84 replies to this topic

[lightowl]

Prometheus,

You are right, we are approaching it from different perspectives. It is true that researchers and engineers have different ways of thinking. But I do not think that should be an immediate concern for the MF. How the solution is discovered or created should be in the hands of the researchers and the engineers. In my view, the main objective for the MF is to promote public interest, not to fund research and development projects. Although promotion should be the objective today, the MF should always be open to changing focus at any time if it sees fit.

We should not wait for any technology to be available before promoting and doing research and development into longevity. But neither should we limit the boundaries of research. The way I se it is, we are not the ones forestalling progress. We are the ones doing something about it, albeit in different ways, and that is a good thing. As to who is willing to be accountable for the lives lost? I think society is to blame. Every single person on earth is to blame. I think, we who try to make a difference is at the end of that line, not in the front. Also, I think it is to early to begin casting out blame. We should rather cast out fame to the people ( like you ) who are willing to do the difficult research.

I am an engineer, and as such, I would love to contribute to the development of the tools that will one day rid us of this awful destiny. But sadly I am preoccupied in making a living. If we succeed in opening the minds of the world, I might be able to earn a living working in my field of passion. Until then, I must fight for my right to live as long as I desire. By helping the MF I feel I am doing the best I can.

[lightowl]

As I stated, it is my view that the main objective for the MF is to promote public interest, not to fund research and development projects.

lightowl: As to who is willing to be accountable for the lives lost? I think society is to blame. Every single person on earth is to blame. I think, we who try to make a difference is at the end of that line, not in the front.

I humbly retract the above statement. It was made not to place any blame on any specific group. I think it is counterproductive and unfair to deal out blame. Also, I think it is unfair to push volunteers in the fight against aging with the threat of blame.

Edited by lightowl, 22 July 2004 - 02:39 AM.

[lightowl]

I to am discouraged by the low voting frequency in this poll, and I agree with you. We should push for more publicity and interest. Especially from within the midst of our fellow immortalists.

The website is currently undergoing a major redesign. We are trying to reach $½ MILLION in cash and pledges. That should help boost publicity significantly. I urge everyone to Join TheThreeHundred to help us reach that goal. We only need 4 more members.

I think maybe more votes will come as time goes. Until then, lets do our best to get the basic notion of the prize promoted throughout the mainstream media. This is, among other things, an effort to fight the death-meme and spread the word that death is not inevitable.

Join TheThreeHundred and fight the grim reaper himself.

[jaydfox]

I'm joining this discussion late, and perhaps have already missed the boat, so to speak.

Prometheus, I will start by admitting that I am not a biologist. But I hope that you will not take that fact and automatically dismiss my opinions out of hand. That's not to say that I believe I'm right on all points. I welcome correction, especially from biologists, as I'm still learning.

I have say that I'm impressed by your conviction to support somatic gene therapies and only somatic gene therapies, and damn the rest of the research.

But I think you are overconfident that somatic gene therapy is the only method that can be achieved in a 15 year time frame. First of all, there are other techniques which, though perhaps not as effective, will be available sooner than 15 years. Drugs, stem cell therapies, etc. While I'm on the subject of drugs, you have made clear that you think that only somatic gene therapies will be relavant to changing the genetics of aging. But Metformin has been shown to actually change the gene expression profiles of something like 60 or 70 different genes. It's primitive now, but that such drugs exist only shows that we cannot discount the possibility of near-term pharmaceutical solutions being as effective or more effective that what somatic gene therapies can accomplish in the same time frame. I foresee drug cocktails that target hundreds of genes, more than CR alone can even accomplish. And this can be achieved much sooner using gene microarrays to figure out which chemicals to use.

Second, I think your 15 year estimate on somatic gene therapies being available for humans is much too aggressive. First of all, this presupposes that we'll have figured out exactly which genes to modify, and HOW (because I think it will be a combination of dozens of genes, and it will be more complex than just turning them on or off). Second, this also presupposes that techniques applicable in mice will automatically apply in humans.

