6 replies to this topic

[caliban]

discussions and info about mitochondrial coupling

[caliban]

From the research description:

The free radical theory of aging (FRTA) proposes that lifelong accumulation of endogenous free radical-mediated macromolecular damage might be a cause of aging (Harman, 1956). A variant of the FRTA, known as the mitochondrial free radical theory of aging (MFRTA), proposes damage to mitochondrial DNA (mtDNA) by mitochondrially derived reactive oxygen species (ROS) to be particularly important in this context (Harman, 1972). However, the relevance of oxidative mtDNA damage to the aging process remains an open and controversial question (for our view on this, see Gruber et al., 2008).
Oxidative phosphorylation involves a proton cycle across the inner mitochondrial membrane that couples electron transfer to ATP synthesis. However, protons naturally leak across the inner mitochondrial membrane. Modulation of this incomplete mitochondrial coupling has been proposed as a mechanism to decrease ROS production, reduce oxidative mtDNA damage and hence slow aging (Brand, 2000). Supporting this hypothesis, careful exogenous modulation of mitochondrial uncoupling using the protonophore 2,4-dinitrophenol (DNP), has been shown to decrease ROS production and decrease DNA damage, resulting in increased lifespan of mice (Caldeira da Silva et al., 2008) and flies (Padalko, 2005). It has been proposed that chemical uncoupling might in this context be considered a caloric restriction mimetic (Caldeira da Silva et al., 2008).

[brokenportal]

From Ending Aging, Aubrey de Grey with Michael Rae:

You Cant Stop a Moving Train (Safely!)

I termed the "over-preventative" approach to combating aging the "gerontology" approach because biogerontologists predominantly favor it. By and large, when my colleagues think seriously about actually doing something about aging rather than just refining their understanding of it, their first instinct is to find some way to make metabolism run more cleanly.

This seems to be talking about projects like the Gruber Project. It would be interesting to see a rebuttal/response to that.

The obvious old school approach would be to try to reduce the formation of mutant mitochondrial DNA by cutting back on the bombardment of the mitochondrial DNA by free radicals. Just such a trick has been pulled off with some success in mice by giving them a copy of the gene for the antixidant enzyme catalase, specifically targeted to their mitochondria.

Also potentially in this project with coupling work via modulation using DNP. Can somebody name other ways this approach has been made?

It goes on to say the mice had 20% gain in not only average, but maximum lifespan and that they did suffer from less aging debilitation. It sounds like we might be able to expect the same kinds of results with DNP?

The book goes on to ask why we may not want to pursue the "gerontology approach" to this.

It lists these reasons, to paraphrase:

• There is no short term disease it can be tested with and so regulatory bodies wont let it move to clinical trials and will never approve it for human use.
  With the exception of pessimism on the potentials of reworking metabolism to burn cleaner, I would expect that de Grey would have been less pessimistic about this. If we think about the bigger picture, he seems to be saying it will be easier to engineer complicated cellular machinery than it would be to influence and change the minds of some regulatory bodies.
• The timescales it requires makes it to risky for venture capital to get involved. To quote, "That probably means that no amount of agitation by scientists or the public will actually put mitochondrially targeted catalase into the hands of clinicians to save peoples youth, health and lives: the interst of those with the power to fund or halt development are aligned against moving forward."
  Same here.
• Why spend resources on this when it can only obviate and not eliminate this mtDNA damage risk, and other experiments, current or yet to be developed could obviate it?
  I would love to see a rebuttal/response to it.
• Some ROS's like hydrogen peroxide, besides being destructive to the mtDNA, are useful in other parts of the cell. The book goes on to say that Catalase would interfere with that in messy ways that would cause more destruction.
  Isnt DNP in that same boat with Catalase?
• The last reason listed is that theres good reason to believe that the Catalase enzyme gene would only take invitro or as early embryos and not in adults.
  DNP seems to get around this argument.

The book suggests that remedial therapies like moving the mtDNA into the nucleus wouldnt take longer than working with the Catalase gene because they both work with gene therapy. The Gruber experiment may be able to help cut to the heart of this matter sooner. It seems that if this works, that a way could be found to allow this to target more of this problem and not just 20% as in catalase. If it succeeds, but cant help with more than around 20% then it seems like that could still be a major breakthrough in the press department to help the field as a whole, and a major breakthrough in the Longevity Escape Velocity department. However, remediation does still seem to be something that we arent going to be able to avoid in the long run.

Edited by brokenportal, 27 August 2010 - 09:40 PM.

[Jan Gruber]

Actually, I think both approaches are complimentary. Personally, I feel metabolic tuning and mitochondrial modifiers as well as using endogenous signaling pathways to mimic CR, block specific detrimental processes or activate stress response pathways / hormesis all have the potential to yield (maybe even rapid) progress that will ultimately extend human life- and/or healthspan.

Of course, I agree with some of the concerns regarding the lack of conventional "business model" for ageing interventions with the resulting lack of interest with big pharma, issues with the FDA process and such - but, in my mind, this is no reason not to do the science and find out how things works and what can be done... As the ImmInst grant call itself shows, alternative and different mechanisms fro doing things are possible and can work.

The other important point is of course that this is predominately a basic science proposal - trying to find out if chemical uncoupling can reduce damage to mitochondria / mtDNA and if this will lead to extended lifespan or not - in C. elegans.

While this is exactly the conservative biogerontology answer mentioned above, this kind of insight has implications for both the SENS and more "classical" biogerontology approaches to intervention. In fact, SENS itself of course is based on a lot of this type of mechanistic science and much of what is presented at the SENS conferences and in related publications deals with exactly these kinds of fundamental questions.

So, I think there is no contradiction really ...

Edited by Jan Gruber, 01 September 2010 - 06:57 AM.

[s123]

Actually, I think both approaches are complimentary. Personally, I feel metabolic tuning and mitochondrial modifiers as well as using endogenous signaling pathways to mimic CR, block specific detrimental processes or activate stress response pathways / hormesis all have the potential to yield (maybe even rapid) progress that will ultimately extend human life- and/or healthspan.

Yes, I agree. Some drugs that are suspected to be CR mimetics (e.g. metformin) are already on the market, approved for human use and we have a great deal of knowledge on their side effects; this makes that if we can prove that these drugs mimic CR and have a high probability that they will increase human lifespan then I can see them legally marketed for life extension purposes within the next 20 years. These drugs will then buy a few extra years for people awaiting more powerful therapies.

Of course, I agree with some of the concerns regarding the lack of conventional "business model" for ageing interventions with the resulting lack of interest with big pharma, issues with the FDA process and such - but, in my mind, this is no reason not to do the science and find out how things works and what can be done... As the ImmInst grant call itself shows, alternative and different mechanisms fro doing things are possible and can work.

The lack of interest by 'big pharma' is mainly caused by the fact that you cannot register a drug as an anti-aging drug today. Therefore if they would develop such a drug they cannot sell it. Some have tried to circumvent this by registering their drugs as drugs against type 2 diabetes while the real intention is to design anti-aging drugs.

Edited by s123, 20 October 2010 - 08:57 AM.

[Jan Gruber]

Actually, I think both approaches are complimentary. Personally, I feel metabolic tuning and mitochondrial modifiers as well as using endogenous signaling pathways to mimic CR, block specific detrimental processes or activate stress response pathways / hormesis all have the potential to yield (maybe even rapid) progress that will ultimately extend human life- and/or healthspan.

Yes, I agree. Some drugs that are suspected to be CR mimetics (e.g. metformin) are already on the market, approved for human use and we have a great deal of knowledge on their side effects; this makes that if we can prove that these drugs mimic CR and have a high probability that they will increase human lifespan then I can see them legally marketed for life extension purposes within the next 20 years. These drugs will then buy a few extra years for people awaiting more powerful therapies.

Of course, I agree with some of the concerns regarding the lack of conventional "business model" for ageing interventions with the resulting lack of interest with big pharma, issues with the FDA process and such - but, in my mind, this is no reason not to do the science and find out how things works and what can be done... As the ImmInst grant call itself shows, alternative and different mechanisms fro doing things are possible and can work.

The lack of interest by 'big pharma' is mainly caused by the fact that you cannot register a drug as an anti-aging drug today. Therefore if they would develop such a drug they cannot sell it. Some have tried to circumvent this by registering their drugs as drugs against type 2 diabetes while the real intention is to design anti-aging drugs.

Yes - and even if they could, what would the business model be? Most insurance or national health schemes would probably not pay for anything that is purely preventative, supposed to show benefits in, say, 25 years, has not been shown to do so (because no 25 year trial will ever happen) and has the potential to having even SOME negative side-effects today. This leaves the supplement market and it is hard to distinguish hard (expensive) science from all the unfounded claims that can often be made without any science to back them up. Off-label use is probably the only way to sneak into this market ? Not sure how to get around this ...

[brokenportal]

This ended up in the sub-forum, "Donor Hall of Fame", it should be in the list of science projects right? http://www.longecity...mmunityscience/

Here are the details of the project and the final results and conclusion.

http://www.longecity...ith-jan-gruber/