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mutations of dna


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#1 brokenportal

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Posted 09 July 2006 - 08:51 PM


I see mitochondrial and chromosomal mutation, but I dont see dna mutation in SENS. Is dna mutation a concern in the process of slowing or stopping aging?

#2 John Schloendorn

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Posted 09 July 2006 - 09:17 PM

I see mitochondrial and chromosomal mutation, but I dont see dna mutation in SENS

Where else is you DNA supposed to be? Mitochondrial DNA is here, chromosomal DNA is here.

#3 brokenportal

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Posted 09 July 2006 - 10:29 PM

Oh ya, I think I was thinking of chromosomal mutation as more of like telomere break off and stuff. Brain freeze...

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Posted 09 July 2006 - 10:45 PM

Where else is you DNA supposed to be? Mitochondrial DNA is here, chromosomal DNA is here.

But if you read carefully, brokenportal, the second "here" points only to cancer as a consequence of DNA damage when in fact it contributes to aging in many different ways which SENS presently does not address and which spawned this. Therefore, your intuition was hardly a matter of

Brain freeze...

:)

#5 brokenportal

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Posted 09 July 2006 - 11:02 PM

Prometheus-

I read your "this" section, which made sense to me, which although, to paraphrase what somebody else wrote in response to it, it seems that neo sense kind of works to drag on the propulsion rate that SENS has into cracking open that door into mainstream attention. I could be wrong though of course, just throwing that out there.

Also, you wrote that sens only covers cancer as an effect of dna damage, what about this quote from the sens site in the chromosomal mutation section.

"[Note: the above is a slight oversimplification, in that DNA damage and mutation may be a significant cause of two of the other problems that SENS seeks to repair, cell depletion and cell toxicity,"

What other significant consequences of dna damage do you say are missing? Im sure there could be/are some, Im just wondering.

#6

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Posted 10 July 2006 - 07:10 AM

Aubrey has intentionally not mentioned aberrant gene expression which may lead to senescence or cell dysfunction without necessarily causing cell depletion, cell toxicity or cancer.

#7 brokenportal

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Posted 09 August 2006 - 01:05 AM

I read your post in your last response. I understand the neosens idea, but then what is its major difference? Do you propose more than 7 deadly things? or more subcatagories with in them?

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Posted 09 August 2006 - 01:31 AM

Not more deadly things - less. My perspective has to do with considering root causes rather than consequences. For example, SENS lists cancer as one of the 7 deadlies, yet the majority of cancers are, primarily a consequence of failure of the immune system to recognise cellular misbehavior. SENS does not touch upon immunity and the extensive pathologies that arise from its dysfunction. Yet, enhancing the immune response would deal with most (if not all) forms of cancer and other non-cancer cellular aberrations that escape apoptosis (such as cells that are accumulating too many insoluble aggregates). Therefore enhancing immunity would correct more than one of SENS's 7 consequences of aging.

The important thing to note about SENS in its present incarnation/version, is that it is stuck in the time that it was conceived (late 90's early 00's?). Our knowledge of science has advanced considerably since then yet SENS has steadfastly ignored these changes. Admittedly there is a method to the madness in that by not changing it is differentiating itself from other evolving theories and increasing its PR value. Nevertheless, scientifically, it is like using a version of Windows 95 on a PC made in 2006.

#9 brokenportal

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Posted 09 August 2006 - 02:08 AM

I went to look for Aubreys diagram that illustrates how gerontology, I think it is, is the form of prevention, isnt it? Then theres geriatrics at the end, or whatever order it goes in, that works to fix it, and that engeneering goes in the middle and is easier to make happen because there are only 7 rather than all the complex things that would come along with the other two. Im sure your familiar with that if you understand what Im trying to describe? Anyways, the point is, I think that was his rebutal to what your writing now, right? What do you say to what he said in that regard?

If I am thinking of the right thing in relation to this topic here, then, I think your proposing to work on the one at the begining of that diagram right? God I wish I could find it, it would make writing this response a lot easier, anyways. If you are, then why not work on that, and, support the engineering in the middle that Aubrey proposes?

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Posted 09 August 2006 - 06:57 AM

I have great respect for Aubrey's engineering approach - it is a very lateral-thinking approach to the aging problem and I agree with it entirely. It's strength is that it does not need to take into consideration all the circumstances surrounding a given problem in order to define a solution - just like the Wright brothers did not need to know all there was to know about aerodynamics in order to design and build a working flying machine.

However, even if one is implementing the "engineering aproach" there is a constantly altering threshold on the minimal amount of information required to solve a particular problem optimally.

#11 brokenportal

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Posted 09 August 2006 - 08:19 AM

What do you mean by the altering threshold? Do you know what that diagram is and or where to find it?

#12 caston

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Posted 09 August 2006 - 01:46 PM

prometheus:

Will you define and document an interventive strategy alternative to SENS?

#13 ag24

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Posted 09 August 2006 - 07:54 PM

> the majority of cancers are, primarily a consequence of failure of the immune
> system to recognise cellular misbehavior.

The immune system certainly plays a key role in eliminating almost all cancers before they become clinically relevant, but so do lots of other systems (angiogenesis control, apoptotic pathways, etc etc). SENS certainly does deal with immunosenescence; indeed, initially (see eg my SAGE KE piece from 2003) it was a SENS strand in its own right. I revised that because I realised that the various things that go wrong with the immune system all fall into the other categories - too many inactive T cells is a type of death-resistant cells, thymic atrophy is a type of too few cells, etc. It's not for nothing that I have such a strong emphasis on the immune system at the SENS conferences.

Prometheus, your dismissive remarks about SENS's movement with the times are offensive and unaccceptable. If you knew how much of my time is spent reading newly-published literature, maybe you would be less hasty. Your assertion that SENS "ignores" this or that is absolutely false, as I have pointed out innumerable times in innumerable threads here. If you say that a particular phenomenon implies the need for a change to SENS and I explain why you're wrong, that's not SENS ignoring anything, it's you being wrong. Kindly get that into your head -- permanently. If you have something new to say, say it, but kindly check back to see whether you've said it and had my reply before, rather than relying on your evidently very short memory. It's a phenomenal waste of my time going around fighting the fires you constantly light in these forums, and that means you're doing active harm to SENS by being so damned irresponsible. Grow up.

#14 caston

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Posted 09 August 2006 - 11:53 PM

etc etc = ?

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Posted 10 August 2006 - 01:54 AM

Prometheus, your dismissive remarks about SENS's movement with the times are offensive and unaccceptable. If you knew how much of my time is spent reading newly-published literature, maybe you would be less hasty. Your assertion that SENS "ignores" this or that is absolutely false, as I have pointed out innumerable times in innumerable threads here. If you say that a particular phenomenon implies the need for a change to SENS and I explain why you're wrong, that's not SENS ignoring anything, it's you being wrong. Kindly get that into your head -- permanently. If you have something new to say, say it, but kindly check back to see whether you've said it and had my reply before, rather than relying on your evidently very short memory. It's a phenomenal waste of my time going around fighting the fires you constantly light in these forums, and that means you're doing active harm to SENS by being so damned irresponsible. Grow up.


I'll thank you not to tell me what to get into my head permanently or otherwise. Under other circumstances I would find the tone of that remark insulting..

Furthermore your statements below:

- "offensive and unacceptable"
- "you're wrong"
- "absolutely false"
- "evidently short memory"
- "damned irresponsible"
- "grow up"


.. reveal the frustration of a child and not the temperament of a mature scientist at the height of his game. I suggest you spend less time telling me how wrong I am and more time proving it - in a scholarly fashion.

Incidentally, had I wanted "to harm" SENS I would have joined sides with Estep and Pontin some time ago. As you very well know, I keep my points scientific and am constantly reminding you that SENS needs an update. I only do this in the friendly confines of ImmInst and more recently on GRG. I do this because I feel it is incumbent on me to do so just like a responsible passer by who knows first aid rushes to help a person who collpases in the street. In your case it appears that you are highly resistant to receive urgently needed help!

I remind you that you have yet not to respond to the implications of the Cui mouse and hTERT's role in mitochondria in the context of WILT and an alternative solution to cancer and genomic stability. You have not accounted for the role of variability in immunologicaly mediated cancer resistance in making your statements of cancer being the only consequence of concern in nuclear DNA damage.

Furthermore, and as I imagine you well know, aging-related immunological deficits (of which the age-related thymic degeneration is a stark example) perturb cancer resistance and stem cell homing.

I'll put this down to you having a bad day and look forward to your typical logical, reasoned and scientifically backed responses..

