93 replies to this topic

[marcus]

All,

I notice a good deal of this discussion occured over a year ago and I am curious to see if there has been any new evidence that may help settle the debate on whether or not AE need be concerned with any potential redox sensing function performed by the mtDNA? It still seems to me to be a matter of scientific judgement whether or not the "correct" stochiometry can be maintained with all the mito genes in the nucleus. By "correct" I mean that not only are they produced in the proper amounts relative to each-other, but also in the correct total amount to allow for optimal fuction of the many processes the mitochondria carries out.

Prometheus main point seems to be that it is possible that the mito genes that remained in the organelle need to be there to sense the redox state in order to produce the correct number of their own products. And that this information about the amounts that were produced in the mitochondria is then relayed on an unknown signaling pathway to the nucleus so that the genes there can produce the appropriate amount of their products to match the products produced in the mitochondria. If you move ALL the genes to the nucleus then you would lose that redox sensing function which could throw off the entire mitochodrial protein production system. That system could be critically dependent on at least some of those genes being right where they are sensing the redox state, producing the correct amount of their own transcripts, and somehow conveying the relative amounts of their transcipt to the nucleus so that the 1:1 stochiometry can be perserved. Forgive me if I've mis-spoken about your view point, but it is my quick summary of what I see your view as.

Aubrey seems to think that any regulation similar to what I summarised above is on the low end of the scale of biological probability. Prometheus seems to think it is on the high end. I am not sure. Is anyone aware of any new information or studies that could shed more light on how exactly the 1:1 stochiometry is currently maintained. I know the engineers approach is to not care how it works as long as it works. But there seems to be at least a plausible arguement that the remaining Mt genes could still be there because they perform a critical function. Key word there being critical, it could also turn out that the mtDNA still being in the organelle plays only a minor function or no function at all.

Marcus

Edited by marcus, 12 September 2006 - 07:49 AM.

[John Schloendorn]

Mt genes could still be there because they perform a critical function

I am not aware of any of the evidence you ask for. Providing a direct test for this hypothesis is the objective of an MF-funded project currently being undertaken in Cambridge (by implementing AE, of course).

[marcus]

Prometheus,

I tend to agree with you that AE may cause some unforseen disruptions in the mitochondrial complex. I haven't given detailed thought to what challenges AE might have specifically for individual cell lines, but certainly neurons would have to be one of the prime target cell types. These types of issues are going to need to be addressed at some point.

However, my main concern lies on what potential disruptions AE may cause in ALL cell types. It's still an open ended question as far as I can tell on whether or not there will be any disruptions in the functioning of the mitochondria with ALL the genes moved over to the nDNA. I understand (ad nauseum) that the 1:1 stochiometry works right now for mito genes that are in the nucleus. But what I don't know is if that 1:1 or as I like to think of it "correct" stochiometry will be preserved if all the genes are moved?

I look forward to results of the M-Foundation funded study. Nothing beats going out and seeing what works to help further refine our theories here.

There are definitely other options out there other than AE to help obviate the effects of mtDNA damage. It would be ideal if we developed truly robust cell therapy that allowed us to manage our cell populations and selectively ablate cells at will, replacing them with "fresh" cells often enough that mtDNA damage won't matter. I'm not going to be too worried about the effects of mtDNA damage when most of the cells in my body are more or less like they were when I was 25. But until we reach that point, AE is certainly an idea worth trying. I do worry that there may be more technical challenges to be overcome then mere hydrophobicity and code disparity. It all depends on that big IF...IF the system is disturbed with the genes no longer being there...IF the nucleus relies on info. from the mito genes(perhaps being there to sense the redox state) to get things right on their end...then AE may have to also come up with a way to mimic that function.

I like your idea for increasing quality control of the mitochondria via increasing autophagy. I think there are all sorts of opportunities for optimizing cellular function via various modifications to the genome. Some of these strategies have been shot down as sub SENS types of ideas(enhanced DNA repair comes to mind), but I think there is real value in exploring how we can make a particular cell function "better" via genetic manipulation. Most of these types of alterations/gene therapies seem to work better when you ex-vivo manipulate the cells. Which is why I see it as so crucial that we develop robust cell therapy so that we can deliver these types of alterations to the organism(us eventually).

