Predicting Lifespan-Extending Chemical Compounds with Machine Learning and Biologically Interpretable Features

Abstract

Recently, there has been a growing interest in the development of pharmacological interventions targeting ageing, as well as on the use of machine learning for analysing ageing-related data. In this work we use machine learning methods to analyse data from DrugAge, a database of chemical compounds (including drugs) modulating lifespan in model organisms. To this end, we created four datasets for predicting whether or not a compound extends the lifespan of C. elegans (the most frequent model organism in DrugAge), using four different types of predictive biological features, based on compound-protein interactions, interactions between compounds and proteins encoded by ageing-related genes, and two types of terms annotated for proteins targeted by the compounds, namely Gene Ontology (GO) terms and physiology terms from the WormBase Phenotype Ontology. To analyse these datasets we used a combination of feature selection methods in a data pre-processing phase and the well-established random forest algorithm for learning predictive models from the selected features. The two best models were learned using GO terms and protein interactors as features, with predictive accuracies of about 82% and 80%, respectively. In addition, we interpreted the most important features in those two best models in light of the biology of ageing, and we also predicted the most promising novel compounds for extending lifespan from a list of previously unlabelled compounds.

Machine learning predicts lifespan and underlying causes of death in agingC. elegans

“…Artificial intelligence(AI)/ machine learning (ML) methods are proving increasingly powerful at yielding biological insight, as exemplified by the capacity of AlphaFold to predict protein function from primary structure 26 . In research on aging in C. elegans , ML has begun to be applied to the prediction of drugs that extend lifespan 27, 28 . Here we take the novel approach of applying AI/ML data-driven approaches to study the mechanistic basis of aging in C. elegans , specifically to explore the relationship between senescent pathology and lifespan across a range of genotypes and conditions.…”