All:
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 (as eg by augmenting, interfering with, or neutralizing the toxic results of normal metabolism and short-lived molecules -- the "gerontologist's approach) or to attempt to prevent this damage from leading to pathology and death (the "geriatrician's approach") (21, 22).
Attempts to increase DNA repair/maintenance, whatever one may think of their likelihood of success as anti-aging interventions, are instances of the preventive/"Gerontologist" school, not the SENS "engineer's" approach (tho' of course implementing them would doubtless entail some molecular or biotechnological "engineering"), so "neoSENS"
as a term for such approaches introduces confusion in the debate.
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]
A case for nuclear DNA damage in aging ...
Comparing nDNA damage to mtDNA damage
The relative amount of DNA damage in mitochondria as compared to the nucleus (some studies report as much as 100 fold) is often cited as evidence to support the limited impact that nuclear DNA damage would presumably have on cell dysfunction other than cancer.[/quote]
As I've
pointed out a couple of times now in response to this misunderstanding of the argument:
[quote]
To observe the
fact that some kind of damage increases, and even accumulates, with age is distinct from showing that the
rate at which this happens it is related to the
rate of aging. To show the latter, we need evidence either from intervention (interventions that
reduce a particular kind of damage with age increase max LS, and interventions that do not do the former do not do the latter) or from interspecies comparisons (more longevous spp suffer
less of this damage with age than more short-lived ones). [CR demonstrates the former;] Barja and others have shown [the latter to be] true of oxidative mtDNA and not of nuDNA [damage].[/quote]
Again,
[quote]
[quote]
Let's go back to the evidence you are presenting:
- 8-oxodG amount is higher in mtDNA than in nDNA
If this is all then it is hardly evidence to support your hypothesis.[/quote]
I agree. I already emphasized that the simple fact of higher mtDNA than nuDNA damage was not the issue. The contention that mt, but not nuclear, DNA damage is causally related to aging lies, as I indicated, in the interspecies and CR data relating the former, but not the latter, to species maximum lifespan [etc -- see original post].[/quote]
[quote]
Direct Evidence: nDNA damage increases with aging.[/quote]
Not disputed, but also not evidential, as indicated above.
[quote]
Indirect Evidence: Some consequences of DNA damage...[/quote]
Sure. As I
said previously,
[quote]
[quote]
On this front, it should be noted that while
individual cells and their progeny certainly can be expected to become dysfunctional when their nuDNA aquire mutations, the low rate of cell division in vivo in most tissues -- and the virtual nonexistance of same in postmitotic tissues like heart and brain -- means that individual cell's mutations get little chance to "take over" the tissue and render the whole dysfunctional. As I suggested in reply to Estep, age-related changes in nuclear gene
expression appear to be most clearly secondary to other, primary lesions: [etc][/quote]
[quote]
You're saying that it is possible for cell nDNA to acquire mutations that result in dysfunction but that it is so rare an event and unlikely have any effect on the overall tissue physiology because of the low mitotic potential of the cell with damage?[/quote]
Yes.[/quote]
See previously-cited comments by de Grey in the same thread on Jan Vijg's data on nuclear mutation accumulation with aging.
[quote]
Some ways that nDNA damage can drive aging
... We know that providing double strand breaks do not occur a cell can survive a great deal of damage to its DNA (8)... Ultimately, however, the accumulation of such events would result in increasing inefficiencies. ...[/quote]
See above; also, in this
already linked post,
[quote]
[quote]
It seems obvious to me (and I expect that Aubrey agrees) that it is likely that nuDNA mutations would eventually become pathological if not repaired over the course of a greatly extended LS, as eventually all cells would have accumulated a great many true mutations; however, evidence to hand indicates that they are not accumulating at high enough levels over the course of a "normal" lifespan to significantly contribute to aging per se.[/quote]
[quote]
So finally the point of contention is when and not if nDNA damage is going to lead to altered cell function.[/quote]
Not quite: the point of contention is
when and not
if non-cancer nDNA
mutations are going to lead to
meaningful increases in pathology and to
contributing to aging per se (as opposed to cancer) in a way that is not obviable by the existing SENS interventions. Aubrey has never claimed that the "Seven Deadlies" include all of the lesions that would ever become pathological in a greatly-extended lifespan -- just that they include all of the lesions that contribute to pathology in a
current, "normal" lifetime. After we correct these defects, other, more subtle forms of damage which are irrelevant to pathology within a current, normal lifetime will emerge, and require increasingly refined therapies to correct in order to further push back aging. Fortunately, as time goes on we will have increasingly powerful tools with which to identify and then obviate these newly-hazardous forms of damage or de-link them from pathology. See his "actuarial escape velocity" paper [ref], and also his chapter in the Immortality Institute's book [ref][cited material and Imminst forums quotes from de Grey -- see linked post][/quote]
[quote]
Indirect Evidence: The premature aging syndromes and mutants[/quote]
Even to refer to these disorders as "premature aging" is a petitio principii. Almost anything that messes up normal gene function but takes a while to kill one will look like "premature aging;" the question is what if any relationship they bear to
normal aging.
