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

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.

Age Related Changes in the Circulating Leukocyte Transcriptome in Dairy Cows

“…These aspects improved comparability between samples but meant that we did not include any data from younger growing heifers of < 2 years. Despite the many differences in physiology, lifestyle and lifespan between species, many of the genes and pathways identi ed in cows were the same as those highlighted in previous studies of ageing in other species [2][3][4]7].…”

“…Studies on model organisms have highlighted that ageing is characterized by many alterations at molecular, cellular and tissue level [3]. Studies of the ageing transcriptome have been performed in species including C. elegans [4], ies [5], rodents [6] and humans [7]. This approach has identi ed various signatures found to occur repeatedly across different tissues and organisms.…”

Deep biomarkers of aging and longevity: from research to applications

“…Many diseases related to aging can be diagnosed using multiple omics data sets in different dimensions including transcriptomics data, which is usually used in targets identification process. Recently, a universal transcriptomic signature of age performed in Caenorhabditis elegans identified a handful of molecules which extend up to 30% of mean lifespan [48]. Combining the synthetic data of different age with other various data sets provides a novel approach to create an aging clock model with pathogenic or aging-related targets identified.…”

Longevity: Lesson from Model Organisms

“…Many key factors that are capable of regulating longevity have been discovered using this model organism [42,43]. In 1993, it was demonstrated that mutations at the daf-2 locus, which encodes an ortholog of the insulin/IGF1 receptor, doubles the life span of the animal [44,45,46].…”