Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
Emory Vaccine Center, Emory University, Atlanta, GA 30329.
Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7506-E7515. doi: 10.1073/pnas.1706464114. Epub 2017 Aug 21.
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 , , 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 , 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.
多项研究已经确定了与不同生物寿命延长相关的保守遗传途径和小分子。然而，延长寿命并不一定导致健康寿命的相应延长，健康寿命是指动物保持健康、没有与年龄相关的虚弱状态的时间比例。相反，延长寿命的突变往往会降低健康寿命并增加脆弱性。问题是，是否存在将这些过程分开、独立延长健康寿命和减少脆弱性而不影响寿命的因素或机制。我们表明，共生微生物群中的吲哚延长了包括线虫、苍蝇和老鼠在内的多种生物的健康寿命，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基烃受体（AHR），AHR 是一种对外源小分子的保守探测器。在秀丽隐杆线虫中，吲哚诱导老年动物的基因表达谱类似于年轻动物的表达谱，但与正常衰老相关的表达谱不同。此外，在老年动物中，吲哚诱导与卵母细胞发生相关的基因，因此延长了生育力和生殖跨度。这些数据表明，与吲哚有关的小分子来源于共生微生物群，通过保守的分子途径在不同的门中发挥作用，促进健康衰老。这些数据提出了一种可能性，即可以开发基于微生物群衍生的吲哚或其衍生物的疗法，以延长人类的健康寿命和减少脆弱性。
