Assessing Nematode Versions of Human Aging-Associated Genes

An ortholog is a gene in one species that serves the same purpose as its equivalent in another species, a pairing that usually implies common ancestry. In the case of humans and nematode worms such as Caenorhabditis elegans, that is a very distant common ancestry, but nonetheless even between such widely diverse species many cellular mechanisms are surprisingly similar. The basic pattern for cellular life is very ancient, and came into being in the earliest stages of evolution, long before the existence of complex organisms. Here, researchers make a list of nematode orthologs of a number of human genes that are known to vary in gene expression levels as aging progresses, and find that more than half of them affect nematode life span if their activity is suppressed. All in all it is an interesting approach to narrowing the scope of further research into the way in which specific human genes impact the pace of aging.

This is characteristic of the approach to aging taken by much of the research community, in aiming first to completely understand how exactly aging progresses, at the detail level, with all of the influences mapped. Where intervention is the goal, that intervention takes the form of adjusting the operation of cells in order to modestly slow the progression of aging. It is far from the most effective path forward, being slow, costly, and producing only limited benefits, but it is the one that dovetails best with the culture of science and funding of science, which seeks greater understanding of biological processes. This is unfortunate, as far better approaches exist if the goal is longer, healthier lives as soon as possible. Aging is an accumulation of damage, and aiming to repair that damage is far better and more cost-effective than aiming to understand exactly how the damage then causes further problems.

Understanding which molecular processes contribute to aging is critical to developing interventions capable of extending healthy human lifespan and delaying onset of age-associated diseases. A key step in this process is building a comprehensive model encompassing the range of genetic and environmental factors that influence lifespan and describing the complex interaction between these factors in an aging organism. Directly screening interventions for lifespan phenotypes in mammals is limited by long lifespans. Despite evolutionary distance and orders-of-magnitude differences in lifespan, processes that contribute to aging are sufficiently conserved that mechanistic knowledge gleaned from short-lived invertebrates can be beneficially applied to mammalian systems. Genetic screens in the nematode, Caenorhabditis elegans, have identified hundreds of genes capable of influencing lifespan.

An approach that is tractable in humans is to characterize systemic changes that occur during normal aging. This approach identifies traits that change with age or during age-associated disease and employs targeted studies to determine which play a causative role in aging. Early applications focused on easily measurable physiological traits, such as body weight or circulating molecules, but has now expanded into the '-omics' realm to provide systems-level insight into molecular changes that occur with age. As part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, we published a large meta-analysis of gene expression in human peripheral blood from 14,983 individuals representing ages across the adult lifespan. This study identified 1,497 genes with significantly different expression at different ages. Gene sets with a defined age-associated expression pattern provide information about molecular processes with altered activity during aging and provide a valuable diagnostic tool for determining individual biological rate of aging and predicting risk of age-associated disease, as demonstrated in follow-up analyses. On a gene-by-gene basis, differential expression alone is insufficient to distinguish between genes that play a causative role in aging and genes that merely respond to the altered physiological environment in an aging organism.

In this study, we selected the human genes with the most significant differential expression with age from the CHARGE meta-analysis and used RNAi to screen C. elegans orthologs for lifespan phenotypes. This selection criterion ensured that every gene identified in the lifespan screen was already of interest in the context of human aging. The short lifespan of C. elegans allowed genes capable of directly influencing lifespan to be rapidly identified and characterized. The resulting C. elegans candidate list was substantially enriched in genes for which knockdown extends lifespan. The five genes with the greatest impact on lifespan (more than 20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator.



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