Department of Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Department of Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Genetics. 2021 Jun 24;218(2). doi: 10.1093/genetics/iyab049.
Studying the evolutionary processes that shaped aging offers a path for understanding the causes of aging. The antagonistic pleiotropy theory for the evolution of aging proposes that the inverse correlation between age and natural selection strength allows positive selection of gene variants with early-life beneficial contributions to fitness despite detrimental late-life consequences. However, mechanistic understanding of how this principle manifests in aging is still lacking. We previously identified antagonistic pleiotropy in the function of the Caenorhabditis elegans JNK homolog KGB-1, which provided stress protection in developing larvae, but sensitized adults to stress and shortened their lifespan. To a large extent, KGB-1's contributions depended on age-dependent and opposing regulation of the stress-protective transcription factor DAF-16, but the underlying mechanisms remained unknown. Here, we describe a role for the microRNA miR-71 in mediating effects of KGB-1 on DAF-16 and downstream phenotypes. Fluorescent imaging along with genetic and survival analyses revealed age-dependent regulation of mir-71 expression by KGB-1-upregulation in larvae, but downregulation in adults-and showed that mir-71 was required both for late-life effects of KGB-1 (infection sensitivity and shortened lifespan), as well as for early life resistance to cadmium. While mir-71 disruption did not compromise development under protein-folding stress (known to depend on KGB-1), disruption of the argonaute gene alg-1, a central component of the microRNA machinery, did. These results suggest that microRNAs play a role in mediating age-dependent antagonistic contributions of KGB-1 to survival, with mir-71 playing a central role and additional microRNAs potentially contributing redundantly.
研究塑造衰老过程的进化机制为理解衰老的原因提供了一条途径。衰老的拮抗多效性理论提出，年龄与自然选择强度之间的反比关系允许对具有早期生命对适应性有利贡献的基因变异进行正向选择，尽管这些变异会对晚年产生有害影响。然而，人们对这一原则如何在衰老中表现出来的机制理解仍然不足。我们之前在秀丽隐杆线虫 JNK 同源物 KGB-1 的功能中发现了拮抗多效性，该基因在发育中的幼虫中提供了应激保护，但使成年个体对应激敏感并缩短了它们的寿命。在很大程度上，KGB-1 的贡献取决于 DAF-16 的应激保护转录因子的年龄依赖性和相反调节，但潜在的机制仍不清楚。在这里，我们描述了 microRNA miR-71 在介导 KGB-1 对 DAF-16 和下游表型的影响中的作用。荧光成像以及遗传和生存分析揭示了 KGB-1 通过上调幼虫中 mir-71 的表达来调节 mir-71 的表达，而在成年个体中下调 mir-71 的表达，并表明 mir-71 既需要 KGB-1 的晚年效应（感染敏感性和寿命缩短），也需要早期对镉的抗性。虽然 mir-71 的破坏不影响在蛋白质折叠应激下的发育（已知依赖于 KGB-1），但 argonaute 基因 alg-1 的破坏，即 microRNA 机制的核心成分，确实如此。这些结果表明，microRNAs 在介导 KGB-1 对生存的年龄依赖性拮抗贡献中发挥作用，mir-71 发挥核心作用，其他 microRNAs 可能具有冗余作用。
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