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The birth of neoSENS


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#31 Michael

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Posted 27 February 2005 - 06:29 PM

All:

[quote]
[quote]
I'd first like to make the parenthetical meta-point that "neoSENS" is an unfortunate choice of terminology for the kind of approaches apparently being suggested under the rubric. The central feature of SENS per se as an approach to biomedical gerontology is to directly attack the accumulating damage that causes dysfunction, rather than attempting to prevent it ...

In short (and the following is intended as a mildly amusing mnemonic pun based on this terminological self-contradiction, not an argument about the merits of the approach), "neoSENS" is actually nonSENS.[/quote]
(see references from original post)

NonSENS - bravo! What a riposte! I can just see the Jason Pontins of this world drooling over such a caption - is SENS really nonSENSe?[/quote]
Prometheus, several times in our discussions I have carefully laid out that I am not saying some particular thing, and you have proceeded to respond by saying that I am making exactly the argument which I am explicitly repudiating. Eg, I have had to repeat, three times, that that I am not arguing that the simple fact of higher mtDNA than nuDNA damage was evidence for the irrelevance of latter to aging pathology within a "normal" lifespan. In the present case, I explicitly stated that:

[quote]
the following is intended as a mildly amusing mnemonic pun based on this terminological self-contradiction, not an argument about the merits of the approach[/quote]

... and you proceeded to take the pun as exactly the kind of empty, rhetorical hand-waving which I was careful to disavow.

In future, can you please read my posts more carefully before responding, and accept that I say what I mean and mean what I say, rather than something else? Thanks!

[quote]
On a more serious note I think we need some firmer footing on the definitions of: neoSENS vs SENS, direct or engineering approaches vs prevention or gerontological approaches

Firstly SENS is no more than a number of hypothetical interventions to address aging.[/quote]
The person who gets to define a technical term is its coiner. The papers which I cited in stating that "The central feature of SENS per se as an approach to biomedical gerontology is to directly attack the accumulating damage that causes dysfunction, rather than attempting to prevent it" and contrasted it with the "geriatrician's" and "gerontologist's" approaches (3,4) document exactly what kind of approaches are embraced by the term. Moreover, this is right there on the SENS website home page:

[quote]
The key to SENS is the appreciation that aging is best viewed as a set of progressive changes in body composition at the molecular and cellular level, caused as side-effects of essential metabolic processes. These changes are therefore best thought of as an accumulation of "damage", which becomes pathogenic above a certain threshold of abundance. The traditional gerontological approach to life extension, namely to try to slow down this accumulation of damage, is a misguided strategy, firstly because it requires us to improve biological processes that we do not adequately understand, and secondly because it can even in principle only retard aging rather than reverse it. An even more short-termist alternative is the geriatric approach, namely to try to stave off pathology in the face of accumulating damage ... Instead, the engineering (SENS) strategy is not to interfere with metabolism per se, but to repair or obviate the accumulating damage and thereby indefinitely postpone the age at which it reaches pathogenic levels.[/quote]

Indeed, if you compare the original SENS paper (3) to more recent publications, you'll see that Aubrey has dropped some potential interventions and refined others. SENS is not the static set of panels, but a strategy for developing such.

NB that enhancing our existing DNA repair mechanisms, aside from "messing with metabolism," cannot repair the key mtDNA lesions: deletions. This requires engineering from without, fixing them via some fundamentally extrabiological technique (as eg via protofection (12)) or simultaneously severing their link to pathology (via allotopic expression).

[quote]
NeoSENS is an approach of formulating hypothetical interventions to address aging that are designed to meet the criteria for consideration by scientists rather than impressing the public. This may sound harsh but is ultimately true - SENS does not care what the scientific community thinks and it positions itself above it.[/quote]

SENS refers to a specific way of attacking the aging problem from an "engineering" perspective by attacking the accumulating, pathological molecular lesions of aging directly, as outlined above. SENS of course does not care what the scientific community thinks, as a therapeutic platform is incapable of caring about anything. de Grey, by contrast, cares what the scientific community thinks, which is why he spends so much effort and paper in disabusing his colleagues of their misapprehensions about SENS and biomedical gerontology generally, but ultimately he cares more about the actual feasibility and likely effectiveness of the interventions that he advocates, even they are counter to prevailing opinion of scientists outside of the relevant area of expertise.

[quote]
NeoSENS seeks to build a bridge between hypothesis and the existing knowledge and technology base. The prime consideration of neoSENS is to satisfy the scientific community that the hypothesis proposed are congruent with and follow along the lines of present research directions.[/quote]
The signing-on of relevant experts to each of the core SENS papers (eg. Campisi, Ames, and Bartke on the original SENS paper (3), and Campbell, Jahoda, and Porterg for WILT (4)) helps to ensure that this is exactly what is realized by the therapeutic panel which de Grey advances.

[quote]
This is better illustrated by comparing the SENS and neoSENS approaches to mitochondrial DNA damage:

SENS: allotopic expression of mitochondrial genome
Supporting research: NEGATIVE
[(1) below][/quote]

That is indeed what (1) reports. However:

A. (6) reports success with allotopic expression the ND4 subunit gene of complex I, including the rescue of the mutant cell -- the same protein found to lead to loss of mitochondrial membrane potential in the transfected cell in (1). The authors of (1) acknowledge this:

[quote]
ND4 expressed from adeno-associated virus (AAV) vectors showed essentially 100% transfection efficiency and the expression levels were reported as strong and mitochondrial localized. We do not have an explanation for these differences at this point. Their system differs from ours in two aspects: (1) the expression vector was the AAV ... and (2) they expressed their construct in osteosarcoma cells. In our hands, 143B-derived osteosarcoma cells have a very low efficiency in expressing transfected plasmids. For this reason we used COS-7 and HeLa cells. Interestingly, their results with an ND4-GFP fusion were similar to ours, where the GFP showed a punctate signal but did not colocalize well with Mitotracker.[/quote]

B. The authors of (1) also note that "Analyses of the hydrophobic patterns of different polypeptides suggest that hydrophobicity of the N-terminal segment is the main determinant for the importability of peptides into mammalian mitochondria."

i. de Grey has been warning of this possible hurdle for years, and advocating its specific solution using inteins ((7), and again in (8)).

ii. King's group has been working on solving import, largely on proteins recalcitrant because of hydrophobicity, by identifying homologues in Chlamydomonas which have already moved the "dirty baker's dozen" into the nucleus -- tricks which they have already shown to lead to successful cell rescue in several cases (9). In one case, King himself tried to put the mammalian ATP6 subunit in and failed, but Schon's group (10) put the unaltered Chlamydomonas protein in and it workded just fine, including rescue of mutant cells. ((9) also reviews work by other groups identifying similar cases in other organisms).

iii. Daley et al (11) found that another protein unimportable due to hydrophobicity could be made transfectable with only a very small number of aminos changed, which may well make several proteins importable with no or minimal loss of function.

C. If allotopic expression fails, a second-best, which would unfortunately require periodic repetition but would still obviate the pathological sequelae of mtDNA deletions, would be the new technique of "protofection" (12) which is in its early stages but looks promising. See the BetterHumans story that just came out the other day on mitochondrial protofection news story.

IOW, (1) is clearly not a deal-breaker for allotopic expression: there are several potential ways around the hydrophobicity problem. It may be a simple matter of using the right vector for the gene. There is a history of overinterpretation of failures on the allotopic expression front to mean that the task itself is impossible; eg (8),

[quote]
In reporting their failure to import even small segments of ATPase 6 and NAD6, Owen and Flotte are guilty of overinterpreting a negative result. The most important recent development in this area is unequivocally the report ([refs]) of robust phenotypic rescue of an inactive ATPase subunit 6 by a nuclear transgene in a mammalian cell culture system. Zullo et al. did not follow Owen and Flotte’s strategy — which, incidentally, has also failed in others’ hands (ref) — of using the leader sequence of a hydrophobic, nuclear-coded mitochondrial protein; they instead used that of ornithine transcarbamylase. By performing their experiment in CHO cells, in which a mutation in ATPase 6 has been isolated that confers resistance to oligomycin (1), they were able to demonstrate unambiguous phenotypic rescue [/quote]

[quote]
neoSENS: increase mitochondrial DNA repair by directing the overexpression of DNA repair enzymes in mitochondria
Supporting research: POSITIVE
[2][/quote]

But Prometheus, you've just posted a study showing that knocking out this same enzyme leads to absolutely no mitochondrial dysfunction (13). This is as one would expect, as (as I've now repeated several times) the lesion which it repairs (8-oxoDG) does not accumulate and is not itself pathological. So the ability to enhance this same process doesn't seem to be very promising as anti-aging biomedicine.

By the nature of the system, there is no way for the body to repair the real culprits -- deletions -- so no enhacing of existing mtDNA repair is going to be much more than a minor stopgap on this front.

