All:
First: Prometheus, I got a mess of pseudo-html when I tried to respond to your post using the "Quote" function. I run into this sometimes on Imminst forums. Did you originally respond using the "Quote" function, or some alternative posting mechanism?
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The rate of aging in mammals is, on good interspecies evidence (5,7), related to the rate of accumulation of mt, but not nuclear, DNA damage and esp deletions.[/quote]
Good God! How on earth do you make such an authoritative sounding statement like that?[/quote]
Because that's what the evidence shows
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Lets look at your references. [In (5),] Barja's main contention in this paper is that the rate of mtDNA damage is higher that nDNA damage ... No one disagrees with the premise that mtDNA has more oxidative damage than nDNA.
However, where is the connection made that mtDNA damage is the limiting factor in maximum lifespan, in contrast to nDNA?[/quote]
From the fact that "long-lived animals show lower levels of oxidative damage in their mitochondrial DNA (mtDNA) than short-lived ones, whereas this does not occur in nuclear DNA (nDNA)." (5) This means longevous species, not individual organisms, and is measured in terms of max LS. Likewise, "the rates of mitochondrial oxygen radical generation [and] oxidative damage to mitochondrial DNA" "are negatively correlated with maximum longevity." (7) This originally goes back to a series of comparative studies, most notably (10):
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If oxidative damage to DNA is involved in aging, long-lived animals (which age slowly) should show lower levels of markers of this kind of damage than short-lived ones. ... In this study, steady-state levels of ... (8-oxodG) referred to deoxyguanosine (dG) were measured ... in the mitochondrial (mtDNA) and nuclear (nDNA) DNA from the heart of eight and the brain of six mammalian species ranging in maximum life span (MLSP) from 3.5 to 46 years. ...
8-oxodG/dG in nDNA did not correlate with MLSP across species either in the heart (r=-0.68; P<0.06) or brain (r = 0.53; P<0.27).
However, 8-oxodG/dG in mtDNA was inversely correlated with MLSP both in heart (r=-0.92; P<0.001) and brain (r=-0.88; P<0.016) tissues following the power function y = a(.)x(b), where y is 8-oxodG/dG and x is the MLSP.[/quote]
... and (11) also finds a more consistent relationship of mtDNA than nuDNA damage to maximum LS, somewhat more weakly because based on comparisons across 2 different orders of vertebrates who already show unexpected differences in rate of mtROS generation based on body size and metabolic rate, rather than within one order as in (10):
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Lower steady-state 8-oxodG values were observed in all cases in the heart mtDNA in birds than in mammals. 8-oxodG levels were also lower in brain mtDNA in pigeons than in rats, in brain nDNA in canaries than in mice, and in heart nDNA in parakeets compared with mice. The rest of the comparisons did not show significant differences between species. These results taken together indicate that oxidative damage to DNA tends to be lower in birds (highly long-lived species) than in short-lived mammals, especially in the case of mtDNA.[/quote]
The fact that CR does not lower mtDNA deletions brain (12,13), unlike in mucle, heart, and liver, may also be important to interpreting this finding.
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Barja does not dare make this assertion directly since there is no evidence to support it, instead he hints that maximum lifespan (MSLP) is negatively correlated in heart and brains with 8-oxodG formation in mtDNA but not in nDNA.[/quote]
But that is exactly evidence that "The rate of aging in mammals is, on good interspecies evidence (5,7), related to the rate of accumulation of mt, but not nuclear, DNA damage", as I'd said.
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On the other hand Barja contradicts his claim by reporting on the findings that increased 8-oxodG levels are equally present in aging organs:
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the majority of the investigations have shown that tissue 8-oxodG levels in brain, heart or liver nDNA or mtDNA are moderately higher in old than in mature adult rodents or humans[/quote][/quote]
Note that this isn't actually a contradiction. 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). Barja and others have shown that this is true of oxidative mtDNA and not of nuDNA.
