Mechanisms linking lipid metabolism to cellular aging in yeast

生物体的衰老是由细胞过程中与年龄相关的变化引起的。这些变化可以通过一些饮食和药物干预来减缓，这些干预可以延缓进化上遥远生物体的细胞衰老。最近的研究表明，脂质的代谢和胞间转运是调节细胞衰老、影响年龄相关病理和决定许多生物体寿命的关键过程之一。然而，脂质代谢与细胞衰老和生物体寿命之间的联系机制尚不清楚。面包酵母是一种单细胞生物，用于确定多细胞生物中细胞和有机体老化的机制。我们的研究项目的长期目标是揭示脂质代谢在调节细胞衰老和定义生物寿命中的重要作用的机制和生物学原理，并将酵母作为一种模式生物。在寻找可以通过重塑脂质代谢和各种细胞器内运输来延长酵母寿命的小分子的过程中，我们发现了许多以前未知的延长寿命的化合物。我们最近的研究结果表明，其中一种胆汁酸石胆酸通过重塑线粒体、内质网、脂滴和过氧化物酶体中协调的脂质动力学来延缓细胞衰老。在所提出的机制中，外源添加的石胆酸进入酵母细胞，被分选到线粒体，主要存在于线粒体内膜，也与线粒体外膜相结合。石胆酸引起两种线粒体膜内脂质合成和运动的重塑，从而改变其脂质组成并引发线粒体大小、数量和形态的变化。协同作用下，所有这些变化通过以下方式延长酵母寿命：(1)改变线粒体中决定寿命过程的年龄相关年表；（ii）减少线粒体断裂的程度，从而减缓线粒体中促凋亡蛋白的释放，减缓与年龄相关的凋亡细胞死亡形式；（iii）引起内质网、脂滴和过氧化物酶体中脂质代谢和转运的年龄相关重塑，从而推迟先前未知的与年龄相关的程序性细胞死亡模式，即“脂质坏死”；（iv）重塑细胞质中的中枢代谢，从而增加细胞ATP水平，延缓与年龄相关的线粒体功能下降。提出的研究计划的目的是揭示酵母脂质代谢与细胞老化的机制。为了实现这一目标，我们将使用石胆酸和各种遗传干预措施，通过操纵酵母细胞线粒体、内质网、脂滴和过氧化物酶体内的脂质代谢和运输来靶向这些机制。我们将采用各种实验方法来监测这些不同的操作如何影响酵母寿命和许多长寿的细胞过程。拟议的研究计划(i)具有高度创新的潜力；（ii）将对发展在进化上遥远的生物体中细胞衰老背后的复杂的室间通讯网络的新范式产生重大影响；（iii）将揭示真核细胞衰老与各种细胞器内协调的脂质动力学之间的新机制；（iv）将从概念上推进当前对细胞衰老固有复杂性的基本机制和生物学原理的理解。

Aging of organisms is caused by age-related changes in cellular processes. These changes can be slowed down by some dietary and pharmacological interventions that delay cellular aging in evolutionarily distant organisms. Recent studies have suggested that the metabolism and interorganellar transport of lipids are among the key processes involved in regulating cellular aging, influencing age-related pathologies and defining organismal longevity in many organisms. However, mechanisms linking lipid metabolism to cellular aging and organismal longevity remain unknown. The baker’s yeast Saccharomyces cerevisiae is a unicellular organism used for defining mechanisms of cellular and organismal aging in multicellular organisms. The long-term goal of our research program is to uncover mechanisms and biological principles underlying the essential role of lipid metabolism in regulating cellular aging and defining organismal longevity using the yeast S. cerevisiae as a model organism. In a quest for small molecules that can increase yeast lifespan by remodeling lipid metabolism and transport within various cellular organelles, we identified many previously unknown longevity-extending compounds. Our recent findings suggest a mechanism underlying the ability of one of them, a bile acid called lithocholic acid, to delay cellular aging by remodeling coordinated lipid dynamics in mitochondria, the endoplasmic reticulum, lipid droplets and peroxisomes. In the proposed mechanism, exogenously added lithocholic acid enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane and also associates with the outer mitochondrial membrane. Lithocholic acid elicits a remodeling of lipid synthesis and movement within both mitochondrial membranes, thereby altering their lipid composition and triggering changes in mitochondrial size, number and morphology. In synergy, all these changes extend yeast longevity by (i) altering the age-related chronology of longevity-defining processes in mitochondria; (ii) reducing the extent of mitochondrial fragmentation, thereby slowing down the release of pro-apoptotic proteins from mitochondria and decelerating an age-related form of apoptotic cell death; (iii) causing an age-related remodeling of lipid metabolism and transport in the endoplasmic reticulum, lipid droplets and peroxisomes, thereby postponing a previously unknown age-related mode of programmed cell death called “liponecrosis”; and (iv) remodeling central metabolism in the cytosol, thereby increasing cellular ATP levels and delaying an age-related decline of mitochondrial functionality. The objective of the proposed research program is to uncover mechanisms linking lipid metabolism to cellular aging in yeast. To achieve this objective, we will use lithocholic acid and various genetic interventions for targeting these mechanisms by manipulating coordinated lipid metabolism and transport within mitochondria, the endoplasmic reticulum, lipid droplets and peroxisomes of yeast cells. We will employ various experimental approaches to monitor how these different manipulations affect yeast lifespan and many longevity-defining cellular processes. The proposed research program (i) has the potential to be highly innovative; (ii) will have a major impact on developing the new paradigm of an intricate network of intercompartmental communications underlying cellular aging in evolutionarily distant organisms; (iii) will uncover new mechanisms that link aging of eukaryotic cells to coordinated lipid dynamics within various cellular organelles; and (iv) will conceptually advance the current understanding of fundamental mechanisms and biological principles underlying the inherent complexity of cellular aging.