[quote]
Secondly, SENS claims to provide a superior methodology to addressing the aging problem since it distinguishes itself from other approaches (termed indirect or gerontological) by so-called "directly attacking accumulating damage". The problem with this statement is the implied increase in efficacy of the "direct" method over the other. One simply cannot compare and contrast on this basis since both methods are in the realm of the hypothetical and require evidence of relative efficacy, let alone proof of concept.[/quote]

That's true enough as far as it goes with respect to the efficacy of any specific therapeutic modality. But again, the key insight of the SENS approach is that preventive, metabolic-tweaking approaches are of necessity messier, more difficult to prove clinically, harder to implement, and more side-effect prone than approaches based on allowing normal metabolism to proceed and either undoing the accumulating lesions directly or severing their link to pathology. If one specific therapy designed SENS-style fails, or looks unlikely to succeed, we should go looking for alternative modalities -- but we should be looking for methods that are fundamentally of this "engineering" school.

Indeed, to go one step further: it would be great to have alternative methods of attacking the "7 Deadlies" direcly, and/or identification of more accumulating molecular lesions clearly linked to aging pathology within a normal lifetime for which a SENS-style intervention could be developed. But the inherent logic of the SENS approach makes therapies designed with its principles more attractive, and should be preferred.

Of course, I'd take a preventive were that all that's available. Eg, I'd take a CR mimetic if it came out tomorrow. But I regard the diversion of financial & intellectual capital into such as a waste of scarce resources when the same resources could be invested in SENS-style interventions.

[quote]
NeoSENS is not a public relations exercise. NeoSENS is about quantifiable problems and implementable solutions.[/quote]

Ditto for SENS. It's just a (a) more clearly-named and (b) more inherently promising approach to developing genuinely powerful gerontological biomedicine, and reaching "actuarial escape velocity" as quickly as possible. Once we're there, we'll need new SENS-type interventions to deal with the pathological processes which are currently too subtle to contribute meaningfully to pathology but which will accumulate sufficiently to be a threat to our newly-extended lifespans.

-Michael


(1) Limitations of Allotopic Expression of Mitochondrial Genes in Mammalian Cells
Jose Oca-Cossio, Lesley Kenyon, Huiling Hao, and Carlos T. Moraesa
Genetics 165: 707–720 (October 2003)

(2) Title: Conditional Targeting of the DNA Repair Enzyme hOGG1 into Mitochondria
Journal of Biological Chemistry 277: (47) 44932–44937 (November 2002)

3. de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter
RJ, Stock G.
Time to talk SENS: critiquing the immutability of human aging.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu12.pdf

4. de Grey AD. An engineer's approach to the development of real anti-aging medicine. Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review. PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu16.pdf

5. de Grey AD, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CA,
Porterg AC.
Total deletion of in vivo telomere elongation capacity: an ambitious but
possibly ultimate cure for all age-related human cancers.
Ann N Y Acad Sci. 2004 Jun;1019:147-70. Review.
PMID: 15247008 [PubMed - indexed for MEDLINE]
http://www.gen.cam.ac.uk/sens/WILT.pdf

6. Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS.
Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy.
Ann Neurol. 2002 Nov;52(5):534-42.
PMID: 12402249 [PubMed - indexed for MEDLINE]

7. de Grey AD.
Mitochondrial gene therapy: an arena for the biomedical use of inteins.
Trends Biotechnol. 2000 Sep;18(9):394-9. Review.
PMID: 10942964 [PubMed - indexed for MEDLINE]

8. de Grey A.
Response to "approaches and limitations to gene therapy for mitochondrial
diseases," Antioxid. Redox Signal. 2001;3:451-460.
Antioxid Redox Signal. 2001 Dec;3(6):1153-5. No abstract available.
PMID: 11813989 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/ARSlet.pdf

9. Gonzalez-Halphen D, Funes S, Perez-Martinez X, Reyes-Prieto A, Claros MG,
Davidson E, King MP.
Genetic correction of mitochondrial diseases: using the natural migration of
mitochondrial genes to the nucleus in chlorophyte algae as a model system.
Ann N Y Acad Sci. 2004 Jun;1019:232-9. Review.
PMID: 15247021 [PubMed - indexed for MEDLINE]

10. Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, Guy J, Schon EA.
Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial
DNA-encoded gene, to the nucleus.
Nat Genet. 2002 Apr;30(4):394-9. Epub 2002 Feb 25.
PMID: 11925565 [PubMed - indexed for MEDLINE]

11. Daley DO, Clifton R, Whelan J.
Intracellular gene transfer: reduced hydrophobicity facilitates gene transfer
for subunit 2 of cytochrome c oxidase.
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10510-5. Epub 2002 Jul 25.
PMID: 12142462 [PubMed - indexed for MEDLINE]

12. Khan SM, Bennett JP Jr.
Development of mitochondrial gene replacement therapy.
J Bioenerg Biomembr. 2004 Aug;36(4):387-93.
PMID: 15377877 [PubMed - in process]

13. Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VA.
No evidence of mitochondrial respiratory dysfunction in OGG1-null mice
deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA.
Free Radic Biol Med. 2005 Mar 15;38(6):737-45.
PMID: 15721984 [PubMed - in process]
http://www.imminst.o...e=post&id=51160

#32

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Posted 28 February 2005 - 06:31 AM

NB that enhancing ourexisting DNA repair mechanisms, aside from "messing with metabolism," cannot repair the key mtDNA lesions: deletions. This requires engineering from without, fixing them via some fundamentally extrabiological technique or simultaneously severing their link to pathology (via allotopic expression).


Michael, thanks for your reply above. I wonder if you wouldn't mind explaining:

1. how it is that the most important mtDNA lesions are deletions (do we know this for a fact?)

2. why an upregulation of DNA repair would not be very effective (don't just refer to the above - there is more damage than deletions)

and most importantly,

3. why have you (the SENS group) not considered increasing mitochondrial organelle turnover in post-mitotic cells as another strategy of keeping mtDNA healthy

Cheers.

#33 jaydfox

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Posted 28 February 2005 - 04:17 PM

3. why have you (the SENS group) not considered increasing mitochondrial organelle turnover in post-mitotic cells as another strategy of keeping mtDNA healthy

Or interfering in the clonal expansion of mutant mtDNA, either within a mitochondrion (preventing homochondrous mutations), or the selective advantage of mutants (preventing homokairotic mutations). Just a thought, as it merited mention in de Grey's papers, but I see no mention in the SENS program.

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#34 Michael

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Posted 28 February 2005 - 10:11 PM

All:

NB that enhancing ourexisting DNA repair mechanisms, aside from "messing with metabolism," cannot repair the key mtDNA lesions: deletions. This requires engineering from without, fixing them via some fundamentally extrabiological technique or simultaneously severing their link to pathology (via allotopic expression).


Michael, thanks for your reply above. I wonder if you wouldn't mind explaining:

1. how it is that the most important mtDNA lesions are deletions (do we know this for a fact?)

The shortish answer would be to note that they:

- actually accumulate with aging,
- clearly lead to pathological phenotype at the cellular level: the accumulating deletions eliminate genes for respiratory chain subunits and knock out tRNA genes, which (due to the lack of redundancy of same in mtDNA) wipes out the capacity of the mt to synthesize any of the mt-encoded proteins, and then these OXPHOS-inactivated mt literally take over the cell or muscle segment, leading to cells or muscle segments that are entirely populated by OXPHOS-incapable mt which only survive by an abnormal bioenergetic pathway characterized by no COX activity and elevated succinate dehydrogenase activity;
- clearly lead to pathological phenotype at the tissue level, most notably in muscle -- see (0) and many other papers by Aiken's group.

But the longer, and probably more important answer, which both explains the above bizarre findings & links them with aging per se, requires folks to read de Grey's papers & book on the subject (1-4).

2. why an upregulation of DNA repair would not be very effective (don't just refer to the above - there is more damage than deletions)

Yes, but the question for practical interventive biogeerontology, esp in view of "actuarial escape velocity" (6), is not to repair, remediate, or obviate all damage, but to first address that which actually causes pathology within a "normal" lifespan. As you and I have each previously documented, eg, 8-OHdG is clearly damage, but is not itself pathological and does not accumulate. Since deletions do drive aging pathology under our current conditions, this is clearly the first priority for intervention -- and conceivably may turn out to be the only therapeutic priority for mt (especially if we fix up the remaining 6 deadlies), tho' we won't know this until we've first fixed the existing 7 lesions and then seen what comes up next.

Once we have fixed or obviated these forms of damage, it will then be important to figure out what damage which does not already contribute to aging pathology within a "normal" lifespan becomes pathological in a newly-extended one, and attack that in turn.

and most importantly,

3. why have you (the SENS group) not considered increasing mitochondrial organelle turnover in post-mitotic cells as another strategy of keeping mtDNA healthy

This is an important point. The reason why OXPHOS-incapable mt with deletions take over cells is now unambiguously known to be due to clonal expansion. There are 2 rival explanations as to why this happens that are consistent with the existing data. One is de Grey's "Survival of the Slowest" (SOS) (1-3), which I favor; the other is the idea that mt with deletions actually have a relative increase in replicative rate and simply "drown out" wt mt (5).

If SOS is right, increasing the rate of turnover will have negligible impact on the progression of clonal expansion; if the alternative is correct, then doing so will not only will fail to forestall clonal expansion but will accelerate it.

In accordance with this, the only anti-aging intervention currently known to be effecive in mammals -- CR -- slows down the rate of generation of muscle segments thus overtaken, but not the rate of progression of the phenotype thru' the muscle fiber once it gets started (7).

