Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans

J Biol Chem. 2008 Jan 4;283(1):350-7. doi: 10.1074/jbc.M705028200. Epub 2007 Oct 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects*
  • Animals
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Line, Tumor
  • Electrophoresis, Polyacrylamide Gel
  • Gene Expression Regulation, Developmental / drug effects*
  • Genome, Helminth
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Immunohistochemistry
  • Lithium Chloride / pharmacology*
  • Longevity / drug effects
  • Longevity / genetics
  • Oligonucleotide Array Sequence Analysis
  • RNA Interference
  • Survival Analysis

Substances

  • Caenorhabditis elegans Proteins
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Lithium Chloride

Associated data

  • GEO/GSE8058