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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

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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

Goldberg, Alexander A. and Richard, Vincent R. and Kyryakov, Pavlo and Bourque, Simon D. and Beach, Adam and Burstein, Michelle T. and Glebov, Anastasia and Koupaki, Olivia and Boukh-Viner, Tatiana and Gregg, Christopher and Juneau, Mylène and English, Ann M. and Thomas, David Y. and Titorenko, Vladimir I. (2010) 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. Aging, 2 (7). 393-414 . ISSN 1945-4589

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Official URL: http://www.impactaging.com/papers/v2/n7/full/10016...

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.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Article
Refereed:Yes
Authors:Goldberg, Alexander A. and Richard, Vincent R. and Kyryakov, Pavlo and Bourque, Simon D. and Beach, Adam and Burstein, Michelle T. and Glebov, Anastasia and Koupaki, Olivia and Boukh-Viner, Tatiana and Gregg, Christopher and Juneau, Mylène and English, Ann M. and Thomas, David Y. and Titorenko, Vladimir I.
Journal or Publication:Aging
Date:July 2010
Keywords:Cellular aging, longevity, yeast, caloric restriction, chemical biology, anti-aging compounds
ID Code:6993
Deposited By:DANIELLE DENNIE
Deposited On:20 Dec 2010 10:49
Last Modified:20 Dec 2010 10:49
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