-Michael

0. McKenzie D, Bua E, McKiernan S, Cao Z, Aiken JM; Jonathan Wanagat.
Mitochondrial DNA deletion mutations: a causal role in sarcopenia.
Eur J Biochem. 2002 Apr;269(8):2010-5. Review.
PMID: 11985577 [PubMed - indexed for MEDLINE]

1. de Grey AD. The reductive hotspot hypothesis of mammalian aging: membrane metabolism magnifies mutant mitochondrial mischief. Eur J Biochem. 2002 Apr;269(8):2003-9. Review. PMID: 11985576 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/mmmmmm.pdf

2. de Grey AD. The mitochondrial free radical theory of aging. 1999; Austin, TX: Landes Bioscience. (ISBN 1-57059-564-X).

3. de Grey AD. A proposed refinement of the mitochondrial free radical theory of aging. Bioessays. 1997 Feb;19(2):161-6. Review. PMID: 9046246 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a.../sens/manu7.pdf

4. de Grey ADNJ. A mechanism proposed to explain the rise in oxidative stress during aging. J Anti-Aging Med 1998; 1(1):53-66.
http://www.gen.cam.ac.uk/sens/pmor.pdf

5. Yoneda M, Chomyn A, Martinuzzi A, Hurko O, Attardi G.
Marked replicative advantage of human mtDNA carrying a point mutation that
causes the MELAS encephalomyopathy.
Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11164-8.
PMID: 1454794 [PubMed - indexed for MEDLINE]

6. de Grey AD Escape velocity: why the prospect of extreme human life extension matters Now. PLoS Biol. 2004 Jun;2(6):723-6.
http://www.pubmedcen...55&blobtype=pdf

7. Bua E, McKiernan SH, Aiken JM.
Calorie restriction limits the generation but not the progression of
mitochondrial abnormalities in aging skeletal muscle.
FASEB J. 2004 Mar;18(3):582-4. Epub 2004 Jan 20.
PMID: 14734641 [PubMed - indexed for MEDLINE]
http://www.fasebj.or...g&pmid=14734641

#35 ag24

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Posted 01 March 2005 - 12:56 PM

Some elaboration on Michael's answer to Jay:

> > why have you (the SENS group) not considered increasing mitochondrial
> > organelle turnover in post-mitotic cells as another strategy of keeping
> > mtDNA healthy
>
> Or interfering in the clonal expansion of mutant mtDNA, either within a
> mitochondrion (preventing homochondrous mutations), or the selective
> advantage of mutants (preventing homokairotic mutations). Just a
> thought, as it merited mention in de Grey's papers, but I see no
> mention in the SENS program.

The main reason these things are not mentioned in the SENS program is not because they haven't been considered but because we don't know the first thing about how to achieve them. It's possible that increasing the rate of mitochondrial fusion would slow down clonal expansion, but since that rate is under cellular control (varies with stress, eg) there is every likelihood that it will have unwanted side-effects. Bob Lightowlers has for a while been working on a system to reverse clonal expansion, which he will present at SENS 2, but it only works on specific mutant sequences so it's not easily applicable to aging.

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Posted 01 March 2005 - 03:52 PM

This is an important point. The reason why OXPHOS-incapable mt with deletions take over cells is now unambiguously known to be due to clonal expansion. There are 2 rival explanations as to why this happens that are consistent with the existing data. One is de Grey's "Survival of the Slowest" (SOS) (1-3), which I favor; the other is the idea that mt with deletions actually have a relative increase in replicative rate and simply "drown out" wt mt (5).

If SOS is right, increasing the rate of turnover will have negligible impact on the progression of clonal expansion; if the alternative is correct, then doing so will not only will fail to forestall clonal expansion but will accelerate it.

In accordance with this, the only anti-aging intervention currently known to be effecive in mammals -- CR -- slows down the rate ofgeneration of muscle segments thus overtaken, but not the rate ofprogression of the phenotype thru' the muscle fiber once it gets started (7).


Whilst I am aware that there is now sufficient evidence for clonal expansion of faulty mitochondria I am troubled by how it begins:

If we look at mitotic cells and the mitochondria within them, then with each cell division cycle the potential for clonal expansion of preferentially reproducing faulty mitochondria increases. Ultimately we would have an entire mitotic cell population with faulty mitochondria. But we don't see this in mitotic cells - we see it in post-mitotic or senescent cells. Mitotic cells' mitochondria seems to be fine.

We know that mitochondria have a fast turnover period of 7 -30 days. This continuous turnover eliminates damaged and mutated mtDNA molecules (if it did not, at the rate that mitochondria turnover we should be seeing damage a lot sooner). When the organism is youthful we don't observe any indications of mtDNA damage (eg as in muscle fiber cytochrome c oxidase (COX) function decline in the old). Were such mtDNA damage responsible for the mitochondrial dysfunction that leads to COX deficiency why is that we only observe this in those over the age of 50 or so? Coincidentally, this is an age where we see lots of altered gene expression changes from nuclear DNA. We do not see a uniform spread of mtDNA damage, rather we see a sharp decline which coincides with altered gene expression from the nucleus.

Thus an interpretation of those observations (an increase in mitochondrial dysfucntion) would be that mtDNA damage repair rate begins to decline (controlled by the nucleus) so that mutation incidence increases and eventually triggering clonal expansion of useless mitochondria. Of course no repair system can be absolutely perfect so unless the cell divides enough damage could accumulate over time to overwhelm the cell, which is why the mitotic cells do fine (as do other examples of cellular immortality including stem cells, germline cells and cancer cells).

#37 ag24

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Posted 01 March 2005 - 04:41 PM

> This continuous turnover eliminates damaged and mutated mtDNA molecules (if it did
> not, at the rate that mitochondria turnover we should be seeing damage a lot sooner)

How does that follow?

#38 jaydfox

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Posted 01 March 2005 - 05:32 PM

I thought the evidence showed pretty clearly that clonal expansion proceeds rapidly; otherwise, we'd expect to see a lot more heteroplasmic mutant cells, when most of the cells are (effectively) homoplasmic wild-type, and a small subset are (effectively) mutant, and very few are in between.

But that depends on the accuracy of the studies. More to learn in the coming few years.

So the rate of accumulation with age is not the rate of clonal expansion, but the rate of the initial lesions that are preferentially expanded. No? Lesions that are not preferentially expanded would take a much longer time to accumulate, and we'd see a variety of mutations per mitochondrion, not one. I'm inclined to favor de Grey's interpretation of clonal expansion.

In fact, if mutant mtDNA does have a selective advantage (in avoiding being digested), we'd expect to see the problem more often in post-mitotic cells. If the advantage is in more rapid replication, then the difference between post-mitotic and mitotic cells would not be so great. Again, I'm inclined to agree with de Grey's interpretation.

#39 ag24

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Posted 01 March 2005 - 08:57 PM

All correct Jay (though disputed by Patrick Chinnery, who has overlooked some of the details in his own simulations in my view). What is unknown (and, I would say, unmeasureable) is the basal rate of formation of new mutations. What is also unknown, and very hard to estimate reliably, is the proportion of mutations that get destroyed by random chance before they start getting selected for -- remember that in my model selection is for dysfunctional mitochondria, not mutant mtDNA per se, and it's highly likely that even one normal genome can keep a mitochondrion breathing pretty well, so mitochondria will only become dysfunctional by randomly segregating copies of a mutation to homochondry and then dividing a few more times (rather than being autophagocytosed) so as to dilute out the functional enzyme complexes it made when it was heterochondrous. Quite an obstacle course -- not many mutations will achieve it.

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#40

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Posted 01 March 2005 - 10:52 PM

> This continuous turnover eliminates damaged and mutated mtDNA molecules (if it did
> not, at the rate that mitochondria turnover we should be seeing damage a lot sooner)

How does that follow?


Mitochondrial DNA damage (including deletions) will prevent mtDNA from being perpetuated into the next cycle because conserved sequences, including those associated with replication and transcription, will not be able to serve as templates. This process, in effect, screens for an appropriate functional template prior to replication. Studies suggest that the majority of mitochondrial replication events are aborted (1,2). So it is more likely that a mutant will be selected against rather than for clonal expansion. As Jay said, clonal expansion must proceed rapidly, yet we only observe it in aged tissue. Given these observations and the timing of the onset of muscle dysfunction suggests a trigger event. Such an event would be an increase in the rate of mutation due to a decrease in the rate of DNA repair.


(1) Multiple protein-binding sites in the TAS-region of human and rat mitochondrial DNA.
Biochem Biophys Res Commun. 1998 Feb 4;243(1):36-40.

(2) Mitochondrial DNA replication in human T lymphocytes is regulated primarily at the H-strand termination site.
Biochim Biophys Acta. 1999 Jul 7;1446(1-2):126-34

#41

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Posted 02 March 2005 - 03:53 AM

Further to my previous post, and in support that nuclear DNA damage is responsible for the events that culminate in mitochondrial DNA damage one may consider the following hypothetical experiment:

We take the mitochondria from a young mitotic cell and transfer them into the cytoplasm of an old post-mitotic cell from which its old mitochondria have been removed (in effect a mitochondrial transplant). Then after a time in culture, we may observe in the transplanted mitochondria of the old cells:
a) the rate of mitochondrial damage/mutation does not change
b) the rate of mitochondrial damage/mutation slows dramatically
c) somewhere in between (a) and (b)

We may also observe changes in the lifespan of the young mitochondrial transplant recipient old cells.

