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.



A complete understanding is not required as ADG himself has said before now.

HPE Plasma exchange or TERT activation would both achieve restoration of youthful phenotypes in the stem cell niche without the need to mess about with metabolism and try to work out the hundreds of pathways.

Dr Michael Fossel I suspect is correct with his approach to target Telomeres as an intervention point and pull the Stem cell niches back to youthful function via gene regulation. Dr Blasco and Dr Briggs are also in favor of this approach.

Eventually they will map all the pathways and their relationships but until they do we have to do the best we can. We dont need to know everything about aging to start tacklking it, just the same as the Vicotrians didn't understand electricity but they still used it to light rooms with it.

So lets try that and see what other SENS damage is left to clear up. ADG recently said of messing with metabolism it may reduce the complexity of the SENS approach (7 SENS but less strands) if enough pathways of use could be utilized. I say activate TERT and see what's left to fix.

Posted by: Steve H at June 1st, 2015 8:34 AM

Hi, are you sure TERT rejunevates stem cell niche ?

Posted by: Martin S. at June 1st, 2015 12:12 PM

"These tissues are characterized by decreased cell proliferation and/or increased apoptosis, showing characteristics of an aged phenotype related to the impairment of adult stem cell survival. Telomerase activity is essential for maintenance of telomere length and regenerative capacity in stem cells."

This is one article that hints at Telomeres role in Stem cell aging and there are plenty of others around. Dr Michael Fossels new book The Telomerase Revolution will being all the work up to date but his previous book is also very informative.

Telomeres are not the cause of aging but they lead to pathology and are an upstream target rather than messing about with myriad pathways, this is in essence what he is saying. The change of gene expression from lengthening telomeres is significant so the thought is that lengthening them should lead to Epigenetic changes back to a more youthful phenotype, this certainly appears to happen with animals and human cells in-vitro.

I think there are possibilities in combining this approach with some SENS ideas like SC replacement, AGE crosslinks, cellular junk removal. But I am inclined to agree with Dr Fossel, Blasco, Briggs, Andrews etc... that Telomeres whilst not a total answer to aging could be a way to reduce the complexity of intervention.

ADG recently said similar about the specific pathways, so what if Telomeres control that Epigenetic drift signifcantly (tests show gene expression shifts to a youthful pattern with TERT lengthening Telomeres) making the task more manageable? I think it is worth trying instead of messing about with metabolism and could potentially reduce the complexity of the task at hand.

Posted by: Steve H at June 2nd, 2015 2:07 AM

These checkpoints protect against an accumulation of genomically unstable cells and cancer initiation. However, the induction of these checkpoints can also limit organ homeostasis, regeneration, and survival during aging and in the context of diseases. The decline in tissue regeneration in response to telomere shortening has been related to impairments in stem cell function. Telomere dysfunction impairs stem cell function by activation of cell-intrinsic checkpoints and by the induction of alterations in the micro- and macro-environment of stem cells.

A number of papers indicate that Stem cell environment is influenced by the longest Telomere lengths, ergo if they are all short the phenotype of the niche will age and decline in function. This is why I agree with the idea of targeting Telomeres because their influence on gene expression seems to be quite considerable and could restore the aged phenotype. Wright and Shay have written a considerable amount about gene expression/regulation and the epigenetic changes they make as has Dr Fossel.

As I said I broadly agree with SENS but I think Telomeres are a viable target and support is growing for this as an intervention. If lengthening them works it could really make SENS job easier as there could be less things to deal with, still the Seven Deadly SENS but less strands.

Posted by: Steve H at June 2nd, 2015 2:36 AM

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