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Caloric Restriction May Slow Genomic Instability

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Building upon previous studies, a new study has unearthed critical facts about the basic biology behind the TORC1 pathway, identifying how caloric restriction leads to a chain of effects that activate the protein Maf1, repress RNA transcription, and slow genomic instability, which is one of the primary hallmarks of aging.

A long chain of causes

While biology is a very complicated series of chemical causes and effects with many factors at play, this particular chain of events has been mapped in an understandable way in this model organism, shedding new light onto one possible reason why caloric restriction has been shown to effectively increase lifespan.

Caloric restriction and rapamycin are known to downregulate the TORC1 pathway. This downregulation dephosphorylates Maf1, activating it; the activated Maf1 then represses Pol III-mediated RNA transcription. This RNA transcription causes breaks in the genome, overwhelming genomic repair mechanisms (such as Rad52) and thus leading to one of the primary hallmarks of aging: genomic instability. By slowing the rate of RNA transcription, Maf1 – and, therefore, caloric restriction – has been shown to decrease the rate at which genomic instability accumulates.

Abstract



Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1’s function in tRNA repression is inhibited by mTOR-dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1? cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1? cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1? cells. Interestingly, maf1? cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1? cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1? cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1? cells. We propose that Maf1-dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes.

Conclusion

This is a yeast study, not a mammalian one, and mice and people obviously have additional concerns. The authors noted the discrepancies between Maf1-knockout mice and other organisms while identifying gaps in current knowledge: previous studies had shown that Maf1-knockout mice do not become obese due to diet and enjoy increased autophagy, which increases lifespan, while Maf1-knockout fruit flies and cell cultures accumulate lipids (fats).

However, basic biological studies such as this are the first step towards identifying fundamental pathways that can potentially be targeted with therapeutic interventions. By mapping the interactions between Maf1, RNA transcription, and genomic instability, this study brings us a small step closer to fully understanding the reasons behind the health benefits of caloric restriction and rapalogs along with the causes of a primary hallmark of aging.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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