Should we observe anything other than (b) it would suggest that the nucleus greatly influences mitochondrial function and that nuclear DNA damage drives mitochondrial DNA damage due to ineffective transcription of DNA repair enzymes (1) as well as other important nuclear encoded mitochondrial components such as the TOM complex . Should we observe (b) then Aubrey's proposition would be supported and we may even discover that the nucleus could be reprogrammed, and thus rejuvenated, by healthy mitochondria (which would be tremendous).

Unless I am mistaken, such an experiment has yet to be performed and I believe we would learn a lot (as well as seeing which theory stands - nDNA & mtDNA damage or mtDNA damage alone as the seat of senescence). The closest experiment to date is a recent one (2) where it was found that oocytes injected with somatic cytoplasm or mitochondria showed reduced survival suggesting that old mitochondria influence a young nucleus - which of course is not surprising since mitochondria are the main drivers of apoptosis.




(1) Prog Nucleic Acid Res Mol Biol. 2001;68:257-71.
Enzymology of mitochondrial base excision repair.
Bogenhagen DF, Pinz KG, Perez-Jannotti RM.

(2) Biol Reprod. 2005 Feb 16; (Attached)
 Microinjection of Cytoplasm or Mitochondria Derived from Somatic Cells Affects Parthenogenetic Development of Murine Oocytes.
Takeda K, Tasai M, Iwamoto M, Onishi A, Tagami T, Nirasawa K, Hanada H, Pinkert CA.

Attached Files



#42

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Posted 02 March 2005 - 11:09 AM

Correction:

I said previously that only post-mitotic cells and not rapidly dividing cells, such as stem cells in bone marrow, show increased mtDNA mutations. This is incorrect - mitotic cells from older individuals do show increased mtDNA mutations (1). The evidence that such mutations increase sharply after the age of 50 (2), however, does indicate that there is a gene expression demarcation point, in my view driven from the nucleus. Thus mutant mtDNA genomes cannot be diluted out of even rapidly dividing cells, if they are aged, which may explain why even stem cells, after a certain age tend to lose their regenerative potential, despite telomerase expression.

On the other hand, cancer cells and fertilized oocytes do not demonstrate such mitochondrial vulnerabilities. The common denominator appears to be altered nuclear expression.


(1) Blood, 15 January 2004, Vol. 103, No. 2, pp. 553-561.
Marked mitochondrial DNA sequence heterogeneity in single CD34+ cell clones from normal adult bone marrow
Myung Geun Shin, Sachiko Kajigaya, J. Philip McCoy, Jr, Barbara C. Levin, and Neal S. Young

(2) Nucleic Acids Res. 1999;27: 2434-2441
Cell-by-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions.
Khrapko K, Bodyak N, Thilly WG, et al.

#43 ag24

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Posted 02 March 2005 - 12:22 PM

There are more clonal expansions in aged tissue, but there are some in young tissue (see Aiken's papers). Since the mitochondrial generation time is a week to a month in rats (and a few times slower in humans it seems - see Rooyackers 1996 PNAS), even a completely perfect selection process (i.e. no mutant mitochondria at all are destroyed) would still take a few years to perform the dozen or more replications needed to take over a cell or a detectably long muscle fibre segment. Since the selection will surely be far from perfect, i.e. some mutant mitochondria will be destroyed anyway, it will take longer. So no trigger event is needed.

Stem cells indeed accumulate mtDNA mutations (best study is J Clin Invest 112:1351) -- but they are slowly-dividing... Cancers have mtDNA mutations too (many many studies - start with Nat Genet 20:291) and they are rapidly dividing -- but they don't have knockout mutations such as deletions (see eg Genet Mol Res 30:395). Similarly Attardi's group has found mutations accumulating in fibrolasts, but only in the control region (eg Science 286:774) and they have tried very hard but without succes to demonstrate any loss of function associated with these mutations. (Again: of the 16.5kb of mtDNA, only 1kb, the control region or D-loop, plus a very small region called OL, is involved in replication or transcription. Deletions or mutations elsewhere do not affect clonal expansion because they do not affect replication.) Oocytes are non-dividing but there are very clever things done both during oogenesis and oocyte maturation to compensate for this, not to mention the quiescence (hence low ROS production) of the oocyte itself.

The experiment you suggest about replacing the mtDNA of a posatmitotic cell is ... technically challenging. Culturing non-dividing cells is also quite tricky and extremely far from physiologically relevant (serum is not like extracellular medium, etc) so even if we could do it it would be uninformative. But anyway, as I always say, if we can fix something let's fix it, rather than wasting time worrying about whether we need to. You would of course say "well then, ditto for nuclear mutations not leading to cancer" and I agree -- but, as I said ages ago and as far as as I know you have not answered (though these threads are getting rather metastatic), you haven't described a practical, foreseeable way to do it. You haven't even described a way to improve DNA repair in normal aging (as opposed to sunburn or other accelerated-damage settings). If I've missed this, perhaps you could describe your proposed therapy again -- in SENSesque detail, please.

#44 jaydfox

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Posted 03 March 2005 - 06:38 AM

But anyway, as I always say, if we can fix something let's fix it, rather than wasting time worrying about whether we need to. You would of course say "well then, ditto for nuclear mutations not leading to cancer" and I agree -- but, as I said ages ago and as far as as I know you have not answered (though these threads are getting rather metastatic), you haven't described a practical, foreseeable way to do it. You haven't even described a way to improve DNA repair in normal aging (as opposed to sunburn or other accelerated-damage settings). If I've missed this, perhaps you could describe your proposed therapy again -- in SENSesque detail, please.

Well, I don't know how others feel about this, but I see the issue as somewhat complex to put forward.

Why? Here's how I see two of the most important "repair" aspects of SENS. WILT and allotopic expression of mtDNA: preventive measures, not repair measures.

Allotopic expression of mtDNA

Allotopic expression of mtDNA would aim to prevent accumulation of mtDNA damage (mutations, deletions, etc.). It wouldn't "fix" the damage, since nuDNA can still be damaged, and there isn't a plan put forward to address that. But it could drastically slow the rate of that accumulation, given certain assumptions (which I won't contend for the moment). By "drastically", I mean that we're not discussing an "incremental" approach to addressing the problem.

Personally, I'm not really against this plan, though I may have come across that way. While I'm open to the possibility that mtDNA damage accumulation can be slowed enough to match the protection offered by allotopic expression, I don't see any reason not to move the mtDNA to the nucleus, because the subsequent plan to increase nuDNA integrity would come full circle and preserve mtDNA integrity. So it's just a question of which is more technically difficult. There's no real drawback to moving the mtDNA to the nucleus that I can see, unless there are any non-protein coding sequences (e.g. mRNA sequences) that must remain "on site".

I think Prometheus's misgivings about this approach might have to do with the timeframe, as he seeks something a little more rapid than the 25 year target de Grey often cites for human implementation of SENS. If our target for completing SENS is 25 years, I'm pretty sure that if it can be accomplished without a complete reengineering from scratch of those 13 genes and/or the necessary targetting sequences, inteins, etc., then it will be accomplished. Whether it can be accomplished in ten to fifteen years is another question altogether. Prometheus envisions therapeutic applications of mtDNA damage prevention being feasible is such a short timeframe, which would serve as another bootstrap in achieving escape velocity for some alive today.

If any of the genes cannot be moved (if, for example, the toxicity of certain mtDNA-coded proteins in the cytosol cannot be trivially solved), other options are available (though not discussed in the SENS website, but de Grey has discussed them in his papers, so I assume they remain on a back burner). I'd like to see these backup options receive a more prominent mention, but this isn't my main point of concern with the SENS platform. Hence, I consider adding these backup options to SENS my "weak refinement" of the SENS solution to mtDNA damage.

WILT as a "fix" for nuDNA damage

Again, a preventive measure. Cells would be ablated through telomeric catastrophe (division beyond the Hatflick limit). This will partially address the problem of accumulation of nuDNA damage. I say partially, because there are a few main causes of DNA damage.

Mitosis is one: the DNA is copied, exposing it to harm. Also, biogenesis in the growing daughter cells is a state of high metabolism, which can cause damage (DNA exposed for transcription, increased oxidative stress from mitochondria to provide energy for certain processes involved in biogenesis, etc.).

Exposure to a toxic environment is another. One example is the gut. But this also happens to be an area of high mitosis, so the gut would seem especially prone to damage. The colon is a prime example here. Funny that the small intestine happens to be an counterexample here, though as I have argued, this gives us hope in the probable success of improving DNA repair.

The third area is general metabolism. In muscles, this would be the energy expended in contraction, plus the constant anabolism and catabolism in muscle tissues. In the brain, this is the very high metabolic rate associated with thought itself, and the metabolic load of building new interneural connections and maintaining those connections.

