• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Research at the Mfoundation


  • Please log in to reply
11 replies to this topic

#1 Michael

  • Advisor, Moderator
  • 1,287 posts
  • 1,788
  • Location:Location Location

Posted 24 March 2009 - 06:57 PM


split from: "Global Integrative Multilevel Multisystem Aging Cure Plan"

--------------

All:

[Reasons why the old-school, "gerontological" approach to intervention in biological aging is a very literal dead end.]

Come on Michael, give it a rest ... you're providing the same old tired defense.

I wasn't providing any defense: I was explaining, for 'old' reasons that are as true now as they were nine years ago, the fundamental flaws in the "gerontological" heuristic.

One hypothesis is as good as another.

(a) SENS is not an hypothesis, it's an engineering project. (b) It is never the case that just any hypothesis is as good as any other.

aside from advocacy and fund raising SENS has made no practical scientific progress since it was conceived.

"No practical scientific progress"?? Egad, we need to do a better job of communicating ...

Let's start by remembering that the Methuselah Foundation didn't even exist until 2004, and having started with the MPrize (which by definition requires a large pool of raised funds before it becomes an effective incentive to spur research), the the generosity of our many donors' support (for which we should all be pathetically grateful -- I don't know if you intended it, but your tone came off as dismissive) gave the Foundation a sufficiently large and reliable funding base to start investing badly-needed funds directly into bottlenecks in key SENS biotechnologies just two years later, leveraging our relationships with leading scientists and their academic labs, and the passion and volunteer spirit of many graduate students now going into SENS research to get big results from precious, scarce funding.

Results in those mere two years:

LysoSENS
We are funding research in 3 labs (at Arizona State, Rice University, and Columbia), working on identification, characterization, and eventual animal and clinical testing of enzymes to degrade specific aggregates whose accumulation is central to atherosclerosis and age-related macular degeneration. Results to date: John Schloendorn, Kent Kemmish, and Jacques Mathieu (and their graduate advisors) have found (but not in all cases precisely identified -- ie, in a couple of cases, they've got the enzyme but can only say what it does, not what exactly it is or what its encoding gene is) microbial hydrolases that can degrade A2E (the stuff that accumulates in retinal pigmented epithelial cells, causes Stargardt’s disease, an inherited form of macular degeneration, and is believed to be the cause of most forms of the age-related variety) and 7-ketocholesterol ( arguably the most important such recalcitrant material in foam cells in atherosclerosis). Some, but not all, of this has been reported in the literature (1,2) ; more has been presented at scientific conferences, including the recent "Understanding Aging: Biomedical and Bioengineering Approaches", hosted at UCLA by (wait for it) the Methuselah Foundation:

Cleaning Out the Junk with Medical Bioremediation
B.E. Rittmann, K. Kemmish, J. Schloendorn, L. Jiang
Center for Environmental Biotechnology, Biodesign Institute, Arizona State University, Tempe, AZ

... As a first step towards testing medical bioremediation, we isolated a range of bacterial species capable of degrading the pro-atherosclerotic model compound 7-ketocholesterol (7KC) and other pathogenic cholesterol derivatives found to accumulate in human atherosclerotic tissue. The fastest-degrading isolates were strains of Nocardia, and we identified key degradation intermediates for one Nocardia strain and proposed a 7KC-degradation pathway that is different from its cholesterol-degradation pathway. This raises the possibility that oxysterol-specific catabolic enzymes may be used for the selective elimination of pathogenic oxysterols from our arteries.

A2E, which accumulates in age-related macular degeneration, is a retinoid compound with strong a visual absorption spectrum. We failed to culture microbes on A2E for over two years. This led us to test the idea that some organisms may have enzymes to degrade A2E without necessarily being able to grow on it as the only carbon and energy source. Thus, we changed our strategy to testing microbial enzymes directly, without requiring growth on A2E as the only carbon and energy source. With our new strategy, we identified two enzymes able to degrade A2E: a peroxidase from horseradish and a cyanobacterial carotenoid cleavage dioxygenase.



