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

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.

Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

“…One of the most impactful applications of DL in biomedicine was in the applications of generative models to de novo molecular design [32][33][34][35][36] . In the context of aging research, these new methods can be combined for geroprotector discovery [37][38][39][40][41] . Indeed, since 2013, many aging clocks have been developed in both humans and other model organisms.…”

Gene expression‐based drug repurposing to target aging

“…Whereas most studies have focussed on model organisms, one study used the known prolongevity drugs from the Geroprotectors database (Moskalev et al, 2015) and asked whether these could be functional in humans (Aliper et al, 2016). Using young and old human stem cell expression profiles, they calculate a geroprotective score based on the GeroScope algorithm, which scores drugs based on the drug targets and age‐associated expression changes in related pathways (Zhavoronkov, Buzdin, Garazha, Borisov, & Moskalev, 2014).…”

Studying the geroprotective effects of inhibitors suppressing aging -associated signaling cascades in model organisms

“…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 [1].…”

“…Another powerful approach is to use computational tools to carry out signaling pathway analysis of gene expression between young and old cells. Based on the signaling pathway results, known compounds may be screened and ranked, in order to identify the best compounds to target those pathways and restore a «young» cellular profile [1]. Using this approach six substances, that demonstrate lifespan-extending effects in animal models, were tested for geroprotective effects in senescent human fibroblast cultures.…”

“…А new opportunity for predicting lifespan-extending chemical compounds provides the using of a computational tools and predictive machine learning methods [1,5].…”