Engel Annika, Wagner Viktoria, Hahn Oliver, Foltz Aulden G, Atkins Micaiah, Beganovic Amila, Guldner Ian H, Lu Nannan, Saksena Aryaman, Fischer Ulrike, Ludwig Nicole, Meese Eckart, Wyss-Coray Tony, Keller Andreas
Clinical Bioinformatics, Saarland University, Saarbrücken, Germany.
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Nat Commun. 2025 May 17;16(1):4588. doi: 10.1038/s41467-025-59860-6.
An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA expression across the mouse lifespan (7 time points) and two aging interventions. MicroRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and mediate aging speed. We first established sex- and brain-region-specific microRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific microRNA expression changes during aging. We identified three sex-independent brain aging microRNAs (miR-146a-5p, miR-155-5p, and miR-5100). For miR-155-5p, we showed that these expression changes are driven by aging microglia and target mTOR signaling pathway components and other cellular communication pathways. In this work, we identify strong sex-brain-region-specific aging microRNAs and microglial miR-155-5p as a promising therapeutic target.
深入了解构成衰老的分子过程对于开发治疗方法至关重要，这些方法可将衰老作为认知衰退的关键风险因素加以降低。在此，我们展示了一个时空脑图谱（15个不同区域），该图谱呈现了小鼠整个生命周期（7个时间点）以及两种衰老干预措施下的微小RNA表达情况。微小RNA是很有前景的治疗靶点，因为它们通过信使RNA的互补碱基对结合使基因沉默，并介导衰老速度。我们首先在年轻成年样本中建立了性别和脑区特异性的微小RNA表达模式。然后我们关注衰老过程中性别依赖性和非依赖性的脑区特异性微小RNA表达变化。我们鉴定出三种不依赖性别的脑衰老微小RNA（miR-146a-5p、miR-155-5p和miR-5100）。对于miR-155-5p，我们表明这些表达变化是由衰老的小胶质细胞驱动的，并且靶向mTOR信号通路成分以及其他细胞通讯通路。在这项工作中，我们鉴定出了强烈的性别-脑区特异性衰老微小RNA，并且小胶质细胞的miR-155-5p是一个很有前景的治疗靶点。
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