Unfortunately, recent research has indicated that although aging may look superficially the same in varied species, the exact mechanisms that the gene profiles are designed to attack can be different. An obvious example is that flies and yeast don't get cancer.

As a specific genetic example, differences in how the Sir2 protein in yeast affects other protein levels, and how Sirt1 in mice affects a wider range of protein profiles (some for similar, some for dissimilar reasons), is enough to convince me that there are going to be aging mechanisms in mice that don't translate to the human genome. This translates into the following interesting scenario: in shorter lived species, apoptosis and cell replacement seems to be favored during stresses such as CR. In longer lived species, this approach would put undue stress on stem cell lines, so apoptosis is downregulated and DNA repair is upregulated in the same situations. I expect many such differences to exist between humans and mice.

I realize that you are passionate about somatic gene therapy, but if you know someone who has only 15 years left, somatic gene therapy is only going to save them if it's a gene profile that would promote near infinite life. Assuming the therapy is available in 15 years, when this person has only a couple years left, or may already be in their deathbed, there's not much that it can do to save them. There's too much damage accumulated already. If they've only got 15 years left today, preventing cancer, CHD, CVD, Parkinson's, and Alzheimer's seem to be the most important needs they have, and somatic gene therapy isn't (currently) their best bet. Their best bet is better cancer treatments, and a reduction in the hurdles to stem cell research. In which case you should be pushing those rather than arguing the merits of PP versus RP. Remember, as Dr. de Grey has pointed out, it's all about actuarial escape velocity. Stem cell therapies will probably buy us 10-50 years of extra life, depending on how much they can actually fix. If your friend(s) with 15 years left received such therapies, that 15 years might turn into 25 or 30 years, or more. That would buy us more time to research somatic therapies.

And as Dr. de Grey pointed out, germline genetic alterations allow us to whittle down what really works and what doesn't, so that somatic therapies, which I can only assume are more difficult, can proceed with an appropriate subset of genes to test. This means that, at least for the next 5-10 years (a timeframe we cannot accurately guess yet), the PP is probably more important that the RP.

If I'm wrong that somatic gene therapy is harder than germline modifications, please let me know. I mean harder from a technical standpoint, as well as financial, as well as whatever else may be preventing this research from being pursued today (patents?).

If your interest in this is not personal (i.e. a dear friend who has 10-15 years left), then you should be willing to think outside the box. Aging is very complex. We understand it very little. Yet there is much evidence that aging is more than just evolution's disregard for organisms once they have reproduced. There is strong evidence that multiple aspects of aging are tied to preventing cancer.

Sure, we could cure cancer and then turn off the senescence-causing genes that were there to protect against cancer. But I'm sure that cancer wasn't the only concern when aging was "designed" into our genome. I don't think we can assume at this point that genetic therapies, not even germline therapies, will be sufficient to push the human lifespan beyond 200 years. It might happen, but it's not a given.

I truly believe that the only way we are going to get past 200 years is with nanomedicine. That's the long term solution, 25 to 60 years from now. Gene therapies are the mid-term solution, 15-40 years from now. Stem cells are the short term solution, 10-20 years from now. And I suppose a healthy lifestyle (exercise, nutrition), CR, and drugs like Metformin, if they are as effective in humans as in mice, are the very short term solution.

With each next step, we get progressive benefits. Just guesses on the numbers here, but 10%, 25%, 50%, 1000%. I stayed conservative (50%) on gene therapies, because by the time we have enough knowledge to push it to 100% or more, nanomedicine will have taken over.

Anyway, enough ramblings from me. I am not in a financial situation to donate to the MMP at this time anyway (other than maybe 20 bucks, but since I plan to join the 300 within the next year, I'll just wait). However, once I do donate, I'll probably put my money in the PP for the first two or three years, then move it all to the RP after that.

Jay Fox

[jaydfox]

Prometheus, thank you for your excellent reply. I see there is some room here for agreement. I'll reply to your points.

1. "Using a drug is a very crude method of controlling gene expression". I agree. I would rather see it done directly. However, I pointed out drugs for three reasons.

