RESEARCH PAPER


Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes

Alexander A. Goldberg1†, Vincent R. Richard1†, Pavlo Kyryakov1†, Simon D. Bourque1†, Adam Beach1, Michelle T. Burstein1, Anastasia Glebov1, Olivia Koupaki1, Tatiana Boukh-Viner1, Christopher Gregg1, Mylène Juneau1, Ann M. English2, David Y. Thomas3 and Vladimir I. Titorenko1
1 Department of Biology , Concordia University, Montreal, Quebec H4B 1R6, Canada
2 Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec H4B 1R6, Canada
3 Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
† These authors contributed equally to this work
Key words:
Cellular aging, longevity, yeast, caloric restriction, chemical biology, anti-aging compounds
Received:
06/25/10; accepted: 07/06/10; published on line: 07/07/10
Corresponding author:
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Abstract

In chronologically aging yeast, longevity can be extended by administering a caloric restriction (CR) diet or some small molecules. These life-extending interventions target the adaptable target of rapamycin (TOR) and cAMP/protein kinase A (cAMP/PKA) signaling pathways that are under the stringent control of calorie availability. We designed a chemical genetic screen for small molecules that increase the chronological life span of yeast under CR by targeting lipid metabolism and modulating housekeeping longevity pathways that regulate longevity irrespective of the number of available calories. Our screen identifies lithocholic acid (LCA) as one of such molecules. We reveal two mechanisms underlying the life-extending effect of LCA in chronologically aging yeast. One mechanism operates in a calorie availability-independent fashion and involves the LCA-governed modulation of housekeeping longevity assurance pathways that do not overlap with the adaptable TOR and cAMP/PKA pathways. The other mechanism extends yeast longevity under non-CR conditions and consists in LCA-driven unmasking of the previously unknown anti-aging potential of PKA. We provide evidence that LCA modulates housekeeping longevity assurance pathways by suppressing lipid-induced necrosis, attenuating mitochondrial fragmentation, altering oxidation-reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria-controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA.