Document Detail

Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity.
MedLine Citation:
PMID:  23020244     Owner:  NLM     Status:  MEDLINE    
Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared with WT mice. CR applied to AC5 KO results in rapid decrease in body weight, metabolic deterioration, and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle, and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD, and olfactory receptors in both young- and intermediate-age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR mice, particularly related to the metabolic phenotype, suggest a unified theory for longevity and stress resistance.
Lin Yan; Ji Yeon Park; Jean-Guillaume Dillinger; Mariana S De Lorenzo; Chujun Yuan; Lo Lai; Chunbo Wang; David Ho; Bin Tian; William C Stanley; Johan Auwerx; Dorothy E Vatner; Stephen F Vatner
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-17
Journal Detail:
Title:  Aging cell     Volume:  11     ISSN:  1474-9726     ISO Abbreviation:  Aging Cell     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-16     Completed Date:  2013-04-18     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  101130839     Medline TA:  Aging Cell     Country:  England    
Other Details:
Languages:  eng     Pagination:  1110-20     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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MeSH Terms
Adenylate Cyclase / deficiency,  genetics*
Apolipoproteins D / genetics,  metabolism
Body Weight
Brain / metabolism
Caloric Restriction*
Gene Expression Profiling
Gene Expression Regulation*
Insulin Resistance / genetics
Liver / metabolism
Longevity / genetics*
MAP Kinase Signaling System / genetics
Mice, Knockout
Muscle, Skeletal / metabolism
Myocardium / metabolism
Receptors, Odorant / genetics,  metabolism
Sirtuin 1 / genetics,  metabolism
Stress, Physiological / genetics*
Grant Support
1R01HL102472/HL/NHLBI NIH HHS; 231138//European Research Council; 5P01AG027211/AG/NIA NIH HHS; 5P01HL069020/HL/NHLBI NIH HHS; 5R01HL033107/HL/NHLBI NIH HHS; 5R01HL091781/HL/NHLBI NIH HHS; 5R01HL095888/HL/NHLBI NIH HHS; 5R21HL097264/HL/NHLBI NIH HHS; 5T32HL069752/HL/NHLBI NIH HHS; DK059820/DK/NIDDK NIH HHS; P01 AG027211/AG/NIA NIH HHS; P01 HL069020/HL/NHLBI NIH HHS; R01 HL033107/HL/NHLBI NIH HHS; R01 HL091781/HL/NHLBI NIH HHS; R01 HL093481/HL/NHLBI NIH HHS; R01 HL095888/HL/NHLBI NIH HHS; R01 HL102472/HL/NHLBI NIH HHS; R01 HL106511/HL/NHLBI NIH HHS; R01HL093481/HL/NHLBI NIH HHS; R01HL106511/HL/NHLBI NIH HHS; R21 HL097264/HL/NHLBI NIH HHS; T32 HL069752/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Apolipoproteins D; 0/Receptors, Odorant; EC 3.5.1.-/Sirt1 protein, mouse; EC 3.5.1.-/Sirtuin 1; EC Cyclase; EC cyclase type V

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