First of all, until just a few years ago, few non-biologists, and I'd wager some biologists, didn't anticipate that drugs could alter gene expression profiles at all. I certainly didn't. I'm not a biologist, but I'm not totally in the dark either.

Secondly, while drugs may be crude and less effective, they can be made available more quickly than gene therapies.

Third, if we alter the gene expression profile with a drug or drug cocktail, and then decide the changes aren't what we wanted, we can back off the drugs (cold turkey or in steps) and let the gene profile return to normal. This is of course not as big a concern in mice, since we can always get more mice. But in human studies, it will be much easier to do short-term drug tests, than to do gene therapies in the hopes that they'll work. However, I do know that mRNA can deliver short term gene therapy benefits without the long term consequences. Perhaps this obviates my safety concerns? Are there effective mRNA delivery techniques? If so, how often do they have to be repeated? Daily? Every four hours? Would it be worth it, even for a small study of a few dozen individuals?

2. "...but in some people it can also cause lactic acidosis which can cause death." Note to self! I wasn't aware of that. And I agree that targetting DNA repair directly is the end target. I was simply inferring that pharmacological methods, however crude, will get us there sooner.

3. While I agree that overaggressive estimates have a long history of success, they also have a long history of failure. Flying cars are still decades behind schedule, as is private space flight. Of course, I suppose that in both those cases, the cause wasn't lack of feasibility, but rather lack of investment. So I suppose this is a mixed bag. However, I think limiting techniques (what we're polling, right?) based on an overaggressive estimate is a bad idea. The last five years have seen a paradigm shift in how we view the genome. The majority concensus was that genes were what mattered. However, that view has shifted to protein expression rates and interactions. Even our view of introns versus exons (sp?) has changed. With increased processor power, I think bioinformatics and proteomics (and the other "-omics") may cause another paradigm shift in the next five to ten years. Progress is just too fast for us to exclude any techniques.

Besides, scientists who enter the competition are free to choose whatever technique they want. They shouldn't have it dictated by the Foundation. If somatic gene therapies are the answer, the results will show that. Let the proof be in the pudding, so to speak.

4. Sir1. I brought it up only to show that gene therapies across species may not be the same. I wasn't picking it as a target of intervention (though it is indirectly related).

5. Amen.

6. I'll start by saying that I'm not against the fruit fly approach. However, allow my to think aloud about this topic.

I don't oppose the use of fruit flies. While I have my reservations due to cross-species techniques, the information will still be useful. Especially if run in tandem with mouse (and other species) experiments. This would allow us to not only target genes faster, but we can compare results.

However, I'm wondering if there are species we can use with shorter lifespans than mice, but that still get cancer. It is my opinion (based loosely on studies I've read) that cancer is intertwined with aging in humans. Extending the lifespan of a species that doesn't get cancer won't convince me.

Of course, I'm not the general public. And that's who we're trying to convince with this prize, right? But I think that the general public will be far less moved to action if we can make flies live 10 or 20 times longer than normal, because, let's face it, they're flies. They're not cute or furry. They're not mammals. Whatever the scientists might say to try to convince them that the results are relavant, I doubt it will work.

So from a research perspective, I agree that fruit flies could be useful. From a PR standpoint, I don't foresee this being beneficial, especially if it pulls resources away from the Mouse Prize. And given how small the prize is at the moment, I don't think we could afford to pull away more resources (the same could be said about the Postponement prize, so I am shooting myself in the foot with this argument, but...).

On the other hand, if there were a variety of well-funded prizes for various species, it would lend more credibility to the Foundation. Fly, Mouse, etc. I'm conflicted on how long-lived of species we should be concerned with, given the urgency of the research.

I have much more to say, but I suppose I've made my point. I don't think we should exclude techniques from the Reversal Prize, so long as they "play fair" about when treatments begin. For example, I don't think CR should be used from weaning, and then somatic gene therapies at age 2.5 years, with the claim that intervention (the somatic gene therapy) wasn't begun until 2.5 years. I'm not sure if the rules are explicit enough about this (I haven't read them in over a month, so I could be wrong).

