Indoles from commensal bacteria extend healthspan
Indoles from commensal bacteria extend healthspan
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DOI：
10.1073/pnas.1706464114
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发表时间：
2017-09-05
影响因子：
11.1
通讯作者：
Kalman, Daniel
中科院分区：
文献类型：
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作者：
Sonowal, Robert;Swimm, Alyson;Kalman, Daniel
多项研究已经确定了保守的遗传途径和小分子与不同生物体的寿命延长有关。然而，延长寿命并不导致健康寿命的伴随延长，健康寿命的定义是动物保持健康且没有与年龄相关的疾病的时间比例。相反，延长寿命的突变往往会减少健康寿命并增加脆弱性。问题是，是否存在因素或机制，使这些过程脱钩，延长健康寿命，减少与寿命无关的虚弱。我们发现，来自肠道微生物群的吲哚延长了不同生物体的健康寿命，包括秀丽隐杆线虫、黑腹果蝇和小鼠，但对最大寿命的影响可以忽略不计。吲哚对蠕虫和苍蝇健康寿命的影响取决于芳烃受体（AHR），这是一种保守的异生物质小分子检测器。In C.在elegans中，吲哚在老年动物中诱导的基因表达谱使人想起在年轻时看到的基因表达谱，但与正常衰老相关的基因表达谱不同。此外，在老年动物中，吲哚诱导与卵子发生相关的基因，从而延长繁殖力和繁殖期。总之，这些数据表明，与吲哚相关的小分子和来自肠道微生物群的小分子通过保守的分子途径在不同的门中起作用，以促进健康的衰老。这些数据提高了开发基于微生物群衍生的吲哚或其衍生物的治疗方法以延长人类健康寿命和减少人类虚弱的可能性。
Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan. We show that indoles from commensal microbiota extend healthspan of diverse organisms, including Caenorhabditis elegans, Drosophila melanogaster, and mice, but have a negligible effect on maximal lifespan. Effects of indoles on healthspan in worms and flies depend upon the aryl hydrocarbon receptor (AHR), a conserved detector of xenobiotic small molecules. In C. elegans, indole induces a gene expression profile in aged animals reminiscent of that seen in the young, but which is distinct from that associated with normal aging. Moreover, in older animals, indole induces genes associated with oogenesis and, accordingly, extends fecundity and reproductive span. Together, these data suggest that small molecules related to indole and derived from commensal microbiota act in diverse phyla via conserved molecular pathways to promote healthy aging. These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans.