Jun 4;330(7503):1304-5
15849206
Science. 2001 Apr 13;292(5515):288-90
11292860
Sci Signal. 2009 Apr 21;2(67):pe27
19383978
Biochem Soc Trans. 2009 Feb;37(Pt 1):289-90
19143648
PLoS Genet. 2008 Feb;4(2):e24
18282106
Cancer Cell. 2007 Aug;12(2):104-7
17692802
Autophagy. 2009 Jul;5(5):725-6
19395872
Nat Rev Cancer. 2008 Nov;8(11):865-73
18923434
J Gerontol A Biol Sci Med Sci. 2009 Jan;64(1):47-60
19168782
EMBO J. 2001 Aug 15;20(16):4370-9
11500364
PLoS One. 2009 Jul 27;4(7):e6348
19633713
Nature. 2003 Jan 16;421(6920):231-7
12529635
Nature. 2006 Aug 17;442(7104):779-85
16915281
Mol Cell. 2007 Mar 23;25(6):903-15
17386266
Sci STKE. 2003 Dec 09;2003(212):re15
14668532
Nature. 2009 Jan 8;457(7226):210-4
19052547
Cell Res. 2008 May;18(5):523-7
18392048
Nature. 2006 Nov 16;444(7117):337-42
17086191
Aging Cell. 2009 Sep;8(5):509-13
19558590
Diabetes Care. 2009 Sep;32(9):1620-5
19564453
Cell. 2009 Feb 6;136(3):521-34
19203585
Mol Cell. 2002 Sep;10(3):457-68
12408816
Cell Stem Cell. 2009 Sep 4;5(3):279-89
19733540
Science. 2007 Aug 10;317(5839):803-6
17690294
PLoS Genet. 2009 Mar;5(3):e1000414
19293945
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17414-9
18955708
Acta Physiol (Oxf). 2009 May;196(1):65-80
19245654
Neurology. 2006 Oct 24;67(8):1340-52
17060558
Nat Cell Biol. 2002 Sep;4(9):648-57
12172553
Science. 2001 Apr 6;292(5514):104-6
11292874
Genes Dev. 2007 Dec 15;21(24):3232-7
18055695
Development. 2006 Feb;133(4):611-9
16407400
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10430-5
10973499
Cell Metab. 2009 Feb;9(2):113-4
19187769
Best Pract Res Clin Endocrinol Metab. 2008 Oct;22(5):671-85
19028351
Cell Cycle. 2009 Aug;8(15):2324
19633411
EMBO J. 1998 Nov 16;17(22):6649-59
9822608
Genes Dev. 2004 Dec 15;18(24):3004-9
15574588
Cancer Res. 2007 Jul 15;67(14):6745-52
17638885
Cell. 2003 Nov 26;115(5):577-90
14651849
Nat Genet. 1998 Jun;19(2):171-4
9620775
Cell Metab. 2010 Jun 9;11(6):453-65
20519118
Science. 2009 Oct 2;326(5949):140-4
19797661
Curr Biol. 2002 Sep 3;12(17):1448-61
12225660
Mol Cell. 2006 Apr 21;22(2):159-68
16603397
Trends Mol Med. 2005 Aug;11(8):353-61
16002336
Genes Dev. 2004 Dec 1;18(23):2879-92
15545626
Gerontology. 1980;26(5):241-6
7390164
Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85
17712357
Cell Metab. 2010 Jan;11(1):35-46
20074526
Nat Genet. 2005 Jan;37(1):19-24
15624019
Diabetes. 2006 Aug;55(8):2180-91
16873680
Genes Dev. 2006 Jan 15;20(2):174-84
16418483
J Biol Chem. 2001 Aug 17;276(33):30914-22
11418588
Aging Cell. 2007 Feb;6(1):111-9
17266680
Mol Cell Biol. 2004 Aug;24(15):6539-49
15254222
Nat Med. 2006 Jan;12(1):122-7
16341243
J Biol Chem. 2008 Nov 7;283(45):30482-92
18676370
Development. 2009 Oct;136(19):3205-14
19736321
Cell. 2005 Nov 18;123(4):569-80
16286006
Nat Cell Biol. 2003 Jun;5(6):578-81
12771962
Science. 2005 May 20;308(5725):1181-4
15905404
Nature. 1997 Nov 6;390(6655):45-51
9363890
Science. 1997 Jul 4;277(5322):99-101
9204908
Mol Cell. 2002 Jul;10(1):151-62
12150915
Genes Dev. 2000 Nov 1;14(21):2712-24
11069888
PLoS One. 2010 Jan 18;5(1):e8758
20090912
Science. 2005 Sep 16;309(5742):1829-33
16123266
Cell Metab. 2006 Aug;4(2):133-42
16890541
Ageing Res Rev. 2009 Jan;8(1):43-51
19022406
Eur J Biochem. 2004 Jul;271(14):2923-36
15233788
Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
19339977
J Biol Chem. 2009 Mar 20;284(12):8023-32
19150980
Mol Cell Biol. 2001 Feb;21(3):743-54
11154262
Cell. 2008 Jan 25;132(2):171-6
18243090
Genes Dev. 2008 Jan 15;22(2):239-51
18198340
Aging Cell. 2003 Apr;2(2):73-81
12882320
PLoS One. 2009;4(4):e5242
19370158
Sci Signal. 2009 Apr 21;2(67):pe24
19383975