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的生物体的细胞衰老。最近的研究表明，在许多生物体中，脂质的代谢和细胞器间的运输是调节细胞衰老、影响与年龄相关的病理和决定生物寿命的关键过程之一。然而，将脂肪代谢与细胞衰老和生物寿命联系起来的机制仍不清楚。酿酒酵母是一种单细胞生物体，用于确定多细胞生物体中细胞和组织衰老的机制。我们研究计划的长期目标是揭示脂代谢在调节细胞衰老中的基本作用的机制和生物学原理，并使用酿酒酵母作为模式生物来定义生物寿命。在寻找可以通过重塑各种细胞器内的脂质代谢和运输来延长酵母寿命的小分子中，我们鉴定了许多以前未知的延长寿命的化合物。我们最近的发现表明，其中一种被称为石胆酸的胆汁酸通过重塑线粒体、内质网、脂滴和过氧化体中的协调脂质动力学来延缓细胞衰老的能力的机制。在所提出的机制中，外源添加的石胆酸进入酵母细胞，分选到线粒体，主要驻留在线粒体膜内，也与线粒体膜外结合。石胆酸引起两个线粒体膜内脂质合成和运动的重塑，从而改变它们的脂组成，并引发线粒体大小、数量和形态的变化。在协同作用下，所有这些变化都通过以下方式延长酵母的寿命：(1)改变线粒体决定寿命的与年龄相关的年表；(2)减少线粒体碎裂的程度，从而减缓线粒体促凋亡蛋白的释放，减缓与年龄相关的细胞死亡；(3)导致内质网、脂滴和过氧化酶体中的脂代谢和运输与年龄相关的重塑，从而推迟先前未知的与年龄相关的称为“脂肪坏死”的细胞程序性死亡模式；以及(4)重塑细胞质的中央代谢，从而提高细胞ATP水平，延缓线粒体功能的衰老。这项拟议的研究计划的目标是揭示酵母中脂肪代谢与细胞老化之间的联系。为了实现这一目标，我们将使用石胆酸和各种基因干预来针对这些机制，通过操纵线粒体、内质网、脂滴和酵母细胞中的过氧化物体内的协调脂代谢和运输。我们将使用各种实验方法来监控这些不同的操作如何影响酵母的寿命和许多定义长寿的细胞过程。拟议的研究计划(I)具有高度创新的潜力；(Ii)将对开发在进化上遥远的生物体中潜在的细胞衰老的复杂的间隔间通信网络的新范例产生重大影响；(Iii)将揭示将真核细胞的衰老与各种细胞细胞器内协调的脂质动力学联系起来的新机制；以及(Iv)将在概念上促进当前对潜在细胞衰老的内在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.