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The birth of neoSENS


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#121 ag24

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Posted 10 March 2005 - 05:37 PM

As I've said, the mechanism by which overexpression could fail is because the enzymes are inherently imperfect -- they can mis-correct a lesion and make a mutation. The best evidence against the hypothesis that simply increasing expression will help is that humans (let alone mice) heterozygous for DNA repair enzymes are healthy and have normal lifespans. If 50% is no worse than 100%, why should 200% be any better?

I thought you cited some human in vivo data on sunburn?

Redundancy of genome - not entirely sure I know what you mean, but if you mean they may be receiving more DNA damage but not suffering shortened lifespan as a result, the same argument applies: if some redundancy confers no life extension (relative to heterozygous knockouts), why should more redundancy confer life extension? I don't see a mechanism for mice having redundancy of DNA damage sensitivity of a sort that is absent in humans (a la telomerase) -- are you suggesting one?

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Posted 11 March 2005 - 09:01 AM

As I've said, the mechanism by which overexpression could fail is because the enzymes are inherently imperfect -- they can mis-correct a lesion and make a mutation.  The best evidence against the hypothesis that simply increasing expression will help is that humans (let alone mice) heterozygous for DNA repair enzymes are healthy and have normal lifespans.  If 50% is no worse than 100%, why should 200% be any better?


I agree that there are some enzymes that have the potential to do more harm than good when overexpressed. But there are others whose mechanism of involvement in repair and degree of substrate specificity make them ideal candidates for over-expression studies. Particularly those that are found to be rate limiting.

Your argument about the percentages seems doubtful to me. Whilst it is likely that compensatory mechanisms (other DNA repair pathways) exist to account for reduced activity in a single type of DNA repair enzyme due to heterozygotic expression, it is not to say that a twofold increase in enzyme concentration would not result in increased activity. Take CR studies, for example: we observe that rates of BER are increased above their basal rate by as much as 50% (in the nucleus). Such increases have yet to be correlated with anything but anti-senescence and health. It should also be pointed out, since you are so concerned on overexpression, that there are no pathologies that have been discovered to date correlated with such an event. Conversely pathologies associated with reduced DNA repair expression are well known. I am thus compelled to question the basis for your adverse view on increasing DNA repair from the perspective that it may be harmful - is there any evidence for it?

I thought you cited some human in vivo data on sunburn?


Quite right, I did and stand corrected. The increased repair rate reduced sunburn/UV damage.

Redundancy of genome - not entirely sure I know what you mean, but if you mean they may be receiving more DNA damage but not suffering shortened lifespan as a result, the same argument applies: if some redundancy confers no life extension (relative to heterozygous knockouts), why should more redundancy confer life extension?  I don't see a mechanism for mice having redundancy of DNA damage sensitivity of a sort that is absent in humans (a la telomerase) -- are you suggesting one?


Yes, due to the difference in lifespan - the mice will not accumulate as much damage as humans - just like in the telomerase studies where it took five generations of telomerase negative mice before their telomeres began to destabilize and manifest the premature aging phenotype.

#123 ag24

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Posted 11 March 2005 - 01:35 PM

1) Will you please please stop giving arguments that apply equally to cancer and to non-cancer as if they only applied to non-cancer? Of course repair is better in CR - it has to be, to postpone cancer. How the BER rates are improved in CR is certainly something worth knowing, because just as with mice if we were to postpone everything else with SENS we could in principle slow down DNA damage by raising repair and that would be great .... but we don't know how BER is raised in CR! In particular we have no evidence (that know of) that a simple rise in expression of some enzyme or other is the mechanism.

2) It's not a matter of more enzyme doing more harm than good, it's a matter of more enzyme having no effect at all because the existing quantity of enzyme is not rate-limiting. You've not given any evidence that any DNA repair enzyme level is rate-limiting.

3) Aargh. Lifespan differences do not tell us that mice are uninformative, because mice die of something! --they don't die of nothing. The fact that telomeres are so long in mice is a weird phenomenon that is indeed the basis for a qualitative difference between mice and humans in terms of the effects of a particular intervention (telomerase deletion), but one has to identify such a thing before one can say mice are irrelevant. We already have better repair, lower ROS production etc, so the mouse/human analogy should be fine despite the

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Posted 11 March 2005 - 11:21 PM

1) Will you please please stop giving arguments that apply equally to cancer and to non-cancer as if they only applied to non-cancer?  Of course repair is better in CR - it has to be, to postpone cancer.  How the BER rates are improved in CR is certainly something worth knowing, because just as with mice if we were to postpone everything else with SENS we could in principle slow down DNA damage by raising repair and that would be great .... but we don't know how BER is raised in CR!  In particular we have no evidence (that  know of) that a simple rise in expression of some enzyme or other is the mechanism.


