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September 24, 2016

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state.

Written and published by Biogerontology Research Foundation staff in collaboration with Insilico Medicine Inc., Pathway Pharmaceuticals, Ltd., Center for Biogerontology and Regenerative Medicine, Moscow Institute of Physics and Technology, University of Tennessee Health Science Center (Department of Genetics, Genomics, and Informatics), D. Rogachev Federal Research and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Life Extension, George Mason University (School of Systems Biology), and the Engelhardt Institute of Molecular Biology of Russian Academy of Sciences.

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging (Albany NY). 2016 Sep 24;8(9):2127-2152.

Aliper A(1), Belikov AV(2), Garazha A(1,2,3), Jellen L(1,4), Artemov A(1), Suntsova M(5), Ivanova A(5), Venkova L(1,6), Borisov N(1,6), Buzdin A(6), Mamoshina P(1), Putin E(1), Swick AG(7), Moskalev A(1,2,8,9,10), Zhavoronkov A(1,11).

(1) Insilico Medicine, Inc, Research Department, Baltimore, MD 21218, USA.

(2) Moscow Institute of Physics and Technology, Dolgoprudny, 141700, Russia.

(3) Center for Biogerontology and Regenerative Medicine, Moscow, 121099, Russia.

(4) Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

(5) D. Rogachev Federal Research and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow, 117997, Russia.

(6) Pathway Pharmaceuticals, Ltd, Hong Kong, Hong Kong.

(7) Life Extension, Ft. Lauderdale, FL 33308, USA.

(8) Laboratory of Molecular Radiobiology and Gerontology, Institute of Biology of Komi Science Center of Ural Branch of Russian Academy of Sciences, Syktyvkar, 167982, Russia.

(9) School of Systems Biology, George Mason University (GMU), Fairfax, VA 22030, USA.

(10) Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, Moscow, 119991, Russia.

(11) The Biogerontology Research Foundation, Oxford, UK.

Abstract: Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.

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