Data from: Early-life inflammation, immune response and ageing

Age-related diseases are often attributed to immunopathology, which results in self-damage caused by an inappropriate inflammatory response. Immunopathology associated with early-life inflammation also appears to cause faster ageing, although we lack direct experimental evidence for this association. To understand the interactions between ageing, inflammation and immunopathology, we used the mealworm beetle Tenebrio molitor as a study organism. We hypothesized that phenoloxidase, an important immune effector in insect defence, may impose substantial immunopathological costs by causing tissue damage to Malpighian tubules (MTs; functionally equivalent to the human kidney), in turn accelerating ageing. In support of this hypothesis, we found that RNAi knockdown of phenoloxidase (PO) transcripts in young adults possibly reduced inflammation-induced autoreactive tissue damage to MTs, and increased adult lifespan. Our work thus suggests a causative link between immunopathological costs of early-life inflammation and faster ageing. We also reasoned that if natural selection weakens with age, older individuals should display increased immunopathological costs associated with an immune response. Indeed, we found that while old infected individuals cleared infection faster than young individuals, possibly they also displayed exacerbated immunopathological costs (larger decline in MT function) and higher post-infection mortality. RNAi-mediated knockdown of PO response partially rescued MTs function in older beetles and resulted in increased lifespan after infection. Taken together, our data are consistent with a direct role of immunopathological consequences of immune response during ageing in insects. Our work is also the first report that highlights the pervasive role of tissue damage under diverse contexts of ageing and immune response.

与年龄相关的疾病常被归因于免疫病理（immunopathology）——即由失调的炎症反应引发的自体损伤。尽管目前尚无直接实验证据证实早期炎症与衰老加速之间的关联，但早期炎症相关的免疫病理似乎也会加速衰老进程。为探究衰老、炎症与免疫病理之间的相互作用，本研究以黄粉虫甲虫（Tenebrio molitor）作为实验生物。我们提出假说：酚氧化酶（phenoloxidase）作为昆虫防御中的重要免疫效应分子，可能通过对马氏管（Malpighian tubules，简称MTs，功能等效于人类肾脏）造成组织损伤而产生显著的免疫病理代价，进而加速衰老。为验证该假说，我们发现：在年轻成虫体内通过RNA干扰敲低（RNAi knockdown）酚氧化酶（PO）的转录本，可减轻炎症诱导的马氏管自体反应性组织损伤，并延长成虫寿命。综上，本研究结果表明早期炎症的免疫病理代价与衰老加速之间存在因果关联。我们同时推断：若自然选择随衰老进程减弱，则老年个体应会表现出与免疫反应相关的更严重免疫病理代价。实验结果确证了这一点：尽管受感染的老年个体比年轻个体更快清除病原体，但它们同时也表现出更严重的免疫病理代价（马氏管功能下降幅度更大）以及更高的感染后死亡率。通过RNA干扰抑制酚氧化酶反应，可部分挽救老年甲虫的马氏管功能，并提升感染后的成虫寿命。综合来看，本研究数据支持昆虫衰老过程中免疫反应所引发的免疫病理后果具有直接作用这一观点。本研究同时也是首项揭示在衰老与免疫反应的多种场景下组织损伤普遍作用的研究报告。