Cell Metab. 2022 May 10. pii: S1550-4131(22)00138-3. [Epub ahead of print]
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.
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.
Keywords: aging; circadian clock; comparative transcriptomics; epigenetic reprogramming; functional genomics; longevity; pluripotency