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LIN-39 functions as a neuron-specific developmental determinant of longevity in Caenorhabditis elegans with reduced insulin/IGF-like signaling [RNA-seq]

ABSTRACT: The nuclear chromatin landscape changes with age – a phenomenon observed across many species, including humans. Notably, perturbing this landscape can alter the rate of aging, indicating at least a partial role in controlling this process. This raises the question of whether chromatin alterations also distinguish animals that age at unusual rates. To explore this, we focused on insulin/IGF-like signaling (IIS) in Caenorhabditis elegans, a well-characterized signaling pathway whose impairment drastically slows aging and extends lifespan of these animals. Specifically, we conducted ATAC- and mRNA-seq in animals with reduced IIS (i.e., daf-2 mutants). Interestingly, we found that enhancer regions tend to close and become transcriptionally repressed with age, but under reduced IIS, they tend to open and become transcriptionally active, suggesting their potential relevance for lifespan regulation. By screening transcription factors (TFs) predicted to bind these regions, we identified the HOX gene LIN-39 as a novel aging-preventive TF required for the longevity of daf-2 mutants. LIN-39 performs this role specifically during development and in neurons. Further investigation showed that LIN-39 was acting around the L3 larval stage and in the hermaphrodite-specific VC class of cholinergic motor neurons – at a time when they undergo maturation. Finally, this LIN-39-dependent longevity required DAF-16/FOXO, a well-established aging-preventive TF that acts downstream of DAF-2, which may synergize with LIN-39 in VC neurons to open enhancer the regions. We ultimately propose a model whereby longevity of daf-2 mutant hermaphrodites requires a longevity-promoting signal emitted by VC neurons – a signal that relies on correct VC neuron maturation around the L3 stage, which in turn is assured by the actions of LIN-39 and resulting chromatin and gene expression changes. This renders LIN-39 a rare example of a developmental determinant of longevity. And given the conservation of IIS, HOX and FOXO TFs, and cholinergic neuron function across species, the here described mechanism may reflect a general principle by which developmental transcriptional programs shape adult longevity.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE271972 | GEO | 2025/05/29

REPOSITORIES: GEO

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Project description:The nuclear chromatin landscape changes with age – a phenomenon observed across many species, including humans. Notably, perturbing this landscape can alter the rate of aging, indicating at least a partial role in controlling this process. This raises the question of whether chromatin alterations also distinguish animals that age at unusual rates. To explore this, we focused on insulin/IGF-like signaling (IIS) in Caenorhabditis elegans, a well-characterized signaling pathway whose impairment drastically slows aging and extends lifespan of these animals. Specifically, we conducted ATAC- and mRNA-seq in animals with reduced IIS (i.e., daf-2 mutants). Interestingly, we found that enhancer regions tend to close and become transcriptionally repressed with age, but under reduced IIS, they tend to open and become transcriptionally active, suggesting their potential relevance for lifespan regulation. By screening transcription factors (TFs) predicted to bind these regions, we identified the HOX gene LIN-39 as a novel aging-preventive TF required for the longevity of daf-2 mutants. LIN-39 performs this role specifically during development and in neurons. Further investigation showed that LIN-39 was acting around the L3 larval stage and in the hermaphrodite-specific VC class of cholinergic motor neurons – at a time when they undergo maturation. Finally, this LIN-39-dependent longevity required DAF-16/FOXO, a well-established aging-preventive TF that acts downstream of DAF-2, which may synergize with LIN-39 in VC neurons to open enhancer the regions. We ultimately propose a model whereby longevity of daf-2 mutant hermaphrodites requires a longevity-promoting signal emitted by VC neurons – a signal that relies on correct VC neuron maturation around the L3 stage, which in turn is assured by the actions of LIN-39 and resulting chromatin and gene expression changes. This renders LIN-39 a rare example of a developmental determinant of longevity. And given the conservation of IIS, HOX and FOXO TFs, and cholinergic neuron function across species, the here described mechanism may reflect a general principle by which developmental transcriptional programs shape adult longevity.

Project description:One of the most important issues in the study of aging is to discover compounds with longevity-promoting activity and to unravel their underlying mechanisms. Queen honey bees are continuously fed royal jelly (RJ), and they live more than 10 times longer than hive workers, derived from the same diploid genome, which are fed it only for a short period of time during their larval stages. Therefore, RJ is likely to contain longevity-promoting agents for queens. RJ has been reported to possess diverse pharmacological properties. Furthermore, protease-treated RJ (pRJ) has additional beneficial activities. How RJ and pRJ exert these effects and which components in them play a critical role is largely unknown. The evolutionally conserved mechanisms that control lifespan have been indicated. The nematode Caenorhabditis elegans has been widely used for study of aging and longevity, due to its relatively short lifespan and well-established genetic pathways. The purpose of the present study was to elucidate whether RJ and its related substances contain the life span-extending activity in C. elegans and to obtain some insight into the active agents and their mechanisms. We found that both RJ and pRJ extended the lifespan of C. elegans. The life span-extending activity of pRJ was enriched by ODS column chromatography (pRJ-Fraction 5). pRJ-Fr. 5 extended the life span partly by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr. 5 induced changes in the expression of 3 genes encoding insulin-like peptides. Moreover, pRJ-Fr. 5 and reduced IIS shared some common features in terms of their effect on gene expression, such as up-regulation of dod-3 and down-regulation of dod-19, dao-4 and fkb-4. The dod-19 is a previously identified life span determinant in C. elegans, and the fkb-4 encodes a homologue of the mammalian FK506-binding protein. 10-Hydroxy-2-decenoic acid (10-HDA), which was present in high concentration in pRJ-Fr. 5, increased the lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extended the life span in C. elegans, suggesting that RJ may contain longevity-promoting factors common to diverse species across phyla. pRJ-Fr. 5 had higher life span-extending activity than either RJ or pRJ and extended the life span in part through the IIS-DAF-16 pathway. We provide the first evidence that 10-HDA, a defined natural product in RJ, extended organismal lifespan. It is noteworthy that 10-HDA performed its lifespan-extending function through a mechanism totally different from the IIS-DAF-16 pathway. Further search and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network of longevity regulation in diverse species and provide the possibility for nutraceutical interventions in the aging process. C. elegans N2 hermaphrodites were untreated or treated with pRJ-Fr. 5 (25mg/ml) for 24 h starting at the larval 4 (L4) stage.

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LIN-39 functions as a neuron-specific developmental determinant of longevity in Caenorhabditis elegans with reduced insulin/IGF-like signaling [RNA-seq]

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