Goldberg Alexander A, Richard Vincent R, Kyryakov Pavlo, Bourque Simon D, Beach Adam, Burstein Michelle T, Glebov Anastasia, Koupaki Olivia, Boukh-Viner Tatiana, Gregg Christopher, Juneau Mylène, English Ann M, Thomas David Y, Titorenko Vladimir I
Department of Biology , Concordia University, Montreal, Quebec, Canada.
Aging (Albany NY). 2010 Jul;2(7):393-414. doi: 10.18632/aging.100168.
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.
在按时间顺序衰老的酵母中，通过给予热量限制（CR）饮食或一些小分子可以延长寿命。这些延长寿命的干预措施针对雷帕霉素（TOR）的适应性靶点以及cAMP/蛋白激酶A（cAMP/PKA）信号通路，这些通路受到热量供应的严格控制。我们设计了一种化学遗传学筛选方法，用于筛选通过靶向脂质代谢和调节维持生命的长寿途径来增加CR条件下酵母按时间顺序寿命的小分子，这些长寿途径调节寿命，而与可用热量的数量无关。我们的筛选确定石胆酸（LCA）是这类分子之一。我们揭示了LCA在按时间顺序衰老的酵母中延长寿命作用的两种机制。一种机制以与热量供应无关的方式起作用，涉及LCA对维持生命的长寿保障途径的调节，这些途径与适应性TOR和cAMP/PKA途径不重叠。另一种机制在非CR条件下延长酵母寿命，包括LCA驱动揭示PKA先前未知的抗衰老潜力。我们提供证据表明，LCA通过抑制脂质诱导的坏死、减轻线粒体碎片化、改变线粒体中的氧化还原过程、增强对氧化和热应激的抵抗力、抑制线粒体控制的细胞凋亡以及增强核DNA和线粒体DNA的稳定性来调节维持生命的长寿保障途径。