- we were more on the topic of enzymes, particularly needing to use engineered or transgenic versions because you say that the endogenous ones are inherently imperfect.
- the CR mechanism appears to be related by IGF > SIR2 > Ku70 and FOXO3a also another pathway is via IGF > PI3 > Akt > FOXO3a. There are more reasonably mapped out pathways linking nutrient sensing to increased DNA repair.

2) It's not a matter of more enzyme doing more harm than good, it's a matter of more enzyme having no effect at all because the existing quantity of enzyme is not rate-limiting.  You've not given any evidence that any DNA repair enzyme level is rate-limiting.


- true, I have focused on DNA repair activity rather than specific DNA repair enzymes or associated proteins. You seem to be very determined to prove that DNA damage/repair has no bearing on aging other than contributing to cancer. Is there a reason you feel so strongly about this (e.g. is there some hard to find research you're aware of) ??

3) Aargh.  Lifespan differences do not tell us that mice are uninformative, because mice die of something! --they don't die of nothing.  The fact that telomeres are so long in mice is a weird phenomenon that is indeed the basis for a qualitative difference between mice and humans in terms of the effects of a particular intervention (telomerase deletion), but one has to identify such a thing before one can say mice are irrelevant. We already have better repair, lower ROS production etc, so the mouse/human analogy should be fine despite the


- I did not say they were irrelevant, I asked if you were *concerned* about the relevance in light of the telomerase studies (e.g. with telomerase -/- mice still getting cancer)

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Posted 13 March 2005 - 02:55 AM

I've pointed out that enzymes that are needed to respond to highly unpredictable events (spikes in ROS production, e.g.) are typically present in considerable excess because it's better not to have to wait for them to be synthesised in response to need.  This is why heterozygous knockouts for all the mouse antioxidant enzymes have a normal lifespan, for example.


Some clarification is necessary in what you mean by "heterozygous knockouts for all the mouse antioxidant enzymes have a normal lifespan", because in the context it is being used, it could be misleading. The study using genes heterozygous for the Sod2 locus (1) showed despite lifelong reduced MnSOD activity, heterozygous (Sod2 +/-) mice had the same lifespan as WT mice but what you did not mention was that the study also showed an increased (doubled) incidence of cancer in Sod2 +/- mice. Therefore, from a DNA damage leading to cancer perspective, heterozygous knockout mutants cannot be said to have a normal lifespan since their rate of cancer has doubled. In the case of antioxidant enzymes, their abundance may not be as in considerable excess as you put, suggesting that an increase beyond their basal rate would have a beneficial effect in reducing the incidence of cancer. A homozygous p66shc mouse mutant, which enables an increase in oxidative stress resistance, increases lifespan by 30% (2) suggesting that if ROS levels are sufficiently lowered lifespan too can be improved.

What both these studies show is that with antioxidant enzymes, at least, WT levels cannot be defined as being in considerable excess from an anti-senescence perspective.



(1) Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A.
Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging
Physiol. Genomics 16: 29-37, 2003

(2) Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, and Pelicci PG.
The p66shc adaptor protein controls oxidative stress response and life span in mammals.
Nature 402: 309–313, 1999

#126 ag24

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Posted 13 March 2005 - 07:15 AM

> You seem to be very determined to prove that DNA damage/repair has no bearing on
> aging other than contributing to cancer. Is there a reason you feel so strongly about this
> (e.g. is there some hard to find research you're aware of) ??

There's plenty of very easy-to-find research, which I've mentioned repeatedly here: Vijg's measurements of the frequency of such damage (and similar work by others).

> The study using genes heterozygous for the Sod2 locus (1) showed despite lifelong
> reduced MnSOD activity, heterozygous (Sod2 +/-) mice had the same lifespan as WT
> mice but what you did not mention was that the study also showed an increased (doubled)
> incidence of cancer in Sod2 +/- mice. Therefore, from a DNA damage leading to cancer
> perspective, heterozygous knockout mutants cannot be said to have a normal lifespan
> since their rate of cancer has doubled.