Fourth is the change in methylation patterns with age, a change in the gene expression profiles and effeciency. Since WILT has been tied with stem cell reseeding, one might say that this problem is addressed, because there is evidence that stem cell transplants of "young" stem cells via the blood can rejuvenate tissues such as muscle, and presumably many other tissues. However, this isn't WILT accomplishing this, it's the stem cell reseeding, which, as Prometheus has rightly pointed out, should be considered separately from the ablation of telomerase. So WILT-proper doesn't actually address the methylation issue at all, and if it is not addressed, rejuvenation and cannot properly be accomplished, meaning an increased risk of the diseases and symptoms of aging.

Now WILT would address the first problem, mitosis. Rapidly dividing tissues would accumulate damage, but that rate would be intimately tied to the number of cell divisions, and I have every confidence that WILT will prevent most blood, skin, and gut cancers. Whether the gut can be reseeded only every ten years or not, I'll leave for later discussion.

However, in slowly dividing tissues, or worse yet, in postmitotic tissues, the rate of DNA damage from toxicity and general metabolism will likely render WILT ineffective at preventing cancer.

Which is why I say that WILT will "partially" address the problem of accumulation of nuDNA damage.

Now, as regards the cancer aspects of DNA damage, WILT is supposed to perform as an ultimate cure, because tumors would presumably not be able to divide beyond the Hayflick limit. If 100% true, this would still leave all the non-cancer problems of nuDNA damage, and these are bot being addressed.

Worse yet, WILT will probably not cure cancer with a 100% success rate. There is an alternate method of lengthening telomeres (termed ALT), and this method is not understood. In theory, this system can be cracked in the next 5-20 years, providing 5-20 years to find a way to remove it and meet our 25-year deadline.

However, telomerase has DNA repair capabilities, and the ALT system most likely also has beneficial effects, and by deleting these effects from the genome, we are further crippling our biology and DNA repair systems, meaning WILT will have a negative impact on DNA integrity.

Furthermore, cancers are notorious for being able to subvert other cells, and if a cancer approaching its Hayflick limit can conscript a cell with 30 divisions left, that gives the cell up to a billion more cells' worth of division capacity. One can see that a cyclical scenario can ensue, where a cancer can reach critical mass if one in a billion cancer cells can conscript one fresh cell.

That's not to say that WILT was worthless. Certainly these crippled cancers will be much easier to fight with traditional cancer therapies, which in 25 years will be quite sophisticated and capable of curing 95%-99% of cancers anyway (well, 95%-99% of today's cancers. Tomorrow's cancers will be the ones hardest to cure, so the actual survival rate of cancer will not be that high...), somewhat obviating the need for such a drastic measure.

So where am I going with all of this? WILT is not a system to prevent the accumulation of nuDNA damage. It will do so in mitotic tissues such as the blood, skin, and gut systems, since those cells will by necessity be exhausted in ten years (or less...). However, several tissues and organ systems will not see any benefit to DNA integrity from WILT, and will actually be more likely to see a decline in DNA integrity due to removal of telomerase, an enzyme with known DNA repair capacity.

So in the end, WILT does not make a serious attempt to address DNA damage accumulation, but only to cure cancer, which it probably won't do. It might push cancer back a few decades, enough maybe to help us reach escape velocity. But to any here under the misguided impression that WILT is the ultimate cure to the nuDNA damage problem, and that technology in the next 50 years won't be able to provide something better than WILT, I'm afraid to say that you need to take a much closer look at what has been proposed. WILT is nothing more than a bootstrap to escape velocity, it is not a means of achieving agelessness. Since it is nothing more than a bootstrap, we should consider whether there are better and/or more cost-effective bootstraps to be found.

DNA integrity

So, am I just going to harp on WILT, or is there an alternative? Well, here I see a possibility for what I call my "strong refinement" of the SENS solution to nuDNA damage accumulation.

nuDNA damage has something that sets it apart from mtDNA damage. For the cancer problem, the one that WILT would supposedly address, we have two components. Before I get to that, we must look at the one component of mtDNA damage.

According the the mitochondrial free radical theory of aging, the toxicity associated with mtDNA damage is proportional to the number of cells affected by such damage. The number of cells affected can be roughly inferred from the statistical rate of damage in one cell, because there hasn't been a good system identified for selectively ablating cells that become overwhelmed by mutant mtDNA.

On the other hand, nuDNA damage has a second component. In addition to a certain rate of damage in individual cells, we also have a system of ablating cells which accumulate certain types or amounts of damage. Two examples of such systems are senescence (which isn't truly ablation, but serves a similar role) and apoptosis. As long as those systems of cell ablation are functioning reasonably well, we'd expect systemic nuDNA damage (the average amount of nuDNA damage per cell) to accumulate much slower than the rate of cellular nuDNA damage accumulation.

In fact, with a high enough tuning of DNA repair/maintenance, high enough sensitivity to DNA damage/mutations with consequent ablation, and high enough degree of regenerative capacity (via adjacent cells and/or stem cells), systemic DNA damage accumulation can be held at a plateau, a dynamic equilibrium where damage accumulates in all cells, but the most damaged cells are ablated and replaced by less damaged cells, maintaining the same overall mosaic of nuDNA damage, with no net increase. Statistical outliers would still be capable of forming cancers, but the doubling period would be greatly increased, and a plateau in that rate would be realised (not just of mortality, but a plateau of the cancer incidence rate).

Because systemic DNA integrity is multifactorial, a tenfold increase in cellular DNA integrity would not be required to accomplish a tenfold increase in systemic DNA integrity. A moderate increase in cellular DNA integrity, combined with tuned upregulation of tumor suppressors, and increased regenerative capacity (perhaps via methylation reprogramming, and/or involving stem cell reseedings, but not because of the need to address a programmed hard limit, but to address the loss of regenerative capacity we already face over a much longer timeframe), that tenfold increase in system nuDNA integrity can be realized. In the context of escape velocity, only a three- to five-fold increase is really needed. So while the proposal appears "incremental", and by implication inferior, on the surface, deeper inspection reveals that there is much merit to this approach, even without consideration of the many societal risks that WILT would place on us.

So, have I said anything new? Not really. Just a summary of discussions so far, and objections raised. The next step is actually to provide a framework for this suggested fix. Luckily, it's not much different from WILT. WILT-proper is the deletion of telomerase, but WILT as de Grey has packaged it involves gene delivery systems and stem cells reseeding technologies yet to be developed. These secondary technologies to WILT should be considered a separate item, as they would serve a similar purpose in implementation of an enhanced DNA integrity solution, one that lowers cancer rates much more effectively in post-mitotic and slowly-mitotic tissues and organs. To the degree that those cancers would not be crippled, cancer therapies of 25 years hence will be more than capable of handling those rare (that's the key, rare) cancers sufficiently to maintain escape velocity.

#45 ag24

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Posted 03 March 2005 - 04:27 PM

Thanks for this Jay. Good timing, as I have just finished some big jobs and have time to reply properly.

First, yes, allotopic expression and WILT are ways to obviate damage rather than repair it, just as Michael mentioned recently and has been stated by me in many places. This is not, therefore, something that needs to be changed in how SENS is presented.

Second, WILT is the name I've given to the set of things we need to do to make telomere shortening an impregnable defence against cancer. It thus encompasses telomerase deletion, corresponding gene deletions for ALT, genetic chemoresistance of stem cells, and all the various stem cell replenishment therapies. It may be that the words that WILT stands for suggest a narrower definition, but hey, acronyms are hard. WILT is what I say it is, by definition, so please stop trying to redefine the term. If you want a term for the telomerase deletion part of WILT, go ahead and coin one -- a different one.

Methylation changes (and all other types of epigenetic change, like histone acetylation) causes changes of gene expression, just like mutations. Thus it can cause cancer, just like mutations. Thus my logic about cancer versus non-cancer applies to epigenetic changes just as much as to mutations. That's why I don't deal with epigenetic changes separately. If you don't buy my logic about non-cancer-causing mutations, that's one thing, but if you do (as I predict you eventually will!), epigenetic changes are covered too.

Fast-dividing versus slowly-dividing cells: you're confusing a few issues here. Other things being equal, cells that divide fast will accumulate fewer mutations before they reach their Hayflick limit than ones that divide slowly, because (as you say) those mutations arise from causes other than cell division -- though this may be balanced by the fact that a slower cell cycle allows more time for DNA repair and thus makes it more faithful on average in the first place. But as you say, other things are not equal -- some cells have more toxicity to cope with than most. Some such cells divide fast, like the gut; others slowly, like the liver. WILT prevents ALL cells from developing into a life-threatening cancer unless/until they devise a new way to extend their telomeres that doesn't need any of the genes we've deleted. Postmitotic cells are not the issue here, because they are constitutionally incapable of ever dividing at all. The cells you're right to be worried about are mitotically competent but slowly-dividing ones, such as glia, hepatocytes, satellite cells. But the reason we need to worry about them more is because deleting their telomerase/ALT genes is far harder than for rapidly-dividing cells, because we can't do it ex vivo. If/when we do get good enough at in situ gene targeting to do that, cells of that class will be very well protected too.

Chemoresistance is a key part of WILT and you're overlooking it. It is important not just for getting telomeraseless stem cells into niches, but also for eliminating cancers later on. It can even be used for eliminating cancers that have developed in chemoresistant cells, because a variety of chemoresistance mutations can be used (resistant to different chemo agents).

