Aging in eukaryotes is accompanied by widespread deterioration of the somatic tissue. Yet, abolishing germ cells delays the age-dependent somatic decline in In adult worms lacking germ cells, the activation of the DAF-9/DAF-12 steroid signaling pathway in the gonad recruits DAF-16 activity in the intestine to promote longevity-associated phenotypes. However, the impact of this pathway on the fitness of normally reproducing animals is less clear. Here, we explore the link between progeny production and somatic aging and identify the loss of lysosomal acidity-a critical regulator of the proteolytic output of these organelles-as a novel biomarker of aging in The increase in lysosomal pH in older worms is not a passive consequence of aging, but instead is timed with the cessation of reproduction, and correlates with the reduction in proteostasis in early adult life. Our results further implicate the steroid signaling pathway and DAF-16 in dynamically regulating lysosomal pH in the intestine of wild-type worms in response to the reproductive cycle. In the intestine of reproducing worms, DAF-16 promotes acidic lysosomes by upregulating the expression of v-ATPase genes. These findings support a model in which protein clearance in the soma is linked to reproduction in the gonad via the active regulation of lysosomal acidification.
CCR4‐NOT is a versatile eukaryotic protein complex that controls multiple steps in gene expression regulation from synthesis to decay. In yeast, CCR4‐NOT has been implicated in stress response regulation, though this function in other organisms remains unclear. In a genome‐wide RNAi screen, we identified a subunit of the CCR4‐NOT complex, ccf‐1, as a requirement for the C. elegans transcriptional response to cadmium and acrylamide stress. Using whole‐transcriptome RNA sequencing, we show that the knockdown of ccf‐1 attenuates the activation of a broad range of stress‐protective genes in response to cadmium and acrylamide, including those encoding heat shock proteins and xenobiotic detoxification. Consistently, survival assays show that the knockdown of ccf‐1 decreases C. elegans stress resistance and normal lifespan. A yeast 2‐hybrid screen using a CCF‐1 bait identified the homeobox transcription factor PAL‐1 as a physical interactor. Knockdown of pal‐1 inhibits the activation of ccf‐1 dependent stress genes and reduces C. elegans stress resistance. Gene expression analysis reveals that knockdown of ccf‐1 and pal‐1 attenuates the activation of elt‐2 and elt‐3 under stress that encode master transcriptional co‐regulators of stress response in the C. elegans, and that overexpression of ELT‐2 can suppress ccf‐1's requirement for gene transcription in a stress‐dependent manner. Our findings reveal a new role for CCR4‐NOT in the environmental stress response and define its role in stress resistance and longevity in C. elegans.
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