SAGE KE Bulletin Board

Re: Making Sense of SENS: Criticisms and Suggestions

13 October 2005

Ben Best

Reply to Aubrey

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. I believe that you have an important message to deliver, Aubrey, and I wish you would do so without neologisms and convoluted locutions such as:

"Allotopic expression is an obviation strategy because it intervenes late -- it lets the mtDNA mutations accumulate but it stops them from having pathogenic downstream effects."

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? 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.

And speaking of convoluted locutions, your use of the word "phenotype" seems idiosyncratic in:

"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."

Please don't misinterpret my intent. I want to be able to understand you and I want others to be able to understand you. More substantively, I would greatly appreciate one or more journal citations supporting that statement if you could provide them.

Yes, good point, the evidence for the value of replacing apoE3 and apoE4 with apoE2 is circumstantial and not conclusive.

It may be that better lysosomal enzymes and mtDNA migration could eliminate most of the problem of toxic metal ion accumulation, but I don't think that we know this with certainty.

I think that your reasoning for subsuming organ transplantation into your existing SENS categories is procrustean, but I won't argue the point further.

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. For neurons I think the emphasis must be on cell repair/"obviation", ie, removal of "intracellular junk" and migration of mtDNA into the nucleus. If you are so sanguine about stem-cell mediated replacement for neurons, then why include strategies for cell repair in SENS at all? You could dispense with cell repair strategies and concentrate on the other strategies (including organ transplantation).

I cannot understand your reasoning in saying that the SENS strategies cannot be ranked in terms of their impact on aging damage. If resources were not scarce, then all seven SENS strategies could be achieved tomorrow. There would be no need for a Methuselah Mouse Prize or an Institute of Biomedical Gerontology. And 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. Every thing else being equal, the SENS categories causing the most amount of aging damage would deserve the highest priorities. But everything else is not equal, because 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.

Science of Aging Knowledge Environment. ISSN 1539-6150