SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

2 November 2005

Ben Best

Reply to Aubrey

[Ben] And I disagree with you that the only significant effect of nDNA damage is cancer.

[Aubrey] Um, but the evidence you cite concerns changes with age that would predispose to all mutational events, i.e. including ones that would lead to cancer. Thus, they do not challenge my assertion that even though damage rates may accelerate with age their rate of accumulation is limited by the need to avoid dying young of cancer.

It seems to me that the ambitions of SENS are grandiose enough without including "cure cancer". As if there isn't enough money being spent that problem -- in comparison to money being spent to eliminate aging damage. If your ideas are sound, why not simply devote more more effort to persuading those who fund cancer research to eliminate telomerase? Yet you say that you would rate priority of SENS money in reverse order of acheivability of SENS, strategies, ie:

Priority: (7) > (6) > (5) > (2) > (4) > (3) > (1)

which makes the top priority of money going to SENS to cure cancer by eliminating telomerase (and using stem cells).

[Ben] I would appreciate citations or arguments to support your assertions. "Perfect" is your word -- I said "more efficient".

[Aubrey]But you also said "dispense with (6) & (7)" - that's what I meant would be true only if prevention of mtDNA and nDNA damage were perfect. Repair of mature mutations is impossible because they are chemically indistinguishable from normal sequences.

You provided no citations. No, neither of us are aiming at perfection. You do not include eliminating toxic metals, giving everyone apoE2 or improving DNA repair in SENS because you don't think that they would have a significant impact. You say that these problems can be addressed eventually, but that (1)−(7) are all of equal lethality and must be eliminated if we are to achieve "escape velocity" allowing us to live long enough to solve the less lethal problems.

I say that with improved DNA repair and reduced free radical production (by Complex I proteins taken from birds) the cancer rate would drop considerably and would not be crucial to achieving "escape velocity". This is not the same thing as perfection. And of at least equal importance is the effect improved DNA repair would have on the aging rate (or rejuvenation).

[Ben] You must believe that the oxidative stress in the mitochondria is an unsafe environment or you would not be wanting to make copies of mtDNA in the nucleus.

[Aubrey] No, that doesn't follow at all. The reason I want to copy the mtDNA in the nucleus is because mtDNA accumulates mutations much faster than nDNA does -- the mechanisms which drive that accumulation are irrelevant to that motivation.

The mechanisms are not irrelevant. You have already acknowledged my citations that DNA repair declines with age. If free radicals are the cause of mtDNA mutations & deletions, and if the superior DNA repair capabilities of the nucleus declines with age, then the purported safety of the nucleus is mistaken.

The segmental progerias are part of my evidence that the weakest link in achieving escape velocity is DNA repair -- along with the fact that DNA repair capability correlates with lifespan in mammals [MECHANISMS OF AGING AND DEVELOPMENT; Cortopassi,GA ; 91(3):211-218 (1996)]. There is much that could be done to improve DNA repair both in the nucleus and in the mitochondria. Aside from oligonucleotide treatment, which I previously cited, we could study organisms like the bacterium Deinococcus radiodurans [SCIENCE; White,O; 286:1571-1577 (1999)] and adapt their enzymes to our cells.

[Ben] I think that you would get more "bang for your buck" by making human Complex I more like the Complex I found in birds. I cannot understand your bias against doing this.

[Aubrey] I am not against doing it -- but I perceive that it would be of only limited value even if it turned out to be feasible (note that it might involve sequence changes to most of the 13 mitochondrial protein-coding genes, which would be harder than allotopic expression unless protofection or related techniques are successful in vivo). Birds are only a little better than us at not fumbling electrons.

Please provide a citation for your assertion. As counter-citation, I quote a paragraph in my first posting in this discussion:

"A comparison of the heart mitochondria in rats (4-year lifespan) and pigeons (35-year lifespan) showed that pigeon mitochondria leak fewer free-radicals than rat mitochondria, despite the fact that both animals have similar metabolic rate and cardiac output. Pigeon heart mitochondria (Complexes I & III) showed a 4.6% free radical leak compared to a 16% free radical leak in rat heart mitochondria [MECHANISMS OF AGING AND DEVELOPMENT; Herrero,A; 98(2):95-111 (1997)]. A comparison of 7 non-primate mammals (mouse, hamster, rat, guinea-pig, rabbit, pig and cow) showed that the rate of mitochondrial superoxide and hydrogen peroxide production in heart & kidney were inversely correlated with maximum life span [FREE RADICAL BIOLOGY & MEDICINE; Ku,HH; 15(6):621-627 (1993)]. A similar study of 8 non-primate mammals showed a direct correlation between maximum lifespan and oxidative damage to mtDNA in heart & brain. There was a 4-fold difference in levels of oxidative damage and a 13-fold difference in longevity, supportive of the idea that mtDNA oxidative damage is not the only cause of aging [THE FASEB JOURNAL; Barja,G; 14(2):312-318 (2000)]."

[Ben] You do not yet have the ten million dollars per year you claim would be required to fulfill the SENS goals within 30 years.

[Aubrey]100 million per year in fact.

$100 million per year to achieve escape velocity in 30 years! Then I suppose at $10 million per year it would take 50 years and at $1 billion per year we could do it in 15 years.

Given your assumption that most of the current SENS strategies are being pursued to cure age-related diseases, how much do you estimate is being spent now?

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