Insect hormone prothoracicotropic hormone (PTTH) regulates lifespan through temporal and spatial activation of NF-?B signaling during Drosophila metamorphosis [1]

The prothoracicotropic hormone (PTTH) is a well-known neuropeptide that regulates insect metamorphosis (the juvenile-to-adult transition) by inducing the biosynthesis of steroid hormones, similar to the hypothalamic-pituitary-gonadal control of mammalian puberty. However, the role of Ptth in adult physiology and longevity is largely unexplored. Here, we show that Ptth loss-of-function mutants are long-lived and exhibit increased resistance to oxidative stress in Drosophila. Intriguingly, we find that loss of Ptth blunt age-dependent upregulation of NF-?B signaling specifically in fly oenocytes, the homolog of mammalian hepatocytes. We further show that oenocyte-specific overexpression of NF-?B/Relish blocks the lifespan extension of Ptth mutants, suggesting that Ptth regulates lifespan through oenocyte-specific NF-?B signaling. Surprisingly, adult-specific knockdown of Ptth did not prolong lifespan, indicating that Ptth might control longevity through developmental programs. Our developmental transcriptomic analysis reveals an interesting activation of NF-?B signaling during fly metamorphosis, which is attenuated in Ptth mutants. Intriguingly, the knockdown of NF-?B/Relish, specifically in oenocytes during metamorphosis, significantly prolongs the lifespan of adult flies. Thus, our findings uncover an unexpected role of insect hormone PTTH in controlling adult lifespan through temporal and spatial activation of NF-?B signaling in developing hepatocytes. Overall design: For all groups, total RNA was collected from ~15 female wholebody flies(1 week old and 5 weeks old, wild type and Ptth mutants), three biological replicates each condition.