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.

总结 年龄引起的器官功能下降涉及多个细胞内在事件。然而，由于大多数 生理过程是由细胞外环境协调的，衰老也是细胞外环境的结果。 细胞外环境的进行性破坏，这为抗衰老治疗提供了潜在的靶点。牛磺酸 是在真核生物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 通过半胱氨酸亚磺酸脱羧酶（Csad）的作用由半胱氨酸产生，并进行多种 重要功能。牛磺酸也可以通过转运蛋白（Slc 6a 6）从外源性来源获得。牛磺酸 补充到年轻的野生型小鼠改善，而先天性牛磺酸缺乏，由于缺乏 在人类和小鼠中，SLC 6A 6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， 牛磺酸对老年动物健康寿命和寿命的影响，发育与出生后起源， 机制不明。我们的初步结果表明，循环和组织水平的牛磺酸下降， 在小鼠、猴子和人类中的年龄。这使我们假设，牛磺酸缺乏是一个驱动程序的规范 衰老与这一假设一致，对中年WT小鼠每日一次口服牛磺酸， 显著增加，没有任何明显的副作用，在女性和男性，寿命的12%， 10%，并抑制发病率。牛磺酸对小鼠的寿命延长作用 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， 水平与几种退行性疾病有关;重要的是体育锻炼，这是众所周知的， 抗衰老的作用，增加人体内牛磺酸的水平。说明上述发现的生物医学相关性， 每日口服牛磺酸6个月，可显著提高老龄猴的几种器官功能。 从机制上讲，我们发现牛磺酸对健康寿命的调节与以下特征的变化有关： 衰老，包括细胞衰老减少，自噬和蛋白质稳态增加， 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个月、6个月或12个月）和终身补充牛磺酸。在目标2中，我们将确定 发育与出生后牛磺酸缺乏在调节衰老标志和健康寿命方面的作用， Slc 6a 6的可诱导条件性消融。在目标3中，我们将开始确定衰老标志的作用， 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， 他们将确定牛磺酸缺乏是衰老的驱动因素，阐明其对发育和出生后的影响， 并将确定牛磺酸调节正常衰老的机制。