Interesting redefinition of lifespan! But that's the point, of course -- the mice had more small cancers (too small to kill them), but their lifespan was unaltered because they had no more big cancers, because the halved enzyme levels were enough.

> A homozygous p66shc mouse mutant, which enables an increase in oxidative stress
> resistance, increases lifespan by 30% (2) suggesting that if ROS levels are sufficiently
> lowered lifespan too can be improved.

One can't make too much of this result as it was in a very short-lived mouse strain so it may just have fixed a congenital problem, but to the extent that we can generalise it it reinforces my point: this mutant does something quite different to raising the levels of DNA repair enzymes.

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Posted 13 March 2005 - 07:59 AM

There's plenty of very easy-to-find research, which I've mentioned repeatedly here: Vijg's measurements of the frequency of such damage (and similar work by others).


I've noted that you are heavily basing your position on Vijg's results. The way Vijg measures damage frequency may not be truly representative of DNA damage because of limitations associated with the technique (lacZ-plasmid transgenic mice) and with extrapolating such figures to humans. What do you think of the technique?

Interesting redefinition of lifespan!  But that's the point, of course -- the mice had more small cancers (too small to kill them), but their lifespan was unaltered because they had no more big cancers, because the halved enzyme levels were enough.


Of course if one were to extrapolate it could imply that those cancers that were too small to kill the mice would have the opportunity to get much larger in humans.

> A homozygous p66shc mouse mutant, which enables an increase in oxidative stress
> resistance, increases lifespan by 30% (2) suggesting that if ROS levels are sufficiently
> lowered lifespan too can be improved.


One can't make too much of this result as it was in a very short-lived mouse strain so it may just have fixed a congenital problem, but to the extent that we can generalise it it reinforces my point: this mutant does something quite different to raising the levels of DNA repair enzymes.


The point was related to the benefits of increasing enzyme activity beyond basal levels, in this case the benefit of increasing antioxidant activity sufficiently to lower ROS and emulate the effect of the altered signaling that is caused by mutant p66shc.

#128 jaydfox

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Posted 14 March 2005 - 04:29 PM

Some clarification is necessary in what you mean by "heterozygous knockouts for all the mouse antioxidant enzymes have a normal lifespan", because in the context it is being used, it could be misleading. The study using genes heterozygous for the Sod2 locus (1) showed despite lifelong reduced MnSOD activity, heterozygous (Sod2 +/-) mice had the same lifespan as WT mice but what you did not mention was that the study also showed an increased (doubled) incidence of cancer in Sod2 +/- mice. Therefore, from a DNA damage leading to cancer perspective, heterozygous knockout mutants cannot be said to have a normal lifespan since their rate of cancer has doubled. In the case of antioxidant enzymes, their abundance may not be as in considerable excess as you put, suggesting that an increase beyond their basal rate would have a beneficial effect in reducing the incidence of cancer.

Interesting redefinition of lifespan! But that's the point, of course -- the mice had more small cancers (too small to kill them), but their lifespan was unaltered because they had no more big cancers, because the halved enzyme levels were enough.

Of course if one were to extrapolate it could imply that those cancers that were too small to kill the mice would have the opportunity to get much larger in humans.

Touche'

Reading of study (1) reveals that the cancers that were found in the SOD2+/- mice were not altered in their proliferative capacity, compared to WT (wild-type = "normal") mice. Therefore, the roughly double incidence of cancers, including potentially fatal cancers, should be evidence enough to support the claim that a 50% reduction in this one enzyme (of the scores involved in DNA repair and/or damage prevention) is enough to double cancer incidence and thus increase the relevance of cancer as a MLSP-limiting factor. No evidence is provided to contradict the reverse of this claim, that a 100% increase in the levels would be enough to halve cancer incidence rates (or at least significantly tenuate those rates), thus decreasing the relevance of cancer as a MLSP-limiting factor.

Of course, there is no evidence that a 100% increase would have increased MLSP, despite the likely decrease in cancer incidence. Yes, there will probably be negative consequences of modulating a single kDRM factor (2). But that's why we need to screen for multiple gene solutions, to try to balance the interplay between these repair and antioxidant enzymes. Or, when all else fails, engineer our way around the non-cancer implications of increased DNA repair/maintenance (e.g. 6/7 SENS).