Marcus

Edited by marcus, 08 September 2006 - 02:03 AM.

[jaydfox]

As you are alluding, the greatest problem with the SENS approaches, including AE, is that even if they work in principle (which remains to be seen) they're entirely reliant on a non-existent technology to mediate their effects throughout the cells of the body. This also holds true for the mitochondrial and DNA repair interventions I have suggested.

I don't necessarily see reliance on unavailable technologies as a large problem, given that the technologies necessary are reasonably foreseeable in a two decade timeframe (available to research labs, even if not FDA approved). I don't see any technologies being developed in a shorter timeframe that will have as significant an impact on aging and mortality as SENS. To be sure, there are technologies that can be developed in the meantime which will have a significant effect, so they should be pursued, but not at the expense of the SENS program. Both research agendas can coexist. In fact, while the Methuselah Foundation is focussed on SENS, ImmInst should be focussed on connecting the dots between technologies of both shorter and longer term scope than SENS.

For me, any attempts to critique SENS should be aligned with finding any of the following:
A) determining the likelihood of failure of any particular strand, so we know where we need to focus effort on backup plans to the current proposals. From a scientific standpoint, credibility (in a Bayesian sense) will be based roughly on adding* the probabilities that any particular strand will fail, plus the probability that seven successful strands will still represent a failure. Proposals that we have the highest expectation of possible failure should have backup plans, to increase the viability of the program as a whole. Otherwise, it's credibility will continue to be suspect.
B) determining if there are alternatives to a particular proposal which will be as effective (or, in the least, effective enough to help effect escape velocity in the context of a particular strand), yet which can reasonably be predicted to be available in less time, perhaps even a decade sooner. This is not to help with credibility per se, but to expedite the timeline for achieving a SENS therapeutic program. This will be the most difficult, as comparing the relative effectiveness of two theoretical proposals in inherently difficult and somewhat suspect.
C) identifying weaknesses in SENS, either in the scientific platform or in the individual proposals, that might weaken SENS as a scientifically credible and/or politically tenable program. WILT is one such example (at the least, from the perspective of what's politically tenable).

If we're thinking of a complete overhaul of SENS, it ain't going to happen. Aubrey has invested five years of his life, and a great deal of his credibility, into the SENS program. At best he may be open to incremental improvements. Anything more dramatic will most likely have to become a new program in its own right.

I suggest we continue to work on incremental improvements (bearing in mind points A-C above), and also work on an alternative, fast-tracked program of interventions based on more current technology.


* Technically, we're multiplying the probabilities of success, each less than 1, leading to an ever diminishing number. For example, a reasonably foreseeable failure rate of 20% for each of seven strands, and a 10% failure rate for the whole program even if all strands are successful, works out to a 19% chance of success overall.

If we can reasonably determined that there is actually a 50% chance of failure for a particular proposal, e.g. AE, then that probability drops to 12%. Having a backup solution on hand with an independent 20% chance of failure increases the probability, not just back up to 19%, but up to 21%. Why? Because in the 50% chance that the primary plan fails, there is only a 20% chance that the the backup plan will fail as well, leading to an overall 10% chance of failure for that strand.

In fact, by having well-defined backup plans, each with an independent chance of success (which would mean, roughly, that the backup proposal is very different from the primary proposal, such as AE and mitochondrial autophagy for mtDNA, or WILT and increased immune response for cancer (not saying these should be the backups, just using examples already discussed)), we can increase the overall likelihood of success for the entire SENS program. I'm not sure how important this is from a scientific standpoint, but it seems critical from the engineering standpoint.

[John Schloendorn]

Unfortunately, all the capital being raised by the SENS/MF people is being allocated towards the views of a single individual's 5-year old scientific interpretations.

Again, for all those reading accusations like this for the first time, I would like to point out that this and most of Prometheus' above statements are utter misrepresentations of what the existing SENS initiatives are really like, for reasons that can be found all over the respective discussion threads.

