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SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

29 October 2005

Aubrey D.N.J. de Grey

[Ben] Although you wrote a book entitled The Mitochondrial Free Radical Theory of Aging, you felt that the fact that free radicals cause aging is so obvious that you did not attempt to justify it in your book.
Oh, that's not quite accurate -- I started from the premise that mitochondrial mutations are major contributors to aging, but I didn't address the pecking order of mechanisms that cause those mutations -- everything in the book applies even if all mtDNA mutations are caused purely by replication errors, for example. I proposed a specific mechanism for how mtDNA mutations cause damage, and that specific proposal indeed involves free radicals as intermediates -- but I certainly spent a long time in the book justifying the plausibility of that specific mechanism.
[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.
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.
[Ben] I question that the nucleus is such a safe haven. Defects in the 100 or so respiratory chain proteins are due to mtDNA deletions and mutations in only about 10−15% of cases, comparable to the percentage of respiratory chain proteins encoded by mtDNA
Um, but that concerns inherited mutations - they say nothing about the relative rates in postmitotic (or indeed any somatic) cell types.
[Ben] (despite multiple copies of mtDNA in mitochondria).
"Despite" is wrong -- the phenomenon of clonal expansion (selective advantage) of mutant mtDNA means that the multiplicity of mtDNA copies per cell makes it more susceptible than if it were only in two copies, not less.
[Ben] And I disagree with you that the only significant effect of nDNA damage is cancer.
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.
[Ben] Senescent cells, cell loss and intracellular garbage accumulation would be greatly lessoned with reduced free radical production and increased DNA- repair. I think that making copies of the 13 mtDNA respiratory chain proteins in the nucleus and trying to find ways to import those proteins into the mitochondria would not be cost-justified.
You may turn out to be right on both counts, but I'd prefer not to guess.
[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.
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.
[Aubrey]Woah - how's that? Perfect repair of premutagenic lesions is impossible; repair of mature mutations is impossible too.

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

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.
[Ben] if there is no scarcity of resourses, why are you making such an effort to raise money for the Institute of Biomedical Gerontology?
Haha - of course there is scarcity of financial resources - but your original comment (as I understood it) was to do with manpower resources. I address the possibility of limited financial resources at the end of this post.
[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.
100 million per year in fact.
[Ben] Both influenza and pneumonia are largely preventable by vaccine, so the urgency would be more to get people vaccinated than to spend money on (2).
Not good enough -- immune system decline sensitises us against all infections and does so progressively, so vaccines can't do the whole job -- vaccines require a reasonably functional immune system in order to work.
[Ben] Death by cancer peaks at age 65, relatively speaking. You have already disqualified the equality of (6) with the other factors.
I'm not with you here. Cancer death only peaks because death from other causes is still rising, and the idea is to fix those other causes -- if we did so, death from cancer would continue to rise with age.
[Aubrey]Because of what I say about impact, my priority ordering is simply the inverse of my achievability ordering -- i.e., we need the most effort on the hardest parts.

[Ben] This is a "the solution is no better than the weakest link" argument. It would seem to follow from your claim that the impact of each factor on aging damage is equal. But what if your claim is wrong? It could be that dramatic improvements of health and longevity could result from one or several of the more easily-achieved categories. If so, this demonstrable success could draw more money and research inot the other areas. That would be a good reason to concentrate efforts on the more easily-achievable (less costly and less time) strategies. That is a danger of being too "dogmatic" of the equality of the impact of the factors.

Um, but if your concern is to prioritise limited financial resources then this is a gamble, right? -- suppose we were to focus on the more easily-achievable parts of SENS and they did not greatly improve health and longevity, because the hard ones happened to be the ones that matter most, then we would have failed to gain the enhanced credibility and fundability and we'd have lost time that could have been spent working on the hard problems.

My policy with regard to attracting finances is that a robust plan is often easier to fund than a cut-price plan. It is often said in the venture capital world that larger sums can be easier to obtain than smaller sums, and I think this is probably why -- the extra expenditure increases disproportionately the chance of success.

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