Jay Fox

[jaydfox]

Thank you for that information, Prometheus. I knew some of the basics, in a ballpark sort of way. Fewer genes, significantly shorter lifespan, less maintenance, etc. But I didn't know the specific numbers, and seeing it tabulated really does make a good case for fly research.

BTW, could you elaborate on "difficulty in generating transformants" for us non-scientists? I assume it has to do with the lower number of genes, but mentioning it twice seems dubious. My other thought is that it has to do with the ease of manipulating the eggs without reducing their viability. Perhaps you meant something else?

As for the prizes, I don't want to see the Mouse prize go, because from a PR perspective it's just too valuable. However, I would support the creation of a Fly prize, and I would be willing to abandon the postponement prize for the Fly prize. After all, the PP's main merits are: 1) quicker realization of the goals than RP, and 2) sooner and more frequent awarding of the prize, for PR value.

However, a Fly Prize would have both these benefits, only better. Quicker realization of the goals, and probably much more frequent awarding of the prize. Given the goal of speed, I would still support the Fly prize being of the Postponement type (germline).

Alas, if funding the prize weren't such an issue, then I'd prefer to see all three prizes (Fly, Mouse PP, Mouse RP). Perhaps, if we created the Fly category and explained it well, we'd see a preferential bias towards the Fly prize, much like the current situation, where the RP is funded about three times better than the PP.

Anyway, this is my opinion as a non-scientist, given the case Prometheus has presented. I would like to see what others think, perhaps even others from the Methuselah Foundation. And since I haven't donated yet (real soon, I hope), I realize my vote doesn't count for much.

BTW, while I'm thinking about it, I'm not sure if we had met any common ground on whether to keep the "reversal" prize open to any and all late onset techniques. Assuming we stipulate basic things like no sleeper genes inserted germline, and no basic treatments left unmentioned like CR used to skew the results, then would you be willing to leave all avenues open, and let the scientists involve decide how they want to proceed?

Jay Fox

[lightowl]

In the spirit of prize development and perfection, here are some words of wisdom from X-Prize founder, Peter Diamandis.

http://www.xprize.or...isTestimony.doc

[lightowl]

Hi Lightowl, perhaps you care to illuminate me on the relevant parallels between the X-prize and the MMP?

Sure thing,

Generally prizes has been offered to spark the public imagination. To show the public that things thought of as impossible or far fetched are indeed within reach if pursued with passion. If you read the Diamandis' testimony closely, you will notice that he makes some statements about prizes in general that most likely will apply in the case of the MMP to.

The fact that the x-prize has been so successful is one of the reasons why the MMP was conceived in the first place. It is important to learn from past efforts to be successful, even though the MMP project might seem grand in comparison, it builds on the same principles for final success. I think it is important to note, that this prize will not result directly in widely available life extension methods. It is primarily an effort to make a proof of concept that will eventually result in immense investments throughout the commercial environment.

PR is very important at this stage, and will continue to be important in the future. We want people to talk about the possibilities of extended healthy lifespans in the sectors of business that is going to make it happen for real for everybody. Just like the private space-industry is seeing that it really is possible to send people to space with limited resources. Even nasa is starting to use the prize concept to promote innovations and breakthroughs.

It is very possible that interventions thought out by contestants of the prize will not be used in commercial products or by the governments. If a very effective intervention is created, it will probably be used as a base for further study. That will effectively kickstart commercial interest and our work would be done by then.

[thethird]

Have any comments been made by research scientists (active in the field)?

Would be good to hear their opinion too.

[thethird]

Not that I am questioning your scientific credentials Prometheus - you know what you are talking about - or those of Dr de Grey, but why is that no other scientists have participated in this discussion? It seems a pity that you can't recruit more scientists to your cause. After all, it is they that will be doing the research!

[lightowl]

Here is the list of those competing and intending to compete for the prize.
http://www.methusela...competitors.php

I agree. It would be nice to have some more scientists contributing to this discussion. I guess either they don't know about this discussion, or they are more interested in doing the research than discussing the prize structure.

