One of the basic questions in the ageing field is whether there is fundamental difference between the ageing of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-ageing Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at early age was observed, indicating its involvement in normal ageing of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal ageing. AAV-delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan (Stern 2017). These findings demonstrate the complexity of ageing in mammals, and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.

中文翻译：

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非编码 RNA Terc-53 和透明质酸受体 Hmmr 调节小鼠衰老。


衰老领域的基本问题之一是低等无脊椎动物和哺乳动物的衰老是否存在根本区别。低等无脊椎动物和哺乳动物之间的主要区别是非编码RNA的丰富性，其中大多数不保守。我们之前已经鉴定出一种非编码 RNA Terc-53，它源自端粒酶 Terc 的 RNA 成分。为了研究其生理功能，我们构建了两种在野生型和早期衰老 Terc-/- 背景下过表达 RNA 的转基因小鼠模型。 Terc-53小鼠表现出与年龄相关的认知能力下降和寿命缩短，尽管没有观察到早期发育缺陷或生理异常，这表明它参与了哺乳动物的正常衰老。随后的机制研究确定透明质酸介导的运动受体（Hmmr）是 Terc-53 的主要效应器。 Terc-53 介导 Hmmr 的降解，导致受影响组织的炎症增加，加速机体衰老。 AAV 在海马体中补充 Hmmr 可逆转 Terc-53 转基因小鼠的认知衰退。 Terc-53 和 Hmmr 在秀丽隐杆线虫中都没有同源物。节肢动物也不表达透明质酸（Stern 2017）。这些发现证明了哺乳动物衰老的复杂性，并为探索非编码 RNA 和 Hmmr 作为治疗与年龄相关的身体虚弱和改善健康寿命的手段开辟了新的途径。