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PMID: 17959600 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans.

The Journal of biological chemistry ·Vol. 283 ·No. 1 ·2008-01-04 ·Pages 350-357

McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S, Lithgow GJ

Abstract

Lithium (Li(+)) has been used to treat mood affect disorders, including bipolar, for decades. This drug is neuroprotective and has several identified molecular targets. However, it has a narrow therapeutic range and the one or more underlying mechanisms of its therapeutic action are not understood. Here we describe a pharmacogenetic study of Li(+) in the nematode Caenorhabditis elegans. Exposure to Li(+) at clinically relevant concentrations throughout adulthood increases survival during normal aging (up to 46% median increase). Longevity is extended via a novel mechanism with altered expression of genes encoding nucleosome-associated functions. Li(+) treatment results in reduced expression of the worm ortholog of LSD-1 (T08D10.2), a histone demethylase; knockdown by RNA interference of T08D10.2 is sufficient to extend longevity ( approximately 25% median increase), suggesting Li(+) regulates survival by modulating histone methylation and chromatin structure.

MeSH Terms
Aging/drug effects Animals Caenorhabditis elegans/drug effects,genetics,growth & development Caenorhabditis elegans Proteins/genetics,metabolism Cell Line, Tumor Electrophoresis, Polyacrylamide Gel Gene Expression Regulation, Developmental/drug effects Genome, Helminth Glycogen Synthase Kinase 3/genetics,metabolism Glycogen Synthase Kinase 3 beta Humans Immunohistochemistry Lithium Chloride/pharmacology Longevity/drug effects,genetics Oligonucleotide Array Sequence Analysis RNA Interference Survival Analysis
Chemicals
Caenorhabditis elegans Proteins Glycogen Synthase Kinase 3 beta Glycogen Synthase Kinase 3 Lithium Chloride
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
McColl Gawain
Buck Institute for Age Research, Novato, California 94945, the. Electronic address: gmccoll@mhri.edu.au.
Killilea David W
Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, California 94609, and the.
Hubbard Alan E
School of Public Health, University of California, Berkeley California 94720.
Vantipalli Maithili C
Buck Institute for Age Research, Novato, California 94945, the.
Melov Simon
Buck Institute for Age Research, Novato, California 94945, the.
Lithgow Gordon J
Buck Institute for Age Research, Novato, California 94945, the.
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M705028200
Email
gmccoll@mhri.edu.au
Published
2008-01-04
Epub
2007-00-24
Pages
350-357
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2739662
Subset
IM
Grants
NIA NIH HHS · R01 AG022868-01 · United States
NIA NIH HHS · AG 21069 · United States
NIA NIH HHS · P30 AG 025708 · United States
NINDS NIH HHS · R03 NS050789 · United States
NIA NIH HHS · R01 AG022868-05 · United States
NINDS NIH HHS · NS 050789-01 · United States
NIA NIH HHS · R01 AG021069 · United States
NIA NIH HHS · R01 AG022868-04 · United States
NIA NIH HHS · R01 AG021069-04 · United States
NIA NIH HHS · P30 AG025708 · United States
NIA NIH HHS · AG 22868 · United States
NIA NIH HHS · R01 AG021069-01 · United States
NIA NIH HHS · R01 AG022868 · United States
NIA NIH HHS · R01 AG021069-03 · United States
NIA NIH HHS · R01 AG022868-03 · United States
NIA NIH HHS · R01 AG021069-02 · United States
NIA NIH HHS · R01 AG018679 · United States
NIA NIH HHS · R01 AG024385 · United States
NIA NIH HHS · R01 AG021069-05 · United States
NIA NIH HHS · R01 AG022868-02 · United States
Databases
GEO
GSE8058
External Links
PubMed source DOI: 10.1074/jbc.M705028200 PMC Full Text View journal details
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