Michael, thanks for the references you've provided on allotopic expression - the Ellouze study is cool. but you haven't made your case, because: 1. Methodologically, the technology required to implement allotopic expression in an adult human does not exist - albeit in vivo, the study you mentioned looked at electroporation with plasmid DNA for transient expression in limited cell numbers
You'll note that I specified that fact in
my post:
we certainly won't use electroporation. But the answer [to how to do this in an adult human] is reasonably obvious: somatic gene therapy,
I see now, however, that I should have been more explicit about the question I was answering in my reply. Your original question was in response to niner's statement that "Most if not all of SENS is based on
applications of known technology", which of course is not literally true as it stands; I assume that he meant (and wrongly assumed that you would understand) the same thing that Aubrey emphasizes in his academic and popular-audience publications, and has done since the first SENS publication with his colleagues in 2002 (1): that the biotechnologies required to develop a comprehensive panel of rejuvenation therapies based on the SENS 'engineering' approach are either available now
or are clearly foreseeable from existing developments in the field:
intervention to remove the accumulating damage [of aging] would sever the link between metabolism and pathology, and so has the potential to postpone aging indefinitely. We survey the major categories of such damage and the ways in which, with current or foreseeable biotechnology, they could be reversed. Such ways exist in all cases, implying that indefinite postponement of aging--which we term "engineered negligible senescence" -- may be within sight.(1)
Certainly, no one is saying that "the technology required to implement allotopic expression (or, for that matter, any other SENS therapy) in an adult humans" is available today -- otherwise, we'd be doing it! But studies like the ones I cited, and other more advanced work in other SENS strands, clearly point the way forward in the foreseeable future toward the development of a comprehensive panel of therapies to remove, repair, replace, or render harmless the cellular and molecular damage that underlies age-related frailty.
2. Despite some evidence of intracellular localization of nuclear-expressed mitochondrial mRNA, there is no evidence of sufficient understanding on the regulation and expression of the transferred genes.
We don't
need to understand the details of their regulation and expression -- only to exploit the machinery governing them, which (again) already does this job for other nu-encoded mt proteins. Thus, for example, cytochrome b of Complex III is mt-coded, but the other dozen subunits are nu-encoded in 1:1 ratio. The Complex can't function if the proteins' stoichiometry isn't maintained, so expressions of all subunits has to be coordinated. Cells already successfully synchronize Rieske protein and other subunits in lockstep with cytochrome b, and do so in response to actual requirements rather than constitutively, despite the fact that the transcription and translation of the various subunits, and the machinery that performs it, are distinct.
It would be interesting and rewarding work for basic scientists to spend a great deal of effort in exploring the details of how this is done -- but
we don't need to understand these details to exploit them. Instead, we take the regulatory sequence of Rieske protein, and we preface it to cyt b, and voilà -- instant lockstep regulation of expression.
I remain dubious about why you would use the name 'replenisens' when you're not actually conducting any research in this area, or at least have a plan..
I remain puzzled as to the reasons for your dubiousness. The only thing that I can think is that you may be confusing SENS -- the "
Strategies for Engineered Negligible Senescence" -- with the Methuselah Foundation -- the concrete medical charity with a mission to advance the development of a comprehensive panel of such therapeutics, which (as Elrond, myself, and others have emphasized) has no intention of developing the entire panel in-house, but instead of opening up the bottlenecks in the path forward.
de Grey's sens is about engineering strategies, isn't it? Where's the associated proposed engineering solution?
Stem cells and tissue engineering. So, for instance:
Surprisingly, the greatest paucity of activity as regards to sens is in this area (stem cell therapies)..
Of course, you're aware that there is an
enormous amount of activity already underway in this area, in both the public and the private sphere; this is advancing the maturation of the "
Strategies for Engineered Negligible Senescence" quite adequately for the time being, making other areas (like the MF-funded work on obviation of mitochondrial mutations noted above) more rate-limiting in our progress and thus the priorities of the Foundation.
It's occurred to me, that what is particularly interesting, is that if you were to actually apply the 'engineering' approach as per de Grey's interpretation, the quickest way to treat aging and associated disease given the practical restrictions of methodological implementation, is to use stem cell treatments, which can be used, incidentally, also to correct genetic defects. In fact, there's a stem cell based solution for all of the '7 causes'.. This is not to say that I agree with 7 but that the 7 described can be addressed with stem cell treatments..
Quite a few problems with that, but most notably: (a) you'd still have to remove the existing, non-stem-cell damage from the biologically aged body (genetically engineered stem cells would not remove extracellular aggregates, cleave AGE crosslinks from vascular collagen, restore the integrity of frayed elastin lamellae, etc), and (b) it would seem that you'd have to replace
all of the cells of an aging body to achieve what would be needed, which would run into some rather serious problems of individual continuity when you got rid of all the existing neurons ...
I suspect that at the time sens was conceived, stem cell research was very different to where it is today. Which supports the notion that sens, like some sort of 10 commandments handed down from God, has crystalized, in principle, to the time it was first conceived and appears to take no notice of ongoing scientific developments.
I am very puzzled as to why you would think that. Cell loss and tissue atrophy were identified as key targets for SENS, and stem cells and tissue engineering identified as the 'engineering' solution, in the first SENS publication (1), and were already in Aubrey's mind when the basic framework of the 'engineering' pathway were conceived in 2000 (2). Subsequent developments have simply confirmed his (and his coauthors') original optimism on this front.
-Michael
References1.
Time to talk SENS: critiquing the immutability of human aging.
de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJ, Stock G.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]
2. de Grey AD, Rae M.
Ending Aging: The rejuvenation breakthroughs that could reverse human aging in our lifetime.
New York, NY: St. Martin's Press, 2007.