That lifespan from all cause mortality was not significantly affected (a strict reading of the limited data would even show a slight benefit, though it wasn't statistically significant) only stresses the point that tweaking kDRM factors at random is not necessarily the best way to try to improve on cancer defense. But, cancer rates can arguably be affected quite easily with small modulations in kDRM factor expression, which has been portrayed to be an unfounded claim. Unfounded indeed.

A similar tradeoff in cancer prevention and mortality from all non-cancer causes (and hence a non-significant or even negative impact on all-cause mortality and MLSP) was seen in the study on overexpression of tumor suppressors and MLSP (3,4). Cancer was virtually eliminated, not just as a cause of death, but its very incidence was radically reduced. Lifespan was negatively affected. A study of similar mechanisms in humans (5) found the same tradeoff, with increased longevity despite higher cancer mortality. Again, a target we can engineer our way around, allowing us to greatly decrease cancer rates, the last enemy of SENS.

From the studies above, does this mean that preventing cancer won't extend life? No, it just means that there are tradeoffs. But if the biggest enemy of SENS is cancer, and if all other causes of mortality become trivial to fix, then the tradeoffs become almost meaningless to us. We'll accept the tradeoffs, because we can fix them by engineering. Tumor suppression causing cell depletion? No problem, SENS has a strategy for that. Alternatively, tumor suppression causing cell accumulation (senescent/dysfunctional cells)? No problem, SENS has a strategy for that too. DNA repair over expression causing buildup of intracellular junk (made that one up)? No problem, SENS has a strategy for that. About the only thing that SENS doesn't have a strategy for is DNA repair, but that's okay, because that's what we're talking about here.

...6/7 SENS would allow geneticists to focus exclusively on DNA repair/maintenance, cancer prevention, and cancer defenses, and ignore issues like trying to reduce mitochondrial inner and outer membrane oxidizability, reducing leakage, increasing mitochondrial ROS scavanging, protecting mtDNA, breaking down and preventing extracellular crosslink buildup, etc., etc.

We can attack the problem piecemeal, with a group focussed on mitochodria, a group focused on intracellular junk, a group focussed on extracellular junk, a group focussed on crosslinks, a group focussed on stem cell therapies, and a group focused on greatly enhancing DNA repair/maintenance.


Which brings us back here.



(1) Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A.
Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging
Physiol. Genomics 16: 29-37, 2003

(2) Pani G, Colavitti R, Bedogni B, Fusco S, Ferraro D, Borrello S, Galeotti T.
Mitochondrial superoxide dismutase: a promising target for new anticancer therapies.
Curr Med Chem. 2004 May;11(10):1299-308.

(3) Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA.
p53 mutant mice that display early ageing-associated phenotypes.
Nature. 2002 Jan 3;415(6867):45-53.

(4) Dumble M, Gatza C, Tyner S, Venkatachalam S, Donehower LA.
Insights into aging obtained from p53 mutant mouse models.
Ann N Y Acad Sci. 2004 Jun;1019:171-7.

(5) van Heemst D, Mooijaart SP, Beekman M, Schreuder J, de Craen AJ, Brandt BW, Slagboom PE, Westendorp RG; Long Life study group
Variation in the human TP53 gene affects old age survival and cancer mortality.
Exp Gerontol. 2005 Jan-Feb;40(1-2):11-5.

#129 ag24

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Posted 14 March 2005 - 10:57 PM

> Tumor suppression causing cell depletion? No problem, SENS has a strategy for that

You seem not to have noticed that this is exactly WILT ....

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#130 jaydfox

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Posted 14 March 2005 - 11:53 PM

> Tumor suppression causing cell depletion? No problem, SENS has a strategy for that

You seem not to have noticed that this is exactly WILT ....

How does WILT proper prevent cell depletion? There are several technologies in WILT (e.g. stem cell therapy with genetic modification), which I have termed the WILT scaffolding, which enable the telomere ablation strategy not only to work, but also to be something other than dramatically fatal.

The WILT scaffolding, although it would need to be tuned to WILT proper, could also be tuned to a more selective and less fatal DNA repair and cell ablation strategy—one that didn't need to be repeated decadally, but perhaps more like twice or thrice a century, and without a rapid onset of symptoms if you delay treatment, but a slow progression similar to what we now call aging.

scaf·fold ( P ) Pronunciation Key (skfld, -ld)
n.
1. A temporary platform, either supported from below or suspended from above, on which workers sit or stand when performing tasks at heights above the ground.
2. A raised wooden framework or platform.
3. A platform used in the execution of condemned prisoners, as by hanging or beheading.