Subverting other cells: you're going to have to come up with references for that, because cell fusion is a concern that has been on the table ever since the WILT roundtable in 2002 and no one has found evidence that I know of that cancers ever do it. Tetraploid cells don't divide well, in general.

Telomerase's roles other than telomere elongation: this is a hot topic, but there is the problem that early-generation telomerase knockout mice (whether mTR or mTERT) have no phenotype whatsoever. So whatever such role telomerase may have, it's evidently non-essential.

Please don't forget that quite a lot of people with quite a lot of biological expertise in all the areas relevant to WILT have thought about it quite hard and put their names to it. Calling it "faith" is the sort of thing I have come to expect from Prometheus, whose unremmittingly abrasive and patronising tone is something those on this side of the pond are perhaps a bit more sensitive to, but you needn't follow his lead.

The main problems with your conclusion that improving DNA repair is the priority are:

- you think non-cancer damage matters in a normal lifetiime
- you think DNA repair can feasibly be improved without serious side-effects
- you think nearly all cancers will be cured by means less drastic than WILT quite soon anyway

I think you're wrong on all three counts, but most especially you're wrong on the last. You clearly appreciate that WILT is a very ambitious project that will take a long time to develop. If we start now, we have a shot at having it available in 25 years. If we don't, we are less likely to have that option that soon. If in 25 years we make only as much progress against cancer as we made in the last 34 -- i.e., if you're as wrong now as Nixon's scientific advisors were in 1971 -- I guess you'll wish we had got on and put effort into WILT in 2005, rather than ptting it on the back burner, no? I am very very scared of cancer, perhaps because I know how ingenious evolution can be, which is something one only really gets a feel for rather slowly as one does biology -- it's beyond one's imagination, quite honestly. So I have every support for trying all the anti-cancer approaches we can come up with, but I'd prefer to make sure we don't exclude any such approaches on the basis that we're bound never to need anything that drastic.

#46 jaydfox

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Posted 03 March 2005 - 06:36 PM

I see I have touched a few nerves, and given your propensity for patience and cool replies, I can only assume that I'm losing points bigtime here in your eyes. I respect you, whether that's apparent or not, so I realize I've put myself out on a line here, and regardless of my lack of a biology background, I am expected to hold to a higher standard in this debate in regards to doing my proper background research.

That said, I still think it's wrong to push WILT as the cure, when it really is the backup plan. If it requires massive research effort to develop in time, for just in case it's needed, I'm not against that, and I've stated such. But just because we need to be working on it as soon as possible, that doesn't mean that it needs to be the primary solution. It's just an expensive, technically challenging, time- and research-intensive backup plan. I have no problems starting on it as soon as possible. But let's admit that it's a backup plan.

I agree that cancer is scary, but evolution shows us a cause for hope. The most obvious is how far cancer defenses have come.

The systemic toxicity of mtDNA damage is a function of the specific rate of mtDNA damage accumulation. Thus, incremental gains in mtDNA integrity are sufficient for incremental gains in MLSP

The systemic toxicity of nuDNA damage, with respect to senescence and dysfunction, is a function of the specific rate of nuDNA damage accumulation. Thus, incremental gains will lead to incremental gains.

But the systemic toxicity of cancer is a funciton of the total rate of nuDNA damage accumulation. If a human weighs about 10,000 times more than a mouse (within half an order of magnitude), and if a human lives 15 times longer than a mouse, then the specific rate of nuDNA damage accumulation must be 150,000 times slower than in mice.

But it's not 150,000 times slower. I realize it's not quite that simple, because what we're really looking for is a specific nuDNA damage rate sufficiently slow that 10,000 mice could survive an average of 85 years without developing cancer, and the doubling time means that a nonlinear formula must be used. But still, DNA integrity should be much much much greater than 15 times better in humans than in mice. At the least, log2(10,000) * 15 times better, or about 200 times better, and probably much better than that.

In fact, as Barja points out, it's not even 15 times better, if I understand Michael Rae correctly (I've read both Barja's papers that MR cited, but the data apparently is not in those papers, but in studies cited from those papers, and I am in the process of tracking those studies down). So clearly, cancer defenses are already extremely sophisticated. The only reason they aren't more sophisticated is the lack of a selective pressure, because humans don't already live 150 years. The fact that DNA damage rates don't correlate negatively with MLSP isn't a sign that fixing DNA damage is hard, because clearly a lot of evolutionary pressure has gone into extending lifespan. The more likely reason is that there is a strong selective pressure to maintain a minimum specific rate of DNA damage: one such selective pressure is the pressure to maintain evolvability, which clearly has benefitted humans in the recent millions of years. Maintaining evolvability while selecting for longer lifespans has given us the seemingly paradoxical state of high DNA damage and high cancer resistance (and, coincidentally, the disconnect between nuDNA damage rates and cancer incidence rates implies that senescence and dysfunction resistance may not have gotten a "free ride" after all).

We don't need that selective pressure to maintain genomic instability anymore, and we can engineer our way around it.

Dr. de Grey wants to keep WILT as the entire WILT superstructure. That's fine. I'm coining WILT proper for the total deletion of the ability to extend telomeres (telomerase and ALT). I'm coining the WILT scaffolding as all the peripheral technologies required to implement WILT proper and ensure that WILT proper doesn't kill us.

The WILT scaffolding is required to a large extent to make the DNA integrity route feasible:
* Effective, safe, and comprehensive somatic gene therapy.
* Effective, safe, and comprehensive stem cell reseeding.
* Tissue rejuvenation, including methylation resets.
* Chemoresistance genes into all affected tissues, to allow strong chemotherapy of residual untreated tissues that form cancers.
* Etc., etc.

With all these in place, will WILT proper be necessary? Time will only tell. I do not suggest that we stop pursuing WILT, because Prometheus and I may end up being wrong, and WILT will be necessary to effect escape velocity.

On the other hand, if WILT is not needed (i.e. if greatly enhanced systemic genomic integrity is possible without WILT, and cancer rates can be brought low enough to be treatable/curable indefintely, or until the technology of 50-75 years hence can do better than WILT), then we will be able to effect escape velocity without putting a 10-year (or even 20-year) expiration date on treated humans, thus avoiding all the societal implications that poses (from threats such as economic depression; inability to pay individual medical procedures; the tremendous financial and resource cost of innumerous frequent reseeding procedures; the Religious Right scenario as Elrond pointed out; societal chaos due to global war, political turmoil, pandemic, or terrorist activity; etc.; etc.; etc.; etc.).

Keep in mind, 80%-90% of the work in researching WILT will be researching the WILT scaffolding. The other 10%-20% for WILT proper is negligible, so it shouldn't be stopped on my account. But, with the WILT scaffolding being researched, we have a vehicle on which to attach serious efforts to increase DNA repair and effective tumor suppressive ablation. (Here the small intestine serves as a model for mitotic tissues, perhaps not as a primary model, but certainly as an example of effective local control of DNA integrity. Postmitotic tissues will necessarily warrant more research with either WILT proper or enhanced DNA integrity, as the most important postmitotic tissues are vital and irreplaceable.)

Such efforts would necessarily benefit from being run in tandem with WILT, because they both rely on the WILT scaffolding, and hence there would be no need for duplication of efforts. Such research only awaits a champion. It only makes sense for it to be championed by the one driving the outline of the WILT scaffolding, which in this case is the one driving the creation of WILT.

If nothing else, as a scientific program designed to get the gerontology community united, such a dual approach shows that you have the situation well under control and that there is no credible reason to believe that SENS cannot be effected, if they would come out and support it and help break the vicious cycle that causes the lack of funding that is holding SENS back.

As a public relations program, the public will be much less turned off by something that makes sense and won't include an expiration date, with WILT proper provided as an ultimate cure for cancer should it become necessary (backup plan).

#47 ag24

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Posted 03 March 2005 - 08:54 PM

> backup plan

That depends on how likely one thinks it is to be needed! When I need to get up promptly at the usual time that I get up, I set an alarm clock as a backup plan in case I'm not awake already by then. When I need to get up three hours earlier, I also set a clock, but I don't call that a backup plan, I call it a plan, because I think I'll quite probably sleep too late if I don't set it.

Your calculations are reasonable, and they show that we have developed more superior systems than mice to stop mutations developing into cancers as well as more superior systems to stop mutations happening in the first place. But you've drawn the opposite of the correct inference re improving DNA maintenance: if evolution has had to resort to post-mutation measures because it couldn't evolve human lifespans with only pre-mutation measures, that shows that improving our DNA maintenance (pre-mutation) machinery is even harder than we might otherwise have estimated. Also, this says nothing at all about the "free ride" business -- if you think it does, please spell out your logic. The evolutionary need for a basal rate of mutations in the genome is a reasonable idea, but even if it is true, as Kirkwood noted in 1977 the optimum mutation rate in the soma and in the germ line will indeed tend to be different but those rates can be regulated independently by (e.g.) having germ-line-specific repair genes (which are known, incidentally).

