Department of Genetics, Development, & Cell Biology, Iowa State University, Ames, IA 50011, USA.
G3 (Bethesda). 2022 Jan 4;12(1). doi: 10.1093/g3journal/jkab381.
Transcriptomic, proteomic, and methylation aging clocks demonstrate that aging has a predictable preset program, while transcriptome trajectory turning points indicate that the 20-40 age range in humans is the likely stage at which the progressive loss of homeostatic control, and in turn aging, begins to have detrimental effects. Turning points in this age range overlapping with human aging clock genes revealed five candidates that we hypothesized could play a role in aging or age-related physiological decline. To examine these gene's effects on lifespan and health-span, we utilized whole body and heart-specific gene knockdown of human orthologs in Drosophila melanogaster. Whole body lysyl oxidase like 2 (Loxl2), fz3, and Glo1 RNAi positively affected lifespan as did heart-specific Loxl2 knockdown. Loxl2 inhibition concurrently reduced age-related cardiac arrythmia and collagen (Pericardin) fiber width. Loxl2 binds several transcription factors in humans and RT-qPCR confirmed that a conserved transcriptional target CDH1 (Drosophila CadN2) has expression levels which correlate with Loxl2 reduction in Drosophila. These results point to conserved pathways and multiple mechanisms by which inhibition of Loxl2 can be beneficial to heart health and organismal aging.
转录组、蛋白质组和甲基化衰老时钟表明，衰老具有可预测的预设程序，而转录组轨迹转折点表明，人类 20-40 岁的年龄范围可能是稳态控制逐渐丧失的阶段，进而衰老开始产生不利影响。在这个年龄范围内与人类衰老时钟基因重叠的转折点揭示了我们假设可能在衰老或与年龄相关的生理衰退中发挥作用的五个候选基因。为了研究这些基因对寿命和健康跨度的影响，我们利用黑腹果蝇中的人类同源物的全身和心脏特异性基因敲低。全身赖氨酸氧化酶样 2（Loxl2）、fz3 和 Glo1 RNAi 均对寿命产生积极影响，心脏特异性 Loxl2 敲低也是如此。Loxl2 抑制可同时减少与年龄相关的心脏心律失常和胶原（Pericardin）纤维宽度。Loxl2 在人类中结合几种转录因子，实时定量 PCR 证实，一个保守的转录靶标 CDH1（果蝇 CadN2）的表达水平与果蝇中 Loxl2 的减少相关。这些结果表明，抑制 Loxl2 可以通过多种保守途径和机制有益于心脏健康和机体衰老。
