Meta-analysis of global metabolomic data identifies metabolites associated with life-span extension

Abstract

The manipulation of distinct signaling pathways and transcription factors has been shown to influence life span in a cell-non-autonomous manner in multicellular model organisms such as Caenorhabditis elegans. These data suggest that coordination of whole-organism aging involves endocrine signaling, however, the molecular identities of such signals have not yet been determined and their potential relevance in humans is unknown. Here we describe a novel metabolomic approach to identify molecules directly associated with extended life span in C. elegans that represent candidate compounds for age-related endocrine signals. To identify metabolic perturbations directly linked to longevity, we developed metabolomic software for meta-analysis that enabled intelligent comparisons of multiple different mutants. Simple pairwise comparisons of long-lived glp-1, daf-2, and isp-1 mutants to their respective controls resulted in more than 11,000 dysregulated metabolite features of statistical significance. By using meta-analysis, we were able to reduce this number to six compounds most likely to be associated with life-span extension. Mass spectrometry-based imaging studies suggested that these metabolites might be localized to C. elegans muscle. We extended the metabolomic analysis to humans by comparing quadricep muscle tissue from young and old individuals and found that two of the same compounds associated with longevity in worms were also altered in human muscle with age. These findings provide candidate compounds that may serve as age-related endocrine signals and implicate muscle as a potential tissue regulating their levels in humans.

A roadmap for the XCMS family of software solutions in metabolomics

“…The challenge of applying simple pairwise comparisons is that knocking out a single protein can lead to hundreds or thousands of changes in feature intensities due to the interconnectivity of related pathways. [31] For instance, knocking out a protein may decrease the product of that protein. However, decreased levels of the protein’s product may then itself lead to a cascade of other context-dependent metabolic alterations.…”

“…When control C. elegans worms were compared to long-lived C. elegans worms in which the germ line had been removed by glp-1 mutation, ~44% of the total detected features (13639) were altered with a p -value <0.05 and a fold change >2. [34] From these data alone, features directly associated with increased life span could not be distinguished from those features that were altered from glp-1 mutation but that did not affect life span. Because germ line induced extensions in life span are dependent upon the FOXO transcription factor DAF-16, double mutant daf-16;glp-1 worms are short lived.…”

“…By performing similar analyses of other long-lived worms with metaXCMS, the number of detected features directly associated with longevity was ultimately reduced to six. [34]…”

The Caenorhabditis elegans lipidome

“…Spectrometry (ToF-SIMS) based techniques have been used with C. elegans in two proof-of-principle publications [82,83]. For routine application of this technology several developments have to be made, especially spatial resolution in MALDI-MS has to be in an acceptable range to visualize different tissues (see also Challenges and Future research directions).…”

“…Application of metabolite imaging using MS in increasing with several areas of application [104], including lipid analysis [105]. MALDI-MS imaging to localize and visualize molecular information in the whole worm has been also described [82]. However, spatial resolution of available instruments is still insufficient for use with C. elegans.…”