Mammals differ more than 100-fold in maximum lifespan. Here, we conducted comparative transcriptomics on 26 species with diverse lifespans. We identified thousands of genes with expression levels negatively or positively correlated with a species’ maximum lifespan (Neg- or Pos-MLS genes). Neg-MLS genes are primarily involved in energy metabolism and inflammation. Pos-MLS genes show enrichment in DNA repair, microtubule organization, and RNA transport. Expression of Neg- and Pos-MLS genes is modulated by interventions, including mTOR and PI3K inhibition. Regulatory networks analysis showed that Neg-MLS genes are under circadian regulation possibly to avoid persistent high expression, whereas Pos-MLS genes are targets of master pluripotency regulators OCT4 and NANOG and are upregulated during somatic cell reprogramming. Pos-MLS genes are highly expressed during embryogenesis but significantly downregulated after birth. This work provides targets for anti-aging interventions by defining pathways correlating with longevity across mammals and uncovering circadian and pluripotency networks as central regulators of longevity.

哺乳动物的最长寿命相差超过 100 倍。在这里，我们对 26 个具有不同寿命的物种进行了比较转录组学。我们确定了数千个表达水平与物种最长寿命呈负相关或正相关的基因（Neg-或 Pos-MLS 基因）。Neg-MLS 基因主要参与能量代谢和炎症。Pos-MLS 基因在 DNA 修复、微管组织和 RNA 运输中表现出丰富。Neg-和 Pos-MLS 基因的表达受到干预措施的调节，包括 mTOR 和 PI3K 抑制。监管网络分析表明，Neg-MLS 基因处于昼夜节律调节之下，可能是为了避免持续高表达，而 Pos-MLS 基因是主要多能性调节因子 OCT4 和 NANOG 的靶标，并且在体细胞重编程期间上调。Pos-MLS 基因在胚胎发生过程中高度表达，但在出生后显着下调。这项工作通过定义与哺乳动物长寿相关的途径并揭示昼夜节律和多能性网络作为长寿的中央调节器，为抗衰老干预提供了目标。