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Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases

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Abstract

A key goal of geroscience research is to identify effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by screening compounds in model organisms; whether they will be effective in humans is largely unknown. Here we present a new strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological interventions that may “reverse” the age-associated transcriptional changes occurred in these subnetworks. We applied ANDRU to human adipose gene expression data from the Genotype Tissue Expression (GTEx) project. For the top 31 identified compounds, 19 of them showed at least some evidence supporting their function in improving metabolic traits or lifespan, which include type 2 diabetes drugs such as pioglitazone. As the query aging genes were refined to the ones with more intimate links to diseases, ANDRU identified more meaningful drug hits than the general approach without considering the underlying network structures. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.

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Acknowledgments

JY was supported by a postdoctoral fellowship from Unity Biotechnology. ZT receives financial support from Unity Biotechnology as a consultant. This work is partially supported by NIH/NIA R01-AG055501, U24-CA210993, and a Leducq foundation award to ZT. This work was also supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

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  1. Jialiang Yang and Shouneng Peng contributed equally to this work.

Authors and Affiliations

  1. Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York City, USA

    Jialiang Yang, Shouneng Peng, Bin Zhang, Sander Houten, Eric Schadt, Jun Zhu & Zhidong Tu

  2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, IMI 3-70F, New York City, NY, 10029, USA

    Jialiang Yang, Shouneng Peng, Bin Zhang, Sander Houten, Eric Schadt, Jun Zhu & Zhidong Tu

  3. Department of Genetics, Albert Einstein College of Medicine, New York, New York City, USA

    Yousin Suh

  4. Department of Medicine Endocrinology, Albert Einstein College of Medicine, New York, New York City, USA

    Yousin Suh

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ZT conceived the concept of the work. JY, SP and ZT performed the analysis. JY, SP, SH, YS, ZT wrote the manuscript. All authors helped to discuss and improve the work.

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Yang, J., Peng, S., Zhang, B. et al. Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases. GeroScience 42, 353–372 (2020). https://doi.org/10.1007/s11357-019-00106-x

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