Juvenile microRNAs promoting healthier adult aging

摘要：本建议回应RFA：青少年保护因素及其对衰老的影响(R01) 鉴于它们广泛的调节作用，microRNA(MiRNA)生物学知识对于 全面了解老龄化。MiRNA介导的调控模式的特殊性在于 单个miRNA可以针对数百个基因，而多个miRNA可以针对同一个基因。 这个框架推荐miRNAs作为复杂表型的关键调节器，通过整合 生物投入和产出。由miRNAs Lead联合的多种途径和过程 到高度复杂的网络图，以更好地了解衰老的生物学，并用于以下应用 治疗学的发展。由于miRNAs具有治疗用途，例如将外源miRNAs应用于 减轻有害衰老相关基因的过度表达，我们希望控制miRNA水平 将成为治疗老年性疾病的一种潜在工具。 我在发育生物学方面的工作启发了我理解microRNAs的作用 (MiRNAs)在干细胞和更复杂的生物体中的癌症中的作用，并有助于理解 衰老中的miRNAs。我们鉴定了第一个与衰老过程有关的miRNA(GerontomiR)，LIN-4。 在秀丽隐杆线虫中LIN-4的敲除降低了蠕虫的寿命，而过度表达 提高了林-4的寿命。此外，miR-71和miR-246在线虫中的过表达增加 长寿。 有趣的是，这些老年激素受体大多在幼年/幼虫和成体早期出现表达高峰。 生命周期的各个阶段，但对成年人的正常衰老很重要。例如，Lin-4和let-7播放 在幼虫干细胞发育时间中的关键作用，而miR-71和miR-246是应激所必需的 在幼虫中，所有的反应都是下调的，但在成虫中都是下调的，是促进健康衰老所必需的。 此外，在个体动物成年期早期，mir-71和miR-246的表达水平增加 与更长的个体寿命相关。在这项新的工作中，将确定更多的老年人并测试 这些老年受体在成人中的异时性表达能够延伸的假设 线虫的寿命。 最近，我们和其他人发现了在哺乳动物中上调或下调的各种miRNAs 衰老，通过比较他们的肝脏或大脑的特异性表达在年轻和老年小鼠。我们也已经开始 确定可以作为人类衰老有用生物标记物的miRNAs。鉴于miRNAs可能会 调节人类衰老的过程，这里我们还将考察人类的衰老途径 在Aim 1中确定的老年癌iRs的同系物可能在miRNAs中发挥作用并测试其是否调节细胞 人类细胞和潜在的小鼠模型的衰老。

Summary: This proposal is responsive to RFA: Juvenile Protective Factors and Their Effects on Aging (R01) Given their broad regulatory roles, knowledge of microRNA (miRNA) biology is essential to a comprehensive understanding of aging. The mode of miRNA-mediated regulation is special in that hundreds of genes can be targeted by a single miRNA while multiple miRNAs can target the same gene. This framework commends miRNAs as key modulators of complex phenotypes by integrating multiple biological inputs and outputs. The multiplicity of pathways and processes that are united by miRNAs leads to highly complex network diagrams to better understand the biology of aging and for applications such as therapeutics development. Since miRNAs have therapeutic uses, e.g. application of exogenous miRNAs to alleviate over-expression of detrimental aging-associated genes, our hope is manipulation of miRNA levels would be a potential therapeutic tool in diseases of aging. My work in developmental biology inspired my move towards understanding the role of microRNAs (miRNAs) in stem cells and cancer in more complex organisms, and towards understanding roles for miRNAs in aging. We identified the first miRNA (gerontomiR) to be implicated in the aging process, lin-4. Knockdown of lin-4 in Caenorhabditis elegans decreased longevity of the worms, whereas over-expression of lin-4 increased longevity. Additionally, overexpression of miR-71 and miR-246 in C. elegans increased longevity. Interestingly, most of these gerontomiRs show peak expression during juvenile/larval and early adult phases of the lifecycle, and yet are important for normal aging in adults. For example, lin-4 and let-7 play key roles in stem cell developmental timing in larvae while miR-71 and miR-246 are required for stress response in larvae, yet all are down-regulated in the adult and are required to promote healthy aging. Additionally, increased expression levels of mir-71 and miR-246 in early adulthood of individual animals is associated with longer individual lifespan. In this new work will identify additional gerontomiRs and test the hypothesis that heterochronic expression of these gerontomiRs in the adult is capable of extending lifespan in C. elegans. Recently, we and other have identified various miRNAs that are up- or down-regulated during mammalian aging, by comparing their liver or brain-specific expression in younger and older mice. We have also begun to identify miRNAs that could be useful biomarkers of aging in humans. Given the possibility that miRNAs may regulate processes involved in human aging, here we will also examine the aging pathways that human homologues of the gerontomiRs identified in Aim 1 may function in and test if miRNAs regulate cell senescence of human cells and potentially, mouse models.