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

被引：87

作者：

Goldberg, Alexander A. ^{[1
]}

Richard, Vincent R. ^{[1
]}

Kyryakov, Pavlo ^{[1
]}

Bourque, Simon D. ^{[1
]}

Beach, Adam ^{[1
]}

Burstein, Michelle T. ^{[1
]}

Glebov, Anastasia ^{[1
]}

Koupaki, Olivia ^{[1
]}

Boukh-Viner, Tatiana ^{[1
]}

Gregg, Christopher ^{[1
]}

Juneau, Mylene ^{[1
]}

English, Ann M. ^{[2
]}

Thomas, David Y. ^{[3
]}

Titorenko, Vladimir I. ^{[1
]}

机构：

[1] Concordia Univ, Dept Biol, Montreal, PQ H4B 1R6, Canada

[2] Concordia Univ, Dept Chem & Biochem, Montreal, PQ H4B 1R6, Canada

[3] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

来源：

AGING-US | 2010年 / 2卷 / 07期

基金：

加拿大自然科学与工程研究理事会; 加拿大创新基金会;

关键词：

cellular aging; longevity; yeast; caloric restriction; chemical biology; anti-aging compounds; CALORIE RESTRICTION MIMETICS; CAENORHABDITIS-ELEGANS; BILE-ACIDS; SACCHAROMYCES-CEREVISIAE; DIETARY RESTRICTION; TRANSCRIPTION FACTORS; OXIDATIVE STRESS; FAT-METABOLISM; KINASE COMPLEX; MICE LACKING;

D O I：

10.18632/aging.100168

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：393 / 414

页数：22

共 85 条

[1] Gene expression profile of long-lived Ames dwarf mice and Little mice [J].

Amador-Noguez, D ;

Yagi, K ;

Venable, S ;

Darlington, G .

AGING CELL, 2004, 3 (06) :423-441

[2] Alterations in xenobiotic metabolism in the long-lived Little mice [J].

Amador-Noguez, Daniel ;

Dean, Adam ;

Huang, Wendong ;

Setchell, Kenneth ;

Moore, David ;

Darlington, Gretchen .

AGING CELL, 2007, 6 (04) :453-470

[3] Bile acids: regulation of apoptosis by ursodeoxycholic acid [J].

Amaral, Joana D. ;

Viana, Ricardo J. S. ;

Ramalho, Rita M. ;

Steer, Clifford J. ;

Rodrigues, Cecilia M. P. .

JOURNAL OF LIPID RESEARCH, 2009, 50 (09) :1721-1734

[4] Resveratrol improves health and survival of mice on a high-calorie diet [J].

Baur, Joseph A. ;

Pearson, Kevin J. ;

Price, Nathan L. ;

Jamieson, Hamish A. ;

Lerin, Carles ;

Kalra, Avash ;

Prabhu, Vinayakumar V. ;

Allard, Joanne S. ;

Lopez-Lluch, Guillermo ;

Lewis, Kaitlyn ;

Pistell, Paul J. ;

Poosala, Suresh ;

Becker, Kevin G. ;

Boss, Olivier ;

Gwinn, Dana ;

Wang, Mingyi ;

Ramaswamy, Sharan ;

Fishbein, Kenneth W. ;

Spencer, Richard G. ;

Lakatta, Edward G. ;

Le Couteur, David ;

Shaw, Reuben J. ;

Navas, Placido ;

Puigserver, Pere ;

Ingram, Donald K. ;

de Cabo, Rafael ;

Sinclair, David A. .

NATURE, 2006, 444 (7117) :337-342

[5] Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster [J].

Bjedov, Ivana ;

Toivonen, Janne M. ;

Kerr, Fiona ;

Slack, Cathy ;

Jacobson, Jake ;

Foley, Andrea ;

Partridge, Linda .

CELL METABOLISM, 2010, 11 (01) :35-46

[6] Aging ROS or TOR [J].

Blagosklonny, Mikhail V. .

CELL CYCLE, 2008, 7 (21) :3344-3354

[7] Aging and immortality - Quasi-programmed senescence and its pharmacologic inhibition [J].

Blagosklonny, Mikhail V. .

CELL CYCLE, 2006, 5 (18) :2087-2102

[8] TOR-driven aging Speeding car without brakes [J].

Blagosklonny, Mikhail V. .

CELL CYCLE, 2009, 8 (24) :4055-4059

[9] Extended longevity in mice lacking the insulin receptor in adipose tissue [J].

Blüher, M ;

Kahn, BB ;

Kahn, CR .

SCIENCE, 2003, 299 (5606) :572-574

[10]

Bourque SD, 2009, JOVE-J VIS EXP, P30, DOI [10.3791/1513, DOI 10.3791/1513]

← 1 2 3 4 5 6 7 8 9 →