Kang Ping, Liu Peiduo, Hu Yanhui, Kim Jinoh, Kumar Ankur, Dorneich-Hayes Marlene K, Murzyn Wren, Anderson Zenessa J, Frank Lexi N, Kavlock Nicholas, Hoffman Elizabeth, Martin Chad C, Miao Ting, Shimell MaryJane, Powell-Coffman Jo Anne, O'Connor Michael B, Perrimon Norbert, Bai Hua
Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, IA 50011.
Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 55455.
Proc Natl Acad Sci U S A. 2025 May 13;122(19):e2420811122. doi: 10.1073/pnas.2420811122. Epub 2025 May 8.
Developmental time (or time to maturity) strongly correlates with an animal's maximum lifespan, with late-maturing individuals often living longer. However, the genetic mechanisms underlying this phenomenon remain largely unknown. This may be because most previously identified longevity genes regulate growth rate rather than developmental time. To address this gap, we genetically manipulated prothoracicotropic hormone (PTTH), the primary regulator of developmental timing in , to explore the genetic link between developmental time and longevity. Loss of delays developmental timing without altering the growth rate. Intriguingly, mutants exhibit extended lifespan despite their larger body size. This lifespan extension depends on ecdysone signaling, as feeding 20-hydroxyecdysone to mutants reverses the effect. Mechanistically, loss of blunts age-dependent chronic inflammation, specifically in fly hepatocytes (oenocytes). Developmental transcriptomics reveal that NF-κB signaling activates during larva-to-adult transition, with PTTH inducing this signaling via ecdysone. Notably, time-restricted and oenocyte-specific silencing of (an NF-κB homolog) at early 3rd instar larval stages significantly prolongs adult lifespan while delaying pupariation. Our study establishes an aging model that uncouples developmental time from growth rate, highlighting NF-κB signaling as a key developmental program in linking developmental time to adult lifespan.
发育时间（或成熟时间）与动物的最大寿命密切相关，成熟较晚的个体通常寿命更长。然而，这一现象背后的遗传机制在很大程度上仍不清楚。这可能是因为大多数先前鉴定出的长寿基因调节的是生长速率而非发育时间。为了填补这一空白，我们对促前胸腺激素（PTTH）进行了基因操作，PTTH是[昆虫名称未给出]发育时间的主要调节因子，以探索发育时间与长寿之间的遗传联系。[昆虫名称未给出]的缺失会延迟发育时间，而不改变生长速率。有趣的是，[昆虫名称未给出]突变体尽管体型较大，但寿命却延长了。这种寿命延长依赖于蜕皮激素信号传导，因为给[昆虫名称未给出]突变体喂食20-羟基蜕皮激素可逆转这种效应。从机制上讲，[昆虫名称未给出]的缺失减弱了年龄依赖性慢性炎症，特别是在果蝇肝细胞（oenocytes）中。发育转录组学表明，NF-κB信号在幼虫到成虫的转变过程中被激活，PTTH通过蜕皮激素诱导这种信号。值得注意的是，在三龄幼虫早期对[昆虫名称未给出]（一种NF-κB同源物）进行时间限制和oenocyte特异性沉默，可显著延长成虫寿命，同时延迟化蛹。我们的研究建立了一个将发育时间与生长速率解耦的衰老模型，突出了NF-κB信号作为将发育时间与成虫寿命联系起来的关键发育程序。
