Cell cycle controls stress response and longevity inC. elegans.
Recent studies have revealed a variety of genes and mechanisms that influence the rate of aging progression. In this study, we identified cell cycle factors as potent regulators of health and longevity inC. elegans. Focusing on the cyclin-dependent kinase 2 (cdk-2)and cyclin E (cye-1), we show that inhibition of cell cycle genes leads to tolerance towards environmental stress and longevity. The reproductive system is known as a key regulator of longevity inC. elegans. We uncovered the gonad as the central organ mediating the effects of cell cycle inhibition on lifespan. In particular, the proliferating germ cells were essential for conferring longevity. Steroid hormone signaling and the FOXO transcription factor DAF-16 were required for longevity associated with cell cycle inhibition. Furthermore, we discovered that SKN-1 (ortholog of mammalian Nrf proteins) activates protective gene expression and induces longevity when cell cycle genes are inactivated. We conclude that both, germline absence and inhibition through impairment of cell cycle machinery results in longevity through similar pathways. In addition, our studies suggest further roles of cell cycle genes beyond cell cycle progression and support the recently described connection of SKN-1/Nrf to signals deriving from the germline.
Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
Matthias
M
Dottermusch
Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
Theresa
T
Lakner
Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
Tobias
T
Peyman
Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
Marinella
M
Klein
Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
Gerd
G
Walz
Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, Germany.
Elke
E
Neumann-Haefelin
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D008136:Longevity / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D051357:Cyclin-Dependent Kinase 2
C. elegans; DAF-16/FOXO; SKN-1/Nrf; aging; cell cycle; germline
Dev Cell. 2009 Sep;17(3):355-64
19758560
Curr Biol. 2006 Jan 10;16(1):47-55
16343905
Development. 2006 Feb;133(4):697-709
16421191
Elife. 2015 Aug 24;4:null
26196144
Nature. 2012 Sep 13;489(7415):263-8
22922647
Mol Biol Cell. 2006 Jul;17(7):3051-61
16672375
Nature. 1998 Dec 24-31;396(6713):743-6
9874369
Genesis. 2002 May;33(1):1-7
12001064
PLoS Genet. 2012;8(7):e1002792
22829775
Development. 2011 Jun;138(11):2223-34
21558371
Cell Cycle. 2009 Dec 15;8(24):4091-102
19829076
Genetics. 1974 May;77(1):71-94
4366476
BMC Biol. 2015 Jul 18;13:51
26187634
Mol Cells. 2009 Jul 31;28(1):43-8
19533027
Cell. 2003 Nov 14;115(4):489-502
14622602
Genome Res. 2004 Oct;14(10B):2162-8
15489339
Cell Cycle. 2016;15(2):196-212
26825227
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):E918-27
23431196
Development. 1999 May;126(10):2227-39
10207147
Cell. 1994 Nov 18;79(4):551-5
7954821
Nature. 1999 May 27;399(6734):362-6
10360574
WormBook. 2008 Jan 24;:1-21
18381800
Cell. 2000 Jan 7;100(1):71-8
10647932
Dev Cell. 2001 Dec;1(6):841-51
11740945
Dev Biol. 2003 Feb 1;254(1):102-15
12606285
Development. 2013 Aug;140(15):3079-93
23861057
PLoS One. 2015 Feb 06;10(2):e0117656
25658117
Science. 2003 Apr 25;300(5619):644-7
12690206
Nat Genet. 2001 Jun;28(2):139-45
11381260
Science. 2002 Jan 18;295(5554):502-5
11799246
Cell. 2001 Nov 16;107(4):465-76
11719187
J Gerontol A Biol Sci Med Sci. 2009 Dec;64(12):1207-11
19776215
Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6368-73
18434551
Cell Metab. 2012 May 2;15(5):713-24
22560223
PLoS Genet. 2011 Mar;7(3):e1001348
21455289
Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16275-80
16251270
Nature. 2003 Jul 17;424(6946):277-83
12845331
Development. 1994 Oct;120(10):2901-11
7607080
Nature. 2010 Mar 25;464(7288):504-12
20336132
Genome Biol. 2001;2(1):RESEARCH0002
11178279
Cell. 1987 Nov 20;51(4):601-11
3677169
Cell Cycle. 2012 Apr 1;11(7):1354-63
22421141
PLoS Genet. 2009 Sep;5(9):e1000639
19749979
Nature. 1997 Oct 30;389(6654):994-9
9353126
Nat Rev Mol Cell Biol. 2005 Oct;6(10):766-76
16314866
Nature. 1990 Apr 5;344(6266):549-52
2320127
Free Radic Biol Med. 2015 Nov;88(Pt B):290-301
26232625
Oncogene. 2005 Apr 18;24(17):2776-86
15838514
Development. 1999 Nov;126(21):4849-60
10518501
Science. 2006 Aug 18;313(5789):971-5
16917064
Methods Enzymol. 2002;353:497-505
12078522
Nature. 2002 Jun 6;417(6889):660-3
12050669
Cell Div. 2006 May 12;1:6
16759361
Cell. 2006 Mar 10;124(5):1055-68
16530050
Proc Natl Acad Sci U S A. 2016 May 17;113(20):E2832-41
27140632
Development. 2004 May;131(10):2241-6
15128665
Aging Cell. 2012 Apr;11(2):192-202
22081913
Science. 2006 Jun 2;312(5778):1381-5
16741121
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5014-9
17360327
Development. 1995 Sep;121(9):2961-72
7555722
Cell. 1987 Nov 20;51(4):589-99
3677168
WormBook. 2005 Aug 15;:1-14
18050413
Aging Cell. 2009 Sep;8(5):524-41
19575768
Dev Biol. 1976 Mar;49(1):200-19
943344
Cell. 2008 Mar 21;132(6):1025-38
18358814
Curr Biol. 2012 Sep 25;22(18):R792-3
23017989
Aging Cell. 2003 Jun;2(3):185-90
12882411