Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. Reducing Insulin/IGF-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematode C. elegans, we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system. This allowed for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi become ineffective. Using this system, we found that AID-mediated depletion of DAF-2 protein surpasses the longevity of daf-2 mutants. Depletion of DAF-2 during early adulthood resulted in multiple adverse phenotypes, including growth retardation, germline shrinkage, egg retention, and reduced brood size. By contrast, AID-mediated depletion of DAF-2 post reproduction, or specifically in the intestine in early adulthood, resulted in an extension of lifespan without these deleterious effects. Strikingly, at geriatric ages, when 75% of the population had died, AID-mediated depletion of DAF-2 protein resulted in a doubling in lifespan. Thus, we provide a proof-of-concept that even close to the end of an individual's lifespan, it is possible to slow aging and promote longevity.

中文翻译：

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生命终结靶向生长素介导的 DAF-2 胰岛素/IGF-1 受体降解可延长寿命，避免与生长相关的病变

优选地，延长寿命的疗法在生命后期应用时应该起作用，而不会引起不希望的病症。减少胰岛素/IGF-1 信号 (IIS) 可延长物种的寿命，但减少 IIS 干预对极端老年期的影响仍然未知。使用线虫秀丽隐杆线虫，我们使用生长素诱导降解 (AID) 系统设计了 DAF-2/胰岛素/IGF-1 跨膜受体的条件消耗。这使得 DAF-2 蛋白水平在时间点上的时间和空间上降低，之后诸如 RNAi 等干预措施变得无效。使用该系统，我们发现 AID 介导的 DAF-2 蛋白消耗超过了daf-2的寿命突变体。成年早期 DAF-2 的消耗导致多种不良表型，包括生长迟缓、种系收缩、卵保留和育雏大小减小。相比之下，AID 介导的 DAF-2 在生殖后的消耗，特别是在成年早期的肠道中，导致寿命延长而没有这些有害影响。引人注目的是，在老年人口中，当 75% 的人口死亡时，AID 介导的 DAF-2 蛋白消耗导致寿命加倍。因此，我们提供了一个概念验证，即使接近个人寿命的尽头，也可以延缓衰老并延长寿命。