[quote]
"Until you show me that you can postpone aging, I don't know that you've done anything," sniffs Michael R. Rose, geneticist at the University of California. "A lot of people can kill things off sooner, by screwing around with various mechanisms, but to me that's like killing mice with hammers -- it doesn't show that hammers are related to aging."[/quote]
((15); see (16-20) for examples).
-Michael
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Evolution of ageing.
Kirkwood, TB
(2) Mech Ageing Dev 125:10-11, 755-65 (2004)
Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution.
Szczesny, B, Bhakat, KK, Mitra, S and Boldogh, I
(3) Mut Res 446 (1999) 215-223
Age-related increases of 8-hydroxy-2'-deoxyguanosine and DNA–protein crosslinks in mouse organs
Alberto Izzotti, Cristina Cartiglia, Maurizio Taningher, Silvio De Flora, Roumen Balansky
(4) Mut Res 237 (1990) 229-238
Steady-state levels of 7-methylguanine increase in nuclear DNA of postmitotic mouse tissues during aging
Boen H. Tan, F. Aladar Bencsath and James W. Gaubatz
(5) Academic Press
Aging, Sex & DNA Repair (1991)
Bernstein, C. and Benstein, H.
(6) Radiat Res. 2004 Dec;162(6):677-86.
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Dahm-Daphi J, Sass C, Alberti W.
(9) Carcinog Compr Surv. 1985;10:481-93.
In vitro models of mutagenesis.
Strauss BS, Larson K, Sagher D, Rabkin S, Shenkar R, Sahm J.
(10) DNA Repair (Amst). 2003 Jun 11;2(6):673-93.
Decline of nuclear and mitochondrial oxidative base excision repair activity in late passage human diploid fibroblasts.
Shen GP, Galick H, Inoue M, Wallace SS.
(11) J Radiat Res (Tokyo). 2003 Mar;44(1):31-5.
Age-associated decrease of oxidative repair enzymes, human 8-oxoguanine DNA glycosylases (hOgg1), in human aging.
Chen SK, Hsieh WA, Tsai MH, Chen CC, Hong AI, Wei YH, Chang WP.
(12) Free Radic Biol Med. 2005 Mar 15;38(6):737-745.
No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA.
Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VA.
(13) J Ster Biochem Mol Bio 88: 1 Jan 2004 61-67
Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells
Cao L , Leers-Sucheta S, Azhar S
15.
http://exn.ca/Storie...98/05/13/66.asp 16: Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. PMID: 15164064 [PubMed - indexed for MEDLINE]
17. Nature 1997 Nov 6;390(6655):45-51
Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Kuro-o M, Matsumura Y, Aizawa H, et al.
PMID: 9363890 [PubMed - indexed for MEDLINE]
18. Mol Cell Biol 2000 Jun;20(11):3772-80
Analysis of ku80-mutant mice and cells with deficient levels of p53.
Lim DS, Vogel H, Willerford DM, Sands AT, Platt KA, Hasty P.
PMID: 10805721
19. Takeda T.
[Senescence-accelerated mouse (SAM): with special reference to age-associated pathologies and their modulation]
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20: Baker DJ, Jeganathan KB, Cameron JD, et al.
BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice.
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21. 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.pdf22. 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