[John Schloendorn]

Please refer to previous posts by me and others in this and the other relevant threads.

After our phone call, I understand that the same pieces of evidence genuinely suggest to you that your accusations are just, and suggest to us that they are injust. This is where we stand, apparently incapable of moving in either direction. What can we make of this situation?

[Lazarus Long]

Why does this have to be a competition between opposing sides rather than a race to demonstrable evidence?

Can everyone agree to disagree at this point and accept that all of you have the passion of their conviction for their interpretations of the present evidence and simply abstain from fixating on one another?

Isn't this the point where competing teams go back to the lab and investigate the critical assumptions with an eye to determining their validity?

Please everyone try and recognize the impasse is also the result of insufficient data and go forth to get it. Build your own team Harold and test your assumptions as I hope Aubrey's team is attempting to and then come back in a year and compare notes again, preferably in the form of published studies.

[eternaltraveler]

Isn't this the point where competing teams go back to the lab and investigate the critical assumptions with an eye to determining their validity?

thats exactly what this team is doing.

[eternaltraveler]

Therefore the claims of SENS, as they stand, to be able to cure aging are invalid and can only be interpreted as spin.

SENS never claimed to be a cure for aging. It's goal, though still ambitious, is to allow us to live long enough for further technological refinments to prolong life further still, with escape velocity being the end result.

[marcus]

Jadyfox,

I agree with you that relying on as yet undeveloped technologies for certain aspects of SENS(specifically delivery) doesn't invalidate the approach. The most direct example I can think of is back in the Cold War days when hydrogen bombs and multiple war-head delivery systems were developed BEFORE there was sophisticated enough rocket technology to deploy them. The researchers back then did the same kind of speculation we are doing today.

I know I am a little new to posting on the boards, but I have been reading and lurking since the beginnings of the Immortality Institute and I think some of the language used(particuarly recently) could be leading to some of the friction we are seeing today between Aubrey, Harold, and others. Terms like "wild" speculation and "utter" misrepresentation tend to inflame the coversations. Sure SENS is speculation at this point, but I don't think it is wild. And as the SENS challenge prooved it is not outside the realm of reasoned debate. And yes Prometheus has some different interpretations of the same data sets and on occasion he may overstep in his interpretations of the data, but I don't think he ever intended to make complete misrepresentations.

Overall, just as an observer, I think some of the quality of debate here has been lessened due to a need for various participants to prove that they are intellectually superior and convince others that their point is totally right. I don't think we are at the stage right now where anyone can say with any certaintly what is the best approach or set of approaches to curing aging and attaining escape velocity. SENS is a great foundation, but I think we could use more of the handicapping approach that you mentioned above as certain strands of SENS(AE and WILT) have alternatives that should be discussed.

Marcus

Edited by marcus, 11 September 2006 - 05:28 AM.

[marcus]

Prometheus,

I wan't thinking in terms of anything specific and meant no offense by the comment. In a sense we are all walking the fine line of interpreting the data and what implications it holds versus going too far in our conclusions we draw. I was trying to point out that the board has been a little more "hostile" of late and that a little more restraint in some of the language as well as more acknowledgement that certain questions are still open-ended and yet to be decided may be helpful in moving the debates forward.

I feel a little like I am nit-picking at your contributions(I have a high respect for your scholarship and understanding of the relevant issues relating to SENS), but since you asked 1 example I can think of which may John may or may not have been referring to was your strong implication that nDNA damage has implications(other than cancer) in ageing in a currently normal lifetime. I still haven't seen any conclusive evidence that it does. I suppose things should also be taken in the context of this forum where they are posted as it would be a little ridiculous to have to qualify every statement you make.

Marcus

Edited by marcus, 10 September 2006 - 06:09 AM.

[marcus]

Prometheus,

After re-reading the thread I think John was more concerned about your implications that SENS is a "cult of science" led by Aubrey rather than to specific scientific arguements you have made. Aubrey has come to the forefront with his scientific proposals, but I'm confident when it comes time to allocate resources and capital for specific projects that it will be a peer-reveiwed process with projects being approved on the basis of their scientific merit and not Aubrey dictating from an ivory tower what gets done. So far, the majority of the capital raised has gone to fund a prize to foster competition for any and all ideas.