I'll use definition 1 here, as 2 seems off-topic and 3 seems, well, contradictory to a discussion of life extension. ;)

scaf·fold·ing ( P ) Pronunciation Key (skfl-dng, skfl-)
n.
1. A scaffold or system of scaffolds.
2. Materials used for constructing scaffolds.

Again, I'll use definition 1, specifically the second portion, a system of scaffolds.

When I say WILT scaffolding, I am in effect saying "a system of temporary platforms and technologies, which provide support, by sheer necessity or as modest supplementation, upon which health workers would implement WILT proper, the deletion of telomere elongation capacity from all or as many cells in the body as possible". As the WILT scaffolding is merely supporting technologies, technologies which do not all necessarily require WILT proper to be of any use, I have agreed with Prometheus in his assertion that WILT should really be broken down into the concept (telomerase ablation, etc.) and the delivery, etc. I have tried to make this simple for discussion by terming the two components WILT proper and WILT scaffolding.

As I see it, WILT proper will not solve the problem of cell depletion; it causes cell depletion. The WILT scaffolding is the solution to cell depletion, or at least one of the solutions. But the WILT scaffolding, minus WILT proper, could be coupled with tumor suppression and DNA repair functions which could prevent cancer to a high degree (perhaps not as well as WILT proper, but well enough to effect escape velocity), but with a system that doesn't program a hard limit of 10 or 15 years before death, and in a manner that is more amenable to widespread adoption (something we would all like to see).

And the rich will still have access to WILT proper, if they see it necessary and the benefits are proven. But for mass adoption, we should be pushing the alternative to WILT proper.

#131

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Posted 02 April 2005 - 01:27 PM

In support for DNA damage as a cause for aging (NeoSens target):

The attached paper (1) discusses the shift in the repair of double strand breaks (DSBs) from homologous recombination (HR) to non-homologous end joining (NHEJ) as a cell becomes older. Whilst both pathways of DSB repair are used in mammalian cells, HR is a far more precise mechanism of repair than NHEJ. The choice of pathway appears to be dependent on cell cycle stage. In post-mitotic cells NHEJ is the only DSB repair pathway available and this mechanism has been observed to itself become less efficient with aging.



(1) Mechanisms of Ageing and Development (2005)
Making ends meet in old age: DSB repair and aging
Vera Gorbunova, Andrei Seluanov

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#132 faith_machine

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Posted 24 September 2005 - 02:36 PM

A quick question for prometheus,

If there are other valid alternatives to SENS, why have scientists been looking for other "causes" of aging for over 24 years and found nothing? (Since 1981)

I feel this is partly why Aubrey de Grey spoke up. Someone needed to ... (again my opinion).

#133

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Posted 25 September 2005 - 08:53 AM

I certainly have no issue with AdG speaking up - on the contrary I am very greatful for his courageous and inspirational stance. If you read over the material here you will see that I have an issue with implementation. I think SENS 1.0 does not place enough importance in genomic instability whereas Aubrey is convinced it is adequately accounted for. Time will tell who is right. Perhaps we may both be entirely wrong. What is important and very exciting is that we can discuss it scientifically and that data from the increasing amount of studies out there can be used to explore how we may support our respective arguments.

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Posted 26 February 2006 - 04:23 AM

Interesting data that supports the role of DNA damage as a cause of aging (and therefore the need to address this in SENS).

One of the findings is that in aged cells an innapropriate increase in trascriptome diversity occurs (see Fig 4 in attachment) which would be in agreement with damage to non-coding DNA that potentially results in decreased siRNA type regulation.


Ann N Y Acad Sci. 2005 Dec;1055:35-47.

Aging and genome maintenance.

Vijg J, Busuttil RA, Bahar R, Dolle ME.

University of Texas Health Science Center, STCBM, 15355 Lambda Drive, Suite 2.200, San Antonio, TX 78245. vijg@uthscsa.edu.

