The Longevity of daf-2 and clk-1 Mutants Depends Upon tts-1
Since little if anything works in isolation inside a cell, many of the varied methods discovered over the past twenty years to modestly slow aging in laboratory species are in fact acting on a much smaller set of underlying mechanisms. Thus a steady flow of new discoveries like the one below continue to take place, a step by step exploration of the vast complexity of metabolism that will likely still be far from done by the time viable rejuvenation technologies exist, built based on a repair approach that bypasses the need for a complete understanding of cellular biochemistry in aging:
Long noncoding RNAs were until recently thought to exist and function predominantly in the nucleus. It is now fast becoming realized that they effusively associate with cytosolic ribosomes. Several functions for short noncoding RNAs bound to ribosomes have been described, such as those that derive from both mRNAs and tRNAs and function as stress-induced inhibitors of protein translation. It is thus becoming clear that ncRNAs, both short and long, are playing roles in protein translation that are only beginning to be fully appreciated.The biogenesis of ribosomes and their coordination of protein translation consume an enormous amount of cellular energy. As such, it has been established that the inhibition of either process can extend eukaryotic lifespan. Here, we used next-generation sequencing to compare ribosome-associated RNAs from normal strains of Caenorhabditis elegans to those carrying the life-extending daf-2 mutation. We found a long noncoding RNA (lncRNA), transcribed telomeric sequence 1 (tts-1), on ribosomes of the daf-2 mutant. Depleting tts-1 in daf-2 mutants increases ribosome levels and significantly shortens their extended lifespan. We find tts-1 is also required for the longer lifespan of the mitochondrial clk-1 mutants but not the feeding-defective eat-2 mutants. In line with this, the clk-1 mutants express more tts-1 and fewer ribosomes than the eat-2 mutants.
The precise mechanism of the tts-1 lncRNA remains to be determined. One intriguing possibility is that it is specifically regulating the translation of ribosomal protein mRNAs. Supporting this notion is the observation that despite the marked reduction of ribosomal proteins in the daf-2 mutant proteome, expression levels of ribosomal protein mRNAs in the daf-2 mutants are actually higher than in wild-types. This suggests that a specific block of ribosomal protein gene expression at the level of translation is imposed in mutants undergoing lifespan extension, and we believe this will be an interesting area of future study. In sum, we propose that the tts-1 lncRNA is able to reduce ribosome levels in a manner that is necessary for lifespan extension. Since many recent reports demonstrate that both genetic and pharmacological manipulations of the translation machinery can extend longevity in eukaryotes, our study puts lncRNAs forward as a compelling area in the field of aging research.