Marcus

[John Schloendorn]

I'm confident when it comes time to allocate resources and capital for specific projects that it will be a peer-reveiwed process with projects being approved on the basis of their scientific merit

This has been happening since about one year in LysoSENS and since recently also in MitoSENS. Like I explained to Prometheus on the phone on the day before he posted this (!), nothing gets done or funded that the respective experts (Rittmann, Alvarez, Holt) do not approve of.

[Mark Hamalainen]

In fact, by having well-defined backup plans, each with an independent chance of success (which would mean, roughly, that the backup proposal is very different from the primary proposal, such as AE and mitochondrial autophagy for mtDNA, or WILT and increased immune response for cancer (not saying these should be the backups, just using examples already discussed)), we can increase the overall likelihood of success for the entire SENS program. I'm not sure how important this is from a scientific standpoint, but it seems critical from the engineering standpoint.

Until such time as SENS becomes grounded in legitimate science rather than artfully composed speculation it will have amounted to nothing more than generating interest and invite discussion about research into aging - in other words PR

This is really getting ridiculous... and is reminding me of Estep's entry in the SENS challenge. Since when is an untested hypothesis built on rational argument 'illegitimate science'? And since when is unacceptable for a hypothesis to be incomplete? How could we ever push the boundaries of science without discussing untested ideas? Should we not suggest a solution to a problem if there is a possibility that the solution is not complete? Is it even possible to make in progress under those standards?

And why does everybody keep missing the entire point of SENS? Its purpose is not to identify every little or even big tweak that could be made to the human body to extend its longevity. What it does do is categorize the types of damage associated with age then look at the big picture and say what modifications and or treatments can be applied to neutralize their accumulation. Aggregates in the lysosomes? Then introduce enzymes that can digest the aggregates. Not, lets examine the entirety of metabolism that leads to the production of these aggregates and see if we can tweak it to reduce that production. Mutations in the mitochondrial genome? Why do we have a mitochondrial genome anyways? Lets get rid of it.

Increasing the immune response to cancer or upreglating autophagy of mitochondria are not without their benefits, but they are of a fundamentally different strategy than those of SENS. I'm sure this has been said before but some people seem to keep forgetting it. Or they seem to think that SENS has some responsibility to expand its scope, even though the strategies they want it to address are already being studied by the majority of scientists in the relevant fields, and the strategies that SENS proposes are mostly being ignored...

[Mark Hamalainen]

What bothers me the most is the destructive form criticism of SENS is taking. How does calling SENS illegitimate science help turn people around to your ideas or further ImmInst's goals in the long run? Instead of trying to force SENS to become what you think it should be, why not start a project to complement it?

Take one of the 7 aspects of SENS that you disagree with, compose your thoughts on what it misses and what alternatives could be and how they would work. Don't just suggest alternatives in a few sentences on a fringe net forum after criticizing SENS for being superficial! I guess I'm mostly addressing prometheus here, so I should just say... you have a lot of great ideas. But instead of attacking the uncertainties in the SENS strategy, it would be great if you drafted papers explaining what you think SENS might be missing, and more importantly, detailed descriptions of what you think are the best alternatives or 'backups'. The rest of us at ImmInst could then review your work, after which you could submit it for peer review and publication in Rej Res. This would be constructive criticism, and has the potential to aid research in life extension. I'm sure Aubrey would be delighted if this happened.

[Mark Hamalainen]

Osiris, you keep on repeating the same defence: that if I think my ideas are so great, why don't I publish them. Let me be clear: I'm not interested in publishing anything related to SENS.

I did not mean it as a defense, I was trying to make a constructive suggestion. You clearly are willing to expend a great deal of energy criticizing SENS. I honestly am interested to know why are you reluctant to submit any of your ideas on SENS or life extension in general to peer reiview.

