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衰退涉及多种细胞内在事件。然而，由于大多数 生理过程是由细胞外环境精心安排的，衰老也是细胞外环境的结果 细胞外环境的逐渐崩溃为抗衰老治疗提供了潜在的靶点。牛磺酸 是在真核生物门中发现的一种半必需微量营养素。在哺乳动物细胞中，牛磺酸是 通过半胱氨酸亚磺酸脱羧酶 (Csad) 的作用从半胱氨酸产生，并执行多种 重要职能。牛磺酸也可以通过转运蛋白 (Slc6a6) 从外源获得。牛磺酸 对年轻野生型小鼠的补充可以改善，而由于缺乏牛磺酸而导致的先天性牛磺酸缺乏症 SLC6A6 在人类和小鼠体内会损害已知在衰老过程中受影响的多个器官系统的功能。 这些证据表明牛磺酸可以调节与衰老相关的过程。然而，效果 牛磺酸对老年动物的健康和寿命、发育与出生后起源及其潜在影响 机制尚不清楚。我们的初步结果表明，牛磺酸的循环和组织水平随着 老鼠、猴子和人类的年龄。这使我们假设牛磺酸缺乏是规范性的驱动因素 老化。与这一假设一致，中年WT小鼠每天口服一次牛磺酸 女性和男性的寿命显着延长 12%，且没有任何明显的副作用 分别为 10%，并抑制发病率。牛磺酸的延长寿命作用也被观察到 蠕虫表明牛磺酸的作用超越了真核生物的进化景观，影响到无脊椎动物。 对老年人牛磺酸水平与临床变量的无偏关联分析表明，牛磺酸 与多种退行性疾病相关的水平；重要的是体育锻炼，众所周知 抗衰老作用，增加人体牛磺酸水平。说明上述发现的生物医学相关性， 每日口服牛磺酸给老年猴子喂食六个月，显着增强了多个器官的功能。 从机制上讲，我们发现牛磺酸对健康寿命的调节与健康特征的变化有关。 衰老，包括细胞衰老的减少、自噬和蛋白质稳态的增加、 线粒体功能障碍和炎症减弱。在目标 1 中，我们将确定 中年时短期补充牛磺酸会影响衰老特征并通过以下方式延长健康寿命 短暂（3、6 或 12 个月）和终生补充牛磺酸。在目标 2 中，我们将确定以下效果： 发育与出生后牛磺酸缺乏在调节衰老特征和健康寿命方面的作用 Slc6a6 的诱导条件消融。在目标 3 中，我们将开始确定衰老特征和 牛磺酸调节健康寿命的上游机制。总之，我们的研究意义重大，因为 他们将确定牛磺酸缺乏是衰老的一个驱动因素，阐明其对发育与产后的影响， 并将确定牛磺酸调节正常衰老的机制。