Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.
Mendelian randomization analyses implicate biogenesis of translation machinery in human aging.
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DOI：
10.1101/gr.275636.121
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发表时间：
2022-03
期刊：
影响因子：
7
通讯作者：
Alic N
中科院分区：
文献类型：
--
作者：
Javidnia S;Cranwell S;Mueller SH;Selman C;Tullet JMA;Kuchenbaecker K;Alic N
在许多动物模型中，蛋白质翻译机制的减少促进了健康的衰老。然而，在人类中，翻译机制的先天性损伤是几种发育障碍的已知原因，统称为核糖体病。在这里，我们使用遗传流行病学中的因果推理方法来研究翻译机制的成人组织特异性生物发生是否驱动人类衰老。我们评估自然发生的变化，在表达的基因编码的两个RNA聚合酶（Pos），转录核糖体和转移RNA，即Pol I和III，和核糖体蛋白（RP）基因的表达的变化，使用孟德尔随机化。我们发现每一种都与人类的寿命有因果关系（β = −0.15 ± 0.047，P = 9.6 × 10−4，q = 0.015; β = −0.13 ± 0.040，P = 1.4 × 10−3，q = 0.023; β = −0.048 ± 0.016，P = 3.5 × 10−3，q = 0.056），并且这似乎不是由对单一疾病的易感性改变介导的。我们发现Pol III，RPs或Pol I的表达减少促进了不同器官的长寿，即内脏脂肪，肝脏和骨骼肌，这与核糖体病的组织特异性相呼应。我们的研究显示了利用表达中的遗传变异来阐明基本细胞过程如何影响人类衰老的效用。这些发现将蛋白质合成的进化保守性扩展为一个关键过程，该过程驱动动物衰老，包括人类。
Reduced provision of protein translation machinery promotes healthy aging in a number of animal models. In humans, however, inborn impairments in translation machinery are a known cause of several developmental disorders, collectively termed ribosomopathies. Here, we use casual inference approaches in genetic epidemiology to investigate whether adult, tissue-specific biogenesis of translation machinery drives human aging. We assess naturally occurring variation in the expression of genes encoding subunits specific to the two RNA polymerases (Pols) that transcribe ribosomal and transfer RNAs, namely Pol I and III, and the variation in expression of ribosomal protein (RP) genes, using Mendelian randomization. We find each causally associated with human longevity (β = −0.15 ± 0.047, P = 9.6 × 10−4, q = 0.015; β = −0.13 ± 0.040, P = 1.4 × 10−3, q = 0.023; β = −0.048 ± 0.016, P = 3.5 × 10−3, q = 0.056, respectively), and this does not appear to be mediated by altered susceptibility to a single disease. We find that reduced expression of Pol III, RPs, or Pol I promotes longevity from different organs, namely visceral adipose, liver, and skeletal muscle, echoing the tissue specificity of ribosomopathies. Our study shows the utility of leveraging genetic variation in expression to elucidate how essential cellular processes impact human aging. The findings extend the evolutionary conservation of protein synthesis as a critical process that drives animal aging to include humans.
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