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SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

21 October 2005

Ben Best

Reply to Aubrey

I appreciate your stamina and patience in maintaining this dialogue. It has greatly helped to clarify my understanding of the larger issues in aging and anti-aging (too often I am buried deep in details). It has also clarified the difference between my views and your current SENS approach.

As I said at first, I believe that SENS is best guided by a good understanding of the mechanisms of aging. 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. I agree that free-radicals are the most important source of the damage known as aging. And I also believe that it is DNA damage rather than damage to lipids or proteins that is the most critical form of aging damage.

I have earlier answer your claim that oxidative damage to mtDNA is negligible. I supplement that answer with this citation that oxidative stress is a major contributor to mtDNA deletions: [EXPERIMENTAL BIOLOGY AND MEDICINE; Wei,Y; 227(9):671-682 (2002)]. 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. 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 [JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY; Rotig,A; 14(12):2995-3007 (2003)] (despite multiple copies of mtDNA in mitochondria).

And I disagree with you that the only significant effect of nDNA damage is cancer. Evidence of significantly reduced oxidative damage to mtDNA and negligible oxidative damage to nDNA in calorie restricted rats [FREE RADICAL BIOLOGY AND MEDICINE; Lopez-Torres,M; 32(9):882-889 (2002)] is misleading because DNA repair capability declines with age. Thymine dimer removal is about five times greater in newborn fibroblasts than in fibroblasts from the elderly [THE FASEB JOURNAL; Goukassian,D; 14(10):1325-1334 (2000)]. Age-associated transcriptional changes due to DNA-damage are dependent upon type of cellular stress [ONCOGENE; Kyng,KJ; 24(32):5026-5042 (2005)].

As I have mentioned previously, the role of DNA repair in segmental progerias is evidence of the central position of DNA damage in aging damage. The oxidative stress/DNA damage mechanism of aging is summarized in [SCIENCE; Hasty,P; 299:1355-1359 (2003)] with further elaboration in [AGING CELL; Hasty,P; 3(2):55-65 (2004)]. DNA-repair induced by Daf−16(FOXO) protein even explains much of the Daf−2(IGF−1) longevity effect [SCIENCE; Tran,H; 296:530-534 (2002)]. I also like the SAGE KE summary by David Sinclair: Is DNA Cut Out for a Long Life?

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. 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. It is an engineering task, although by your hair-splitting distinctions between obviation and pre-emption it is not a SENS strategy. Supportive of Complex I reconstruction, you could increase saturation of inner membrane lipids (reducing cardiolipin peroxidation), provide histones (or similar protection) to mtDNA and improve mtDNA repair capabilities. Age-associated decline of nDNA repair capability has already been shown to be reversible with oligonucleotide treatment [THE FASEB JOURNAL; Goukassian,DA; 16(7):754-756 (2002)].

[Ben] By adding more efficient DNA repair to SENS you could dispense with (6) & (7).

[Aubrey]Woah - how's that? Perfect repair of premutagenic lesions is impossible; repair of mature mutations is impossible too.

I would appreciate citations or arguments to support your assertions. "Perfect" is your word -- I said "more efficient". Nonetheless, although I have questioned whether (6) is worth the cost/effort, I do think that (7) might be an effective stragegy for defeating cancer.

Thanks for specifying the fatal age-related diseases you say are associated with your SENS categories. This allows me to complete the table:

SENS CATEGORIES
(#)DAMAGESTRATEGYFATAL AGE-RELATED DISEASE
(1)cell lossstem cells heart failure
(when the sinus node has too few cells to maintain a heartbeat)
(2)senescent cellsimmune activation immune senescence
(leading to death from influenza)
(3)protein cross-linksdrugs/enzymes arteriosclerosis/hypertension
(and thus heart attacks and strokes)
(4)extracellular junkimmune activation congestive heart failure
(better accepted than Abeta's role in Alzheimer's)
(5)intracellular junkbetter lysosome enzymes atherosclerosis
(foam cells are the start of a plaque)
(6)mtDNA damagemtDNA to nDNA "no clear answer"
(7)cancerdelete genes for telomerase/ALTcancer

My interest was motivated by your assertions (which I am still grappling with):

[Aubrey]I'm not convinced that prioritising the SENS strands is important in terms of impact, because (a) there is not really a scarcity of the relevant resources, since different scientists will be working on each one whatever the funding levels, and (b) apart from mtDNA mutations it is reasonably clear that all the SENS categories are the dominant category for at least one major age-related cause of death or disability, i.e. my observation about the need to include cancer as "part of aging" applies to all the others too. (It quite probably applies to mtDNA mutations -- just that the evidence isn't so conclusive there yet.)

and

[Aubrey]If every SENS category is the dominant one for something that kills us, leaving it out (or letting research to repair/obviate it proceed less rapidly than the others) will delay achievement of the main goal, namely etting people live a lot longer. The measure of the "amount" of damage that makes most sense is the age at which the SENS category kills people, and I'm saying that age is roughly the same for all categories.

As I have said, if there is no scarcity of resourses, why are you making such an effort to raise money for the Institute of Biomedical Gerontology? Of what value is the Methuselah Mouse Prize? You do not yet have the ten million dollars per year you claim would be required to fulfill the SENS goals within 30 years. The scarcity of resources seems so self-evident from these facts that I am at a loss as to how to argue the point.

Your measure of "amount" of aging damage (impact of damage) as being the age at which the SENS category damage kills is a reasonable one. To claim that this age is roughly the same for all categories does not seem reasonable. 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). Pneumonia is a very frequent cause of death for Alzheimer's patients, but this is primarily due to the circumstances of the way in which they die (in an institution, with people eager to see the process end).

Cardiovascular disease is by far the biggest killer among elderly of all ages. If you equate four of your categories with cardiovascular disease, it is not surprising that they all occur at the same time. But I would not agree that each of these four factors contribute equally to death by cardiovascular disease. Death by cancer peaks at age 65, relatively speaking. You have already disqualified the equality of (6) with the other factors.

When I said that priority must be a function of impact and achievability:

[Ben]Impact: (5) > (6) > (7) > (1) > (3) > (4) > (2)

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

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

you said:

[Aubrey]In terms of achievability my ranking would be exactly the same as yours except that I place number 7, cancer, as even more difficult than mitochondrial mutations.

[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.

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.


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