Alzheimer's disease (AD) is an age‐associated disease. Mutations in the amyloid precursor protein (APP) may be causative or protective of AD. The presence of two functionally redundant APP‐like genes (APLP1/2) has made it difficult to unravel the biological function of APP during aging. The nematode Caenorhabditis elegans contains a single APP family member, apl‐1. Here, we assessed the function of APL‐1 on C. elegans’ lifespan and found tissue‐specific effects on lifespan by overexpression of APL‐1. Overexpression of APL‐1 in neurons causes lifespan reduction, whereas overexpression of APL‐1 in the hypodermis causes lifespan extension by repressing the function of the heterochronic transcription factor LIN‐14 to preserve youthfulness. APL‐1 lifespan extension also requires signaling through the FOXO transcription factor DAF‐16, heat‐shock factor HSF‐1, and vitamin D‐like nuclear hormone receptor DAF‐12. We propose that reinforcing APL‐1 expression in the hypodermis preserves the regulation of heterochronic lin‐14 gene network to improve maintenance of somatic tissues via DAF‐16/FOXO and HSF‐1 to promote healthy aging. Our work reveals a mechanistic link of how a conserved APP‐related protein modulates aging.

中文翻译：

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老年痴呆症相关蛋白APL-1通过秀丽隐杆线虫中的异时基因调控来调节寿命。

阿尔茨海默氏病（AD）是一种与年龄相关的疾病。淀粉样前体蛋白（APP）中的突变可能是AD的病因或保护因素。两个功能上类似APP的功能冗余基因（APLP1 / 2）的存在使得在衰老过程中难以揭示A​​PP的生物学功能。线虫秀丽隐杆线虫包含一个APP家族成员apl-1。在这里，我们评估了APL-1对秀丽隐杆线虫的功能寿命，并发现APL-1过表达对寿命有组织特异性影响。神经元中APL-1的过表达导致寿命缩短，而皮下组织中APL-1的过表达通过抑制异时转录因子LIN-14的功能来延长青春期，从而导致寿命延长。APL-1寿命的延长还需要通过FOXO转录因子DAF-16，热休克因子HSF-1和维生素D类核激素受体DAF-12进行信号传递。我们提出，增强皮下组织中APL-1的表达可以保留对lin-14异时基因网络的调节，从而通过DAF-16 / FOXO和HSF-1促进体细胞组织的维护，从而促进健康的衰老。我们的工作揭示了保守的APP相关蛋白如何调节衰老的机制联系。