Genomic instability in somatic cells has been implicated as a major stochastic mechanism of aging. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we found mutations to accumulate with age at an organ- and tissue-specific rate. Also the spectrum of age-accumulated mutations was found to differ greatly from organ to organ; while initially similar, mutation spectra of different tissues diverged significantly over the lifetime. To explain how genomic instability, which is inherently stochastic, can be a causal factor in aging, it is proposed that randomly induced mutations may adversely affect normal patterns of gene regulation, resulting in a mosaic of cells at various stages on a trajectory of degeneration, eventually resulting in cell death or neoplastic transformation. To directly address this question we demonstrate that it is now possible to analyze single cells, isolated from old and young tissues, for specific alterations in gene expression.

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#135 jaydfox

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Posted 12 July 2006 - 03:03 PM

*bump*

#136 ag24

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Posted 12 July 2006 - 10:37 PM

I don't see anything in the figure Prometheus refers to (or in the rest of the paper) over and above what I've worn myself out answering here in the past. FYI, Vijg had a paper in Nature 441:1011 a few weeks ago that reproduces the beta-actin data as part of a broader study.

Prometheus, my posting access to LA-GRG is currently broken but I've just seen your latest post there, which likewise seems to be a regurgitation of questions I've answered repeatedly. I don't have time to go round in circles forever. It's up to you to read my past posts here to remind yourself of my answers to questions you've already asked before. I'd be grateful if you'd (a) do that, and (b) post those answers of mine to LA-GRG in repsonse to your own questions.

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Posted 13 July 2006 - 02:09 AM

Prometheus, my posting access to LA-GRG is currently broken but I've just seen your latest post there, which likewise seems to be a regurgitation of questions I've answered repeatedly.


The price of trying to accomodate someone as thick as me. The discussion was actually initated there by Ray Bradbury (I'm not trying to give you a hard time). I have a feeling that LSC, like RB is of the view that nDNA mutations are important contributors to aging. Since this "neoSENS" topic was initiated there is also the matter of telomerase's new role which you haven't yet addressed in the context of WILT and nDNA damage. Anyway, here it is.. (my responses in italics).

On 6 Jul 2006, at 8:39 AM, L. Stephen Coles, M.D., Ph.D. wrote:

To Members and Friends of the Los Angeles Gerontology Group:

        This just in from Aubrey de Grey from his new E-mail address
at Aubrey@SENS.ORG.  -- Steve Coles

Harold wrote:
> This essay involves use of a transgenic mouse model that has
> integrated into its genome a lacZ reporter plasmid construct. Based
> upon disruptive events detected in this region assumptions are made as
> to DNA damage. I don't have a clear idea of where this plasmid
> integrates but have you considered that it may relate to the
> tissue-specificity observed in the results? For example, different
> cell types have different chromosomal, methylation, RNAi expression
> and splicing patterns. Any of these could alter the focus of damage in
> relation to the lacZ construct.

    It's rather unlikely that such differences would alter the frequency
of chromosomal rearrangements -- that's not found in Drosophila, for
example -- but I agree it's not impossible.  However, Vijg's studies
were actually done using two independent strains, one with the lacZ
inserted on chromosome 3 and one with the insertion on chromosome 4,
and he reported no difference between the two in which tissues did
and did not accumulate mutations.

The issue of the validity of the lacZ plasmid construct as an accurate reporter of DNA damage merits some further investigation. We know that the mutational landscape across the genome varies from mutational hotspots to relatively damage -resistant regions and this landscape can be dynamic since methylation increases mutagenesis. Finally the technique involves salvaging the plasmid construct from the mouse genome prior to culturing in E. coli. It could be, for example that some mutations may interfere with this step and thereby not be representative of the damage rate. Putting all this speculation aside, however, it's important to underline that the technique's discoverer is convinced that the frequency of mutations increases with age in most cell types as his research indicates.

> Why refer to epimutations which are independent of DNA sequence when
> there are other forms of damage that can also alter transcriptional
> profile?

    Because epimutations, being intrinsic side-effects of the imperfect
nature of DNA maintenance,

Yet "the imperfect nature of DNA maintenance" is selected for - what evolutionary purpose do you think that would that serve? Also does this admission not contradict your argument that the existing DNA repair system is already more than sufficient?

are certain to happen at a basal rate even
if we were to fix everything else that goes wrong in aging,
whereas
systematic changes (the same gene being affected in the same direction
on average across all cells while other genes are not) is necessarily
a consequence of a change in the environment (e.g., the redox state)
surrounding that DNA. 

