Back to allotopic regulation one more time:
In fact I did not miss your point, I wanted to illustrate other regulatory and signaling concerns that emerge eg. Ca++, mt DNA transcription factor binding sites. I appreciate the 1:1 of a nuclear DNA encoded component to mt DNA encoded component and also read,
But we don't need to know **anything** about how it does that
(ouch!) meaning we can just ignore an entire regulatory system. How can you possibly say that when the presence of signaling ligands is going to be different in the nucleus than in mitochondria. You can only try it and see what happens, I suppose.
Then I am dismayed by your effortless dismissal, obviously designed as a riposte for any such concerns:
For a scientist it is just really difficult to think in terms of factoring out unknowns, i.e. finding solutions that don't depend on those unknowns, because finding things out is the whole deal. For an engineer it's central to factor unknowns out, because finding things out is just a means to an end.
Whilst it may ring well for the average reader - it is really not good enough - it sounds arrogant will be your greatest impediment, in getting mainstream scientists to follow. At the very least a mention is deserved that one component of the SENS objectives is going to be the determination of whether such regulatory networks will impact on the allotopic solution and if so, a strategy to emulate their function from the nuclear perspective. That's all it would take to give SENS more credibility with mainstream science.
So to put this issue to rest I take it that at this stage no there is no plan for dealing with the regulatory network of mt gene expression once it has been transplanted to the nucleus.
On telomerase & Hayflick limit
You said: "I don't know why you think exogenous telomerase-mediated stem cell expansion in culture is impractical." I don't. So this is how you're going to get around it.
So the highest frequency of cell division in humans, you say must be, as per blood cells. This is a tenuous argument if it is going to be based on the mouse studies alone for reasons I mentioned previously.
So the point of contention is what are the most rapidly dividing cells in humans and which tissues do they predominate in, as this is going to determine the required rate of stem cell replenishment and ultimately determine the strength of entire foundation that WILT rests upon. In certain epithelial cells, particularly mucosal types in the GI where damage and replacement is occurring daily at very high rate suggests a similar frequency of cell division.
On WILT
You said: "RNAi unfortunately is no easier to make sufficiently comprehensive than suicide adenoviruses" At present it has room for improvement but that is no reason to delay using it for the purposes of validating your theory.
On cancer vaccines
You said: "my point was that they can also avoid, rather more easily, being infected by a virus, because a virus uses particular cell characteristics to get in and get itself expressed, and those characteristics can be altered by the cancer cell to avoid being infected" Of course, it is an evolving therapeutical strategy and a legitimate one until something better can be developed. There are delivery alternatives, however, such as liposomes that can be used to complement such treatments.
On DNA repair enhancement
There is some literature on a positive effect (1), nil effect (2) and a system (3) of XP overexpression; on the naturally induced overexpression of Rad50 and DNA topoisomerase as protection against cardiac ischemia (4); on the effects of imbalanced DNA repair factor overexpression (5); on reduction of mt DNA damage via hOGG1 overexpression (6); the protective effects of overexpression of SIR2 alpha in cardiac myocytes (7).
The list goes on and supports the view that overexpresison of key DNA repair/maintenance (kDRM) factors are of benefit in the reduction of DNA damage and its phenotypic effects.
What we do not but need to see is a study on the effects of overexpression of kDRM factors in aging. The ideal experiment would involve a short lived species treated with various combinations of overexpressed kDRM factors using gene therapy as means of introducing the foreign genes.
Refs
(1) Overexpression of the XPA repair gene increases resistance to ultraviolet radiation in human cells by selective repair of DNA damage.
Cancer Res 55:24, 6152-60 (1995)
(2) Low amounts of the DNA repair XPA protein are sufficient to recover UV-resistance.
Carcinogenesis 23:6, 1039-46 (2002)
(3) Overexpression and purification of human XPA using a baculovirus expression system.
Protein Expr Purif 19:1, 1-11 (2000)
(4) Antibody-array technique reveals overexpression of important DNA-repair proteins during cardiac ischemic preconditioning.
J Mol Cell Cardiol 38:1, 99-102 (2005)
(5) APE1 overexpression in XRCC1-deficient cells complements the defective repair of oxidative single strand breaks but increases genomic instability.
Nucleic Acids Res 33:1, 298-306 (2005)
(6) MITOCHONDRIAL DNA DAMAGE TRIGGERS MITOCHONDRIAL DYSFUNCTION AND APOPTOSIS IN OXIDANT-CHALLENGED LUNG ENDOTHELIAL CELLS.
Am J Physiol Lung Cell Mol Physiol , (2004)
(7) Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes.
Circ Res 95:10, 971-80 (2004)