
Aging is associated with a systemic length-driven transcriptome imbalance - tomq
https://www.biorxiv.org/content/10.1101/691154v1.full
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tgb
A 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 sequencing and again basically any
experiment has a "GC-content effect" of some sort. But I don't interpret those
as meaning that there is something directly acting on long transcripts or
high-GC transcripts, rather that whatever is happening biologically ends up
appearing as a length or GC effect after sequencing. It's a little fishy that
the only features they find are features that I would expect to always find.

The most compelling reason to think that's not simply the case here is that
seem to be noticing a consistent _downward_ trend across all long transcripts
with age which is more compelling than merely noting that long transcripts
change (some up and some down).

~~~
tomq
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.

~~~
tgb
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.

~~~
tomq
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!

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JPLeRouzic
My understanding of the text, is that there is a reduced expression in long
genes (or locus) when people age.

 _Is this correct?_

The text mentions an ALS gene (FUS) and contains this sentence which I have
problem to understand (I am not an English native): Furthermore, we observe an
anticorrelation among neurodegenerative disorders such as amyotrophic lateral
sclerosis (ALS) and Alzheimer’s disease.

 _Please, what does those findings mean for Amyotrophic lateral sclerosis
(ALS) and Alzheimer’s disease?_

~~~
AstralStorm
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.

~~~
tgb
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 seems to be specifying the
"anticorrelation" that they're talking about and the sentence in question is
saying it holds in ALS and Alzheimer's as well as in aging.

~~~
JPLeRouzic
Thanks tgb, it makes sense for me the way you describe it!

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AstralStorm
Yes, so longer genes are more likely to be impacted as expected given genomic
damage theories and random damage model. (Likewise if transcription cellular
machinery starts to introduce more random errors longer proteins would be
impacted more.)

What to do about it? Edit whole genomes so they're more stable somehow? You
cannot reasonably expect to remove all environmental insults.

~~~
lumost
In theory couldn't we introduce fresh copies of longer genes via crispr or a
similar process? How many long encoding genes are there?

~~~
tgb
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 bottom 5% by length of those genes
so you'd be looking to over-express 1500 genes - I've never heard of a study
doing anything like that but it might be possible.

On top of that, there are also feedback loops so if you put more of a certain
transcript in it may induce more/less of another or get the cell to stop
production of that transcript and therefore counter-act what you've done. So
it would be extremely hard to get to the desired levels in all of them.

~~~
lumost
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.

------
inlined
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.

~~~
sansnomme
The problem is cancer, not how to trigger telomerase formation.

