The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration.
A central focus of aging research is to determine how calorie restriction (CR) extends lifespan and delays diseases of aging. SIRT1, the mammalian ortholog of Sir2 in yeast, is a longevity factor which mediates dietary restriction in diverse species. In addition, SIRT1 plays a protective role in several models of neurodegenerative disease. We tested the role of SIRT1 in mediating the effects of CR in a mouse model of prion disease. Prion diseases are protein misfolding disorders of the central nervous system with many similarities to other neurodegenerative diseases, including deposition of aggregated protein, gliosis, and loss of synapses and neurons. We report that the onset of prion disease is delayed by CR and in the SIRT1 KO mice fed ad libitum. CR exerts no further effect on the SIRT1 KO strain, suggesting the effects of CR and SIRT1 deletion are mechanistically coupled. In conjunction, SIRT1 is downregulated in certain brain regions of CR mice. The expression of PrP mRNA and protein is reduced in the brains of CR mice and in SIRT1 knockout mice, suggesting a possible mechanism for the delayed onset of disease, as PrP levels are a critical determinant of how quickly mice succumb to prion disease. Surprisingly, CR greatly shortens the duration of clinical symptoms of prion disease and ultimately shortens lifespan of prion-inoculated mice in a manner that is independent of SIRT1. Taken together, our results suggest a more complex interplay between CR, SIRT1, and neurodegenerative diseases than previously appreciated.
Chen
Danica
D
Department of Biology, MIT, Cambridge, MA 02139, USA.
Steele
Andrew D
AD
Hutter
Gregor
G
Bruno
Joanne
J
Govindarajan
Arvind
A
Easlon
Erin
E
Lin
Su-Ju
SJ
Aguzzi
Adriano
A
Lindquist
Susan
S
Guarente
Leonard
L
D000375:Aging / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins
Sci Am. 2006 Mar;294(3):48-51, 54-7
16502611
Science. 2003 Oct 31;302(5646):871-4
14593181
J Biol Chem. 2006 Aug 4;281(31):21745-21754
16751189
Science. 2004 Jul 16;305(5682):390-2
15205477
Nat Rev Mol Cell Biol. 2007 Jul;8(7):552-61
17585315
Rev Sci Tech. 1998 Apr;17(1):278-90
9638817
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2911-6
12589027
Cell. 2005 Feb 25;120(4):473-82
15734680
Genes Dev. 2003 Feb 1;17(3):313-21
12569120
J Biol Chem. 2002 Feb 15;277(7):5675-82
11739375
Nature. 2003 Sep 11;425(6954):191-6
12939617
Nature. 1996 Jan 25;379(6563):339-43
8552188
Science. 2004 Mar 26;303(5666):2011-5
14976264
Nat Rev Drug Discov. 2006 Jun;5(6):493-506
16732220
Science. 2007 Jul 27;317(5837):516-9
17588900
Prion. 2007 Apr-Jun;1(2):83-93
19164918
Trends Mol Med. 2007 Feb;13(2):64-71
17207661
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
9811807
Nature. 2000 Feb 17;403(6771):795-800
10693811
Cell. 2006 Jul 28;126(2):257-68
16873059
J Immunol. 1983 Jul;131(1):491-6
6408182
Genes Dev. 2006 Nov 1;20(21):2913-21
17079682
Science. 2005 Dec 9;310(5754):1641
16339438
Science. 2004 Aug 13;305(5686):1010-3
15310905
Nat Rev Microbiol. 2006 Oct;4(10):765-75
16980938
Mol Cell Biol. 2003 Jan;23(1):38-54
12482959
EMBO J. 2007 Jul 11;26(13):3169-79
17581637
Aging Cell. 2007 Dec;6(6):759-67
17877786
J Neurosci. 2007 Nov 21;27(47):13022-7
18032675
Neurobiol Aging. 2005 Jul;26(7):995-1000
15748777
Nat Genet. 2005 Apr;37(4):349-50
15793589
J Biol Chem. 2005 Dec 2;280(48):40364-74
16183991