Insect hormone PTTH regulates lifespan through temporal and spatial activation of NF-κB signaling during metamorphosis.

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. However, the role of PTTH in adult physiology and longevity is largely unexplored. Here, we show that loss-of-function mutants are long-lived and exhibit increased resistance to oxidative stress in . Intriguingly, we find that loss of blunt age-dependent upregulation of NF-κB signaling specifically in fly hepatocytes (oenocytes). We further show that oenocyte-specific overexpression of blocks the lifespan extension of mutants, suggesting that PTTH regulates lifespan through oenocyte-specific NF-κB signaling. Surprisingly, adult-specific knockdown of did not prolong lifespan, indicating that PTTH controls longevity through developmental programs. Indeed, knockdown of PTTH receptor in prothoracic gland (PG) during fly development prolongs lifespan. To uncover the developmental processes underlying PTTH-regulated lifespan, we perform a developmental transcriptomic analysis and identify an unexpected activation of NF-κB signaling in developing oenocytes during fly metamorphosis, which is blocked in mutants. Importantly, knockdown of specifically in oenocytes during early pupal stages significantly prolongs the lifespan of adult flies. Thus, our findings uncover an unexpected role of PTTH in controlling adult lifespan through temporal and spatial activation of NF-κB signaling in developing hepatocytes and highlight the vital role of developmental NF-κB signaling in shaping adult physiology.