Study: “Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity”
Publisher: Nature
Published date: September 2022
PubMed link to study: https://pubmed.ncbi.nlm.nih.gov/37118503/
A study published in Nature Aging has uncovered a new mechanism linking spliceosome fidelity, intron retention, and mTORC1 signaling to longevity. Researchers found that specific mutations in spliceosome components can enhance lifespan by modulating gene expression and mTORC1 activity. These findings could pave the way for new anti-aging interventions by targeting these cellular processes.
Feel welcome to share your own thoughts on this research in the comment section below as well. I will be happy to discuss and learn more about how you see its potential in this field.
How Splicing Fidelity Modulates Lifespan
The spliceosome is a complex cellular machinery that removes introns from pre-mRNA, a crucial step in gene expression regulation. This study concentrated on a specific spliceosome component, RNP-6, and a mutation known as G281D, in the model organism Caenorhabditis elegans (C. elegans). The G281D mutation in RNP-6 was found to be a selective reduction-of-function mutation that significantly extends the lifespan of C. elegans without causing major defects under normal conditions.
Intron Retention and Its Impact on Lifespan
Intron retention, where specific introns are not spliced out from pre-mRNA, leads to changes in gene expression. The study discovered that the RNP-6(G281D) mutation causes intron retention in the egl-8 gene, which encodes a phospholipase enzyme. This retention reduces EGL-8 protein levels in neurons, contributing to the extension of lifespan in C. elegans.
Further experiments confirmed the role of intron retention in longevity. Mutations that weakened the intron 8 splice site of egl-8 resulted in increased intron retention and extended lifespan, although not to the same extent as the RNP-6(G281D) mutation. This evidence strongly supports the hypothesis that intron retention in egl-8 plays a critical role in promoting longevity.
Interaction with mTORC1 Signaling Pathway
The study also explored how splicing fidelity modulates lifespan by interacting with the mTORC1 signaling pathway, which is known to regulate aging and lifespan. It appears mTORC1 integrates various signals, such as nutrients and growth factors, to control cell growth and metabolism. Inhibition of mTORC1 signaling has been associated with extended lifespan in many organisms.
The researchers found that the RNP-6(G281D) mutation inhibits mTORC1 signaling through decreased EGL-8 function. This was indicated by increased nuclear localization of the transcription factor HLH-30 and elevated levels of phosphorylated AAK-2/AMPK, markers of reduced mTORC1 activity. Genetic interactions showed that the longevity effects of RNP-6(G281D) were nonadditive with those of a known mTORC1 pathway component, suggesting they function in the same pathway.
Conservation Across Species
The significance of these findings extends to mammalian cells. The researchers examined PUF60, the human homolog of RNP-6, and found that knocking down PUF60 in human cells led to decreased mTORC1 activity and altered its cellular localization. This conservation across species highlights the potential relevance of these mechanisms in human aging.
Implications for Anti-Aging Research
The study sheds some light on the complex relationship between spliceosome fidelity, intron retention, and mTORC1 signaling in regulating lifespan. These insights could potentially lead to the development of new interventions targeting these pathways to promote healthy aging and extend lifespan. Understanding how these cellular processes interact offers promising avenues for future research in anti-aging therapies.
Specifically, the study suggests that targeting components of the splicing machinery, such as PUF60, could be a novel approach to modulating mTORC1 signaling for health benefits. Thereby utilizing how the splicing fidelity modulates lifespan by interacting with the mTORC1 signaling pathway.
In Summary
This research highlights the importance of cellular mechanisms in aging and provides a potential foundation for developing strategies to manipulate these pathways to delay aging and mitigate age-related diseases.