Most recently, in as-yet-unpublished work, Dr. Janet Sparrow of Columbia University’s Department of Ophthalmology, who is one of the most distinguished scientists working in this very area, has repeated and confirmed the ASU group’s results on A2E, and is now being funded by the Foundation to lend her expertise to the further characterization and development of the candidate enzymes. After identifying the products of A2E degradation by the enzymes, her lab will perform preliminary safety and efficacy screens by delivering them into A2E-loaded retinal pigment epithelial cells; if the cell culture results are promising, the Foundation will fund the testing of any viable-looking enzymes in vivo, in a mouse model of Stargardt’s.

MitoSENS
After investing MF funds to revive a dorman research program into allotopic expression in Ian Holt's lab at Cambridge,(3) we developed the earlier work extensively enough work to convince ourselves that the initial strategy they had used was going to be extremely challenging (you can hear about some of the progress and problems encountered on the video presentation from the third SENS scientific conference). Happily, at about the same time, Aubrey became aware of early, promising-looking work on a new allotopic expression technique, targeting the allotopically-expressed mRNA to the mitochondrial outer membrane -- work that was also featured, along with several other approaches, at SENS3,(5) by which point it had made even further progress. The results were sufficiently robust that the Foundation redirected its funding to Dr. Corral-Debrinski's newly-opened lab at the Fondation Voir et Entendre in Paris, where (as attendees of "Understanding Aging" were again the first to hear) she has made a huge leap forward with Foundation support:

Optimized Allotopic Expression of the Human Mitochondrial ND4 Prevents Blindness in a Rat Model of Mitochondrial Dysfunction

Mitochondrial diseases due to mutations in mitochondrial DNA can no longer be ignored in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress in identification of their molecular mechanisms, little has been done with regard to therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1, and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in the human fibroblasts in which these genes were mutated. ... To create an animal model of Leber Hereditary Optic Neuropathy (LHON), we introduced the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, to rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells (RGCs), which were 40% less abundant in treated eyes than in control eyes. ... Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wild-type ND4 prevented both RGC loss and the impairment of visual function. Hence, these data provide the proof-of-principle that optimized allotopic expression can be an effective treatment for LHON, and they open the way to clinical studies on other devastating mitochondrial disorders.(6)


You can now watch Dr. Corral-Debrinski's original "Understanding Aging" presentation online.

Of course, there's also work that is still ongoing, because it just takes more than a year or 2 to complete, and still other work that, while the protocols have been established and the researchers brought on board, is unfortunately currently delayed, because the global economic downturn has hit Foundation supporters large and small and forced a downward revision of the Foundation's research budget projections. Notable projects discussed in a recent SENS progress report include:

- a project to test the widely-held (but very probably mistaken (7)) belief that low-level, non-cancerous, non-apoptosis and -senescence-inducing age-related (epi)mutations affect enough cells to meaningfully impair tissue function; a definitive resolution to this question will be central to knowing whether WILT will provide sufficient obviation of nuclear (epi)mutations that, in combination with other SENS biotech, it will allow us to achieve "escape velocity." This work is under way the lab of Dr. Jan Vijg, Chair of the Department of Genetics at Albert Einstein College of Medicine, arguably the lead researcher into age-related nuclear mutations and a proponent of the "general cellular malaise" hypothesis.

-a project to ablate anergic T-cells from aging mice, in expectation of substantially reversing immune senescence, in the lab of Dr. Janko Nikolich-Zugich, head of the Department of Immunobiology and co-director of the Arizona Center on Aging at ASU;

-a project to replace the bone marrow of normal mice with telomerase-deficient stem cells, as a key proof-of-concept of WILT and a test for possibly deal-breaking non-telomere-maintenance functions of the telomerase enzyme, in the lab of Dr. K. Lenhard Rudolph at Medical School Hannover in
Germany, whose extensive experience with telomerase-deficient mice and existing research into possible alternative functions of telomerase make him the best choice for principal investigator (as well as having a strong existing interest in this very question).

And, there's the Foundation's hosting of several highly successful, intellectually thrilling interdisciplinary scientific conferences on the key biotechnologies of SENS, which have helped get researchers working quietly locked in their silos to see the broader picture in which their work is embedded and raised the profile of biomedical gerontology both within the scientific community and without; we've raised awareness and excitement about the real potential to achieve the indefinite control of biological aging through the MPrize and Dr. de Grey's tireless efforts to promote serious biomedical gerontology in scientific, public policy, and public arenas; we've helped to nurture a new generation of prolongevist "Young Turks" within the biogerontology establishment, helping life sciences students with a dream of contributing to the cure of the Grey Plague to get a foothold in SENS science by guiding them into relevant postgraduate work (including in many cases positions within Foundation-supported labs) and by providing tools for independent projects for undergraduate students through the MF Undergraduate Research Initiative ...

Dude, what do you want? :) Oh, wait, I know: a cure for aging! Point being, the Foundation is working assiduously on it, and making substantial progress, especially in key 'bottlenecks' in the progress of the overall SENS platform. I'm sorry if this hasn't been announced clearly or widely enough, and hope that we internally -- and the community more broadly -- will be more effective in communicating our progress in future.

-Michael

References
1. Microbial degradation of 7-ketocholesterol.
Mathieu J, Schloendorn J, Rittmann BE, Alvarez PJ.
Biodegradation. 2008 Nov;19(6):807-13. Epub 2008 Mar 15.
PMID: 18344006 [PubMed - in process]

2. Engineering away lysosomal junk: medical bioremediation.
Rittmann BE, Schloendorn J.
Rejuvenation Res. 2007 Sep;10(3):359-65. Review.
PMID: 17708688 [PubMed - indexed for MEDLINE]

3. Expression of algal nuclear ATP synthase subunit 6 in human cells results in protein targeting to mitochondria but no assembly into ATP synthase.
Bokori-Brown M, Holt IJ.
Rejuvenation Res. 2006 Winter;9(4):455-69.
PMID: 17105386 [PubMed - indexed for MEDLINE]

4. Holt IJ, Bokori-Brown M, Hamalainen M.
Allotopic expression: mitochondrial to nuclear gene transfer.
Rejuvenation Res. 2007 Sep;10(Suppl1):S32(Abs53).

5. Ellouze S, Bonnet C, Augustin S, Kaltimbacher V, Forster V, Simonutti M, Sahel JA, Corral-Debrinski M.
Allotopic mRNA localization to the mitochondrial surface: a tool for rescuing respiration deficiencies.
Rejuvenation Res. 2007 Sep;10(Suppl1):S24(Abs 23).

6. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M.
Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.
Am J Hum Genet. 2008 Sep;83(3):373-87. Epub 2008 Sep 4.
PMID: 18771762 [PubMed - indexed for MEDLINE]

7. de Grey AD.
Protagonistic pleiotropy: Why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging.
Mech Ageing Dev. 2007 Jul-Aug;128(7-8):456-9. Epub 2007 May 21. Review.
PMID: 17588643 [PubMed - indexed for MEDLINE]

Edited by Michael, 15 April 2009 - 11:37 AM.


#2 Prometheus

  • Guest
  • 592 posts
  • -3
  • Location:right behind you

Posted 24 March 2009 - 10:55 PM

"Dude", I'll tell you what I want - science. Not hype, not marketing - just science. The labcoat stuff. Where's the published data on a single SENS hypothesis? (and it ceases to be an engineering plan if you're relying on untested technology). :) The rules are the same for all scientists. I know the cause is noble, but either you're doing science or you're not and nobody cares about unpublished data and speculations are frowned upon.

Anyway, if an enzyme has been 'found' but not characterized what does that mean? Have they isolated the protein and it been sequenced?

a project to test the widely-held (but very probably mistaken (7)) belief that low-level, non-cancerous, non-apoptosis and -senescence-inducing age-related (epi)mutations affect enough cells to meaningfully impair tissue function

Why "very probably" mistaken when the scientific consensus is against your position. Show me the money - where's the evidence? ("very probably" Vijg will nail the final nail into WILTs coffin :) )

You write so well Michael and I always enjoy reading your posts but it would be good if we could respect the work thats gone into this Multilevel Multisystem Plan rather than seeking to discredit their approach. All strategies have potential until proven otherwise and aspiring researchers should not have to be shoehorned into the SENS paradigm.

