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SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

15 October 2005

Aubrey D.N.J. de Grey

[Ben] Although I believe that I know what you mean, the term allotopic is not in my medical dictionary and, in fact, typing "allotopic" or "allotopic expression" into Google leads to the SENS website.

So it does - but only the top two of 622 hits... I didn't invent the term, it was first used by Nagley's group in 1992. I prefer PubMed to Google when seeking help on obscure biomedical terms.

[Ben] How does moving mtDNA into the nucleus let "mtDNA mutations accumulate" but stop "pathogenic downstream effects"? Doesn't changing mtDNA to nDNA pre-empt mtDNA mutations by greatly reducing superoxide/ peroxide exposure?

AE isn't "changing mtDNA to nDNA" -- it's making modified copies of the mtDNA and placing them in the nucleus. So the bona fide mtDNA still exists, mutations in it accumulate, but the proteins it encodes are not depleted as a result because they're also being expressed from the new nuclear genes.

[Ben] Concerning categories, the "obviation" of protecting mtDNA from reactive oxygen species by moving it into the nucleus resembles a gerontologist planting a tree far more than it resembles an engineer repairing a roof.

Well, not to me.

[Ben] "The relevance of 8OHdG to either aging or cancer is challenged, incidentally, by the lack of phenotype of mice with a homozygous deletion of the gene encoding the enzyme that repairs it." ... I would greatly appreciate one or more journal citations supporting that statement if you could provide them.

Klungland A et al., Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci USA 96(23):13300-13305. Abstract says: "OGG1-deficient mice ... show no marked pathological changes". Main text says: "Null animals remained viable and apparently healthy into adulthood (oldest mice are 18 months) with no overt phenotype; systematic histopathological examination of two such animals sacrificed at 8 and 11 months of age did not reveal any abnormalities".

[Ben] I don't think that stem cell-mediated replacement of neurons is a good strategy for the whole brain because I don't think it can be done in a way that retains the synaptic connections that form the basis of memory and personal identity.

If we needed to connect a new neuron to exactly the same other neurons as the one it's replacing was connected to, I would agree, but I think we can say with confidence that memory and personal identity are stored more "holographically" than that.

[Ben] If you are so sanguine about stem-cell mediated replacement for neurons, then why include strategies for cell repair in SENS at all?

Because there will be a limit to the rate at which cells can be replaced without compromising tissue function in some tissues - especially the brain, but probably the heart and skeletal muscle too. So it makes sense to use cell repair to minimise the required rate of cell replacement.

[Ben] If resources were not scarce, then all seven SENS strategies could be achieved tomorrow.

Even I at my most optimistic would not say that!

[Ben] even if it is true that every SENS category is a "dominant category for at least one major age-related cause of death or disability", that does not mean that every SENS category is associated with an equal amount of damage.

I don't see what you mean here. 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.

[Ben] each SENS category is not equally achievable. Therefore, priorities must be based on both amount of damage associated with the category and the cost/difficulty of achieving the repair associated with that category.

I agree -- though, for reasons just stated, I claim the amount of damage (by the appropriate measure) is equal for all categories.

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