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And one more thing, you may be interested to know that your mentor is not fond of 8-oxodG as an indicator of DNA damage:
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One of the most pervasive errors in DNA analysis is to presume that rises in the amount of a pre-mutagenic lesion translate to proportional rises in that of bona fide mutations: in fact the relationship is nowhere near that, because the chance of a given 8oxodG becoming a mutation depends on its halflife, i.e. how long on average before it is repaired.[/quote][/quote]
Aubrey is not saying that 8-OHdG is not an indicator of
any damage to DNA, but hat it is not a reliable proxy of actual
mutations. 8-OHdG is not an accumulating lesion but a steady-state damage snap shot, and in fact it
directly measures the rate of
repair of oxidative DNA lesions rather than their rate of
formation. But you have to swallow the whole pill. It's fortunate that the evidence from the CR model avaialable, as it has drawn the link to actual damage
accumulation in the form of mtDNA
deletions (5-9, 12, 13). Likewise, the fact that 8-OHdG is more readily repaired in nuDNA than mtDNA further strengthens the non-relevance of the former in aging (although, of course, it causes cancer).
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:
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Many recent experiments, especially large-scale microarray transcript profiles of aging, support this general concept of time-dependent decay of orderliness (for examples, see references [21, 22, and 23]).[/quote]
However, such changes are in fact almost certainly addressed by the SENS platform because there is a very strong case to be made that such shifts in gene expression with age are secondary to other changes whcih are themselves subject to the SENS panel of interventions.
That is: such shifts are either the result of an "aging program," or they are secondary to some primary, and fundamentally entropic, aging process. Since the former is rejected on theoretical grounds by the consensus of researchers into the role of evolutionary pressure into aging (8), the latter must hold. And indeed, the most useful investigations into such shifts -- those in which shifts in gene expression associated with normal aging are compared with those undergone in animals subjected to calorie restriction (CR) (29), which (as Estep well knows) is the sole intervention known to retard biological aging in mammals. These studies have found that the most prominent classes of genes undergoing shifts which both occur with aging are retarded by CR (and which are thus most likely related, as cause or as effect, to primary aging processes) are those involved in inflammation and antioxidant defense -- gene classes, that is, whose natures imply precisely that their expression has been altered in response to underlying, [primary] molecular lesion(s). [Compare the parallel findings in humans (30)]. But all such entropic processes appear to be embraced by the SENS platform (24,25); therefore, the redressing of such processes via the SENS panel of interventions is predicted to obviate the secondary shifts in gene expression associated with aging.[/quote]
By contrast, of course, cells with
cancerous lesions by their very nature quickly multiply to pathological levels.
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. Of course, WILT will itself deal with much of this by replacing and/or supplementing such cells periodically wth pristine stem cells.
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Perhaps Michael, you can enlighten us as to why you think oocyte mitochondria appear to be so comparatively robust - potentially biologically immortal, in fact.[/quote]
Careful.
Individual oocyte mt are not necessarily terribly robust, nor are oocytes themselves. The immortality and agelessness of the germ line has been rather misrepresented. One of the main reasons that the germ line is retained intact is that the body is so much more rigorous in apoptosing (neologism!) defective cells in the line -- not that the cells themselves are individually retained pristine. The body selects for healthy ova using atresia, keeping ova quiescent until ovulation, and even more rigorous selection of teh fittest during oogenesis. Also, defective mitochondria in the germ line (I seem to recall -- but perhaps others can provide either documentation or correction) are more likely to lead to flat-out cell death than the same phenomenon in somatic cells.
Result: a woman is born with 1-2 million ovarian follicles; by puberty she has only 300,000 & despite the fact that ovulation per se only leads to the "wastage" of 1 (or a few) eggs per month, only a few hundred remain at menopause.
Really, then, the germline is only immortal/ageless in the sense that the species is: individuals die, but the line passes forward, from generation unto generation.
I now see that Aubrey has
elsewhere given reasons why mt in oocytes also have less damage -- but again, not because the mt are actually, individually more robust:
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It's complicated. (a) When the germ line is rapidly dividing (in early embryogenesis) there may be selection against mutant mitochondria (see below). (b) When it's not dividing (in the oocyte during the mother's life until fertilisation) the host cell has very low energy requirements so is respiring very little, so is producing few mutagenic free radicals. © The mitochondria that get into the oocyte are apparently put through a population bottleneck, which means that if any mutant mitochondria get into a given oocyte then it is virtually guaranteed that lots will; this is good because it will cause that oocyte to fail to ovulate (or to abort very early in embryogenesis) whereas a small number of mutants may not kill the offspring until much later. Kearns-Sayre syndrome is likely to be a case of this last trick not working.[/quote]
Whatever you think about the value of keeping up your germ line, let's fix the problem in individual humans, people! Give till it hurts to
the Methuselah Mouse Prize, and
take political action for anti-aging biomedicine.
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I will read your references before responding, to avoid wasting any more time.
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Except (2), which is $115 web-price, list-price $139. I apologize, as that ref might address the crux of the matter.[/quote]
If you actually want to own a hard copy, you can get it used for ~US$86:
http://www.bookfinde...64X&mode=directAlternatively, it appears that the entire volume is available online from Eurekah:
http://www.eurekah.c...kid=44&catid=42For US$39, you can get access to their entire online library, including this, for a year.
As well, I'm sure you can get it for free or for a few dollars via interlibrary loans.
de Grey's book is unbelievably useful: in addition to explaining his MiFRA in greater detail than is available elsewhere, it provides an extremely readable introduction to mitochondria generally. I highly reccomend it.
-Michael
4. de Grey AD.
Mitochondria in homeotherm aging: will detailed mechanisms consistent with the evidence now receive attention?
Aging Cell. 2004 Apr;3(2):77. No abstract available.
PMID: 15038822 [PubMed - indexed for MEDLINE]
5. Barja G.
Endogenous oxidative stress: relationship to aging, longevity and caloric restriction.
Ageing Res Rev. 2002 Jun;1(3):397-411. Review.
PMID: 12067594 [PubMed - indexed for MEDLINE]
6. Lee CM, Aspnes LE, Chung SS, Weindruch R, Aiken JM.
Influences of caloric restriction on age-associated skeletal muscle fiber characteristics and mitochondrial changes in rats and mice.
Ann N Y Acad Sci. 1998 Nov 20;854:182-91. Review.
PMID: 9928429 [PubMed - indexed for MEDLINE]
7. Barja G.
Rate of generation of oxidative stress-related damage and animal longevity.
Free Radic Biol Med. 2002 Nov 1;33(9):1167-72. Review.
PMID: 12398924 [PubMed - indexed for MEDLINE]
9. 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]
10. Barja G, Herrero A.
Oxidative damage to mitochondrial DNA is inversely related to maximum life span
in the heart and brain of mammals.
FASEB J. 2000 Feb;14(2):312-8.
PMID: 10657987 [PubMed - indexed for MEDLINE]
11. Herrero A, Barja G.
8-oxo-deoxyguanosine levels in heart and brain mitochondrial and nuclear DNA of
two mammals and three birds in relation to their different rates of aging.
Aging (Milano). 1999 Oct;11(5):294-300.
PMID: 10631878 [PubMed - indexed for MEDLINE]
12: Kang CM, Kristal BS, Yu BP.
Age-related mitochondrial DNA deletions: effect of dietary restriction.
Free Radic Biol Med. 1998 Jan 1;24(1):148-54.
PMID: 9436624 [PubMed - indexed for MEDLINE]
13: Cassano P, Lezza AM, Leeuwenburgh C, Cantatore P, Gadaleta MN.
Measurement of the 4,834-bp mitochondrial DNA deletion level in aging rat liver and brain subjected or not to caloric restriction diet.
Ann N Y Acad Sci. 2004 Jun;1019:269-73. Review.
PMID: 15247027 [PubMed - indexed for MEDLINE]
21. Ly DH, Lockhart DJ, Lerner RA, Schultz PG. Mitotic misregulation and human aging. Science. 2000 Mar 31;287(5462):2486-92.
22. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, Brown PO. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1896-901. Epub 2003 Feb 10.
23. Welle S, Brooks AI, Delehanty JM, Needler N, Thornton CA. Gene expression profile of aging in human muscle. Physiol Genomics. 2003 Jul 07;14(2):149-59.
>
24: De Grey AD.
Challenging but essential targets for genuine anti-ageing drugs.
Expert Opin Ther Targets. 2003 Feb;7(1):1-5.
PMID: 12556198 [PubMed - in process]
15: 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]
29. Weindruch R, Kayo T, Lee CK, Prolla TA.
Gene expression profiling of aging using DNA microarrays.
Mech Ageing Dev. 2002 Jan;123(2-3):177-93.
PMID: 11718811 [PubMed - indexed for MEDLINE]
30. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA.
Gene regulation and DNA damage in the ageing human brain.
Nature. 2004 Jun 24;429(6994):883-91. Epub 2004 Jun 09.
PMID: 15190254 [PubMed - indexed for MEDLINE]v