As for PR -- you are arguing for me to champion everything that might be worth doing. I think it's more effective for me to highlight those things that are (a) worth doing and (b) not being done, or not nearly energetically enough. It's not been my experience that the public are particularly turned off by WILT. Consider: the key to my message is that SENS is a plan that is potentially comprehensive. Whether or not it's the *best* comprehensive plan is secondary, PR-wise: what matters is that it's *a* comprehensive plan. Thus, adding more bits to it when it's already comprehensive is a retrograde step, because SENS's complexity, while in a scientific sense being its strength (it's detailed), is in a PR sense its main weakness.

#48 jaydfox

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Posted 03 March 2005 - 09:32 PM

But you've drawn the opposite of the correct inference re improving DNA maintenance: if evolution has had to resort to post-mutation measures because it couldn't evolve human lifespans with only pre-mutation measures, that shows that improving our DNA maintenance (pre-mutation) machinery is even harder than we might otherwise have estimated.

Quite the contrary. I believe it is proof of Prometheus's theory that mutation rates are kept high by design, to facilitate evolvability. Given our recent rapid evolution, would this have been possible if our DNA repair mechanisms were 200 times better than those in mice?

While you see an intractible problem, I see design. I see a selective pressure against increased DNA integrity, a pressure we are now free to ignore as biological engineers.

The evolutionary need for a basal rate of mutations in the genome is a reasonable idea, but even if it is true, as Kirkwood noted in 1977 the optimum mutation rate in the soma and in the germ line will indeed tend to be different but those rates can be regulated independently by (e.g.) having germ-line-specific repair genes (which are known, incidentally).

Nonetheless, recent evidence (1) shows a flurry of mutation in our recent evolution, a flurry which would not have been possible without programmed mutation. If humans had had increased DNA repair of the sort that we advocate, this evolution would not have been possible.

Thus, our apparent lack of increased genomic stability compared to mice is beneficial, and selected for. We already know of a disconnect in somatic and germline mutation rates, but given the relative quiescence of germline cells, this is hardly unexpected. Modulating the base efficacy of DNA repair/maintenance factors is the easiest route, and if extrinsic mortality sufficiently exceeds intrinsic mortality (i.e. somatic mutations, e.g. cancer), then this seemingly paradoxical approach would suffice.

Anti-cancer sophistication is more likely the result of an inability to deal with extreme statistical outliers, and of the simplicity of the reliability theory, than of an inability to upregulate/improve DNA repair in general. If we can increase DNA repair, then the worst case scenario of this observation is that we'll obviate all phenotypes of aging except cancer, which we should at least be able to reduce significantly (the extreme outliers). In the end, cancer may still be a big problem, but the scale of that problem is clearly amenable (by up to an order of magnitude) to engineering. If the scale can be made sufficiently small, "traditional" cancer therapies of the mid-future (20-40 years hence) will suffice.

All of which is why WILT remains my backup option. The need for WILT proper is a self-fulfilling prophecy, as I see it. If we focus too much on the backup option, we only assure its necessity.

And I see your point about the alarm clock analogy. I hope you're wrong. If you're right, then I suppose I'll be glad that you championed such a draconian measure. But from where I stand, I think it's too early to assume you're right (or that I am), and hence the need for the dual approach.


(1) Evidence for Widespread Degradation of Gene Control Regions in Hominid Genomes
Peter D. Keightley , Martin J. Lercher , Adam Eyre-Walker
PloS Biology, Volume 3 | Issue 2 | February 2005
DOI: 10.1371/journal.pbio.0030042

#49 ag24

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Posted 03 March 2005 - 11:36 PM

You don't seem to have addressed my point that somatic and germ-line mutation rates can be modulated independently of each other.  Maybe we have indeed needed (as a species) a certain mutation rate in the germ line -- but that doesn't impose a lower bound on our somatic mutation rate.

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Posted 04 March 2005 - 03:18 AM

You don't seem to have addressed my point that somatic and germ-line mutation rates can be modulated independently of each other.  Maybe we have indeed needed (as a species) a certain mutation rate in the germ line -- but that doesn't impose a lower bound on our somatic mutation rate.


They can appear to be modulated independently of each other, on the surface at least. The extent of that independence, however, determines whether this singular observation is sufficient to repudiate the evolution/genome stability/aging (EGA) theory.

Lets consider Kirkwoods premise that process efficiency is the prime imperative of informational maintenance in biological systems. It would then be likely that the necessary similarity between the genomic stability activities of germ cells and somatic cells are so interwoven, that there is an inherent limitation of variance possible between the two. If we look at the differences in the mechanisms that maintain genomic stability between germ and somatic cells we find, that with a few exceptions, that they are not remarkably different. Due to the Kirkwood process economies, these activities are likely more dependent than independent. Evidence from progeroid syndromes where DNA repair is impaired suggests that such deficiencies affect stem and germ line cells in a different but proportional manner.

Thus if somatic and germ-line mutation rates are in some way coupled then it would justify the need for a somatic mutation rate ceiling and would explain the biological inevitability of senescence and death as part and parcel of the mechanism of evolution. More importantly relevant to the topic at hand, however, it could underline the prime mechanism of aging and thereby indicate where lines of investigation must converge.

#51 kevin

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Posted 04 March 2005 - 05:32 AM

Quite the contrary. I believe it is proof of Prometheus's theory that mutation rates are kept high by design, to facilitate evolvability. Given our recent rapid evolution, would this have been possible if our DNA repair mechanisms were 200 times better than those in mice?


Pardon me for interjecting into this most excellent discussion but I thought I would make a quick point regarding the above.

It is not certain whether DNA damage has had anything to do with the rapid evolution of humans. DNA sequence changes due to transposable elements, such as the Alu sequence which is thought may be involved in the evolution of intelligence in the great apes, are not mutations in the way we normally think of them. Although I think DNA damage and random mutation is good for building a basic set of biological elements, for higher organisms mutational mechanisms which can alter regulatory relationships are more important. In fact transposable elements may play a more important role in building biological complexity as they can be used to make predictable changes in sequence. A good example of this is the use of transposable elements in embryogenesis in mice recently reported where they insert themselves and act as alternative promoters at a specific time in the development of the embryo and effectively alter gene expression on demand. It would seem that if evolution is attempting to facilitate evolvability, it has developed a more sophisticated approach with "jumping genes" than we might have previously appreciated.

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Posted 04 March 2005 - 07:24 AM

It is not certain whether DNA damage has had anything to do with the rapid evolution of humans. DNA sequence changes due to transposable elements, such as the Alu sequence which is thought may be involved in the evolution of intelligence in the great apes, are not mutations in the way we normally think of them. Although I think DNA damage and random mutation is good for building a basic set of biological elements, for higher organisms mutational mechanisms which can alter regulatory relationships are more important. In fact transposable elements may play a more important role in building biological complexity as they can be used to make predictable changes in sequence. A good example of this is the use of transposable elements in embryogenesis in mice recently reported where they insert themselves and act as alternative promoters at a specific time in the development of the embryo and effectively alter gene expression on demand. It would seem that if evolution is attempting to facilitate evolvability, it has developed a more sophisticated approach with "jumping genes" than we might have previously appreciated.


This is a good point. Alu element retrotransposition can occur in somatic or germline cells resulting in all sorts of transcriptional mischief, but even so, they only account for 0.1% of all human genetic disorders (1). It is certainly true that transposons are part of the evolutionary picture - a picture that also includes point mutations and small insertions and deletions that cause frameshifts. From a genome stability perspective, however, the greatest rates of mutation are observed when DNA repair pathways are compromised (2). Mice and rats have poorer DNA repair enzymes than humans (3) and this has been correlated in their respective rates of evolution (4) and has been suggested to be associated with lifespan by Jay and myself. This variability in repair is also reflected in the cell where we see that the mitochondrial DNA polymerase-gamma has a higher error rate than the other DNA polymerases (5).

It is a tad of an overreach to question the importance of DNA mutation in human evolution, irrespective of the interesting role of Alu repeats. Alu repeats and other transposons, however, present an important mutator for which neither the SENS or neoSENS hypotheses account for.



(1) Nature Reviews Genetics May Vol 3 p370-381 (2002)
ALU REPEATS AND HUMAN GENOMIC DIVERSITY
Mark A.Batzer and Prescott L.Deininger

(2) Nature387, 703–705 (1997)
Evolution of high mutation rates in experimental populations of E. coli.
Gerrish, P. J. & Lenski, R. E.

(3) Proc Natl Acad. Sci. USA71, 2169–2173 (1974)
Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammal species.
Hart, R. W. & Setlow, R. B.

(4) Mol. Phylogenet. Evol.5, 182–187 (1996)
Rates of nucleotide substitution in primates and rodents and the generation-time effect hypothesis.
Li, W.-H., Ellesworth, D. L., Krushkal, J., Chang, B. H.-J. & Hewett-Emmett, D.

(5) Annual Review of Biochemistry Vol. 73: 293-320 (2004)
DNA POLYMERASE , THE MITOCHONDRIAL REPLICASE 1
Laurie S. Kaguni

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#53

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Posted 04 March 2005 - 10:18 AM

Keep in mind, 80%-90% of the work in researching WILT will be researching the WILT scaffolding. The other 10%-20% for WILT proper is negligible, so it shouldn't be stopped on my account.


