Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans.
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.
McColl
Gawain
G
Buck Institute for Age Research, Novato, California 94945, the. Electronic address: gmccoll@mhri.edu.au.
Killilea
David W
DW
Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, California 94609, and the.
Hubbard
Alan E
AE
School of Public Health, University of California, Berkeley California 94720.
Vantipalli
Maithili C
MC
Buck Institute for Age Research, Novato, California 94945, the.
Melov
Simon
S
Buck Institute for Age Research, Novato, California 94945, the.
Lithgow
Gordon J
GJ
Buck Institute for Age Research, Novato, California 94945, the.
D000375:Aging / Q000187:drug effects*; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D049751:Genome, Helminth; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D018021:Lithium Chloride / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D016019:Survival Analysis
D029742:Caenorhabditis elegans Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride