Inhibition of PAR-1 delays aging via activating AMPK in C. elegans.
Inhibition of PAR-1 delays aging via activating AMPK in C. elegans.
复制标题
在线虫中，抑制 PAR-1 可通过激活 AMPK 延缓衰老。
DOI：
10.18632/aging.104180
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发表时间：
2020-11-20
期刊：
影响因子：
--
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Wu D;Cai W;Zhang X;Lan J;Zou L;Chen SJ;Wu Z;Chen D
衰老的拮抗多效性理论表明，对生长和发育至关重要的基因可能会在以后的生活中调节衰老。以前的研究在C.秀丽隐杆线虫证明，在成年期抑制某些发育必需基因可显著延长寿命。PAR-1是一种高度保守的丝氨酸/苏氨酸激酶，在胚胎发育过程中起着关键的细胞极性调节作用。然而，PAR-1在成年期的作用仍然未知。在这里，我们表明，通过温度敏感突变体或RNAi敲除仅在成年期抑制par-1足以延长C.优雅的抑制par-1还可以改善健康寿命，表现为抗应激能力增强、抗蛋白毒性增强以及肌肉功能随时间下降减少。此外，组织富集的RNAi敲低分析揭示PAR-1主要在表皮中起调节寿命的作用。进一步的遗传上位性和分子研究表明，par-1对寿命的影响需要AMP活化蛋白激酶（AMPK），并且par-1的RNAi敲低导致年龄依赖性AMPK活化和代谢组织中脂质积累减少。综上所述，我们的研究结果揭示了PAR-1在成年期的一种以前未描述的功能，这将有助于理解发育和衰老之间的分子联系。
The antagonistic pleiotropy theory of aging suggests that genes essential for growth and development are likely to modulate aging later in life. Previous studies in C. elegans demonstrate that inhibition of certain developmentally essential genes during adulthood leads to significant lifespan extension. PAR-1, a highly conserved serine/threonine kinase, functions as a key cellular polarity regulator during the embryonic development. However, the role of PAR-1 during adulthood remains unknown. Here we show that inhibition of par-1 either by a temperature-sensitive mutant or by RNAi knockdown only during adulthood is sufficient to extend lifespan in C. elegans. Inhibition of par-1 also improves healthspan, as indicated by increased stress resistance, enhanced proteotoxicity resistance, as well as reduced muscular function decline over time. Additionally, tissue-enriched RNAi knockdown analysis reveals that PAR-1 mainly functions in the epidermis to regulate lifespan. Further genetic epistatic and molecular studies demonstrate that the effect of par-1 on lifespan requires the AMP-activated protein kinase (AMPK), and RNAi knockdown of par-1 results in age-dependent AMPK activation and reduced lipid accumulation in the metabolic tissue. Taken together, our findings reveal a previously undescribed function of PAR-1 in adulthood, which will help to understand the molecular links between development and aging.
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