• Open Access

Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells

Authors

  • Taotao Chen,

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
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    • These authors contributed equally to this work.

  • Li Shen,

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
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    • These authors contributed equally to this work.

  • Jie Yu,

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
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    • These authors contributed equally to this work.

  • Hongjiang Wan,

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
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    • These authors contributed equally to this work.

  • Ao Guo,

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
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  • Jiekai Chen,

    1. Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine at Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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  • Yuan Long,

    1. State Key Laboratory for Drug Research, National Center for Drug Screening, Shanghai, China
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  • Jian Zhao,

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
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  • Gang Pei

    1. Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
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Gang Pei and Jian Zhao, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. Tel.: +86-21-54921373; fax: +86-21-54921372; e-mail: gpei@sibs.ac.cn; jzhao@sibs.ac.cn

Summary

Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. This seminal work was followed by numerous studies reporting alternative (noninsertional) reprogramming methods and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency. Here we report that inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition, the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. We further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin), and an activating adenosine monophosphate-activated protein kinase activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. Our results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity based on the regulation of cellular reprogramming.

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