#3 DJS

  • Guest
  • 5,798 posts
  • 11
  • Location:Taipei
  • NO

Posted 25 March 2009 - 05:21 AM

"Dude", I'll tell you what I want - science. Not hype, not marketing - just science. The labcoat stuff.


Dude! I have no idea where you're coming from right now. Michael just presented you with an impressive list of research being funded by the MF and you're asking him "where's the science?" :) I mean, I'm all about being critical, but when you take it too far it becomes unreasonable expectations.

Why "very probably" mistaken when the scientific consensus is against your position. Show me the money - where's the evidence? ("very probably" Vijg will nail the final nail into WILTs coffin :~ )



Then so be it. If WILT isn't a viable option, then I believe we'd all like to know that sooner rather than later.

For myself, one of the things about the SENS program that really stands out is the degree to which it is lending itself to falsification. Foundation funds are being given to scientists (Rudolph, Vijg) who are professionally motivated to falsify elements of the platform. It's like saying, "You think we're wrong? Here's some money. Go prove it." :)

This high degree of intellectual honesty is a hallmark of strong science.

Edited by DJS, 25 March 2009 - 05:23 AM.


#4 Prometheus

  • Guest
  • 592 posts
  • -3
  • Location:right behind you

Posted 25 March 2009 - 08:58 AM

"Dude", I'll tell you what I want - science. Not hype, not marketing - just science. The labcoat stuff.


Dude! I have no idea where you're coming from right now. Michael just presented you with an impressive list of research being funded by the MF and you're asking him "where's the science?" :|? I mean, I'm all about being critical, but when you take it too far it becomes unreasonable expectations.


Michael presented me with some typically impressive prose. :)

Really, I'm looking for some published research. Not opinion pieces, no reviews but actual publication of research data. Are there any?

#5 DJS

  • Guest
  • 5,798 posts
  • 11
  • Location:Taipei
  • NO

Posted 25 March 2009 - 02:16 PM

"Dude", I'll tell you what I want - science. Not hype, not marketing - just science. The labcoat stuff.


Dude! I have no idea where you're coming from right now. Michael just presented you with an impressive list of research being funded by the MF and you're asking him "where's the science?" :|? I mean, I'm all about being critical, but when you take it too far it becomes unreasonable expectations.


Michael presented me with some typically impressive prose. :)

Really, I'm looking for some published research. Not opinion pieces, no reviews but actual publication of research data. Are there any?


Here's one: Microbial degradation of 7-ketocholesterol

(Immorta - sorry for highjacking your thread. Perhaps when I have time I'll split off the extraneous dialog)

#6 caliban

  • Admin, Advisor, Director
  • 9,134 posts
  • 570
  • Location:UK

Posted 25 March 2009 - 06:19 PM

DJS is right: the fact that we are drifting away from Immorta's initial post lead me split the original thread.

Michael & H@rry,
I think you are both right that, sometimes, Methuselah Foundation does not communicate clearly enough what actual science it is funding right now. Much of that data is buried a bit on the website. From that perspective I very much appreciate Michaels efforts at presenting a partial compilation.
Everyone can build their own view from studying this post and the appended references whether it is right to dismiss the scientific collaborations and publications referred to above as entirely inconsequential.

Edited by caliban, 25 March 2009 - 06:24 PM.


#7 Prometheus

  • Guest
  • 592 posts
  • -3
  • Location:right behind you

Posted 26 March 2009 - 02:05 PM

Here's one: Microbial degradation of 7-ketocholesterol


Good. (I was aware of that one - it is the *only* one though.)

I think we should revisit this topic in a couple of years when further research results are hopefully published.

NB Dont be surprised (I wont be) when SENS workers find themselves getting their hands dirty with the dreaded vagaries of metabolism they have for so long claimed they will avoid. :|?

In any case, DJS, I hope you agree that it's uncouth to shove SENS down every budding biotheorists throat like some bible bashing door knocker.

As nature so clearly teaches, the greater the diveristy of approaches the greater the likelihood of eventual success.

