Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging.
Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.
Ben-Zvi
Anat
A
Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
Miller
Elizabeth A
EA
Morimoto
Richard I
RI
D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D011487:Protein Conformation; D017510:Protein Folding
D029742:Caenorhabditis elegans Proteins
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16690-5
16269543
Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10438-43
9294229
Science. 2002 Oct 25;298(5594):830-4
12399591
Biol Lett. 2005 Jun 22;1(2):247-9
17148178
J Mol Biol. 1977 Jul;114(1):133-40
909083
Science. 2008 May 9;320(5877):811-4
18467592
FEBS J. 2008 Apr;275(7):1377-1383
18279377
Mol Biol Cell. 2004 Feb;15(2):657-64
14668486
Science. 2006 Sep 15;313(5793):1604-10
16902091
PLoS Biol. 2007 Sep;5(9):e237
17850180
Nat Genet. 2005 Aug;37(8):894-8
16041374
Cell. 2008 Jul 25;134(2):341-52
18662548
J Cell Biol. 2008 Aug 25;182(4):663-73
18725537
Free Radic Biol Med. 2002 Oct 15;33(8):1021-5
12374613
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3498-503
14993615
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10417-22
12122205
J Intern Med. 2008 Feb;263(2):117-27
18226090
Genetics. 1997 Jun;146(2):553-65
9178006
Genes Dev. 1998 Mar 1;12(5):654-66
9499401
J Biol Chem. 2008 Jan 11;283(2):784-91
17993648
Science. 2004 Mar 26;303(5666):2011-5
14976264
Dev Cell. 2007 Feb;12(2):235-46
17276341
Curr Biol. 2002 Sep 17;12(18):1566-73
12372248
Cell. 1998 Jun 12;93(6):939-49
9635424
Science. 2009 Feb 20;323(5917):1063-6
19229036
Science. 1992 Aug 28;257(5074):1220-4
1355616
Nature. 2001 Feb 15;409(6822):928-33
11237013
Nature. 2008 Feb 28;451(7182):1069-75
18305538
Genetics. 2002 Jul;161(3):1101-12
12136014
Nat Biotechnol. 2001 Mar;19(3):242-7
11231557
Nature. 1976 Feb 12;259(5543):489-91
176591
Science. 2008 Feb 15;319(5865):916-9
18276881
Cell. 1997 Aug 8;90(3):537-48
9267033
Science. 2006 Mar 10;311(5766):1471-4
16469881
Genetics. 2001 Sep;159(1):133-45
11560892
Cell. 1998 Aug 21;94(4):471-80
9727490
Trends Cell Biol. 2008 Jun;18(6):264-72
18495480
J Neurosci Methods. 1999 Jul 1;89(1):33-40
10476681
Science. 2003 Apr 25;300(5619):644-7
12690206
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8084-9
15141086
Annu Rev Genomics Hum Genet. 2006;7:61-80
16824020
Science. 2000 Oct 6;290(5489):147-50
11021802
Nat Rev Neurosci. 2001 Nov;2(11):806-19
11715057
Mech Ageing Dev. 2006 Oct;127(10):763-70
16893561
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7540-4
7638227
Aging Cell. 2003 Apr;2(2):131-9
12882326
J Proteome Res. 2003 Jan-Feb;2(1):23-35
12643540
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6403-8
15084750
Curr Biol. 2001 Dec 11;11(24):1975-80
11747825
J Biol Chem. 2001 Jun 8;276(23):20551-8
11278828
Genes Dev. 2008 Jun 1;22(11):1427-38
18519635
J Mol Biol. 1991 Jun 5;219(3):429-41
2051482
PLoS Genet. 2009 Mar;5(3):e1000399
19266020
Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
17565364
Nature. 2002 Oct 24;419(6909):808-14
12397350
Science. 2003 May 16;300(5622):1142-5
12750521
Aging Cell. 2005 Jun;4(3):127-37
15924569
Nat Genet. 2004 Feb;36(2):197-204
14730301
J Cell Biol. 1987 Dec;105(6 Pt 1):2763-70
3320053