Hi guys,
Sorry I am joining this only so late, and many thanks to all the participants! I have met my objective to learn a great deal from your debate, and I'll be happy to try and "sort some things out".
Maybe some classification is useful. I think it's clear to everyone that in order to achieve very long lives, WILT is a mitotic strategy. That is, it is deliberately reducing the lifetime of individual cells, but increasing their turnover, along with (hopefully) the organism's life span. Allotopic expression, on the other hand, is a purely postmitotic strategy, if WILT, or any other relatively rapid cellular replacement scheme is employed as well. (That is, cellular replacement in the broadest sense, including cell therapy, tissue engineering and transplantation.) No one will live a minute longer by having cells that could maintatin their mitochondrial proteins for hundreds of years, if these cells are replaced every decade anyways. I think this was made less than perfectly clear here, as well as on the SENS pages.
(The same holds for holds for enhancing nuclear DNA repair and epimutation repair. In the WILT scheme, telomere length determines longevity. I do not see how enhanced DNA repair could change that.)
Therefore, allotopic expression is needed only in tissues where rapid cellular replacement is out of the question, which is primarily the neuronal fraction of the brain. That means also, allotopic expression must rely on postmitotic gene therapy, with all its current problems and pitfalls. The involvement of mitochondrial dysfunction in many brain degenerative diseases makes allotopic expression particularly promising. What I also like about it is its straightforward implementation and its promise to rejuvenate its target organelle independently of the time of onset of the therapy.
We also should clarify some semantics about WILT: A general anti-cancer strategy is to replace chronologically old cells with young ones. This takes two things: A way to introduce fresh cells, and a way to ablate existing cells. Literally, WILT makes only reference to the latter (small WILT). But, in our casual language, the acronym is normally used to include both (big WILT).
The introduction of fresh cells is not the real matter of debate here. I think we all agree it is necessary. The matter of debate is the utility of small WILT as a cell ablation strategy. (I.e. the issue is not even as big as it may sound to some.)
So far, I would grant one major point to Prometheus, as long as only scientific arguemts are considered: It remains to be assessed by future experiment, how competitive small WILT is in comparison with other cell ablation schemes, such as maker-based tumor-specific ablation or unspecific chemotherapy. Small WILT is probably the most effective ablation strategy, but other cell ablation strategies, which are much less of a hassle, may prove sufficiently efficient. Small WILT may not be feasible due to ALT diversity and/or its genes' possibly critical physiological role. Thus, I would suggest to priorize the cell replacement part of big WILT over small WILT, unless there is a strong reason to believe that the cell replacement part will be developed in time, even without our stimulation. I am presently not qualified to assess this, but Aubrey provided some arguments that go in this direction.
Furthermore, in the footsteps of Prometheus last post, I have a sociological reason to keep WILT as a key SENS proposal at this time: WILT is just extremely cool! It's an eyecatcher. It makes people think "hmm, yeah, this guy even thought something up to defeat cancer, which is radically different from the continuously failing mainstream approaches, how ecouraging!" Clearer seperation of small WILT and cell replacement could help the reader to understand this tree of concepts.
All in all, it seems to me that Aubrey met his objective to show that
[quote]the challenges to allotopic expression and WILT that you mention are less daunting than you suggest, and why the challenges to the alternatives you mention are more daunting than you suggest[/quote]
Prometheus objectives were
[quote]1. Allotopic expression of mitochondrial genes is a proposed method of protecting the
mitochondrial genome from damage that would be technologically more difficult to implement than a more direct means of increasing DNA maintenance/repair such as overexpression of key DNA repair/maintenance genes.
2. It is possible to combat cancer without resorting to the ablation of telomerase expression in every cell of the body.
3. The chief assumption on which the implementation of WILT is based upon, namely the frequency with which certain cells in the body divide, is very likely to be wrong. [/quote]
I think the degree of success was 2>3>1.
2: (see above)
3: [quote]We don't have to understand why the gut stem cells hold out as long as blood and skin stem cells; we only prove whether or not that statement is true.[/quote]
I think it is likely through a low division rate along Aubrey's lines, but WILT may have to prepare for some surprises from the crypt.
1: I can't see any challenge that survived Aubrey's defense. I was not aware of that 1:1 stochiometry thing before. By pointing this out, you wiped my last doubts in the utility of allotopic expression.
