Aging is associated with a systemic length-driven transcriptome imbalance

[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.

[astazangasta]

It could still be an artifact of something else, e.g. differential digestion associated with age produces length and GC artifacts.

[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.

[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?

[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.