9 replies to this topic

[Mixter]

It occurred to me that we may not know yet enough about gene expression
changes with regard to development aging (esp. post-translational) to root
them in either the cellular atrophy / hypertrophy sections of aging or the
DNA mutations section (regarding RNAi and methylation).

Holding epigenetic post-translational gene expression both as part of the
other aging problems or as its own problem would be speculative, but doesn't
it deserve its own category to make sure to cover all bases?

I am not up to date with how e.g. the gerontologists view this issue
at the moment, but if anyone has information on the present status
in mainstream life science, I'd be happy if you could post more about it.

What makes me think that expression should perhaps be considered
as SENS pillar #8 (or at least mentioned in more detail, maybe renaming
DNA "mutations" to DNA "changes"), is that AFAIK, many interactions of
siRNA / snRNA can occur later in life, and can trigger hundreds to thousands of
gene expression activation/inactivation changes, leading to degenerative disease.

Two important reasons:

One, as long as SENS would use targeted cell replacement and/or gene therapy,
it MIGHT cover this damage under cell loss/hypertrophy and DNA mutation
remediation, but this is not assured - especially if approaches like the
somatic protein therapy, which looks more practical, will be used.

Worst cases without controlling expression regulation might be when siRNA interactions
trigger gene expressions over a vast range of cells, so that whole organs with intact DNA
suffer from destructive metaplasia (then, the only method would be organ transplantation).

And, in case we find out that some gene therapy approaches (due to the viral vectors, or
due to gene changes at all) would trigger changes in gene expression elsewhere - so that
gene therapy may be devastating unless siRNA/snRNA interactions may be controlled. Even
if gene therapy, we may find that DNA repairing (and remethylating) may not be enough in
the long run and that some more post-transcriptional things have to be understood, if
they represent yet-unknown aging markers and interfere even with transcription in junk-free
cells with intact DNA.

Anyhow, I don't mean to be negative with this, I don't think that even if extra aging
mechanisms of this kind exist, that they'd be orders of magnitude harder. The positive
aspect about acknowledging a potential eigth aging would be another SENS frontier that
overlaps with very latest mainstream research with corresponding project opportunities.
And should this plays a big role in molecular aging, then it's very important to include on
the list. However, if not, some of the other aging-damage could be regulated easier if
SENS research acknowledges development of snRNA/siRNA 'tools' as important, i.e., it
might be that some of the gene therapy needed by SENS is easier accomplished by triggering
gene silencing and activation using those mechanisms than actually modifying DNA.

[caston]

Mixter: Although I'm still wet behind the ears what you are saying sounds similar (yet MUCH more informed) to what I hope to do with SMEY in the RNA Damage Theory of Ageing except the RNA damage is seen as the root cause rather than the 8th cause of ageing.

[John Schloendorn]

You ask the right question: Would fixing the seven SENS damage-types fix the expression changes? I have of course no anwer.

You are also right on target with

renaming DNA "mutations" to DNA "changes"

It has already been done. The jargon for "DNA changes" of the kind you describe, is "mutations and epimutations".

As for overlap with the mainstream:
It is actually a criterion of SENS agenda items *not* to overlap with mainstream research, because mainstream research (by definition) gets done anyway, no matter what we do. As long as important items exist which would not get done anyway, it is those that we try to promote. By this policy, we certainly acknowledge the importance of the tools and results accomplished by the mainstream. Attempts to control aging would be completely hopeless without mainstream research. Luckily, there is indeed a huge interest among other investigators to develop RNA-based tools and therapies, and it is very reasonable to expect that SENS-based treatments of the far future may utilize or imitate some of them.

[enki273]

I think the answer Aubrey would give (and has given elsewhere) is that expression changes reflect the increasing oxidative stress in the cell. Thus, if we fix the main causes of mutations and damage, gene expression would return to normal levels by itself.
Gene expression as an additional pillar of SENS has long been an issue, I remember endless discussions about it here at imminst. In my view, the approach simply lacks a decisive argument. If you want to include gene expression you have to refute the claim that nothing but cancer matters, which seems actually hard to do.
Caston, why should RNA be involved in aging? Can you explain?

[caston]

enki273: I hope to find out but in the example of micro RNA according to the wikipedia page (http://en.wikipedia.org/wiki/Micro_RNA) they are "single-stranded RNA molecules of about 21-23 nucleotides in length thought to regulate the expression of other genes." or mRNA's "Messenger Ribonucleic Acid (mRNA) is RNA that encodes and carries information from DNA during transcription to sites of protein synthesis to undergo translation in order to yield a gene product"

If ageing is about gene failure and the collapse in stability (self repair) of the genome and RNA is so heavily related to genes (and many genes are related to DNA repair) then I think RNA is involved in ageing.

I think evolution of longer life spans might be related to improvements in *NA repair.

Now does a cell that reaches the Hayflick limit stop dividing because it was "designed" with planned senescence or does it stop simply because it no longer has enough genetic information to divide and physically cannot do it?

Edited by caston, 06 January 2007 - 12:44 AM.

[Mixter]

Thank you esp. John, very cool to know the possibility is under consideration...
But sure it's more an internal SENS topic and maybe a future issue,
I guess we don't know enough about it yet.

With not overlapping with current mainstream science you're very right.
Also it seems wise to be cautious when building on very latest (<1-2 years)
detail findings at any time, there's just too much data and discoveries
today and a corresponding possible high error rate IMO.

(Interesting example, Munich has an interesting bioinformatics scene, one of
the projects here include investigating the mitochondrial genome with bioinformatics
methods, however, I've heard of some findings (but unsure if/where published, and
couldn't find any links), that some statistical/bioinformatics methods showed human
mitochondria to contain hundreds to thousands of (overlapping?) active genes in the
pseudogene regions... I don't really know enough to even understand if that was the
final implication, but I'd doubt such things, although many surprises are uncovered by
purely data-mining driven research recently (including theories on epigenetics). Data
mining is very interesting/efficient/powerful for biomolecular stuff, but ultimately needs
experimental verification to build the really important stuff upon, which will probably
NOT often happen in basic research right away due to time and resource reasons.)

[enki273]

As far as I understand, the DNA is nevertheless the origin of the damage. RNA are transient molecules that are synthesized and degraded quickly. More importantly, all RNAs are transcriptions of DNA sequences. A faulty RNa will soon disappear; a faulty DNA will produce more and more faulty RNA, won´t it?
Cells approaching the Hayflick limit stop dividing because they are programmed so. Actually, the divisions stop before the telomeres are cut off entirely.

[John Schloendorn]

hundreds to thousands of (overlapping?) active genes in the pseudogene regions...

Sounds to me as if hundreds of typical "active genes" would fail to fit into 16 kilobasepairs, even if overlapping in all six reading frames. So I'm afraid I can't tell what this might be referring to. Perhaps a copy number thing? (The number is also suspiciously similar to the number of nuclear genes imported into the mito)

[caston]

As far as I understand, the DNA is nevertheless the origin of the damage. RNA are transient molecules that are synthesized and degraded quickly. More importantly, all RNAs are transcriptions of DNA sequences. A faulty RNa will soon disappear; a faulty DNA will produce more and more faulty RNA, won´t it?
Cells approaching the Hayflick limit stop dividing because they are programmed so. Actually, the divisions stop before the telomeres are cut off entirely.

If these are true you must understand that I wish to learn them the hard way and in very intricate detail.

[John Schloendorn]

Caston, I think a ribosome subunit can be a pretty long-lived thing. I don't know how long or if anything happens to them over their lifetime. Just a study suggestion for you.