A universal transcriptomic signature of age reveals the temporal scaling of Caenorhabditis elegans aging trajectories

Andrei E Tarkhov,Ramani Alla,Robert J Shmookler Reis,Leonid I Menshikov,Peter O Fedichev,Srinivas Ayyadevara,Mikhail Pyatnitskiy

doi:10.1038/s41598-019-43075-z

Abstract

We collected 60 age-dependent transcriptomes for C. elegans strains including four exceptionally long-lived mutants (mean adult lifespan extended 2.2- to 9.4-fold) and three examples of lifespan-increasing RNAi treatments. Principal Component Analysis (PCA) reveals aging as a transcriptomic drift along a single direction, consistent across the vastly diverse biological conditions and coinciding with the first principal component, a hallmark of the criticality of the underlying gene regulatory network. We therefore expected that the organism’s aging state could be characterized by a single number closely related to vitality deficit or biological age. The “aging trajectory”, i.e. the dependence of the biological age on chronological age, is then a universal stochastic function modulated by the network stiffness; a macroscopic parameter reflecting the network topology and associated with the rate of aging. To corroborate this view, we used publicly available datasets to define a transcriptomic biomarker of age and observed that the rescaling of age by lifespan simultaneously brings together aging trajectories of transcription and survival curves. In accordance with the theoretical prediction, the limiting mortality value at the plateau agrees closely with the mortality rate doubling exponent estimated at the cross-over age near the average lifespan. Finally, we used the transcriptomic signature of age to identify possible life-extending drug compounds and successfully tested a handful of the top-ranking molecules in C. elegans survival assays and achieved up to a +30% extension of mean lifespan.

Highlights

The largest relative lifespan extension yet recorded has been in C. elegans, and corresponds to an almost 10-fold increase with the mg[44] nonsense mutation in the age-1 gene[1,2]
Principal Component Analysis (PCA) of gene expression reveals aging in all strains and treated groups as a transcriptomic drift in a single direction, consistent across the vastly diverse biological conditions and coinciding with the first principal component of the combined dataset, which is a hallmark of the criticality of the underlying regulatory network[12]
To identify a set of genes universally associated with aging across many different biological conditions, the aging signature, and to evaluate the theoretical model, we performed a meta-analysis of publicly available gene-expression measurements in C. elegans

Summary

Introduction

The largest relative lifespan extension yet recorded has been in C. elegans, and corresponds to an almost 10-fold increase with the mg[44] nonsense mutation in the age-1 gene[1,2]. Late-life pharmacological interventions yielded even smaller effects on lifespan in flies[4,5], nematodes[6,7] and mice[8,9,10] It is not fully understood why a single nonsense mutation can dramatically extend animal lifespan, while an RNAi block of the same gene does not produce a comparable effect, especially when administered later in life. Perhaps the gene regulatory network is sufficiently robust that a therapy can reduce the pace of aging without qualitative alterations of the relevant molecular mechanisms To address these alternatives, we compiled an RNA-seq dataset of age-dependent transcriptomes produced from C. elegans isogenic strains and populations that have vastly different lifespans. We used the transcriptomic signature of age to identify possible life-extending drug compounds and successfully tested a handful of them in C. elegans survival assays

Methods

Results

Conclusion