Taurine, an endogenously produced semi-essential micronutrient, as a regulator of lifespan and healthspan

牛磺酸，一种内源性产生的半必需微量营养素，作为寿命和健康寿命的调节剂

• 批准号: 10901014
• 负责人: Vijay K Yadav
• 金额: $ 41.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901014
• 关键词: Ablation; Acceleration; Address; Adult; Affect; Age; Aging; Animals; Anus; Autophagocytosis; Carboxy-Lyases; Cell Aging; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Cysteine; DNA Damage; Data; Degenerative Disorder; Development; Environment; Event; Female; Functional disorder; Genetic; Genomic Instability; Goals; Health; Hormones; Human; Impairment; Inflammaging; Intervention; Invertebrates; Letters; Life; Longevity; Mammalian Cell; Measurement; Micronutrients; Mitochondria; Molecular; Monkeys; Morbidity - disease rate; Mus; Obesity; Oral; Oral Administration; Organ; Organism; Pathway interactions; Phenotype; Physical Exercise; Physiological Processes; Pregnancy; Process; Regulation; Shock; Source; Supplementation; Taurine; Therapeutic; Tissues; Transcend; Wild Type Mouse; Yeasts; age effect; aged; anti aging; attenuation; body system; cohort; cysteine sulfinate; detection of nutrient; diabetic; exhaustion; extracellular; feeding; functional disability; healthspan; improved; male; middle age; mitochondrial dysfunction; novel; postnatal; proteostasis; senescence; side effect; stem cells; telomere; transcriptomics

Summary The age-induced decline in organ functions involves multiple cell intrinsic events. However, and since most physiological processes are orchestrated by extracellular environment, aging is also a consequence of progressive breakdown of extracellular milieu which proffers potential targets for anti-aging therapeutics. Taurine is a semi-essential micronutrient found in organisms across eukaryotic phyla. In mammalian cells, taurine is produced from cysteine by the action of cysteine sulfinate decarboxylase (Csad) and performs a variety of important functions. Taurine can also be obtained from extrinsic sources through a transporter (Slc6a6). Taurine supplementation to young wild-type mice improves, while congenital taurine deficiency due to the lack of SLC6A6, in humans and in mice, impairs functions of multiple organ systems known to be affected during aging. These evidences suggest that taurine may regulate processes associated with aging; however, the effect of taurine on healthspan and lifespan in aged animals, developmental versus postnatal origin, and the underlying mechanisms are unknown. Our preliminary results show that circulating and tissue levels of taurine decline with age in mice, monkeys, and humans. This led us to hypothesize that taurine deficiency is a driver of normative aging. Consistent with this hypothesis, once-daily oral administration of taurine to middle-aged WT mice significantly increases, without any noticeable side effects, in both females and males, the lifespan by 12% and 10%, respectively, and suppresses morbidity. The lifespan extending effect of taurine was also observed in worms suggesting that the effect of taurine transcends the eukaryotic evolutionary landscape to invertebrates. An unbiased association analysis of taurine levels with clinical variables in aged-humans shows that taurine levels associate with several degenerative diseases; and importantly physical exercise, which is known for its anti-aging effects, increases taurine levels in humans. Illustrating the biomedical relevance of above findings, daily oral feeding of taurine to aged-monkeys for 6 months significantly enhanced the functions of several organs. Mechanistically, we find that taurine regulation of healthy lifespan is associated with changes in hallmarks of aging, including a reduction in cellular senescence, increase in autophagy and proteostasis, suppression of mitochondrial dysfunction, and attenuation of inflammaging. In Aim 1, we will determine the degree to which short-term taurine supplementation at mid-life affects aging hallmarks and extends healthy lifespan through transient (3-, 6- or 12-month) and life-long taurine supplementation. In Aim 2, we will determine the effect of developmental versus postnatal taurine deficiency in regulating aging hallmarks, and healthy lifespan through inducible conditional ablation of Slc6a6. In Aim 3, we will begin to identify the contribution of aging hallmarks and upstream mechanisms through which taurine regulates healthy lifespan. Together, our studies are significant as they will establish taurine deficiency as a driver of aging, elucidate its developmental versus postnatal effects, and will identify the mechanisms through which taurine regulates normative aging.

概括 年龄引起的器官功能下降涉及多个细胞固有事件。但是，由于大多数 生理过程是由细胞外环境精心策划的，衰老也是结果 细胞外环境的进行性分解，这为抗衰老治疗剂提供了潜在的靶标。牛磺酸 是一种在真核门的生物体中发现的半必需微量营养素。在哺乳动物细胞中，牛磺酸是 通过半胱氨酸硫酸脱羧酶（CSAD）的作用从半胱氨酸产生，并执行多种 重要功能。也可以通过转运蛋白（SLC6A6）从外部源获得牛磺酸。牛磺酸 补充对年轻的野生型小鼠的补充有所改善，而先天性牛磺酸不足由于缺乏 SLC6A6在人类和小鼠中，会损害已知在衰老期间受到影响的多器官系统的功能。 这些证据表明牛磺酸可以调节与衰老相关的过程。但是， 牛磺酸在老年动物，发育和产后起源以及基础的牛磺酸 机制是未知的。我们的初步结果表明，牛磺酸的循环和组织水平与 老鼠，猴子和人类的年龄。这导致我们假设牛磺酸缺乏是规范的驱动力 老化。与这一假设一致，每天一次口服牛磺酸到中年WT小鼠 在女性和男性中，寿命都显着增加，没有任何明显的副作用，寿命增加了12％，并且 分别为10％，并抑制发病率。在 蠕虫表明牛磺酸的作用超越了真核进化景观到无脊椎动物。 牛磺酸水平与临床变量的无偏关联分析表明牛磺酸 与几种退化性疾病相关的水平；重要的是体育锻炼，以其 抗衰老效应，增加了人类的牛磺酸水平。说明上述发现的生物医学相关性， 牛磺酸每天口服喂食6个月，可以显着增强多个器官的功能。 从机械上讲，我们发现健康寿命的牛磺酸调节与标志的变化有关 衰老，包括降低细胞衰老，自噬和蛋白质的增加，抑制 线粒体功能障碍和炎症的衰减。在AIM 1中，我们将确定哪个程度 中期的短期牛磺酸补充会影响衰老的标志，并延长健康的寿命 瞬态（3-，6或12个月）和终身牛磺酸补充。在AIM 2中，我们将确定 发育与产后牛磺酸的缺乏在调节衰老标志和健康寿命方面的缺乏症 SLC6A6的诱导条件消融。在AIM 3中，我们将开始确定衰老标志的贡献 牛磺酸调节健康寿命的上游机制。一起，我们的研究很重要 他们将建立牛磺酸缺乏症作为衰老的驱动力，阐明其发育与产后效应， 并将确定牛磺酸调节规范衰老的机制。