[lightowl]

Hmmm... Lightowl, are you saying that the investigative scientists are not concerned about what the general public thinks about their research?

I definitely think they are interested in what the general public thinks about their research. I am merely suggesting that they might have other channels to discuss these matters, and the MMP might not be one of the main talking points yet when the subject is being discussed with the general public. After all, the MMP is still very young. I am not suggesting that we should not discuss the MMP at these forums, by all means. I am only guessing as to why more researchers has not contributed to this debate at this time in this forum.

[lightowl]

go for it lightowl!

I don't se what it is I have to go for. It is not my role to defend validity of any contestants attempt to win the prize. If they win on those grounds, well, great. It will be that much harder for the next contestant to push the limit and take the prize.

I think it is important to remember that this prize will be around for many years to come. It is still very young. Contestants are important when having a prize, so better to have contestants with limited chance of great success than no contestants at all.

[kevin]

Hi prometheus et al.

FYI..

Phil Moheno has pulled out of the competition. He is pursuing research with CalPterin via other avenues.

The Foundation has since obtained the participation of Leonard Guarente of MIT who we imagine will be using his research with Sir2 to simulate caloric restricted mice affecting fat metabolism and a whole host of other metabolic processes.

[jaydfox]

Prometheus,

I have much I want to say, but I've become so focused on the details of our conversation that I'm starting to lose sight of the bigger picture. I'll be taking a while to reread this topic and others from start to finish, to try to get my bearings back.

In the meantime, however, I must admit I'm intrigued by the prospect of creating a Fly prize category, whether in place of the Postponement Prize or in addition to it. Given that time is critical, and progress on the mouse prizes, at least for new participants, will take at least five years, it does make sense to do something that moves more quickly.

However, I do have one burning question. How would we validate it? Although I would hope that researchers are honest, the MMP has a "failsafe" built in, the aspartate racimation (I know I probably butchered the spelling).

Is there a similar hope for legitimately quantifying chronological age in flies, regardless of the actual rate of physiological age?

Jay Fox

[jaydfox]

I do agree that sending the flies to other labs, or to the MF itself, would allow easy validation. For research in the public sector, this should pose no problem.

However, for those in the private sector, or at least those with private funding, who want to participate without risking losing control over their "IP", do you see this as a potential roadblock to their willingness to enter the competition (honest question, I don't know the answer.)?

At any rate, I will go ahead and attempt to create a poll for a Fly prize. I will keep it simple, with few options, and leave it up to the community to explain their positions. If it is well received, we could further refine it with more polls.

The question of whether or not there will be a Methuselah Fly prize is tied to whether or not the [Mouse] Postponement Prize is kept. (I'm not saying that they both can't be kept.) It seems that this poll is (currently) tied on whether to drop the prize or keep it, with no one voting to drop the Reversal Prize. However, there were only 22 votes so far. I'm not sure how many "active" members there are here who may not have voted. I'm also curious about how many of the ones who did vote are current donors to the MMP, or have other ties to the Methuselah Foundation. I should disclose that I voted to keep both prizes, but I haven't donated yet, due to lack of funds. I could probably donate $20 or something like that, but I was just going to wait until I'm in a position to join the three hundred.

Jay Fox

[kevin]

Hi prometheus..

I was disappointed too in regards to Phil Moheno not competing.

We are still in the setting up process with the competitors and that section of the website will take on more substance as we are able. I have only the most cursory idea of what they are proposing to do. Formal proposals are being submitted at this time.

The current competitors can be found at.. http://www.methusela...competitors.php

Richard Cutler - transgenic mouse, added copies of thioredoxin2 mitochondrial antixoxidant

Christiaan Leeuwenburgh - anti-inflammatory agents

Leonard Guarente - manipulation of Sir2

Christian Sell - IGF1 mutant

David Sinclair - resveratrol

Rick Weindruch - undeclared

We have a couple of other possibilities but nothing firm enough to warrant discussing as yet.