Jay:
[quote]But as I must sometimes remind myself, I am not a biologist...[/quote]
Glad you overcame your shyness, Jay. I could think of someone here who managed to forget that he's not a biologist with some incredible success. So this would be a bad excuse for not daring to venture on thin ice. This is no criticism, I think your way of joining this debate is just right ;-) I encourage everyone attempt the same, not only in this thread but in your life as immortalists.
[quote]At any rate, I suspect he's more in support of de Grey's view[/quote]
Well suspected ;-)
[quote]increasing the rate and responsiveness of DNA repair to damage can be implemented by identifying the upstream regulators responsible for DNA maintenance and selectively overexpressing[/quote]
and Aubrey's counter:
[quote]what a review of the literature reveals is that very little has been published. I think we all know the fate of negative results in contemporary science.[/quote]
I clearly don't have the experience to weigh these points against each other, but I would suspect that a man who single-handedly created nearly all professional anti-aging initiatives out there, has.
One could also find commercially viable pharmacological solutions, rather than overexpression. This could be a way to get some venture capital in, once we have piled up enough fundamental knowlege. But is this type of fundamental research an IBG's job?
Jay:
[quote]Note that the DNA maintenance approach is not necessarily viewed as a way to cure aging. You can't stop all DNA damage. Well, some day maybe, but not soon.[/quote]
Barring a "chronometer" style breakthrough as it could be inspired by a fly prize. This could essentially be the answer to the question "how do germ cells do it?" If we had the money to do it without impacting the mouse prize, I'd be full for a fly prize.
Jay:
[quote]I'm not familiar with Campisi[/quote]
Familiarize yourself ;-) This is an excellent talk, with a revealing grand-scheme-of-things view.
Jay:
[quote]Can we ensure that each mitochondrion will get the proper amounts of the proteins that we are moving out of the mtDNA?[/quote]
If this question means something like if 50 subunits are needed, how do we assure one mito does not get 75 subunits, while another one gets only 25, then the answer is simple. We don't. For statistical reasons, distributions close to the average are just much more likely than distributions that are far away. This is ultimately due to the same forces that drive the universe towards ever increasing entropy, but I would recommend to google a little bit for introductory thermodynamics, which can be quite revealing about this kind of phenomena.
Prometheus:
[quote]You say it's a tough project. C'mon, do you realize how silly a statement that is coming from de Grey.[/quote]
My local carpenter here has a hand-written quote pinned to the wall next to his workbench, which goes roughly
[quote]The key to success is the readiness to avoid tough problems where possible, the will to tackle them where there is no other option, and the wisdom to tell one from the other.[/quote]
Aubrey:
[quote]This is a great example of what I say about the difference between the creativity of basic scientists and the creativity of engineers. 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.[/quote]
and Prometheus:
[quote]it sounds arrogant. [/quote]
Aubrey is trying to teach you, and everyone who just WANTS to live an invaluable attitude here. The lack of this attitude in the sciences is the one reason for Reason's:
[quote]Serious efforts towards radical life extension comprise such a small fraction of total efforts - this is the real problem we must address[/quote]
From the beginning, I studied science as a means to an end, which is indefinite heath. Give me a compelling reason to believe that I cannot make a difference (such as achieve this goal for me), and I drop on the beach, right here, right now. (Well, at least for a while

) From this point of view, the greatest mistake one can make is to solve problems that are not actually required for the goal.
Btw, Reason, I'm a great fan of nearly anything you post. You have a wonderful bird's eye view thingy.
One thing about arrogance. When one happens to be right, and has a compelling reason to demonstrate this to others, then one has to sound arrogant by definition. At least between each other, we must not let such obviously hardwired emotions impair our productivity towards our common end.
Prometheus:
[quote]So I ask the question: with the mitochondria of fertilized oocytes potentially immortal, and clearly capable of enormous innate self-repair (certainly enough to keep them going for countless generations) should we be not looking at how we can coax somatic cell mitochondria out of their limited lifespan?[/quote]
Sure, good thing, how do we go about it? I mean, we would need a (preferably peer-reviewed) argument that this is more efficient and/or likely to succeed than allotopic expression.
This is my general piece of advice to anyone who thinks they have a productive life-extension idea. Publish it. For example in rejuvenation research. When it can stand the scrunity of peer-review, then you will have a very good stand in discussing it publicly in places like this.
Edited by John Schloendorn, 13 February 2005 - 02:50 AM.