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Posted 10 August 2006 - 02:16 AM

prometheus:

Will you define and document an interventive strategy alternative to SENS?


I set out to do this in a series of discussions here under the topic "neoSENS". Unlike how SENS has thus represented itself, neoSENS is designed to represent a fluid, dynamically adaptable set of solutions that is responsive to rapidly changing technologies and knowledge bases. Covertly neoSENS was meant as a catalyst to induce the next generation of SENS by fostering discussion and scientific debate. As yet it has failed to spawn a new version of SENS but it has attracted discussion.

#17 John Schloendorn

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Posted 10 August 2006 - 10:12 AM

It's a phenomenal waste of my time going around fighting the fires you constantly light in these forums, and that means you're doing active harm to SENS

I don't think this is true. From what I hear, the theoretical, repetitive, and unproductive nature of these arguments is totally evident to most imminsters. The passing-by scientist on the other hand, will understand that you do not have the time to respond to every entry in a pop science forum.

Caston: Will you define and document an interventive strategy alternative to SENS?

Prometheus: I set out to do this in a series of discussions here under the topic "neoSENS".

Which means, mostly among laypeople and not with a single peer-reviewed publication. I can't imagine anyone can be seriously fooled by presenting a forum thread called "neoSENS" as on par with or superior to the 50+ scientific paper-backed, multi million dollar effort called SENS, unless you have a truly remarkable rethoric ability. Prometheus, in order to receive more respect for your ideas, you simply need to develop them into something more professional, first of all utilizing peer-review.

#18 ag24

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Posted 10 August 2006 - 10:29 AM

John, if you're saying I shouldn't repeatedly correct prometheus's errors, you may be right - at first. What I can't let go is his blatant and repeated denials that I've ever corrected his errors, his "reminders" that SENS is inadequate, his accusations that I "disregard" such input, etc. If anyone want to save me time they could reply to prometheus's posts of that nature themselves pointing out my prior replies, *then* I might not need to do it myself. Well volunteered.

#19 caston

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Posted 10 August 2006 - 10:36 AM

It's a fantastic idea though that we could piece these strategies together just on the forums.
Ideally we want progress. While a repected scientific journal has far more weight than a forum post perhaps the ease of access, reply and revision makes it a flexible medium for distributed collaboration and brain storming.

Are there other forms of distributed research we should be considering?

Edited by caston, 10 August 2006 - 11:17 AM.


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Posted 10 August 2006 - 10:48 AM

I don't think this is true. From what I hear, the theoretical, repetitive, and unproductive nature of these arguments is totally evident to most imminsters. The passing-by scientist on the other hand, will understand that you do not have the time to respond to every entry in a pop science forum.

Unproductive? Yes - because it reveals the glaring holes in SENS and thus compromise its public relations mission.
Theoretical? Maybe - SENS is just as theoretical. neoSENS, however, is founded and designed to implement solutions using pragmatic experimentation that is avaliable today. SENS relies on speculative extrapolations of where science hopes to be in the future.
Repetitive? Yes - Indeed when my basic questions go on unanswered.


I can't imagine anyone can be seriously fooled by presenting a forum thread called "neoSENS" as on par with or superior to the 50+ scientific paper-backed, multi million dollar effort called SENS, unless you have a truly remarkable rethoric ability. Prometheus, in order to receive more respect for your ideas, you simply need to develop them into something more professional, first of all utilizing peer-review.

Which 50+ papers are you referring to John? What multimillion dollar effort? Has any SENS-based research initiative been seriously enough considered to obtain funding from traditional sources? Instead some of the momentum of the PR efforts of the MPrize is now being diverted to lysoSENS. neoSENS was an internal exercise to raise awareness on the flaws in SENS and stimulate healthy debate and better science. I don't have any agenda to achieve "respect for my ideas" via neoSENS..

But seeing as you have opened the Pandoras box, John, why is that SENS cannot obtain traditional funding for its research initiatives and must instead rely on raising money via public donations? Is it that there is no defined experimental roadmap? Is it that there is insufficient scientific grounding in what it seeking to achieve?

#21 John Schloendorn

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Posted 10 August 2006 - 10:50 AM

Caston, a peer-reviewed journal has the primary function to filter out pseudoscience and outright junk, so people don't have to waste as much time researching what's junk and what isn't.