There are DNA repair mechanisms that can address this type of damage too.

Don't lose sight of the question we're trying
to answer here, which is: if we fixed everything else that goes wrong
at the molecular and cellular level in aging, might changes of gene
expression still occur at a rate that could contribute to functional
decline in a normal lifetime?

Everything else except for DNA repair?


> No, this was not a single-cell study nor did it aim to
> examine epimutation events but it does not discount its value in the
> context of age-related changes in the transcriptional profile of key
> genes, which in this case were genes critical to neuron function. DNA
> repair gene upregulation indicates an increase in DNA damage - this
> was not just observed in just the "elderly" - the median time of when
> transcriptional changes were observed to manifest in this study was 40
> years.

    Right -- and plasma redox state (Cys/CySS) does this too -- see papers
by Dean Jones, including his latest in Rejuvenation Research.

But how do you interpret this study as not supportive of DNA damage being a contributor to aging?


> > So what?  A quantitative difference is still a difference.
>
> Your point, however, was that a different system is operating in
> somatic versus germ-line cells.

    Ah - no, that wasn't my point.  If you go back to the beginning of this
part of the thread, I said this:

> Germ-line DNA repair is
> generally found to be better than in the soma (as Kirkwood predicted),
> but it could just as easily be worse if the evolutionary pressure not to
> age were high enough and the evolutionary pressure to allow sufficient
> mutations to evolve were also high enough, and in either case the two
> optima (one for soma, one for germ line) could be and would be achieved
> by regulating the tissue-specificity of repair and maintenance machinery,
> not by the presence of machinery that opposes maintenance and repair.

and it's true that you replied thusly:

> There is no evidence to suggest that soma and germ line cells have
> independent or mutually exclusive repair pathways.

and I didn't spot that you were here assuming a qualitative difference,
but as you see, I was NOT assuming that -- I spoke about "regulating
the tissue-specificity", and regulation can of course be quantitative.

> What is so tricky about upregulating key DNA repair systems when
> compared to SENS's allotopic expression of mtDNA and WILT?

    My answer to this sort of question is at the root of SENS, of course.
I'm very happy that people are trying to slow down aspects of aging by
improving natural maintenance/repair systems, because there's always a
chance that some such interventions might succeed (even if only to a
modest extent).  However, my belief is that the overwhelming evidence
of the history of gerontology is that attempts to improve our existing
repair/maintenance processes do not usually succeed, partly because of
homeostatic mechanisms that downregulate the intrinsic process and so
negate the "assistance" and partly because of unforeseen side-effects.

When have we attempted to increase repair/maintenance processes in a genomic context? Only if genomic vulnerability were associated with a process other than facilitating evolution would there be homeostatic pressure to correct it.

SENS is immensely ambitious and complex, I've never denied that, but it
has a chance of avoiding these problems by targeting the side-effects
of metabolism rather than trying to improve metabolism itself.

Cheers,

Aubrey
L. Stephen Coles, M.D., Ph.D., Co-Founder
Los Angeles Gerontology Research Group
URL: http://www.grg.org
E-mail: scoles@grg.org

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#138 jaydfox

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Posted 13 July 2006 - 06:31 AM

discussion was actually initated there by Ray Bradbury (I'm not trying to give you a hard time).

I'm confused, this is the second time I can recall that you've mentioned Ray Bradbury recently. Do you mean Robert Bradbury, or do you actually mean the Ray Bradbury? Or just a Ray Bradbury, but not the Ray Bradbury.

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Posted 13 July 2006 - 08:29 AM

Oops. (it is Robert Bradbury)

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Posted 25 October 2006 - 07:43 AM

A report that supports the DNA damage/Evolution/Aging Hypothesis:

In a nutshell: young drosophila utilize more error prone repair mechanisms whilst older flies utilize more accurate ones.

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#141 enki273

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Posted 28 October 2006 - 02:38 PM

It seems that a considerable amount of recent posts has been deleted.
This is understandable if personal tensions occurred, but such intransparent editing as is present here is not helpful in gaining credibility. Furthermore I would have appreciated any mention of the fact that Aubrey de Grey is no longer posting here since a while. The homepage at least suggests something else.

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#142

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Posted 29 October 2006 - 01:41 AM

They weren't deleted, they were split into another topic called "Critiques on NeoSENS motivation".

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