Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation

• DOI: 10.1016/j.cmet.2022.04.011
• Publication Date: 2022-05-16T14:30:05Z
• Authors: J. Yuyang Lu; Matthew Simon; Yang Zhao; Julia Ablaeva; Nancy Corson; Yongwook Choi; KayLene Y.H. Yamada; Nicholas J. Schork; Wendy R. Hood; Geoffrey E. Hill; Richard A. Miller; Andrei Seluanov; Vera Gorbunova
• Keywords: Reprogramming; Homeobox protein NANOG

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.