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

Alexander Aliper,Alexey Moskalev,Artem Artemov,Maria Suntsova,Nicolas Borisov,Alex Zhavoronkov,Evgeny Putin,Anton Buzdin,Polina Mamoshina,Larisa Venkova,Alena Ivanova,Andrew Garazha,Aleksey V Belikov,Leslie Jellen,Andrew G Swick

doi:10.18632/aging.101047

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.

Highlights

A significant rise in the proportion of seniors worldwide is underway [1, 2], resulting in increasing rates of chronic, debilitating disease and long term residential care [3], shrinking the supporting workforce [1, 2], and threatening to sink current health care systems
While hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans
Drug GeroScore ratings were calculated from a database of known geroprotectors and their targets (Supplementary Table S2)

Summary

Introduction

A significant rise in the proportion of seniors worldwide is underway [1, 2], resulting in increasing rates of chronic, debilitating disease and long term residential care [3], shrinking the supporting workforce [1, 2], and threatening to sink current health care systems. The outward features of aging, including decline in function and rise in susceptibility to stress and disease, are associated with a set of structural and functional changes at the cellular level While these changes vary by tissue, many are genetically regulated, and many genes mediating longevity, termed gerontogenes, have been identified [5]. The identification of these genes and experimental manipulation of their products to extend lifespan in model organisms [12] has bolstered the notion that aging is not just a natural process but a treatable disease [8, 13, 14] and added credence to the movement to identify drugs or other factors that may extend lifespan, or, more favorably, healthspan, in humans.

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Results

Conclusion