Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan. We show that indoles from commensal microbiota extend healthspan of diverse organisms, including Caenorhabditis elegans, Drosophila melanogaster, and mice, but have a negligible effect on maximal lifespan. Effects of indoles on healthspan in worms and flies depend upon the aryl hydrocarbon receptor (AHR), a conserved detector of xenobiotic small molecules. In C. elegans, indole induces a gene expression profile in aged animals reminiscent of that seen in the young, but which is distinct from that associated with normal aging. Moreover, in older animals, indole induces genes associated with oogenesis and, accordingly, extends fecundity and reproductive span. Together, these data suggest that small molecules related to indole and derived from commensal microbiota act in diverse phyla via conserved molecular pathways to promote healthy aging. These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans.C. elegans | aging | frailty | aryl hydrocarbon receptor | microbiota R ecent advances in health care have contributed to a significant increase in life expectancy of individuals, especially in developed countries, which predict an expansion of geriatric populations by as much as 350-fold over the next 40 y (1). However, extension of lifespan is often accompanied by increased frailty, and attendant increases in global healthcare expenditures are expected to be both massive and unsustainable (2). Such data highlight the need to develop means to extend healthspan, which is broadly defined as the length of time that an individual remains healthy and free of age-related infirmities (3, 4).Healthspan has often been convolved with lifespan, and extended healthspan has been associated with slowed onset of normal age-related changes (e.g., sarcopenia). Thus, mutations that extend lifespan might be expected to likewise extend healthspan. Recent studies in Caenorhabditis elegans indicate that, relative to wild-type animals, mutations that extend lifespan do indeed extend the period of youthfulness, in which animals are motile and resistant to bacterial infection (healthspan), but also extend the period of decrepitude or frailty, where animals are relatively immobile (5, 6) Other studies in C. elegans that take into account multiple measures of health, each normalized to maximal lifespan, indicate that mutations or conditions that extend lifespan minimally impact or ev...

The nematode Caenorhabditis elegans constitutes a leading animal model to study how signaling pathway components function in conserved biological processes. Here, we describe the role of an Axin family member, PRY-1, in lipid metabolism. Axins are scaffolding proteins that play crucial roles in signal transduction pathways by physically interacting with multiple factors and coordinating the assembly of protein complexes. Genome-wide transcriptome profiling of a pry-1 mutant revealed differentially regulated genes that are associated with lipid metabolism such as vitellogenins (yolk lipoproteins), fatty acid desaturases, lipases, and fatty acid transporters. Consistent with these categorizations, we found that pry-1 is crucial for the maintenance of lipid levels. Knockdowns of vit genes in a pry-1 mutant background restored lipid levels, suggesting that vitellogenins contribute to PRY-1 function in lipid metabolic processes. Additionally, lowered expression of desaturases and lipidomic analysis provided evidence that fatty acid synthesis is reduced in pry-1 mutants. Accordingly, an exogenous supply of oleic acid restored depleted lipids in somatic tissues of worms. Overall, our findings demonstrate that PRY-1/Axin signaling is essential for lipid metabolism and involves the regulation of yolk proteins.

Aging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate aging, including insulin/insulin-like growth factor-1 signaling (IIS). In Caenorhabditis elegans, the key regulator of IIS is DAF-16/FOXO. One of the kinases that affects DAF-16 function is the AMPK catalytic subunit homolog AAK-2. In this study, we report that PRY-1/Axin plays an essential role in AAK-2 and DAF-16-mediated regulation of life span. The pry-1 mutant transcriptome contains many genes associated with aging and muscle function. Consistent with this, pry-1 is strongly expressed in muscles, and muscle-specific overexpression of pry-1 extends life span, delays muscle aging, and improves mitochondrial morphology in AAK-2-DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Taken together, our data demonstrate that PRY-1 functions in muscles to promote the life span of animals. This study establishes Axin as a major regulator of muscle health and aging.

Scaffold proteins serve important roles in cellular signaling by integrating inputs from multiple signaling molecules to regulate downstream effectors that, in turn, carry out specific biological functions. One such protein, Axin, represents a major evolutionarily conserved scaffold protein in metazoans that participates in the WNT pathway and other pathways to regulate diverse cellular processes. This review summarizes the vast amount of literature on the regulation and functions of the Axin family of genes in eukaryotes, with a specific focus on Caenorhabditis elegans development. By combining early studies with recent findings, the review is aimed to serve as an updated reference for the roles of Axin in C. elegans and other model systems.

Background Caenorhabditis elegans seam cells serve as a good model to understand how genes and signaling pathways interact to control asymmetric cell fates. The stage-specific pattern of seam cell division is coordinated by a genetic network that includes WNT asymmetry pathway components WRM-1, LIT-1, and POP-1, as well as heterochronic microRNAs (miRNAs) and their downstream targets. Mutations in pry-1 , a negative regulator of WNT signaling that belongs to the Axin family, were shown to cause seam cell defects; however, the mechanism of PRY-1 action and its interactions with miRNAs remain unclear. Results We found that pry-1 mutants in C. elegans exhibit seam cell, cuticle, and alae defects. To examine this further, a miRNA transcriptome analysis was carried out, which showed that let-7 ( miR-48, miR-84, miR-241 ) and lin-4 ( lin-4, miR-237 ) family members were upregulated in the absence of pry-1 function. Similar phenotypes and patterns of miRNA overexpression were also observed in C. briggsae pry-1 mutants, a species that is closely related to C. elegans . RNA interference-mediated silencing of wrm-1 and lit-1 in the C. elegans pry-1 mutants rescued the seam cell defect, whereas pop-1 silencing enhanced the phenotype, suggesting that all three proteins are likely important for PRY-1 function in seam cells. We also found that these miRNAs were overexpressed in pop-1 hypomorphic animals, suggesting that PRY-1 may be required for POP-1-mediated miRNA suppression. Analysis of the let-7 and lin-4 -family heterochronic targets, lin-28 and hbl-1 , showed that both genes were significantly downregulated in pry-1 mutants, and furthermore, lin-28 silencing reduced the number of seam cells in mutant animals. Conclusions Our results show that PRY-1 plays a conserved role to maintain normal expression of heterochronic miRNAs in nematodes. Furthermore, we demonstrated that PRY-1 acts upstream of the WNT asymmetry pathway components WRM-1, LIT-1, and POP-1, and miRNA target genes in seam cell development. Electronic supplementary material The online version of this article (10.1186/s12861-019-0197-5) contains supplementary material, which is available to authorized users.