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Cell Metab. 2019 Sep 3;30(3):573-593.e8. doi: 10.1016/j.cmet.2019.06.018. Epub 2019 Jul 25.

Identification and Application of Gene Expression Signatures Associated with Lifespan Extension.

Author information

1
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Skolkovo Institute of Science and Technology, Moscow 121205, Russia; Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia.
2
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow 117485, Russia.
4
Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, NY, USA.
5
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
6
Skolkovo Institute of Science and Technology, Moscow 121205, Russia; Comparative Biology group, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai 200031, China; Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig 04103, Germany; School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
7
Broad Institute, Cambridge, MA, USA.
8
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA, USA. Electronic address: vgladyshev@rics.bwh.harvard.edu.

Abstract

Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.

KEYWORDS:

GENtervention; aging; caloric restriction; feminizing effect; gene expression; growth hormone; lifespan extension; lifespan-extending interventions; longevity; longevity signatures; rapamycin

PMID:
31353263
DOI:
10.1016/j.cmet.2019.06.018

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