RNA splicing is the process by which RNA is assembled from intron and exon sequences in genes. A given gene can be assembled into different RNAs depending on what is included or excluded. The balance of different RNAs produced from a gene tends to change with age, and this may be a cause of dysfunction. Starting from a position of screening for compounds that reduce age-related dysregulation in RNA splicing in nematode worms, researchers happen upon a compound that achieves this goal and extends life by manipulating the activities of gut microbes. Determining how and why life extension occurs in this case will take somewhat longer than the discovery of the approach - it need not have anything to do with RNA splicing. It seems unlikely that this specific compound will be relevant to mice or humans, given the large differences in the gut microbiome between lower animals and mammals, but someone will get around to checking in mice at some point.
Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drugs can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative used in chemotherapy, rescues age-associated AS defects and extends lifespan.
Combining bacterial DNA sequencing, proteomics, metabolomics, and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate the drug's functions through complex interplay among drug, bacteria, and host.
Link: https://doi.org/10.1...al.pgen.1011648
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