I lightly follow the current understanding of telomerase, which is responsible for adding back the “buffers” (telomeres) at the end of genes that RNA can’t copy. It was clear this was part of what we’d need for anti-aging treatment, but last I heard we didn’t understand the mechanisms or how to activate them. Is transcriptome part of this process? It wasn’t immediately clear from the article.
Aging is associated with a systemic length-driven transcriptome imbalance
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Re: Aging is associated with a systemic length-driven transcriptome imbalance
#12I lightly follow the current understanding of telomerase, which is responsible for adding back the “buffers” (telomeres) at the end of genes that RNA can’t copy. It was clear this was part of what we’d need for anti-aging treatment, but last I heard we didn’t understand the mechanisms or how to activate them. Is transcriptome part of this process? It wasn’t immediately clear from the article.
The problem is cancer, not how to trigger telomerase formation.
Re: Aging is associated with a systemic length-driven transcriptome imbalance
#13A reason to take this with a grain of salt: transcript length is the biggest technical effect in RNA sequencing. Longer transcripts get broken into more fragments and get sequenced more deeply. What this means is that if you perform any experiment you tend to get a "length effect" of some sort. The second feature they mention in the GTEx data is GC-content, which is probably the second biggest technical bias in RNA s…
It could still be an artifact of something else, e.g. differential digestion associated with age produces length and GC artifacts.
Re: Aging is associated with a systemic length-driven transcriptome imbalance
#14Earlier quoted context omitted.
In theory couldn't we introduce fresh copies of longer genes via crispr or a similar process? How many long encoding genes are there?
There's such a thing as gene over-expression to artificially increase the number of transcripts of a gene expressed. It's generally less easy or reliable than gene under-expression where you interfere with the expression. Doing it to get all of the affected genes back to their "healthy" levels at once would be very challenging. There's about ~30,000 genes total and at one point the study was looking at the top and bo…
Makes sense, I wonder if it would be feasible to reduce the number of genes to be over expressed by correlation with known medical conditions e.g. cardiovascular disease, kidney disease, or other cosmetic signs of aging.
Re: Aging is associated with a systemic length-driven transcriptome imbalance
#15A reason to take this with a grain of salt: transcript length is the biggest technical effect in RNA sequencing. Longer transcripts get broken into more fragments and get sequenced more deeply. What this means is that if you perform any experiment you tend to get a "length effect" of some sort. The second feature they mention in the GTEx data is GC-content, which is probably the second biggest technical bias in RNA s…
It's a good point. Why would the length effect you describe be be associated with age, across many organs, cell types, datasets, and species? The technical effect would be a good explanation for this finding in one dataset, but it seems unlikely that many datasets would have a technical length effect that correlates with age by chance.
Re: Aging is associated with a systemic length-driven transcriptome imbalance
#16Earlier quoted context omitted.
It means people with ALS don't get Alzheimer's according to a correlation. Now, how is the inherent lifetime and lifestyle difference bias corrected? No idea.
I think it's actually a poorly worded sentence and it's saying that there's an anticorrelation between gene length and the relative expression levels between healthy people and those with ALS (and also between healthy people and those with Alzheimer's). This means that ALS and Alzheimer's both have similar effects as aging does and decrease expression of longer genes, according to their study. The sentence before it…
Thanks tgb, it makes sense for me the way you describe it!
Re: Aging is associated with a systemic length-driven transcriptome imbalance
#17A reason to take this with a grain of salt: transcript length is the biggest technical effect in RNA sequencing. Longer transcripts get broken into more fragments and get sequenced more deeply. What this means is that if you perform any experiment you tend to get a "length effect" of some sort. The second feature they mention in the GTEx data is GC-content, which is probably the second biggest technical bias in RNA s…
It's a good point. Why would the length effect you describe be be associated with age, across many organs, cell types, datasets, and species? The technical effect would be a good explanation for this finding in one dataset, but it seems unlikely that many datasets would have a technical length effect that correlates with age by chance.
What I'm saying is that it looks like there's an effect and that effect is visible as a change in expression vs length but that I wouldn't expect it to be too related to length in a meaningful way biologically. If you take one population of transcripts and another and you measure the lengths, it's likely that you'll see a shift in the median - regardless of whether length is important, particularly due to the specific ways in which length relates to sequencing depth. And on top of that, comparing across genes requires compensating in some way for the length of the gene and it's not obvious how to do that correctly - could they be finding an artifact of how they normalized for length? (Eg: a "gene" actually doesn't have a single length, it's multiple possible variations in transcripts of different lengths and most reads from the sequencer is ambiguous as to which it came from. Quantify the different transcripts incorrectly - and it's impossible to do it correctly - and you may be mis-estimating the effective length and mis-normalizing.) It's a starting point of an investigation, not an end point.
(And they do try to take the next step to make that investigation and they report that they see a further decrease in a gene related to transcribing long transcripts. However it's 27th in their list of related genes and I'm not sure how unlikely having one of the top N genes has a reported connection to transcription. Hopefully they will follow up with a biological experiment involving knock-down of this gene and seeing an accelerated aging phenotype or something of that sort.)
The most compelling piece of evidence in my mind here is that the effects they report are consistent in direction across conditions. The most worrisome is that they tested a bunch of factors and the only ones they report as consistently informative are the ones that confound technical aspects the most and therefore are confounded with any number of underlying biological changes.
Re: Aging is associated with a systemic length-driven transcriptome imbalance
#18Earlier quoted context omitted.
It's a good point. Why would the length effect you describe be be associated with age, across many organs, cell types, datasets, and species? The technical effect would be a good explanation for this finding in one dataset, but it seems unlikely that many datasets would have a technical length effect that correlates with age by chance.
What I'm saying is that it looks like there's an effect and that effect is visible as a change in expression vs length but that I wouldn't expect it to be too related to length in a meaningful way biologically. If you take one population of transcripts and another and you measure the lengths, it's likely that you'll see a shift in the median - regardless of whether length is important, particularly due to the specifi…
Thanks, your points make sense. It’s definitely a worrisome coincidence given the multiple tests they ran but didn’t correct for. I hope to see that knockout experiment you describe!