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J. Biol. Chem., Vol. 283, Issue 1, 350-357, January 4, 2008

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Pharmacogenetic Analysis of Lithium-induced Delayed Aging in Caenorhabditis elegans^*

Gawain McColl, Supported by the American Federation for Aging Research¹, David W. Killilea, Alan E. Hubbard^¶, Maithili C. Vantipalli, Simon Melov², and Gordon J. Lithgow³

From the Buck Institute for Age Research, Novato, California 94945, the Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, California 94609, and the ^¶School of Public Health, University of California, Berkeley California 94720

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 (25% median increase), suggesting Li⁺ regulates survival by modulating histone methylation and chromatin structure.

Received for publication, June 19, 2007 , and in revised form, October 9, 2007.

^* All microarray data are available in Gene Expression Omnibus under accession number GSE8058 [NCBI GEO] . Gene expression studies were facilitated by a Nathan Shock award (P30AG025708). All other nematode strains were obtained from the Caenorhabditis Genetics Center, funded by the National Institutes of Health (NIH) National Center for Research Resources. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures," Figs. S1 and S2, and Tables S1–S5.

² Supported by the Ellison Medical Research Foundation and NIH Grants AG24385 and AG18679.

³ Supported by NIH Grants AG21069, AG22868, and NS050789-01, the Ellison Medical Resarch Foundation, the Glenn Foundation for Medical Research, the American Federation for Aging Research, the Larry L. Hillblom Foundation, and the Herbert Simon Family Medical Foundation.

¹ To whom correspondence should be addressed (present address): Mental Health Research Institute of Victoria, 155 Oak St, Parkville, Victoria 3052, Australia. Tel.: 61-3-9389-2971; Fax: 61-3-9380-6182; E-mail: gmccoll{at}mhri.edu.au.

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