Not to mention overcoming the supreme obstacle that all of these hypothetical interventions rely on to be tenable : gene therapy that can treat the hundred trillion cells in a human being. For WILT to work, not even a handful of cells can escape treatment lest they become carcinogenic. So, aside from the stem cell re-population targeting problem we must solve the gene therapy problem.

Eventually they will be solved - in 10, 20 or 50 years. For the present or near present the neoSENS alternative is as follows:

The facilitation of expression of genetic material encoding a molecule or molecules that induces the death of the target cell. In particular, this method will conditionally facilitate the expression of genetic material exclusively in cancer cells in order to induce the death of such cells. This conditional expression can be mediated by tumor specific promoters (1), or it can be be made more specific by the use of mRNA (2) such that expression only takes place under extremely stringent conditions.

The main problems with your conclusion that improving DNA repair is the priority are:

- you think non-cancer damage matters in a normal lifetiime
- you think DNA repair can feasibly be improved without serious side-effects
- you think nearly all cancers will be cured by means less drastic than WILT quite soon anyway

I think you're wrong on all three counts, but most especially you're wrong on the last.


Especially on the last there is a concrete alternative for, as per the above methodology.

What is particularly contrasting about this methodology over the WILT restriction of literally "whole body" interdiction (ie needing every cell to be telomerase negative) is that it can continue to be repeated as required because even if it does not destroy all cancer cells it would sufficiently reduce their mass so that tumors become substantially less pathological, if at all. As importantly, this is a strategy that directly attacks cancer cells exclusively rather than any cell that expresses telomerase. When treated in parallel with a DNA repair enhancement strategy would eventually result in genetically unstable and cancer type cells to be diluted out. Finally, this proposed cancer treatment has already been proven to work from a tumor induced promoter perspective (1) and thus most of the technology has been worked out.

I will, of course, address the first two shortly.



(1) Gene Ther. 2003 Aug;10(17):1519-27
Directed apoptosis in Cox-2-overexpressing cancer cells through expression-targeted gene delivery.
Godbey WT, Atala A.

(2) Nature. 2004 May 27;429(6990):423-9. Epub 2004 Apr 28.
An autonomous molecular computer for logical control of gene expression.
Benenson Y, Gil B, Ben-Dor U, Adar R, Shapiro E. (attached)

Attached Files



#54 ag24

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Posted 04 March 2005 - 11:44 AM

> For WILT to work, not even a handful of cells can escape treatment lest they become carcinogenic.

Wrong. If we hit 99% of the cells, we neutralise 99% of the cancer potential.

> The facilitation of expression of genetic material encoding a molecule or molecules that induces the death of the target cell.

Fine idea, being extensively worked on (as you note, and as I noted long ago in this forum), and thus not in any need of promotion by some "strange beardy bloke" (google that). Also, in my view no more likely to work as well as we need than immunotherapy (which is also based on differences in gene expression between the cancer cell and other cells), as I have likewise explained long ago in this forum. Fundamentally Prometheus, your error is that you have insufficient respect for the ingenuity of evolution.

#55 ag24

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Posted 04 March 2005 - 11:46 AM

A word on the maximal degree of uncoupling of somatic and germline mutation rates. In principle there probably is such a degree, but the observed rates are in the other order (just as Kirkwood predicted) -- somatic rates are higher. Tell me a way in which there could be a lower bound on somatic mutation rates dictated by a much lower lower bound on germline ones and I'll buy you a beer in September.

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Posted 04 March 2005 - 01:29 PM

> For WILT to work, not even a handful of cells can escape treatment lest they become carcinogenic.

Wrong. If we hit 99% of the cells, we neutralise 99% of the cancer potential.


That's semantics, but it is one way of looking at it.

A word on the maximal degree of uncoupling of somatic and germline mutation rates. In principle there probably is such a degree, but the observed rates are in the other order (just as Kirkwood predicted) -- somatic rates are higher. Tell me a way in which there could be a lower bound on somatic mutation rates dictated by a much lower lower bound on germline ones and I'll buy you a beer in September.


Did I ever suggest that somatic rates weren't higher? Of course they're going to always be higher than germ-line cells - you're just trying to weasel out of buying me a beer. ;) But I note that whilst I suggested they may be coupled and that there would be variance between them, I did not clarify that somatic mutation rates must invariably be higher - proportionally. I would, however, appreciate if you could unleash on the EGA theory - what other weaknesses are apparent?

Now since we're on the topic of beers, do you recall the study on post-mortem human brains (1), gene expression and nuclear DNA damage? As an aside this is one of my favorite papers and I encourage everyone who reads the SENS forums to take their time reading it, because the implications are very sobering. I believe I've brought it to your attention before. In any case, what they saw was that lots of nuclear genes were damaged and had altered expression - not cancer type genes - but genes important to neural function. And all this was well under way in subjects that were 40 years old.

So when you say,

- you think non-cancer damage matters in a normal lifetiime



I wonder how you rationalize the results of such studies. (Explain how the above study does not support the theory that nuclear DNA damage is responsible for far more than cancer and I'll buy you dinner) ;)


(1) Nature. 2004 Jun 24;429(6994):883-91.
Gene regulation and DNA damage in the ageing human brain.
Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. (Attached)

Attached Files



#57

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Posted 04 March 2005 - 02:44 PM

"strange beardy bloke" (google that)


surely you don't mean...

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#58 ag24

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Posted 04 March 2005 - 08:35 PM

> Did I ever suggest that somatic rates weren't higher?

Yes -- you were proposing that the lower bound on germline mutation rate (which is hypothetical, but I'll accept for sake of argument that there is one) enforces a lower bound on the somatic mutation rate because "there is an inherent limitation of variance possible between the two". Since somatic rate is higher than germline rate, however, that variance (disparity, to be more precise) will be **reduced** if somatic rate falls.

> I wonder how you rationalize the results of [Nature 429:883].
> (Explain how the above study does not support the theory that nuclear
> DNA damage is responsible for far more than cancer and I'll buy you
> dinner)

I look forward to it. What was shown in that study was that some genes are more sensitive to oxidative damage (to their promoters) than others both in vitro and in vivo: specifically, to oxidation of guanine bases forming 8-oxodG and to unspecified changes altering expression patterns. Since no mutation accumulation was shown, this says nothing about nuDNA damage being a primary component of aging. There is no evidence here that the steady-state level of these lesions is not simply a readout of the oxidation state of the DNA's environment -- the nucleoplasm and the more distant environment (cytoplasm, CSF, circulation). If that's all it is, these levels and the consequent gene expression patterns will automatically revert to youthful levels when the systemic and hence cellular redox state is restored to youthful levels by fixing the things that are causing the oxidation, e.g. mutant mitochondria, arterial junk.

#59 jaydfox

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Posted 04 March 2005 - 09:58 PM

> Did I ever suggest that somatic rates weren't higher?

Yes -- you were proposing that the lower bound on germline mutation rate (which is hypothetical, but I'll accept for sake of argument that there is one) enforces a lower bound on the somatic mutation rate because "there is an inherent limitation of variance possible between the two". Since somatic rate is higher than germline rate, however, that variance (disparity, to be more precise) will be **reduced** if somatic rate falls.

If the somatic rate is 20 times higher than the germline rate, and the germline rate is pushed down by a factor of two, then the somatic rate would also be pushed down by a factor of two. But the 20-fold difference between the two rates remains. Isn't that what Prometheus said?

Perhaps pushing the germline rate down by a factor of 2 pushes the somatic rate down by a factor of 1.9, or 2.1. There is wiggle room, and clearly the disparity between the two will depend not only on the DNA repair factors involved, but the relative damage load between quiescent germline cells and metabolically active somatic cells.

There's the (unrepaired) damage load D, which is clearly higher in somatic cells, and there's the repair rate (as a very high percentage, roughly speaking) R, and there's the net damage rate, which is the low rate of nonrepair (1-R) times the damage load. That low rate of non-repair is what's predicted to be tied together between germline and somatic cells, and the damage load just obfuscates the data.

Dg * (1-Rg) = net damage rate in germline cells
Ds * (1-Rs) = net damage rate in somatic cells

Dg << Ds, but we're positing that (1-Rg) ~ (1-Rs), within some factor (the variance, or disparity, as you two respectively call that factor). If (1-Rg) > (1-Rs) [i.e., unrepaired germline damage is favored because of Prometheus's theory], then you can still end up with the multipled factors showing higher net somatic damage.

Dg << Ds
(1-Rg) > (1-Rs)
Dg * (1-Rg) < Ds * (1-Rs)

I suppose that didn't make any sense, but I don't have time to pretty it up.

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#60 ag24

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Posted 04 March 2005 - 10:41 PM

> Isn't that what Prometheus said?

No -- though it may have been what he meant. But the point is that there isn't the faintest chance that the two things could be tied together so tightly. As I said, evolution thinks nothing of having whole genes that are germline-specific DNA repair genes. The whole of gametogenesis is an entire system that can evolve its own DNA repair or lack of it, or selection away of damage, etc, completely independently of the rest of the body. There is no way that the constraint you're proposing is one that evolution would have a problem escaping. I have no idea why this isn't obvious, even to non-biologists.




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