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.
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.
Goldberg
Alexander A
AA
Department of Biology , Concordia University, Montreal, Quebec, Canada.
Richard
Vincent R
VR
Kyryakov
Pavlo
P
Bourque
Simon D
SD
Beach
Adam
A
Burstein
Michelle T
MT
Glebov
Anastasia
A
Koupaki
Olivia
O
Boukh-Viner
Tatiana
T
Gregg
Christopher
C
Juneau
Mylène
M
English
Ann M
AM
Thomas
David Y
DY
Titorenko
Vladimir I
VI
D031204:Caloric Restriction; D016922:Cellular Senescence / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics; D008095:Lithocholic Acid / Q000502:physiology; D008136:Longevity / Q000235:genetics; D008957:Models, Genetic; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology; D020123:Sirolimus / Q000032:analysis; D015003:Yeasts / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D008095:Lithocholic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D020123:Sirolimus