For example, the NeoSENS proposals were designed to illustrate how SENS could be improved upon as part of that critique on SENS... Instead, they were received with the now familiar defence reflex which one is more accustomed to expecting from Scientologists rather than scientists or students of science.

Failing to convince a group of your argument does not mean they are being reflexively defensive. They may simply not be convinced and have a difference of opinion. SENS has not obligation to submit to other ideas of how it should be, and you are not obligated to agree with the way it is. Yes they called for criticism, but they listened, responded, and disagreed. Let us not repeat this cycle ad naseum.

As for a scientific advisory council, I don't see why it is currently necessary. If all research was initiated only an a consensus basis, many radical ideas would be ignored that go on to be revolutionary.

[Mark Hamalainen]

There is no hidden agenda there. Preparing a scientific article does take time and energy. This would not be a research report since there is no data to present, nor would it be of the form of a review which are normally by invitation (and what is there to review, in any case?). Therefore it would be an "opinion" type article. Now, what would I be expressing an opinion on? My thoughts on the incompleteness of SENS? Why bother when the scientific community already is aware of that? Or perhaps I can publish my own ideas on how SENS should be pursued which is equally pointless. It is simply not how science is done. If it were, there would be countless hypotheses out there on countless way of solving things.

True, it is not the typical way that science is done, but that didn't stop me. My article was not invited yet it was accepted, peer reviewed, and published much more quickly than anybody had expected. I think science would benefit greatly from widening the idea of what is an acceptable publication to include more speculation and hypothesizing, because that is where all great ideas start, where the creative process begins. You could for example publish an article with a title like: "Solving the Mitochondrial Problem: A Review/Critique of Current Proposals and Some Alternative Hypothesis". Of course 'mitochondrial' could be replaced by nuclear dna damage, or intracellular junk. Make it a series! I would be delighted to read and even contribute.

I would say that when that group has not done (or is unable to do) the due diligence of examining my arguments and the evidence I have presented in the context of the counterargument/s of my detractor then they are being reflexive (particularly when in the same breath they are seeking to mimic the theatrical departure of the protagonist in this matter).

I would say you under estimate the degree of self criticism we have for SENS. In addition, we prefer to focus on strategies that are not being focused on by other people. If that's not acceptable to you, then lets just agree to disagree.

That is a different response than I got from John on that one. Perhaps you guys need to talk to ensure you represent SENS in a congruent manner. In any case, I suspected you would say something like that... I would not be holding my breath for a Nobel.

We're not as much of a clique as many probably imagine, we all have our own viewpoints and ideas. As for a nobel, that is not my goal. Besides, how many nobel prizes were awarded to people that stuck to the consensus?

[enki273]

Happy to see such a controversial, yet sometimes somewhat off-the-topic discussion.
What I believe hasn´t been noted yet is however that mitoSENS may not have that much of a beneficial effect on nDNA mutations as John and others proposed. In fact, a great number of mutations has not chemically-induced causes, such as spontaneous mutations, UV light, transposons etc. The amount of these mutations, I think, at least matches, probably surpasses those caused by ROS.
Given this, isn´t nDNA mutations a quite different issue?

[enki273]

Indeed, nothing beats empirical results.
My point was simply that solving the mtDNA mutations problem would not necessarily make the other "deadly things" of SENS much easier.
Besides, a special idea occurred to me lately concerning mitochondrial stability: Defectiveness in mitochondria is mainly attributed to ROS leaking damaging mtDNA and the oxidative phosphorylation chain. There are however subunits and other proteins encoded in the nucleus that also experience damage in the course of aging. To be concrete, I remember for example a decrease in Cardiolipin (diphosphatidylglycerol) over the time, a lipid attaching cytochrome c to the inner mitochondrial membrane. Do I suffer from brain blockage or am I right in thinking that this decline cannot be a result of "mitochondriogenic" damage?

Edited by enki273, 20 October 2006 - 03:59 PM.

[enki273]

Here is the article I was referring to:

Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E.
Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin.
FEBS Lett. 1997 Apr 7;406(1-2):136-8.

As far as I understand it, the decrease is not due to oxidative damage.