#8 caston

  • Guest
  • 2,137 posts
  • 23
  • Location:Perth Australia

Posted 26 March 2009 - 02:32 PM

The atheromatous plaque is divided into three distinct components:

1. The atheroma ("lump of porridge", from Athera, porridge in Greek,), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery
2. Underlying areas of cholesterol crystals
3. Calcification at the outer base of older/more advanced lesions.
source:
http://en.wikipedia....Atherosclerosis

Now SENS will be good for degrading the cholesterol crystals. We may need some sort of chelation therapy to clear the vessels of calcium deposits.
But what causes the accumulation of dead macrophages?

My guess is that they were killed by infection. An attack on the body and its immune system. If so then if we can stop macorphages being infected and attacked we should have much less build up of plaque.

Edited by caston, 26 March 2009 - 02:35 PM.


#9 DJS

  • Guest
  • 5,798 posts
  • 11
  • Location:Taipei
  • NO

Posted 26 March 2009 - 10:12 PM

Here's one: Microbial degradation of 7-ketocholesterol


Good. (I was aware of that one - it is the *only* one though.)

I think we should revisit this topic in a couple of years when further research results are hopefully published.


I'm still trying to figure out what your point is.

As Michael stated, there is a healthy amount of research now being funding by the MF. This is something I think we can all be happy about. That being said, you're making an implication which I do not believe is justified. Although it's both desirable and effective to fund research, this has no bearing on the Foundation's ability to interpret the latest scientific data available to it.

So again, what's your point? We all know the MF doesn't have an NIH sized budget, which is why we judge it according to scale. And for what it has to work with, I say the MF is doing a great job.

In any case, DJS, I hope you agree that it's uncouth to shove SENS down every budding biotheorists throat like some bible bashing door knocker.

As nature so clearly teaches, the greater the diveristy of approaches the greater the likelihood of eventual success.


I have no problems with a diversity of opinion and lively debate. It just wasn't the right thread for the lively debate, which is why I expressed a desire to split the thread.

#10 Prometheus

  • Guest
  • 592 posts
  • -3
  • Location:right behind you

Posted 27 March 2009 - 12:57 AM

So again, what's your point? We all know the MF doesn't have an NIH sized budget, which is why we judge it according to scale. And for what it has to work with, I say the MF is doing a great job.

NIH has to support thousands of researchers and is irrelevant to this topic - what's your point? :|? My point is that there's lots of talk and little action. MF have raised millions according to their site yet labs with budgets of a couple of hundred G's per annum can churn out 3 or 4 papers in that period. You've shown me one publication - maybe its just too early or maybe SENS doesnt have legs - time will tell. But, if that's all it takes to satisfy you, that's OK by me. I just don't appreciate the used-car salesman talk, despite the eloquent delivery. Whatsmore, I dislike SENS being shoved down everyone's throat because along with SENS you get the distorted view of biology (telomerase is main cause of cancer, metabolism should be ignored, DNA damage doesnt contribute to aging, eminent scientists dont know what theyre talking about, and bla bla bla.. )

SENS is definitely a cool idea but we dont know if its the solution and immortalism is not about SENS its about immortalism. Lets keep our minds open and properly informed.

#11 caston

  • Guest
  • 2,137 posts
  • 23
  • Location:Perth Australia

Posted 28 March 2009 - 03:09 AM

H@arry: I'm inspired by SENS and how encompassing it is. Audrey's strongest suit is gaining widespread publicity and support for rejuvenation.

I just think there is important parts missing. Aubrey chooses not to get into the complexities of metabolism and instead just to repair the damage caused. If however, we take into consideration the human microbiome and the loss of commensal and symbiotic bacteria as more pathogenic strains gradually shutdown the defense and repair systems in the body and alter protein function it quickly becomes apparent that rejuvenation techniques as proposed by SENS are not addressing the full picture.

What if the damage was not mistakes in metabolism but deliberate and constant attacks from pathogens that indiscriminately view us as a big juicy lump of protein?

SENS needs to be expanded to include anti-bacterial, anti-viral and anti-fungal protocol followed by the restoration of symbiosis to the microbiome.

Edited by caston, 28 March 2009 - 03:11 AM.


#12 Prometheus

  • Guest
  • 592 posts
  • -3
  • Location:right behind you

Posted 28 March 2009 - 07:18 AM

H@arry: I'm inspired by SENS

Me too! Just dont like it being shoved down peoples throats is all. :)




1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users