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Posted 10 August 2006 - 10:51 AM

What I can't let go is his blatant and repeated denials that I've ever corrected his errors, his "reminders" that SENS is inadequate, his accusations that I "disregard" such input, etc.


A good starting point:

The Cui mouse.
The newly discovered role for hTERT.

#23 John Schloendorn

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Posted 10 August 2006 - 10:54 AM

why is that SENS cannot obtain traditional funding for its research initiatives and must instead rely on raising money via public donations?

Aubrey responds to this on his web page in detail. The good news is that the situation is changing thanks to the philantropes and our NIH application for LysoSENS is nearing completion.

#24 John Schloendorn

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Posted 10 August 2006 - 11:05 AM

Instead some of the momentum of the PR efforts of the MPrize is now being diverted to lysoSENS

Yes, we are distributing our resources to our projects as we see fit, and do not under all circumstances do the bidding of someone who has no experience with anything similar.

#25 John Schloendorn

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Posted 10 August 2006 - 11:09 AM

I don't have any agenda to achieve "respect for my ideas" via neoSENS

Thereby you will likely condemn "neoSENS" to be ignored but by the occasional lay person attracted by your rhetorics.

#26 ag24

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Posted 10 August 2006 - 11:11 AM

> A good starting point:
>
> The Cui mouse.
> The newly discovered role for hTERT.

Less than a month ago I replied to you on both of these points at the GRG list. If you didn't want to waste my time you could have copied those responses to here (as I do below), rather than accusing me of not responding. I deduce that you either want to waste my time or have the memory of a below-average ant. Which is it?

======================

Date: Mon, 17 Jul 2006 21:29:20 +0100 (BST)
From: Aubrey de Grey
Subject: [GRG] Re: SENS: Aubrey Responds to Harold
To: grg@lists.ucla.edu

Harold wrote:

...

> (incidentally, I think the discovery by Hicks et al
> (PNAS 2006 v103 n20) highlights that the direction we should be
> looking towards for a cure for cancer has more to do with immunology
> rather than telomerase downmodulation or in SENSspeak, interdiction).

I'm well aware of the various approaches to cancer immunotherapy and
they are certainly very exciting, but they are also a long-established
cancer therapy field that has not delivered much. I'll be as keen as
anyone to see what the Cui mice end up telling us when their genetics
are better elucidated, but I'm not betting my life on them.

...

> Speaking of which, how do
> you reconcile the observation that hTERT has a mitochondrial
> localization sequence in a WILT context?

Lots of things have mitochondrial localisation sequences for unknown
reasons, because those sequences are very loosely defined -- it was
once determined that 10% of all coding sequences would act as such a
sequence. For all we know, hTERT is localised to mitochondria only
by accident and because there is no selection not to do this. There
is certainly no reason to ascribe it a mitochondrial role solely on
the basis of its localisation, and the finding that nonphysiological
hTERT expression sensitises cells to stress-induced apoptosis tells
us nothing either, since the physiological level of hTERT in any
compartment of the cells in question, stress or no stress, is zero.

#27

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Posted 10 August 2006 - 11:16 AM

As I said before, John, neoSENS was an effort to stimulate SENS and not to compete with it. Furthermore my criticisms are designed to stimulate scientific discussion. If Aubrey is experiencing some male version of PMS at present that is preventing him from responding with courtesy and good manners then that does not entitle you to also conduct yourself direspectfully. Unless, of course his condition is contagious..

#28 caston

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Posted 10 August 2006 - 11:24 AM

prometheus: You may need to call it something else entirely. After all Ubuntu is not called NeoDebian.

#29

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Posted 10 August 2006 - 11:26 AM

Aubrey and John: we really need to relax here and remember that we are on the same side. You should know that I'm not one to take even velied insults lightly. I feel like I'm being drawn into a fight which I really don't want to fight - and I am a fighter, on many levels. So I urge you both to moderate your tone with me and focus on the science.

I will continue to scientifically debate the merits of SENS because I am motivated to see it succeed - not to see its mission fail.

#30 John Schloendorn

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Posted 10 August 2006 - 01:14 PM

Again, good intentions and rhetorics, but you will not have "scientifically debated" SENS before we see your paper in rejres or elsewhere (med hypotheses?). I have confidence in your ideas and am sure the better ones of them will be publishable if you invest the effort to organize them better and mount a coherent defense.




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